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Acute kidney injury case study with questions and answers

Single best answer question based on renal clinical case:

Single best answer question 1.

• A 50 year old alcoholic male presents with sepsis secondary to klebsiella pneumonia. His background includes IHD, previous pneumonia, hypercholesterolaemia and hypertension. Medications include: furosemide, enalapril, aspirin, clopidogrel, co-amoxiclav (current) and simvastatin
• He is treated with IV antibiotics and is managed on an ITU setting for 1 week
• Potassium 5.0
• Urea 24 (from 8)
• Creatinine 390 (from 60)
• Clinically he is mildly dry, with a BP 135/83, HR 90, he is catheterised with a U/O 35ml/hr

Which one of the following is the best management option?

• Switch to high dose IV furosemide, stop enalapril, give IV fluids to maintain urine output, daily bloods
• Stop furosemide, stop enalapril, add in dopamine and maintain adequate hydration to maintain urine output, daily bloods
• Stop furosemide, stop enalapril, adequate fluids to maintain urine output, daily bloods
• Continue furosemide, stop enalapril, high dose corticosteroids and continue adequate fluids to maintain urine output, daily bloods
• None of the above
• This man has risk factors for AKI (hypertension and dehydration) and is on various renotoxic medications including aspirin, enalapril (ACE-I) and furosemide (loop diuretic).
• The key is to maintain hydration to keep urine output reasonable (>0.5ml/kg/hr) while stopping as many renotoxic medications as possible.
• Fluids should be given and frusemide and enalapril stopped. He has a history of ischaemic heart disease so stopping aspirin is not ideal. Daily bloods to monitor response is advised.
• There is no evidence for dopamine (mentioned in option 2) or hydrocortisone (mentioned in option 4).

Introduction

Case report, statement of ethics, disclosure statement, funding sources, author contributions, a case of acute kidney injury in a patient with renal hypouricemia without intense exercise.

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Daiki Aomura , Kosuke Sonoda , Makoto Harada , Koji Hashimoto , Yuji Kamijo; A Case of Acute Kidney Injury in a Patient with Renal Hypouricemia without Intense Exercise. Case Rep Nephrol Dial 12 May 2020; 10 (1): 26–34. https://doi.org/10.1159/000506673

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Exercise-induced acute kidney injury (EIAKI) frequently develops in patients with renal hypouricemia (RHUC). However, several cases of RHUC with acute kidney injury (AKI) but without intense exercise have been reported. We encountered a 15-year-old male with RHUC who experienced AKI. He reported no episodes of intense exercise and displayed no other representative risk factors of EIAKI, although a vasopressor had been administered for orthostatic dysregulation before AKI onset. His kidney dysfunction improved with discontinuation of the vasopressor and conservative treatment. Thus, AKI can develop in patients with RHUC in the absence of intense exercise, for which vasopressors may be a risk factor.

Exercise-induced acute kidney injury (EIAKI) is a major complication in patients with renal hypouricemia (RHUC). EIAKI usually develops after intense exercise, such as anaerobic exertion, and is not accompanied by rhabdomyolysis [ 1 ]. However, there are several case reports of patients experiencing EIAKI without intense exercise [ 2-4 ]. Although the pathomechanism and risk factors of EIAKI remain unclear, many reports suggest that an oxidation-reduction imbalance is associated with EIAKI onset [ 5 ]. We herein report a case of acute kidney injury (AKI) in a patient with RHUC in the absence of intense exercise, which may have been caused by an oral vasopressor.

A 15-year-old male complained of strong fatigue after intense exercise since childhood. He had no remarkable medical history apart from allergic rhinitis. After entering high school, he often felt unwell, especially in the morning, and frequently missed classes. He was diagnosed as having orthostatic dysregulation and prescribed amezinium metilsulfate 10 mg/day, but his symptoms persisted. Eight days after the start of treatment he was switched to etilefrine 5 mg/day. However, his fatigue progressively worsened. He was found vomiting and unresponsive after collapsing in the bathroom on the eighth night following the prescription change and taken to the hospital by his family. In the emergency room he exhibited mild consciousness disturbance (Glasgow Coma Scale: E4V4M6) and complained of right lower abdominal pain. Laboratory tests (blood and urine), whole-body computed tomography, and head magnetic resonance imaging did not indicate any abnormalities (serum creatinine level 1.0 mg/dL, uric acid level 7.2 mg/dL). His conscious state and abdominal pain were improved on the next day, but his blood pressure gradually increased from 100/60 to 180/80 mm Hg and his serum creatinine level rose from 1.0 to 5.5 mg/dL during 5 days of admission. He was then transferred to our institution for the treatment of AKI and severe hypertension.

At the time of admission to our hospital the patient was fully conscious and alert. His body temperature was 37.2°C, blood pressure was 161/98 mm Hg, heart rate was 83 beats/min, and respiratory rate was 17 breaths/min. His height was 174 cm and his body weight was 54 kg. Physical examination detected no signs of dehydration, rash, or other abnormalities of the neck, chest, abdomen, or extremities. He had been taking loratadine 10 mg/day for his allergic rhinitis for several months. Both loratadine and etilefrine had been discontinued upon admission to the previous hospital. There was no family history of kidney dysfunction, and he reported no episodes of intense exercise other than daily commuting by bicycle to school. No alcohol consumption, smoking, or illegal drug use were reported. His laboratory data at the time of transfer to our hospital are summarized in Table 1 . Urinalysis showed mild proteinuria (0.66 g/gCr) and elevation of the tubulointerstitial injury marker β2 microglobulin (1,498 μg/L). Hematuria was not observed. His serum level of uric acid was low at 3.2 mg/dL and his fractional excretion of uric acid was high at 49.7%. Laboratory markers of rhabdomyolysis, diabetes mellitus, infection, and collagen diseases such as creatine phosphokinase, hemoglobin A1c, C-reactive protein, and autoimmune antibodies were all within normal range. An electrocardiogram disclosed left anterior hemiblock and nonspecific intraventricular conduction delay that had been detected when he was an elementary school student. A chest X-ray revealed no abnormalities. Ultrasound echography showed bilateral mild kidney swelling with increased renal cortical echogenicity (Fig.  1 ). No stenotic lesions were detected in the aorta or renal arteries, although the resistance index of the intrarenal arteries was slightly high (left 0.69, right 0.69), indicating a circulatory disturbance in the renal microvessels. Hydronephrosis and renal calcification were absent. An ultrasound-guided kidney biopsy performed 3 days after arrival at our hospital showed mild interstitial edema, vascular endothelial cell swelling in the renal interlobular arterioles, and no obvious signs of acute tubular necrosis (ATN) (Fig.  2 ). Treatment with continuous intravenous infusion of extracellular fluids and nicardipine gradually improved his kidney function and hypertension. His serum uric acid level decreased to 1.0 mg/dL (Fig.  3 ), and his fractional excretion of uric acid was at 55.9% at 10 days after admission. He was ultimately diagnosed as having AKI with RHUC and discharged 12 days after transfer to our hospital. Hypouricemia was found in his parents and a sister, indicating a hereditary condition. However, genetic screening did not detect any known causative RHUC mutations on URAT1/SLC22A12 or GLUT9/SLC2A9 .

Main laboratory data on admission to our hospital

Renal ultrasound showed mild kidney swelling with increased renal cortical echogenicity. Hydronephrosis and renal calcification were not observed. Renal imaging findings were similar bilaterally (left 105 × 62 mm, right 115 × 63 mm).

Kidney biopsy specimen findings. Mild interstitial edema and vascular lumen narrowing by endothelial cell swelling (arrow) were detected (periodic acid-methenamine silver stain). No other abnormalities were found, including signs of acute tubular necrosis.

Clinical course of the present case. Vasopressors that had been administered for 15 days were discontinued on admission. After transfer to our hospital, his renal function improved gradually with continuous intravenous infusion of extracellular fluids and nicardipine. The serum uric acid level decreased steadily to 1.0 mg/dL during hospitalization.

Ishikawa et al. [ 6 ] first described EIAKI as AKI with accompanying abdominal or lower back pain after intense exercise, such as a 100-meter dash. EIAKI is differentiated from AKI with rhabdomyolysis by normal or slightly elevated serum myoglobin and creatine phosphokinase levels. EIAKI typically occurs in young males, with more than half having RHUC. Enhanced computed tomography often displays a wedge-shaped contrast defect in the kidneys. As for the clinical course of EIAKI, kidney dysfunction improves naturally without any special treatment [ 1, 7 ]. Although the reported patient had no intense episodes of exercise, EIAKI was diagnosed because he had RHUC, his kidney function recovered naturally, and he was young and male.

Blood pressure and serum creatinine level in our patient increased gradually following admission to the former hospital. As high blood pressure alone might cause AKI, we could not exclude the possible involvement of hypertension in AKI development. However, his serum creatinine level ultimately improved to 0.7 mg/dL after the final discharge despite having been 1.0 mg/dL on first admission, indicating that it had already been elevated by 0.3 mg/dL at the former hospital. Considering the fact that his blood pressure was normal on admission, AKI was thought to have developed before blood pressure elevation. Furthermore, his serum uric acid level was much higher on first admission (7.2 mg/dL) than at discharge (1.0 mg/dL), suggesting AKI onset prior to the former hospital visit. We suspected that AKI caused hypertension, which in turn worsened AKI. The elevation of blood pressure was assumed to be an exacerbation factor of EIAKI rather than its main cause.

The reported patient had no intense episodes of exercise. Lee et al. [ 3 ] described 17 AKI patients with abdominal or lower back pain who exhibited the characteristic patchy kidney sign on enhanced computed tomography. Among them, 5 patients reported no episodes of intense exercise. To the best of our knowledge, there have been 8 patients with EIAKI who did not have any episodes of intense exertion [ 2-4 ], with 5 experiencing infection or analgesic usage before EIAKI onset (Table 2 ), thought to be risk factors of EIAKI in addition to RHUC [ 3, 8, 9 ]. These reports support the notion that EIAKI can develop without intense exercise and the existence of risk factors other than strong exertion. However, to date no reports have focused on the relationship between lack of intense exercise and the etiology and development mechanism of EIAKI.

Clinical findings of current and previous reported cases of EIAKI without strenuous exercise

The pathomechanism of EIAKI is unclear, but renal circulatory disturbance by reactive oxygen species (ROS) is thought to be a main cause [ 5 ]. Intense exercise, such as anaerobic exertion, produces large amounts of ROS, which are rapidly removed by uric acid and other scavengers in the healthy population [ 8 ]. Patients with RHUC have insufficient scavengers, resulting in inadequate ROS removal and the subsequent activation of vasoconstrictive factors, vasoconstriction, and renal ischemia [ 2 ]. Since renal vasoconstriction is known to trigger further vasoconstriction and oxidative stress via activation of the renin-angiotensin system and blood pressure elevation [ 10 ], EIAKI patients are thought to show a vicious cycle between oxidative stress and vasoconstriction – oxidative stress causes stronger vasoconstriction and vasoconstriction causes more oxidative stress – culminating in acute and severe renal injury. In the present case, the patient had been taking vasopressors for orthostatic dysregulation for 15 days prior to the onset of AKI. Amezinium metilsulfate inhibits monoamine oxidase activity and suppresses the uptake of noradrenaline, while etilefrine activates type α1 and β1 adrenaline receptors. Thus, both vasopressors increased cardiac output and the constriction of peripheral vessels [ 11, 12 ]. Bellomo et al. [ 13 ] reported that activation of type α1 adrenaline receptors could cause excessive renal vasoconstriction and decreased renal blood flow in models of healthy renal hemodynamics. Radaković et al. [ 14 ] described that adrenaline induction increased ROS and caused a disruption in oxidant/antioxidant balance. Considering these results and the developmental mechanism of EIAKI (i.e., ROS and renal ischemia), we suspect that the vasopressors may have affected the onset or worsening of EIAKI by increasing ROS, exacerbating vasoconstriction, and forming a vicious cycle of diminished renal hemodynamics. Karasawa et al. [ 15 ] reported a case of EIAKI who was given midodrine, another vasopressor, before the onset of EIAKI, and Saito et al. [ 16 ] described that vasoexpansion by low-dose dopamine improved the resistance index of renal arterioles in 2 cases of EIAKI, implying the relation between vasopressors and EIAKI in clinical settings. Although no studies have directly addressed the relationship between vasopressors and EIAKI, past reports and our own results indicate an importance of catecholamine level homeostasis in the pathogenesis of EIAKI. We suspect that vasopressors may be associated with AKI onset in RHUC patients and may be a risk factor of EIAKI.

Renal biopsy showed no significant abnormalities in the present case. Although patients with EIAKI generally exhibit ATN, Ohta et al. [ 2 ] reported no abnormalities in 6 of 28 renal biopsies from EIAKI patients, which implied that EIAKI could develop without ATN. AKI with renal ischemia often causes ATN. However, tubular necrosis is sometimes absent without a sufficient degree or duration of ischemia, and early treatment for renal ischemia leads to a rapid improvement in renal function in such cases [ 17 ]. In the present patient, vasopressors, which might be a risk factor for EIAKI, were discontinued and intravenous antihypertensive medication was induced just after the first admission. The serum uric acid level was temporarily elevated on admission by AKI, and the patient’s scavenging ability with serum uric acid was thought to be temporarily improved. These factors could have mitigated the vicious cycle between renal vasoconstriction and oxidative stress, reduced the severity of renal ischemia, and prevented ATN development. However, as no studies have addressed the cause or meaning of a lack of ATN in some EIAKI patients, a greater number of studies are needed.

In conclusion, AKI can develop in patients with RHUC without intense exercise, possibly through the use of vasopressors. Further related case reports are needed to clarify the association between vasopressor use and AKI in patients with RHUC.

The present case report adhered to the Declaration of Helsinki. Informed consent for publication was obtained from the patient.

The authors declare no conflicts of interest.

The authors received no specific funding for this work.

D. Aomura drafted the article. K. Sonoda, M. Harada, and K. Hashimoto revised the article critically for important intellectual content. Y. Kamijo revised the article critically for important intellectual content and gave final approval of the version to be submitted.

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Case Report

Case scenario: hemodynamic management of postoperative acute kidney injury.

Received from the Department of Anesthesiology and Critical Care, Lariboisière Hospital, Assistance Publique-Hopitaux de Paris; University of Paris 7 Denis Diderot, Paris, France. Submitted for publication September 23, 2012. Accepted for publication January 29, 2013. Funding was received from the Ministère de la Recherche, Paris, France, plan quadriennal EA3509. Figures 1–4 were drawn by Annemarie B. Johnson, C.M.I., Medical Illustrator, Wake Forest University School of Medicine Creative Communications, Wake Forest University Medical Center, Winston-Salem, North Carolina.

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Matthieu Legrand , Didier Payen; Case Scenario: Hemodynamic Management of Postoperative Acute Kidney Injury. Anesthesiology 2013; 118:1446–1454 doi: https://doi.org/10.1097/ALN.0b013e3182923e8a

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Acute kidney injury (AKI) is associated with poor outcome both in critically ill patients and after major surgery. 1   The occurrence of AKI has been associated with poor short-term and long-term outcome, increased risk of chronic renal failure, and increased risk of death. 2   Several risk factors of postoperative AKI have been identified, and may help identifying patients with the highest risk of AKI. However, recognizing contributors to AKI ( e.g. , systemic inflammation, systemic hemodynamics alterations, nephrotoxic agents, and others) remains a challenge for anesthesiologists and intensivists because these factors are often associated and AKI multifactorial.

The early diagnosis of AKI remains another issue. Interest in the development and validation of AKI biomarkers has increased among the medical community. In this article, we analyze the risk factors of and contributors to AKI after major surgery, and specifically discuss the strategy of fluid management and potential negative outcome associated with inappropriate fluid administration, with a case scenario intended to illustrate the current knowledge of perioperative AKI. We emphasize hemodynamic management for the prevention and correction of acute renal failure.

A 59-yr-old woman with a history of diabetes and hypertension underwent abdominal surgery for recurrent ovarian cancer. She had received systemic chemotherapy during the 18 months preceding the surgery, including paclitaxel, carboplatin, bevacizumab, doxorubicin, and cyclophosphamide, and had remained asymptomatic since then. The surgery included an ovarian resection and peritoneal carcinosis cytoreduction. The only preoperative medication was an angiotensin-converting enzyme inhibitor to treat arterial hypertension. The preoperative creatinine clearance was estimated at 80ml/min (Modification of Diet in Renal Disease formula). Because she was asymptomatic (no dyspnea or recent change in her clinical status), left ventricular function was not preoperatively assessed.

The known large fluid losses associated with peritoneal carcinosis cytoreduction, intraoperative oliguria, and hypotension led to the infusion of a total of 24 ml·kg −1 ·h −1 of crystalloids during the 9-h surgery (half saline and half Ringer’s lactate solutions). Perioperative maintenance of mean arterial pressure at 70 mmHg was achieved by intravenous infusion of neosynephrine (0.35 μg·kg −1 ·min −1 ). In the recovery room, cold extremities and discrete knee mottles were noted, which motivated a switch to norepinephrine infusion (0.2–0.3 μg·kg −1 ·min −1 ). Because of oliguria during the surgical procedure and anuria in the immediate postoperative period, with urine output less than 0.5 ml·kg −1 ·h −1 , the patient was transferred to the postoperative intensive care unit (ICU). Blood analysis showed a metabolic acidosis, with a chloride concentration of 114 m m and bicarbonates of 12 m m , with a normal anion gap (14 m m ). Serum alanine aminotransferase and alanine transaminase were increased (245 and 257U, respectively), and serum troponin T was 0.223 μg/l. ICU-admission urine level of neutrophil gelatinase-associated lipocalin was 353 ng/mmol urine creatinine. Serum cystatine C was 1mg/l, urine -1 microglobulin was 90mg/l, and the fractional excretion of urea was 29%.

At admission, central venous pressure (CVP) was measured at 24 mmHg, with central venous oxygen saturation (ScvO 2 ) at 66%. Transthoracic echocardiography revealed a severe left ventricular dysfunction, with an ejection fraction of 25%, global hypokinesia, right ventricular dilation, systolic pulmonary arterial pressure at 30 mmHg, and low cardiac output (2 l/min). The serum level of brain natriuretic peptide was 1244 ng/ml.

Norepinephrine was switched to epinephrine, which led to an increase in cardiac output to 4.5 l/min and ScvO2 to 88% and a CVP decrease to 15 mmHg. Intravenous infusion of furosemide was initiated, which increased urine output. AKI was reversed within 72h and epinephrine was stopped 24h later. The patient was discharged from the ICU after 5 days. Serum creatinine at hospital discharge was 60 μ m . A cardiac magnetic resonance imaging performed 2 months later showed global hypokinesia (left ventricular ejection fraction 21%) with no sign of hypoperfusion. The final diagnosis was acute decompensated heart failure due to chemotherapy toxicity after major abdominal surgery complicated by AKI.

Can Preoperative Patients Who Have a High Risk of Postoperative AKI Be Detected?

AKI affects 1–30% of patients after surgery. This case scenario raises the question of the preoperative evaluation of the risk of postoperative AKI. Several risks factors have been associated with postoperative AKI.

Cardiac Surgery Patients

Cardiovascular surgery is by far the highest risk procedure associated with postoperative AKI, with up to 30% of patients experiencing AKI. In comparison, the prevalence of AKI after major noncardiac surgery procedures 1   such as in the presented case, is approximately 1%. The preoperative estimation of the risk of postoperative AKI by an anesthesiologist relies on checking the risk factors of AKI. Most of the risk factors are nonmodifiable because they are procedure-related (urgent surgery, need for surgical reexploration, and cardiopulmonary bypass duration) or patient-related (age >70 yr, diabetes, atrial fibrillation, left ventricular dysfunction, preoperative intraaortic balloon pump, or chronic renal insufficiency). Preoperative evaluation ( e.g. , with echocardiography) of left and right ventricular functions is recommended in patients with a dyspnea of unknown origin or worsening dyspnea with a known cardiomyopathy. 3   In addition, Karkouti et al. 4   identified a per-cardiopulmonary bypass hematocrit of less than 20% and erythrocyte transfusion as potential modifiable risk factors for postoperative AKI. These findings are in line with experimental data showing the impact of normovolemic hemodilution promoting renal hypoxia. 5   However, perioperative erythrocyte transfusion was associated with an increased risk of AKI. The negative impact of erythrocyte transfusion supports the poor tolerance of multiple morphological and functional changes induced by erythrocyte storage (less deformability, depletion of 2, 3-diphosphoglycerate, inflammation, and decrease of bioavailability of nitric oxide with the liberation of free hemoglobin). These storage-induced modifications may induce a poor restoration of microcirculatory oxygenation associated with inflammation and changes in immune status. These observations emphasize the need for strategies that limit perioperative anemia and transfusion. 6  

The presence of proteinuria in the preoperative period, which is easily detected by dipsticks, can indicate a risk of AKI. Mild (trace to 1+) or heavy (2+ to 4+) proteinuria has been associated with increased odds of the postoperative need for renal replacement therapy (odds ratio 7.29; 95% CI, 3.00–17.73) and mortality after cardiac surgery (hazard ratio: 1.88 for mild and 2.28 for heavy proteinuria). 7  

Noncardiac Surgery Patients

In a large monocentric prospective study, Kheterpal et al. 1   identified age, emergent surgery, liver disease, high body mass index, high-risk surgery ( i.e. , surgeries with the potential for large fluid shifts or blood loss), peripheral vascular occlusive disease, and chronic obstructive pulmonary disease as independent preoperative risk factors for postoperative AKI after major noncardiac surgery in patients with previously normal renal function (defined as creatinine clearance >80ml/min). The authors created a predictive model of postoperative AKI with reasonable sensitivity and specificity but insufficient predictive values for a single patient-centered prediction. Finally, patients with poor preoperative physiological conditions, estimated by the classification of the American Society of Anesthesiologists as class IV or V, were found to be at high risk for AKI. 8   In our case scenario, three risk factors were present: age, hypertension, and intraperitoneal surgery with large fluid losses.

Diagnosis of AKI

AKI is defined by a decrease of glomerular filtration rate (GFR). AKI is defined under the Risk, Injury, Failure, Loss, and End-stage Kidney (RIFLE), the acute kidney injury network (AKIN), or the kidney disesase improving global outcome (KDIGO) classification 9   as an increase in serum creatinine level and decrease in urine output. The use of GFR estimation by Cockcroft–Gault or the Modification of Diet in Renal Disease formulae should be restrained to preoperative evaluation of GFR when renal function is stable because these formulae yield substantial disagreements regarding creatinine in patients with AKI. However, anesthesiologists must be aware of two important factors while interpreting serum creatinine levels. First, it takes time for serum creatinine to reach a steady state after a fall in GFR because of its large volume of distribution (~60% of total body weight). It is therefore difficult to predict the course of AKI when serum creatinine increases (in other words, when the plateau of GFR is reached). Second, fluid loading and hemodilution may underestimate the increase in serum creatinine levels. Macedo et al. 10   described a simple formula to correct serum creatinine for fluid balance and overcome this limitation (adjusted creatinine = serum creatinine × correction factor with correction factor= (hospital admission weight [kg]) × 0.6 + Σ (daily cumulative fluid balance [l])/hospital admission weight × 0.6). In the present case scenario, the correction of serum creatinine with respect to fluid overload allows reclassification as stage 1 AKI according to the AKIN classification in the immediate postoperative period, with earlier diagnoses. The baseline serum creatinine was 69 μ m and increased postoperatively to 77 μ m . This value became 94 µ m after adjustment on cumulative fluid balance, which corresponds with stage 1 AKI.

Can Postoperative AKI Be Prevented?

Successfully preventing AKI requires the correction of factors that contribute to AKI in the perioperative period, presented in figure 1 .

Schematic representation of factors contributing to the development of acute kidney injury (AKI) in the perioperative period and the risk associated with fluid overload. RAAS = renin–angiotensin–aldosterone system.

What Is the Contribution of Hypoperfusion to Postoperative AKI?

Although profound and prolonged interruption of renal blood flow leads to oxygen debt, renal ischemia, and tubular necrosis, 11   the total interruption of renal blood flow is a rare clinical scenario. Suprarenal aortic clamping, renal transplantation, renal artery thrombosis or dissection, and prolonged cardiac arrest can cause renal ischemia with parenchymal injury, including some degree of tubular necrosis. Intraoperative hypotension has been statistically associated with AKI only in patients with preoperative multiple risk factors for AKI. 12   Renal blood flow and GFR decrease with a decrease in mean arterial pressure below the lower autoregulation threshold for renal blood flow and glomerular filtration. If targeting a mean arterial pressure above 65 mmHg is not necessary for preventing the development of AKI in ICU patients with preserved autoregulation of GFR, an increase in mean arterial pressure may be necessary in other cases with impaired glomerular filtration autoregulation, such as that observed in advanced age, atherosclerosis, chronic hypertension, or diabetes. Ischemic injuries and inflammatory states, cardiopulmonary bypass, and oxidative stress are conditions prone to affect renal blood flow autoregulation. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers impair glomerular filtration autoregulation but do not impair renal blood flow autoregulation.

The so-called “prerenal azotemia” ( i.e. , with renal structural integrity) is often associated with tubular injury and might be considered a milder form of AKI on a continuum that includes more severe forms of AKI. The rapid reversibility of AKI with low sodium excretion is not sufficient to make the diagnosis of pure prerenal azotemia because transient AKI is associated with the increase of some biomarkers of renal damage. 13   Furthermore, persistent AKI cannot be designated as “acute tubular necrosis.” Kidney biopsies in the immediate postmortem period of septic shock rarely identified tubular necrosis but often identified infiltration by inflammatory cells and cellular apoptosis with vascular microthrombosis. 14   Consequently, the term “acute tubular necrosis” as it is classically used to describe a persistent AKI in an acute state seems inappropriate when histologic analysis of kidney has not been performed.

Perioperative Hemodynamic Optimization: A Goal-directed Therapy

Fluid resuscitation is central in the prevention and treatment of AKI. Futier et al. 15   observed a higher incidence of postoperative complications ( e.g. , anastomotic leak and sepsis) and lower urine output in the restrictive group compared with the liberal group, after abdominal surgery. This postoperative complication might arise in patients with a higher incidence of hypovolemia (defined as pulse pressure variation of 13% or more) and lower ScvO2 in the restrictive group because both are independently associated with postoperative complications. Unfortunately, anesthesiologists were blinded to ScvO2, an important variable to guide fluid resuscitation, and no clear mechanistic relation can be mentioned. Fasting has furthermore been shown to blunt renal blood flow autoregulation in rats. In contrast, there is also evidence from preclinical and clinical studies indicating that excessive fluid-administration strategies can induce the development of organ failure. 16   Excessive fluid resuscitation can induce transient hemodilution by increasing renal oxygen consumption while decreasing renal oxygen transport and leads to renal hypoxia. Such a decrease of renal parenchyma oxygen bioavailability may further compromise tissue oxygenation in conditions of potential renal injury. 5   In the worst scenario, fluid loading can worsen renal injury function due to renal congestion and increased intracapsular pressure. Therefore, more than the total amount of fluid administered is tailored and based on a perioperative stroke volume optimization, which may better prevent postoperative AKI. A recent review of randomized controlled trials 17   reported that fluid resuscitation based on goal-directed therapy resulted in fewer postoperative AKIs, but any additional administered fluid was limited (median: 555ml). The decrease in AKI was greatest in the 10 studies in which fluid resuscitation was the same between the goal-directed therapy and control groups. More importantly, inotropic drug use in goal-directed therapy patients was associated with decreased AKI, whereas studies not involving inotropic drugs found no effect. The greatest protection from AKI occurred in patients with no difference in total fluid delivery or use of inotropes. These and other results suggest that goal-directed therapy aiming to increase flow with volume, inotrope, or a combination might be the protective factor. This treatment has been formalized in multifaceted protocols for decision-making processes to administer fluids, inotropes, and erythrocyte transfusion. Although goals differed among studies, targeting a cardiac index more than 2.5 lmin −1 m −2 , a central venous oxygen saturation (ScvO2) of more than 70%, and/or an oxygen delivery index of more than 600 mlmin −1 m −2 appears to be a sound approach. In the present scenario, the intraoperative monitoring of cardiac output and ScvO2 would have indicated a need for inotropic support and not pure vasopressive therapy ( i.e. , neosynephrine).

Some differences between inotropes might be observed. For example, the use of dopexamine appears to efficiently improve organ blood flow and prevent an episode of AKI, whereas the infusion of dopamine did not. 18   The consequences of using vasopressor drugs on renal blood flow and renal function remain under debate because the renal hemodynamic consequences may depend on the inflammatory context. High doses of nonphysiological norepinephrine in healthy animals decreased renal blood flow and promoted renal ischemic injury. 19   However, during vasodilatory shock, the infusion of norepinephrine could restore renal perfusion pressure and increase renal conductance and renal blood flow. 20   Deruddre et al. 21   observed a decrease in the renal resistive index, likely reflecting a decrease of renal vascular resistance in septic patients when blood mean arterial pressure increased from 65 to 75 mmHg with the use of norepinephrine. Similarly, Redfors et al. 22   found that increasing blood mean arterial pressure with norepinephrine increased renal blood flow and the GFR after cardiac surgery. In a recent study we found no association between norepinephrine infusion for septic shock treatment and incidence/severity of AKI 23   Finally, it is worth mentioning that no strategy other than hemodynamic optimization has proven to protect kidney function in patients undergoing surgery. 24  

How Should Fluid Administration with Urine Output Be Guided in the Perioperative Setting?

Urine output is often used to guide fluid therapy in the perioperative setting, and oliguria is considered a marker of hypovolemia. However, a transient decrease in urine output is not necessarily associated with a decrease in the GFR but may result from a normal renal adaptation to maintain homeostasis. The risk of fluid overload may occur if oliguria reflects surgical- and anesthesia-related neurohormonal adaptation with modest hypovolemia. An increase in intraabdominal pressure during laparoscopic surgery, mechanical ventilation with positive end-expiratory pressure, and pain and surgical stress with release of an antidiuretic hormone are all factors inducing antidiuresis. 25   Even a minor surgical injury can impair renal fluid elimination after fluid loading. 26   In a randomized controlled trial, urine output and postoperative creatinine serum concentration were not affected in obese patients undergoing laparoscopic surgery, who were randomly assigned to intraoperatively receive high (10 ml·kg −1 ·h −1 ; n = 55) or low (4 ml·kg −1 ·h −1 ; n = 52) volumes of Ringer’s lactate. 27   Finally, Holte et al. 28   did not observe signs of lower plasma volume when infusing 15ml/kg compared with 40ml/kg of Ringer’s lactate over 1.5h during laparoscopic cholecystectomy.

The clinical context and risk assessment of AKI appear central in the therapeutic response to oliguria in a patient. Oliguria in a patient undergoing surgery for a bowel obstruction or hemorrhage indicates associated hypovolemia requiring fluid infusion. Fluid deficit is also easily identified in patients with preoperative diarrhea or dehydration due to diuretics. Tachycardia, low mean arterial pressure, encephalopathy, capillary refill time, mottles, and cold extremities are important clinical signs of hypoperfusion, indicating the initiation of fluid resuscitation. However, resuscitation should be rapidly guided by physiological endpoints obtained by monitoring the optimization of cardiac output and central venous saturation ( fig. 2 ) during the perioperative period if oliguria persists despite initial fluid resuscitation (500–1000ml of crystalloids).

Avoid Fluid Overload and Venous Congestion in the Postoperative Period

A role of renal venous congestion in renal injury has emerged in experimental studies. In patients with acute heart failure, increased CVP was found to be associated with the progression of AKI, whereas cardiac output did not show this association. 29   Damman et al. 30   also found that increased CVP was associated with a reduced GFR. Interestingly, the negative impact of increased CVP is additive to compromised renal blood flow due to low cardiac output. 30   In acute lung injury, a restrictive fluid-administration strategy for surgical patients (CVP ≤4 mmHg and pulmonary artery occlusion pressure ≤8 mmHg) in the absence of shock and oliguria with a cardiac index of more than 2.5 l·min −1 ·m −2 resulted in more ventilator- and ICU-free days compared with a liberal strategy, 31   but was not associated with more episodes of severe AKI.

A relationship between fluid overload and mortality in critically ill patients was recently reported. The recent post hoc analysis of the Vasopressin in Septic Shock Trial study reported that a positive fluid balance and increased CVP were associated with increased risk of death in patients with septic shock. 32   However, the survival rate improved when the fluid balance was positive in patients with a CVP of less than 8 mmHg, suggesting that only excessive fluid restriction may be deleterious. In a randomized control trial of critically ill patients, achieving supranormal values for the cardiac index or normal values for mixed venous oxygen saturation did not reduce the incidence of acute renal failure or reduce morbidity or mortality among critically ill patients. 33  

These observational studies highlight the importance of CVP monitoring in patients with heart failure or hemodynamic instability, who are undergoing major surgery. Observing the response of CVP to a fluid challenge is important because it provides information on the reach of the limit of cardiac compliance, which leads to the potential halting of fluid administration to avoid the risk of venous congestion and further organ damage. 34  

Which Fluid Solution Should Be Used for the Kidney?

Crystalloids..

A more physiologic chloride concentration provides the advantage of balanced solutions (Ringer’s lactate or acetate or Hartmann solution) over normal saline. Although normal saline is the solution of choice in hypochloremic states ( i.e. , vomiting, gastric drainage, and treatment with diuretics), normal saline induces hyperchloremic acidosis in patients with normal initial serum chloride concentrations in the perioperative setting. Experimental and clinical data show that increased plasma chloride concentration increases renal vascular resistance and decreases renal blood flow and a reduced GFR. This strategy to reduce chloride-containing solutions appears to prevent episodes of AKI in ICU patients. 35  

Hydroxyethyl Starches Are Associated with Negative Outcome.

The fluid resuscitation of brain-dead organ donors, based on hydroxyethyl starches (HES), is associated with an increased risk of AKI in kidney transplantations. In another randomized controlled trial, Schortgen et al. 36   found that septic patients treated with HES 200/0.6 showed a higher incidence of AKI compared with patients treated with gelatins. The Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis study showed a higher incidence of AKI in septic patients treated with HES 200/0.5 compared with those treated by crystalloids. Developed HES with lower molecular weight (130 kd) have been proposed because of the expected better risk/benefit ratio. The recently published 6S and Crystalloid versus Hydroxyethyl Starch trials did not confirm these expectations because the risk of AKI persisted with smaller molecular weight HES (HES 130/0.4), which induced a higher rate of mortality and/or dialysis. 37 , 38   Together, these trial data indicate an increased risk of AKI when HES are used. Precautions can be extended to other conditions, especially with the presence of acute inflammation ( e.g. , burns, cardiopulmonary bypass, postcardiac arrest syndrome). The safety profile of HES remains matter of debate during surgery. 39   Gelatins appear to have a safer profile, but there is little evidence for the potential risk of AKI. Finally, extra physiologic plasma oncotic pressure after the administration of a large amount of hyperoncotic solutions can decrease the GFR.

Use of Biomarkers

Urine biochemistry is frequently used to diagnose prerenal azotemia and guide fluid administration in the perioperative setting and in ICU patients, suggesting that the given parameters are indicators of renal tissue integrity and preserved tubular function. Recent evidence has suggested that urine chemistry is not a reliable tool for predicting the rapid reversibility of AKI. Preserved renal tubular sodium or urea handling does not necessarily indicate an absence of renal injury. Recently, Nejat et al. 13   found that patients with suspected prerenal azotemia showed evidence of structural injury, with increased biomarkers of renal injury. However, increased sodium excretion does not indicate tubular necrosis. Inflammation mediators have been shown to induce tubular cell dysfunction with conformational changes of the tubule Na+/H+ exchanger, urea, or chloride channels, which influence urine composition independent of any structural damage. 13 , 40   Biomarkers of renal injury ( i.e. , neutrophil gelatinase-associated lipocalin, kidney injury molecule-1) are expected to be used in diagnosis of tubular damage. 41   Many uncertainties remain regarding their validity at the bedside. The most promising biomarkers for renal injury appear to be the neutrophil gelatinase-associated lipocalin and kidney injury molecule-1. As an example, mild renal structure damage can lead to the profound loss of glomerular and/or tubular function in a patient with underlying structural alteration ( e.g. , chronic hypertension, diabetes); however, the same injury will not alter the function of an intact kidney ( fig. 3 ). A combination of biomarkers of structural injury may therefore provide a more accurate picture of renal injury compared with a single-biomarker approach.

Knowledge Gap

The optimization of systemic hemodynamics is believed to increase renal perfusion. However, the true contribution of renal hypoperfusion to the development of AKI, especially in severe sepsis and septic shock, remains a matter of debate. Intrarenal microcirculatory defects, regional and systemic inflammatory cell infiltration, and apoptosis are believed to be central in the development of AKI. Although a correlation between cardiac output and renal blood flow has been described in patients with AKI, the relationship among cardiac output, renal blood flow, renal injury, and renal function remains poorly explored. Although the development of new biomarkers of renal injury may allow the assessment of renal structure damage, tools to reliably assess renal perfusion and rapid changes in renal perfusion in patients at the bedside remain lacking. Renal Doppler of renal interlobar arteries can provide information on renal vascular resistance; however, this method does not measure renal blood flow per se . Therefore, developing tools to measure renal perfusion ( i.e. , renal blood flow and distribution of renal microvascular blood flow within the renal parenchyma) will allow a better understanding of the role of renal perfusion in renal damage.

The development of biomarkers of renal injury has been a major step forward. However, further investigation is needed to explore the significance of increased serum and urine levels of biomarkers, including neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, fatty acid-binding protein 1, and α-1 microglobulin, the influence of underlying processes ( e.g. , systemic inflammation), the influence of comorbidities and their source of production ( i.e. , extra renal production), and the specificity and sensibility of assays ( fig. 4 ). A combination of methods to assess renal structural injury, renal perfusion, and renal function will likely help develop new strategies and treatments that prevent or limit the development of AKI in surgical and critically ill patients.

Proposed strategy algorithm for treatment of oliguria in the postoperative period. Left and right ventricular function should be assessed, with estimation of cardiac output and signs of congestion. Functional hemodynamic monitoring provides guidance for resuscitation with vasopressors, inotropes, fluid or blood transfusion. When no sign of ineffective circulation ( e.g. , cardiac index >2.5 l·min −1 ·m −2 , central venous oxygen saturation–ScvO 2 >75%, no clinical sign of hypoperfusion, and others) and/or presence of acute lung injury can be identified, a restrictive fluid strategy should be preferred. Depletion should be considered in case of renal congestion including high central venous pressure (CVP) ± right heart failure, tricuspid regurgitation, and dilated inferior vena cava. Finally, titration of norepinephrine based on interlobar arteries on renal Doppler has been proposed for a tailored adjustment of renal perfusion pressure. AKI = acute kidney injury; LV = left ventricle; RV = right ventricle; NSAID = nonsteroidal antiinflammatory drug; CO = cardiac output; PAC = pulmonary artery catheter.

Graphic representation of the respective contribution of chronic renal damage (comorbidities) and acute injury in the development of acute kidney injury (AKI) and the fall of glomerular filtration rate (GFR). An acute insult will lead to profound renal injury and definitive loss of function in the kidney with chronic renal damage ( e.g. , diabetes, hypertension, mild chronic renal dysfunction) while only transiently and mildly decreasing GFR in healthy kidney. Urine and/or serum level of renal injury biomarkers may help to assess the degree of structural injury to the kidney. Note that renal function may not fully recover.

Contributing factors of acute kidney injury (AKI). Note that the respective contribution of each may vary. For instance, an episode of septic AKI is mainly related to the systemic and regional inflammatory response to infection causing microvascular disorders, apoptosis, necrosis. However, a superimposed nephrotoxic agent or severe hypoperfusion can lead to further damage and/or impaired recovery. Future research should help in the understanding of the relative contribution of each factor in the development of AKI, and provide clinicians with tools to better assess the preoperative risk and help predicting the development of AKI. ACE = angiotensin enzyme converting inhibitor; CO = cardiac output; CPB = cardiopulmonary bypass; HLA = human leukocyte antigens; NADPH = nicotinamide adenine dinucleotide phosphate-oxidase.

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• Research article
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• Published: 20 July 2022

Patient outcomes following AKI and AKD: a population-based cohort study

• Huan Wang 1   na1 ,
• Emilie Lambourg 1   na1 ,
• Bruce Guthrie 2 ,
• Daniel R. Morales 1 , 3 ,
• Peter T. Donnan 1 &
• Samira Bell   ORCID: orcid.org/0000-0001-9100-1575 1 , 4  

BMC Medicine volume  20 , Article number:  229 ( 2022 ) Cite this article

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Acute kidney injury (AKI) is common and associated with adverse outcomes as well as important healthcare costs. However, evidence examining the epidemiology of acute kidney disease (AKD)—recently defined as AKI persisting between 7 and 90 days—remains limited. The aims of this study were to establish the rates of early AKI recovery, progression to AKD and non-recovery; examine risk factors associated with non-recovery and investigate the association between recovery timing and adverse outcomes, in a population-based cohort.

All adult residents of Tayside & Fife, Scotland, UK, with at least one episode of community or hospital-managed AKI using KDIGO creatinine-based definition during the period 1 January 2010 to 31 December 2018 were identified. Logistic regression was used to examine factors associated with non-recovery, and Cox modelling was used to establish associations between AKI recovery timing and risks of mortality and development of de novo CKD.

Over 9 years, 56,906 patients with at least one AKI episode were identified with 18,773 (33%) of these progressing to AKD. Of those progressing to AKD, 5059 (27%) had still not recovered at day 90 post AKI diagnosis. Risk factors for AKD included: increasing AKI severity, pre-existing cancer or chronic heart failure and recent use of loop diuretics. Compared with early AKI recovery, progression to AKD was associated with increased hazard of 1-year mortality and de novo CKD (HR = 1.20, 95% CI 1.13 to 1.26 and HR = 2.21, 95% CI 1.91 to 2.57 respectively).

Conclusions

These findings highlight the importance of early AKI recognition and management to avoid progression to AKD and long-term adverse outcomes.

Peer Review reports

Globally, 13 million people worldwide are thought to be affected by acute kidney injury (AKI) every year [ 1 ]. The incidence is estimated between 7 and 18% amongst hospital in-patients with rates ranging between 30 and 70% in the critically ill [ 2 ], making it one of the most common complications following hospital admission. AKI also affects about 400 per 100,000 persons per year in community-based populations with an increasing incidence [ 3 ]. It is well established that acute kidney injury (AKI) is associated with adverse outcomes including development or worsening of CKD, [ 4 , 5 ] kidney failure, cardiovascular events [ 6 , 7 ], and reduced survival [ 8 ]. There is however limited evidence examining post-AKI renal recovery and how short-term recovery affects longer term outcomes. Even though community-acquired may be the most common form of AKI [ 9 ], evidence regarding community-acquired/community-managed AKI is sparse. Compared to those managed in-hospital, AKI cases managed in the community could represent a different sample of patients with fewer risk factors, milder cases and better outcomes [ 10 ] or conversely a palliative care population. Including these patients allows for a comprehensive depiction of real-word AKI burden and therefore generalizable findings. Over the past 15 years, definitions of both AKI and CKD have been agreed in formal consensus studies, and these definitions are currently applied widely in both research and clinical practice. However, no official definition for AKI recovery currently exists with a lack of consensus on how recovery should be defined [ 11 ]. Recently, the term acute kidney disease (AKD) has been proposed by Acute Disease Quality Initiative (ADQI) Workgroup to define an “acute or subacute damage and/or loss of kidney function for a duration of between 7 and 90 days after exposure to an AKI initiating event” [ 12 ]. This bridges the gap between AKI and CKD, reflecting increasing recognition that AKI and CKD are interconnected and likely represent a continuum, with patients who have sustained an episode of AKI having an increased risk of either developing de novo CKD or experiencing worsening of underlying CKD [ 13 , 14 ]. However, important knowledge gaps on the epidemiology including the clinical course of AKD need to be addressed before this terminology can be meaningfully used in clinical practice or research to differentiate early (in the first 7 days) and delayed (between 8 to 90 days) renal recovery after AKI. Furthermore, with the exception of some general key recommendations proposed by KDIGO [ 15 ], there are a lack of guidelines targeting AKI and AKD follow-up care.

The aim of this study is to (i) establish the rates of early recovery, progression to AKD and non-recovery following AKI using population based routinely collected healthcare data, (ii) understand which factors are associated with progression to AKD and non-recovery and (iii) explore the relationship between recovery timing and survival as well as development of de novo CKD.

Study population

This was a population-based cohort formed of all adults (aged 18 or above) in Tayside & Fife, Scotland, UK, who had at least two serum creatinine measurements on different days and presented an AKI episode between 1 January 2010 and 31 December 2018. Cohort entry (index date) was defined as the first day of the first AKI diagnosis during the study period.

Data sources

Data were provided by the Health Informatics Centre (HIC) [ 16 ] at the University of Dundee which enables anonymised linkage of health records of all residents of Tayside and Fife, Scotland (population of approximately 800,000 individuals), using the unique Community Health Index (CHI) number, which is used across the whole National Health Service (NHS) healthcare system. The following datasets were linked: creatinine laboratory results (community and hospital), Scottish Morbidity Record of hospital admissions (SMR01), medicines dispensed by community pharmacies, the Scottish Care Initiative-Diabetes Collaboration, National Records of Scotland (NRS) death records and the Scottish Renal Registry.

Linkage to SMR01 data provided information on all hospital admission and discharge dates as well as reasons for admission. Deprivation category was derived from the Scottish Index of Multiple Deprivation [ 17 ]. Information on diabetes type and date of diagnosis was obtained from the Scottish Care Information-Diabetes Collaboration [ 18 ]. Patients receiving chronic dialysis or with a kidney transplant were identified using the Scottish Renal Registry [ 19 ]. Comorbidities were identified at the index date and computed based on past ICD-10 hospitalisation codes using the Quan adaptation [ 20 ] of the Deyo Charlson mapping algorithm [ 21 ].

The primary outcomes were AKI recovery/non-recovery, death and progression to chronic KRT (Kidney Replacement Therapy). These were assessed at day 7 and day 90 post AKI diagnosis.

Secondary outcomes included progression to de novo chronic kidney disease and recovery timing—in terms of “days to recovery from the first day of AKI diagnosis”. Secondary outcomes were only assessed in a subset of the cohort: amongst patients without pre-existing chronic kidney disease and amongst patients with hospital-managed AKI respectively. The association between recovery timing and 1 year-mortality as well as 1-year de novo CKD were also explored.

Definitions

Detailed descriptions of all the concepts defined below are also available in Table 1 and illustrated in Fig. 1 .

AKI, AKD and CKD definitions

Acute kidney injury (AKI)

AKI definition was based on the Kidney Disease: Improving Global Outcomes (KDIGO) creatinine-based criteria [ 22 ], using the NHS England AKI e-alert algorithm [ 23 ]. The mean creatinine was calculated if there was more than one serum creatinine (SCr) measurement taken on the same day. By linking creatinine measurements to hospital admission data, AKI was further classified into 3 categories: community-acquired/community-managed (CA-CM), community-acquired/hospital-managed (CA-HM) and hospital-acquired (HA). An AKI episode diagnosed in the community was categorised as CA-CM AKI if there was no hospital admission within 7 days post AKI diagnosis. CA-HM AKI was defined as either an AKI episode diagnosed in the community with hospital admission within 7 days post AKI diagnosis or an AKI episode diagnosed on the day (J0) or the next day (J1) following an hospital admission. Finally, the definition of HA AKI was met for patients developing an AKI episode after 2 days in hospital (J2) or later.

Acute kidney disease (AKD)

AKD was defined as a loss of kidney function for a duration between 7 and 90 days after exposure to an AKI initiating event, as per the ADQI Workgroup definition [ 12 ]. By default, patients tested within the first 7 days post AKI diagnosis who did not meet criteria for recovery at day 7 entered the AKD phase at that point (provided they did not die or initiate chronic KRT before day 7). Their loss of kidney function was described as AKD until either criterion for recovery was met or day 90 after the AKI initiating event, whichever came first.

Chronic kidney disease (CKD)

CKD was defined according to the KDIGO definition [ 24 ] where eGFR was calculated using the CKD-EPI Creatinine Equation [ 25 ] using standardised SCr level.

Therefore, the presence of 2 eGFR records below 60 mL/min/1.73 m2 separated by more than 90 days was used to define CKD. Pre-existing CKD was determined using all SCr measurements strictly prior to the index date (first day of AKI diagnosis) whilst de novo CKD was determined using all SCr measurements sampled strictly after the 90 th day following the index date.

Progression to CKD was only investigated in patients who had no pre-existing CKD identified prior to the index date.

AKI recovery

Creatinine-based recovery was defined as having a creatinine measurement within 90 days post AKI diagnosis that was either < 1.2 times higher than reference value 1 (RV 1 ) (for AKI identified by creatinine ratio) or < 1.2 times higher than RV 1 and < 26.5 μmol/L higher than reference value 2 (RV 2 ) (for AKI identified by creatinine increment) [ 26 ]. All SCr measurements within the 90 days post AKI diagnosis were used to search for creatinine-based recovery. The earliest date with a SCr measurement meeting the recovery criteria described above was defined as the date of recovery. In order to avoid misclassification, two additional criteria had to be met to fulfil the definition of creatinine-based recovery: (1) absence of chronic KRT initiation in the 30 days following the date of creatinine recovery and (2) recovery status sustained for at least 3 days (day of creatinine recovery + the two following days—although this could only be applied if tests were available over 3 consecutive days, thereby only avoiding misclassification of detected early relapses as recoveries). Recovery timing was then defined as early if the patient recovered within the first 7 days (day 7 included) or as delayed if criteria for recovery were not met in the first 7 days but were further met during the AKD phase (day 8 to day 90 following AKI diagnosis).

At day 7 and day 90 post AKI diagnosis, patient status was classified into one of the states described in Table 1 . Patients who either recovered, died or started chronic KRT during a time period were excluded from the sub-cohort for the next time period (or censored on the date of recovery, death or chronic KRT initiation in survival analyses).

Patients untested within the first 7 days, who did not die or commence chronic KRT during that period, were described but excluded from all statistical analyses as no assumption can be made regarding their recovery status.

Chronic KRT

Chronic KRT was defined as either dialysis initiation (haemodialysis or peritoneal dialysis) or kidney transplantation. The date of chronic dialysis initiation or kidney transplantation is recorded in the Scottish Renal Registry for all patients starting chronic KRT in Scotland with 100% coverage.

Statistical analysis

Characteristics of the study population were summarised by medians and interquartile ranges for continuous measurements (due to non-Normal distributions) and as percentages for categorical factors. Scottish Index of Multiple Deprivation (SIMD) quintiles were summarised as a categorical factor. Age was converted to a categorical variable with approximately similar numbers within each category (less than 65, 65 to 74, 75 to 84, 85+ years old) and youngest patients (< 65 years old) taken as the reference level. Multivariable logistic regression models were implemented to identify risk factors associated with progression to AKD, taking patients with early recovery as the reference level. We then considered patients who entered the AKD phase and determined risk factors associated with non-recovery at day 90 post-AKI diagnosis, using another multivariable logistic model. For both models, we excluded patients who died or initiated chronic KRT, between day 1 and day 7, and between day 8 and day 90 respectively. In a sensitivity analysis, the models were rerun keeping patients who died or initiated chronic KRT during the period considered in the non-recovery group, and risk factors for non-recovery were re-identified. The same candidate risk factors were included in both models: demographic characteristics (age at AKI diagnosis, sex and social deprivation); baseline comorbidities (decreased baseline eGFR, cancer, coronary artery disease, congestive heart failure, diabetes and hypertension) and medications (ACE inhibitors or ARBs, loop diuretics, metformin, NSAIDs, statins) received in the 90 days prior to the index date. Those variables were checked for multicollinearity using a correlation matrix and the variance inflation factor. Frequency of creatinine measurements can provide additional important information that other variables cannot capture and was therefore included in the models as a continuous variable.

Associations between recovery timing and 1-year mortality or de novo CKD were evaluated in the recovery cohort (patients with proven recovery within the 90 days following AKI diagnosis) amongst those who had been tested within the first 7 days, using multivariable Cox proportional hazards (PH) models. People in the recovery cohort were followed up from the recovery date (time 0) until either occurrence of one of the study outcomes (death or de novo CKD) or censored at the last date of data availability (29-05-2019). Development of de novo CKD was assessed using a cause-specific Cox proportional hazard model with all-cause mortality as a competing endpoint. All AKI categories were included when exploring the association between delayed versus early recovery and adverse outcomes. However, the association between days to recovery and adverse outcomes was only investigated in patients with hospital-managed AKI, since the testing frequency (number of SCr measurements divided by number of days from AKI to recovery) was too low in those with community-managed AKI to allow for a precise determination of recovery timing, hence the exclusion of this AKI subgroup from this specific analysis. Days to recovery was included as a continuous variable using P-splines [ 27 ] to allow for non-linear effects on the hazard of study outcomes, with reference set as the median recovery time (4 days, HR = 1). Previous work has demonstrated good accuracy of penalised spline smoothing methods to account for nonlinear effects of covariates in Cox models [ 28 ]. Selection of the optimal smoothing parameter controlling the penalty applied to the curve was determined on the basis of the Akaike Information Criteria (AIC) [ 29 ]. For each individual Cox model, the proportional hazards (PH) assumption was checked using graphical diagnosis based on the scaled Schoenfeld residuals and testing of independence between residuals and time.

All data were analysed using the R statistical programming language (Version 3.6.2, Vienna, Austria) using the following packages: dplyr, data.table, survival, survminer, networkD3, graphics and sjPlot.

Description of the cohort

The study cohort consisted of 56,906 patients who had at least one AKI episode during the period 1 January 2010 to 31 December 2018 (Fig. 2 ). They were followed-up for a median time of 2.1 years (IQR: 0.4 to 4.7 years). Of those 56,906 patients, 13,443 (24%) had AKI diagnosed and managed in the community (community-acquired/community-managed), 22,637 (40%) had AKI diagnosed in the community but managed in hospital (community-acquired/hospital-managed), and for 20,826 (36%), AKI was acquired and managed in-hospital (hospital-acquired). Out of all first AKI episodes during the study period, 45,361 (80%) were stage 1 at diagnosis, 7599 (13%) were stage 2, and 3946 (7%) were stage 3. The median age of the cohort was 75 years old (IQR: 63 to 83) with an evenly distributed men/women ratio. Patients with community-acquired/community-managed AKI were younger (median: 69 years old, IQR: 52 to 80), with a larger proportion of women (65%) and fewer comorbidities, compared to those managed in hospital. Patients’ characteristics at baseline stratified by AKI category are summarised in Table 2 . Table 3 summarises outcomes at 90 days and 1 year following the AKI episode, stratified by AKI category and AKI severity. At 1-year post-AKI, 18,381 patients (32.3%) had died, with the lowest crude mortality observed amongst those with community-acquired/community-managed AKI (15.8%) followed by community-acquired/hospital-managed AKI (36.4%) and hospital-acquired AKI (38.5%). Additional file 1 : Fig. S1 depicts the overall survival following the AKI episode, stratified by AKI category. Mortality was associated with AKI severity, with 1-year survival of 69.8% and 57.3% for those with AKI stage 1 and 3 respectively.

Flow chart of cohort design

From the 56,906 patients in the cohort, only 535 (0.94%) commenced chronic KRT after the AKI episode. This was strongly associated with AKI severity, with 6.9% of patients with AKI stage 3 further initiating chronic KRT.

Additional file 1 : Table S1 summarises recovery status at 7 and 90 days post AKI, stratified by AKI category and AKI stage at diagnosis. During the first 7 days post AKI diagnosis, 20,041 (35.2%) out of 56,906 recovered, 18,773 (33.0%) were tested but had not recovered, 13,154 (23.1%) were not tested, 4892 (8.6%) died and 46 (0.08%) initiated chronic KRT. Proven recovery rate was highest in people with community-acquired/hospital-managed AKI (47.0%), followed by hospital-acquired (38.4%), and was only 10.4% in people with community-acquired/community-managed AKI. However, a large proportion (66.7%) of patients with community-acquired/community-managed AKI were not tested in the first 7 days, which was not the case amongst those with community-acquired/hospital-managed AKI (8.7% untested) or hospital-acquired AKI (10.7% untested). In a sensitivity analysis, we compared the characteristics of patients with community-acquired/community-managed AKI who were tested versus untested within the first 7 days post-AKI. This analysis, which only included those who had survived and not initiated chronic KRT at day 7, showed that untested patients tended to be younger (median age: 68 vs 72 years old), with fewer comorbidities, a higher baseline eGFR (eGFR> 90 in 47% vs 29%) and milder AKI (stage 1: 93% vs 83%) compared with tested patients (Additional file 1 : Table S2). Compared with community-managed AKI, those with hospital-managed AKI (community- and hospital-acquired) were also more often tested within 90 days post-AKI (median number of SCr tests: 6 versus 2).

At day 8, 18,773 (33%) patients from the initial cohort entered the AKD cohort. Of these, 7698 (41%) had a delayed recovery, with a similar proportion in the different AKI categories, whilst 5059 (27%) had still not recovered at day 90. A total of 3695 (19.7%) patients with AKD died between day 8 and day 90, with a higher proportion amongst those who were managed in hospital (21.8% for community-acquired/hospital-managed AKI and 21.4% for hospital-acquired AKI versus 8.7% for community-acquired/community-managed AKI). Of note, 11.7% of those who had been tested but had not recovered at day 7 were not retested between day 8 and day 90 whilst 36.2% of those who had not been tested within the first 7 days had still not been tested at day 90 (Additional file 1 : Table S3).

Day 7 status for the whole cohort, as well as day 90 status for those who entered the AKD phase, can be visualised in the Sankey diagrams, with and without stratification by AKI categories (Figs. 3 and 4 a,b,c respectively).

Sankey diagrams showing patient status at 7 and 90 days post-AKI diagnosis (all AKI categories)

a–c Sankey diagrams showing patient status at 7 and 90 days post-AKI diagnosis, by AKI category

Factors associated with progression to AKD and non-recovery

Risk factors associated with progression to AKD amongst tested individuals are summarised in Table 4 and Additional file 1 : Figure S2 for the main analysis, in Additional file 1 : Table S4 and Figure S3 for the sensitivity analysis (in which patients who died or initiated chronic KRT within the first 7 days were not excluded but rather considered as having not recovered during that period). More severe AKI at diagnosis (stages 2 and 3), a history of cancer diagnosis, a history of congestive heart failure and recent exposure to loop diuretics or metformin were significantly associated with progression to AKD. Conversely, prior exposure to ACE/ARB was associated with early AKI recovery (adjusted OR = 0.85, 95% CI 0.81 to 0.89, p < 0.001). The adjusted odds of progressing to AKD were 2.3 times higher (95% CI 2.2 to 2.5) in those with community-acquired/community-managed AKI than in those with community-acquired/hospital-managed AKI. An older age was negatively associated with progression to AKD, however this trend disappeared in the sensitivity analysis.

The results also showed that a higher number of SCr tests performed over the first 7 days was associated with early AKI recovery (OR = 0.89 for one supplementary test, 95% CI 0.88 to 0.90, p < 0.001). Risk factors associated with non-recovery at day 90 are summarised in Table 5 and Additional file 1 : Figure S4 for the main analysis, in Additional file 1 : Table S5 and Figure S5 for the sensitivity analysis (in which patients who died or initiated chronic KRT between day 8 and day 90 were not excluded but rather considered as having not recovered during that period). Later AKI stages, hospital-acquired/hospital-managed AKI, community-acquired/community-managed AKI, a history of cancer or chronic heart failure increased the odds for non-recovery in the main and sensitivity analyses. Prior recent exposure to ACE/ARB was also consistently associated with proven recovery at day 90 (aOR = 0.84, 95% CI 0.77 to 0.92 in main analysis, aOR = 0.76, 95% CI 0.70 to 0.81 in the sensitivity analysis). Lower baseline eGFR values were associated with recovery during the AKD phase.

Age was linearly associated with increased odds of non-recovery at day 90 in the sensitivity analysis only. However, community-acquired/community-managed AKI was no longer a risk factor for non-recovery at day 90 in the sensitivity analysis (aOR = 0.99, 95% CI 0.90 to 1.09).

No multicollinearity was detected between the different predictors investigated, with all correlation coefficients below 60% (Additional file 1 : Figure S6).

Timing of recovery and long-term outcomes

Tested people with either early or delayed proven recovery formed a recovery cohort ( n = 29,330) with 14,486 individuals free of pre-existing CKD. Of those, 2805 (19.4%) subsequently developed de novo CKD with similar proportions across the different AKI categories (19.3%, 257/1334 of those with community-acquired/community-managed AKI, 19.4% 1534/7890 of those with community-acquired/hospital-managed AKI, and 19.3% 1014/5262 of those with hospital-acquired AKI).

Compared to early recovery, delayed recovery was significantly associated with higher risk of death (HR = 1.20, 95% CI 1.13 to 1.26) and de novo CKD (HR = 2.21, 95% CI 1.91 to 2.57) in the subsequent year following the AKI episode (Additional file 1 : Table S6, and Fig. 5 ). This trend was observed in all AKI categories, but the risk was highest in those with community-acquired/community-managed AKI (HR = 1.55, 95 % CI 1.23 to 1.95 for 1-year mortality and HR = 3.25, 95% CI 1.99 to 5.31 for 1-year risk of de novo CKD). Cox analyses showed that the association between delayed recovery and adverse outcomes was time-varying, with the strongest risks observed over the year following the AKI episode and subsequent wearing off, and no significant association after 2 years.

Forest plot displaying risks of 1-year mortality and de novo CKD associated with progression to AKD compared to early recovery

Figure 6 shows the association between all values of recovery timing comprised within 1 and 90 days and relative rates of 1-year mortality (a) as well as development of de novo CKD (b) in patients with hospital-managed AKI (including community-acquired/hospital-managed and hospital-acquired AKI) tested within the first 7 days. Since we would not be able to derive an accurate recovery timing for patients with community-acquired/community-managed AKI (due to the lack of repeat testing), they were excluded from this analysis as well as patients from any AKI category that were untested within the first 7 days post AKI diagnosis. The relative hazard for 1-year mortality increased with recovery timing in a nonlinear fashion, with a sharp initial rise over the first 14 days followed by a plateau. The risk of developing de novo CKD increased more progressively and linearly with recovery timing over the first month following the AKI episode. Beyond this period the risk then stabilised or may even decline.

a , b Association between recovery timing and 1-year relative hazard of death ( a ) and development of de novo CKD ( b ) in patients with hospital-managed AKI

In this large comprehensive population-based cohort study, there were 56,906 patients with community or hospital-acquired AKI, with a median follow-up of 2.1 years. Overall, 35% of the initial cohort had proven creatinine-recovery at day 7 and 49% at day 90 post AKI diagnosis. Risk factors for progression to AKD included AKI severity, pre-existing cancer or chronic heart failure, recent use of loop diuretics, community-managed AKI as well as hospital-acquired AKI. Of note, being exposed to ACE/ARB was consistently associated with AKI recovery at both day 7 and day 90 (adjusted OR: 0.85, 95% CI 0.81-0.89 and 0.86, 95% CI 0.78–0.95 respectively). Compared with early AKI recovery, progression to AKD was associated with increased risks of 1-year mortality and de novo CKD (HR = 1.20, 95% CI 1.13 to 1.26 and HR = 2.21, 95% CI 1.91 to 2.57 respectively). The first 14 days following an AKI episode were identified as a critical window where each additional day was associated with a rapid increase in risk for adverse outcomes.

It is concerning that in our cohort, a remarkably high proportion of patients with community-acquired/community-managed AKI (67%) were untested at day 7. Amongst those, 36% remained untested at day 90. Patients untested within the first 7 days appeared to be younger, with a higher baseline eGFR and milder AKI which may explain the lack of repeat testing in this fitter population. Furthermore, it is worth noting that in this area of Scotland, repeat testing within 7 days post AKI diagnosis only became more common after the introduction of the National Health Service England Acute Kidney Injury electronic alert algorithm in 2015 [ 30 ]. Therefore, a major part of our data captures the practices in place prior to the introduction of this system. Although testing is not always appropriate, for example in palliative care settings or in the context of particularly frail patients, these findings raise questions regarding the management of AKI in the community setting. Moreover, we showed that AKI severity, history of cancer, chronic heart failure and receiving loop diuretics were consistent risk factors for progression to AKD. In line with our result, a previous study aiming to predict recovery following dialysis-requiring AKI showed that patients who recovered were less likely to have a history of heart failure [ 31 ]. The same study also identified younger age as a predictor for recovery. Our sensitivity analysis showed that an older age was associated with an increased risk of early death following the AKI episode but not with non-recovery. In both unadjusted and adjusted analyses, we consistently found that prior use of ACE/ARB was significantly associated with AKI recovery at both day 7 and day 90. The use of ACE/ARB in the context of AKI is widely debated. The KDIGO recommendation is to stop potentially nephrotoxic drug (including ACE/ARB in this category) during AKI. However, emerging evidence suggests that ACE/ARB should not be considered as nephrotoxic [ 32 ] and could even be associated with improved AKI recovery and reduced subsequent mortality [ 33 , 34 , 35 ]. The association between NSAIDs exposure and non-recovery was either non-significant or protective at both day 7 and day 90. NSAIDs-related AKI remain rare events and this observed association may be related to some residual confounding by indication where physicians avoid prescribing NSAIDs to frailer patients they perceive to be at higher risk of NSAIDs-related adverse outcomes such as AKI [ 36 ]. Another hypothesis for this finding is the usually rapid renal recovery of NSAIDs-induced AKI (typically within 72 to 96 h provided diagnosis is made early and NSAIDs are promptly discontinued) [ 37 ]. Surprisingly, our models suggested an association between lower baseline eGFR values and AKI recovery. This may be because those with lower baseline eGFR values will have greater fluctuations in serum creatinine related to volume status. Recent metformin use appeared as a risk factor for AKD but then as a strong protective factor in our sensitivity analysis when considering non-recovery at day 90. The latter is consistent with previous work reporting improved short-term survival following incident AKI in those exposed to metformin [ 38 , 39 ].

The association between AKI, AKD and CKD is complex and mortality as well as progression to CKD after an AKI episode have been documented in many studies [ 8 ]. Our results showed that compared with early AKI recovery, progression to AKD was associated with both 1-year mortality and development of de novo CKD. This is consistent with previously published data conducted amongst patients admitted for cardiovascular reasons, which demonstrated that AKD was associated with both short- (90 days) [ 40 ] and long-term (5 years) [ 41 ] risk of death and adverse renal events. However, in a cohort of patient admitted for sepsis-associated AKI, individuals with early AKI reversal had similar mortality rates as those developing AKD [ 42 ].

Similarly, we found that risk of death and de novo CKD increased progressively with recovery timing. This is in line with previous work conducted in a cohort of adult US veterans, suggesting that recovery timing may act as an independent predictor for future loss of kidney function [ 43 ]. Bhatraju et al. found that recovering within the first 72 h immediately following the AKI episode may be crucial to avoid major adverse kidney events [ 44 ]. Compared to a rapid reversal (within 48 h), persistent AKI was also significantly associated with a higher 1-year mortality rate [ 45 ]. Recovery timing therefore appears to be a major factor in the context of AKI recovery, which adds important prognostic information regarding adverse long-term outcomes following an AKI episode. In this study, modelling of precise recovery timing showed that the first 2 to 3 weeks following an AKI episode represent a critical window where risk for adverse outcomes increase most rapidly and where interventions are therefore most likely to reduce risk of progression to CKD or early mortality. Mechanisms potentially explaining the association between longer recovery timing and worse outcomes include persistent inflammation, prolonged renin-angiotensin system activation with long-term hypertension even after recovery and repeated cellular injury due to local ischemia leading to kidney damage such as tubular or glomerular injury [ 46 ].

Our study has several strengths. These include the comprehensive nature of the unselected population-based cohort covering a large geographical population of Scotland (about 790,000 individuals), the large number of AKI episodes recorded over a 9-year period and the robust methodology accounting for major confounders, with sensitivity analyses ensuring the consistency of findings. The inclusion of community-managed AKI brings new insights regarding level of care and risks associated with treatment outside hospitals, for which data are currently lacking. Finally, our strict definition of sustained recovery reduces misclassification of relapse as recovery. This work helps fill important knowledge gaps in the current understanding of renal recovery after AKI but also comes with a number of limitations. Firstly, this study was conducted in a specific geographic area of Scotland and may not be generalizable to other AKI cohorts worldwide. However, it remains an unselected population-based cohort whose characteristics are similar to that of previous studies and therefore generalizable to other high-income countries. It should be noted that a large proportion (67%) of patients with community-managed AKI were untested during the first 7 days post AKI diagnosis; hence, all conclusions made on this subgroup were based on the subset of patients who had available follow-up SCr data, with subsequent risks of ascertainment and selection bias. However, our sensitivity analysis showed that patients with community-acquired/community-managed AKI tested within the first 7 days have very similar characteristics to that of patients with hospital-acquired AKI, making comparisons relevant. It should be noted that in the absence of any accepted definition [ 11 ], we chose the definition of AKI recovery (< 1.2 times higher than baseline SCr) as per previous work [ 26 ] but other studies in the field may have used different thresholds, making between-study comparisons less straightforward. Furthermore, we chose to focus on AKD occurring after an AKI event and do not examine AKD occurring without a preceding AKI episode [ 47 ]. Another limitation of this study is the lack of data availability regarding the use of temporary dialysis for AKI management, with subsequent risk of AKI recovery misclassification in a small proportion of hospital-managed AKI episodes. Finally, due to the observational nature of this study, risk of residual confounding remains, despite our efforts to control for all important variables.

Our data demonstrates that AKD is common in patients with AKI and associated with deleterious outcomes such as early mortality or de novo CKD, especially when AKI management takes place outside hospitals. Patients with community-managed AKI should be more widely tested within the first 7 days post AKI diagnosis to ensure optimal management. As risks for adverse outcomes increase sharply during the immediate period (2 to 3 weeks) following AKI diagnosis, this work stresses the importance of early AKI recovery to avoid long-term consequences. Patients with cancer, chronic heart failure and those exposed to diuretics may be at particularly high risk of progression to AKD and non-recovery, therefore deserving extra attention. Although more evidence is needed to guide clinical practice, our results suggested that ACE/ARB may have a protective effect in a context of AKI, with improved recovery amongst recently exposed individuals. Increased awareness and strategies for the management of patients with AKD are needed to maximise early recovery and minimise AKI-related harms.

Availability of data and materials

The data controller of the data analysed is NHS Tayside. Patient level data are available subject to standard information governance requirements for use of anonymised, unconsented NHS data https://www.dundee.ac.uk/hic/ .

Abbreviations

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

Acute Disease Quality Initiative

• Acute kidney disease
• Acute kidney injury

Community-acquired/community-managed AKI

Community-acquired/hospital-managed AKI

• Chronic kidney disease

Estimates glomerular filtration rate

Hospital-acquired/hospital-managed AKI

Health Informatics Centre

Hazard ratio

International Classification of Diseases – version 10

Interquartile range

Kidney Disease Improving Global Outcomes

Kidney replacement therapy

Kidney transplant recipients

National Health Services

National Record of Scotland

Nonsteroidal anti-inflammatory drugs

Reference value

Serum creatinine

Scottish Index of Multiple Deprivation

Scottish Morbidity Record of hospital admissions

United Kingdom

United States

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Acknowledgements

We wish to thank the Health Informatics Centre (HIC), University of Dundee, for providing the data.

This work was funded by Tenovus Tayside (Grant No. T18-26).

Author information

Huan Wang and Emilie Lambourg contributed equally to this work.

Authors and Affiliations

Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK

Huan Wang, Emilie Lambourg, Daniel R. Morales, Peter T. Donnan & Samira Bell

Advanced Care Research Centre, Usher Institute of Population Health Sciences and Informatics, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK

Bruce Guthrie

Department of Public Health, University of Southern Denmark, Odense, Denmark

Daniel R. Morales

Renal Unit, Ninewells Hospital, Dundee, UK

Samira Bell

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HW and SB conceived the study. HW, SB and EL designed the study. HW and EL analysed the data and performed the statistical analyses. EL, HW and SB wrote the manuscript. All authors edited the manuscript and approved the final version.

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Correspondence to Samira Bell .

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Data linkage and anonymisation was carried out under HIC Standard Operating Procedures which have been approved by the NHS Research Ethics Service, and all analyses were conducted on anonymised data in the HIC secure Safe Haven. The study was approved by the NHS Tayside Caldicott Guardian, and individual study approval by the NHS Research Ethics Service was therefore not required.

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Supplementary Information

Additional file 1: figure s1.

: Survival curve stratified by AKI category. Table S1 : Recovery status at 7- and 90-days post-AKI diagnosis. Table S2 : Characteristics of tested versus untested patients with CA-CM AKI. Table S3 : 90-day status of patients untested within the first 7 days post AKI diagnosis. Figure S2 : Association between individual predictors and progression to AKD (main analysis). Table S4 and Figure S3 : Association between individual predictors and non-recovery at day 7 (sensitivity analysis). Figure S4 : Association between individual predictors and non-recovery at day 90 in patients who entered the AKD phase (main analysis). Table S5 and Figure S5 : Association between individual predictors and non-recovery at day 90 in patients who entered the AKD phase (sensitivity analysis). Figure S6 : Correlation matrix for pairs of candidate risk factors. Table S6 : Association between progression to AKD and subsequent risk of death or development of de novo CKD.

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Wang, H., Lambourg, E., Guthrie, B. et al. Patient outcomes following AKI and AKD: a population-based cohort study. BMC Med 20 , 229 (2022). https://doi.org/10.1186/s12916-022-02428-8

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Acute Kidney Injury Case Study (60 min)

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Case Study Objectives

• Analyze and interpret clinical data and patient assessments to identify signs and symptoms of acute kidney injury (AKI) in a real-life patient scenario.
• Apply critical thinking skills to recognize the physiological mechanisms contributing to the development of AKI, considering factors such as dehydration, contrast dye exposure, and prolonged NPO status.
• Evaluate the appropriate nursing actions and interventions required at various stages of AKI management, including fluid resuscitation, diuretic therapy, and ongoing assessment.
• Anticipate and suggest potential preventive measures for AKI, emphasizing the importance of pre- and post-contrast scan IV fluid administration in vulnerable patients.
• Understand the significance of monitoring laboratory values, such as BUN, creatinine, GFR, and electrolytes, to assess kidney function and guide treatment decisions in AKI cases.

By actively engaging with this acute kidney injury case study, nursing students will enhance their clinical reasoning skills and gain valuable insights into the assessment, management, and prevention of AKI in real-world healthcare scenarios.

Kidney Injury Case Study

Ms. Barkley is a thin, frail 64-year-old female presenting from a nursing home for acute abdominal pain, nausea, and vomiting x 2 days. She receives a CT scan with IV contrast. Findings show no acute bleeding, but a possible small bowel obstruction.  She is admitted for bowel rest, with the following written orders from the provider:

• Continuous Telemetry
• Strict I&O measurements
• Keep SpO 2 > 92%
• Keep NPO (strict)
• Hydrocodone/Acetaminophen 5-325 mg PO q6h PRN moderate to severe pain
• Ondansetron 4mg PRN nausea

She is admitted to the unit at the beginning of shift, and the UAP reports the following vital signs: HR 103 RR 16 BP 118/68 SpO 2 96% Pain 6/10

Which order would you question or request clarification for? Why?

• The Ondansetron order is incomplete. There is no route or frequency ordered

What additional nursing assessments need to be performed?

• Assess abdomen – inspect, auscultate, palpate and percuss. Assess for tenderness over specific areas, feel for masses, and look for guarding.
• Listen to heart and lung sounds to ensure no cardiac involvement
• Assess pain with a detailed pain assessment so that pain can be treated appropriately
• Assess skin – the patient has had nausea/vomiting for 2 days, there may be some dehydration – check for tenting.

At the end of the 12-hour shift, vital signs are as follows: HR 96 RR 22

BP 147/80 SpO 2 93%

The nurse recognizes that the patient has not voided all day and assists the patient to the bathroom. The patient voids 200 mL dark, concentrated urine.

What nursing action(s) should be implemented at this time? Who should this information be passed on to?

• Document the output, notify the provider of the decreased urine output
• This information needs to be passed onto the oncoming nurse so that he or she can closely monitor the patient’s urine output.

What diagnostic tests would you expect the provider to order? Why?

• Expect an order for a Basic Metabolic Panel or a Renal Function panel
• It seems like her kidneys aren’t making urine as they should, or she may be severely dehydrated. A chemistry panel can tell us more information about the source of decreased urine output.

Provider orders a 500 mL bolus of Normal Saline (0.9%) IV over 1 hour and a renal function panel, which is drawn promptly by the nurse. After 6 hours, Ms. Barkley still has had no further urine output. A bladder scan shows approximately 60 mL of urine in the bladder. A head-to-toe assessment now reveals crackles in Ms. Barkley’s lungs and her SpO 2 is 89%

The renal function panel has resulted: BUN 56 mg/dL Na 132 mg/dL Cr 3.6 mg/dL Ca 7.7 mg/dL GFR 47 mL/min/m 2 Phos 4.8 mg/dL K 5.5 mEq/L Mg 1.4 mg/dL

What nursing action(s) should be implemented at this time?

• Administer O2 2 lpm via nasal cannula (to keep sats > 92%)
• Notify provider of lab results, especially BUN/Cr, GFR, and Potassium – as these indicate there is kidney involvement.

What orders should be anticipated from the provider?

• The patient may need more fluids, she’s been vomiting for 2 days and NPO for another 12 hours with no IV fluids.
• The patient may require diuretics to remove the excess fluid from her lungs and to determine the level of function of her kidneys

What is going on physiologically with Ms. Barkley at this time? Explain what contributed to the development of this condition

• Ms. Barkley seems to have developed an acute kidney injury or acute kidney failure.
• The likely contributors are the severe dehydration coupled with the IV contrast and 12+ hours of being NPO and having no IV fluids. This caused a low-flow state to the kidneys (pre-renal) as well as possible damage to the kidneys themselves because of the contrast (intra-renal).

The provider orders to give 1L bolus of Normal Saline (0.9%) over 1 hour, then 125 mL/hr of Normal Saline continuously. The provider also orders a one-time dose of 40 mg Furosemide IV push and to re-check the Renal Function Panel in 6 hours.  Ms. Barkley diuresis approximately 600 mL in 2 hours and her lungs now sound clear to auscultation.

Over the next two days, Ms. Barkley’s hourly urine output begins to improve and her BUN, Creatinine, and GFR return to normal ranges.  Her small bowel obstruction resolves on its own and she is able to begin taking PO food and fluids.

What could have been done, if anything, to prevent Acute Kidney Injury for Ms. Barkley?

• The best option would have been to give Ms. Barkley IV fluids before and after her contrast scan, and to make sure she had maintenance IV fluids infusing while she was NPO. 
• Depending on the patient’s kidney function, it isn’t always preventable, but in this case, it seems there was more that could have been done.

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Acute Renal Failure Case Study

Our kidneys are incredible organs that get rid of toxins, retain substances needed by our bodies, and maintain the right balance of electrolytes, minerals, and water. Find out what happens to this 27-year-old when toxins accumulate in her kidneys leading to acute renal failure.

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• Consensus Statement
• Published: 23 February 2023

Sepsis-associated acute kidney injury: consensus report of the 28th Acute Disease Quality Initiative workgroup

• Alexander Zarbock 1 , 2   na1 ,
• Mitra K. Nadim 3   na1 ,
• Peter Pickkers 4 ,
• Hernando Gomez   ORCID: orcid.org/0000-0001-5605-3513 5 ,
• Samira Bell 6 ,
• Michael Joannidis   ORCID: orcid.org/0000-0002-6996-0881 7 ,
• Kianoush Kashani   ORCID: orcid.org/0000-0003-2184-3683 8 ,
• Jay L. Koyner   ORCID: orcid.org/0000-0001-6873-8712 9 ,
• Neesh Pannu 10 ,
• Melanie Meersch 1 ,
• Thiago Reis   ORCID: orcid.org/0000-0002-7071-117X 11 , 12 ,
• Thomas Rimmelé 13 ,
• Sean M. Bagshaw 14 ,
• Rinaldo Bellomo   ORCID: orcid.org/0000-0002-1650-8939 15 , 16 , 17 , 18 ,
• Vicenzo Cantaluppi 19 ,
• Akash Deep 20 ,
• Silvia De Rosa 21 , 22 ,
• Xose Perez-Fernandez   ORCID: orcid.org/0000-0002-5903-6927 23 ,
• Faeq Husain-Syed 24 ,
• Sandra L. Kane-Gill   ORCID: orcid.org/0000-0001-7523-4846 25 ,
• Yvelynne Kelly 26 , 27 ,
• Ravindra L. Mehta   ORCID: orcid.org/0000-0002-0908-2968 28 ,
• Patrick T. Murray   ORCID: orcid.org/0000-0001-8516-1839 29 ,
• Marlies Ostermann   ORCID: orcid.org/0000-0001-9500-9080 30 ,
• John Prowle   ORCID: orcid.org/0000-0002-5002-2721 31 ,
• Zaccaria Ricci 32 , 33 ,
• Emily J. See 15 , 18 , 34 ,
• Antoine Schneider 35 ,
• Danielle E. Soranno 36 ,
• Ashita Tolwani 37 ,
• Gianluca Villa 38 ,
• Claudio Ronco   ORCID: orcid.org/0000-0002-6697-4065 39 , 40 , 41 &
• Lui G. Forni   ORCID: orcid.org/0000-0002-0617-5309 42 , 43  

Nature Reviews Nephrology volume  19 ,  pages 401–417 ( 2023 ) Cite this article

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Acute kidney injury

• Prognostic markers

Sepsis-associated acute kidney injury (SA-AKI) is common in critically ill patients and is strongly associated with adverse outcomes, including an increased risk of chronic kidney disease, cardiovascular events and death. The pathophysiology of SA-AKI remains elusive, although microcirculatory dysfunction, cellular metabolic reprogramming and dysregulated inflammatory responses have been implicated in preclinical studies. SA-AKI is best defined as the occurrence of AKI within 7 days of sepsis onset (diagnosed according to Kidney Disease Improving Global Outcome criteria and Sepsis 3 criteria, respectively). Improving outcomes in SA-AKI is challenging, as patients can present with either clinical or subclinical AKI. Early identification of patients at risk of AKI, or at risk of progressing to severe and/or persistent AKI, is crucial to the timely initiation of adequate supportive measures, including limiting further insults to the kidney. Accordingly, the discovery of biomarkers associated with AKI that can aid in early diagnosis is an area of intensive investigation. Additionally, high-quality evidence on best-practice care of patients with AKI, sepsis and SA-AKI has continued to accrue. Although specific therapeutic options are limited, several clinical trials have evaluated the use of care bundles and extracorporeal techniques as potential therapeutic approaches. Here we provide graded recommendations for managing SA-AKI and highlight priorities for future research.

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Introduction

Sepsis is characterized by a dysregulated host response to infection that leads to life-threatening organ dysfunction, commonly including acute kidney injury (AKI) 1 . Sepsis accounts for 45–70% of all cases of AKI among critically ill patients 2 , 3 . Sepsis-associated AKI (SA-AKI) portends a worse prognosis than either syndrome in isolation 3 , 4 and is associated with longer intensive care unit (ICU) and hospital stays, higher mortality, increased rate of long-term disability and reduced quality of life in adult and paediatric populations 5 , 6 , 7 , 8 , 9 . AKI associated with sepsis can present with different phenotypes and prognoses 10 , 11 . Many aspects of SA-AKI remain poorly described, especially in the paediatric population, including its clinical definition, epidemiology, pathophysiology, impact of resuscitative and fluid strategies, role of biomarkers in risk stratification, diagnosis, and treatment guidance, and the effect of extracorporeal and novel therapies on patient outcomes. The 28th Acute Disease and Quality Initiative ( ADQI ) was aimed at identifying these knowledge gaps in both the adult and the paediatric populations, propose definitions, develop a common framework for further research in this important area, and provide recommendations for clinical practice.

The Conference Chairs of the 28th ADQI consensus committee (L.G.F., A.Z., M.K.N. and C.R.) convened a diverse panel of adult and paediatric clinicians and researchers representing relevant disciplines — critical-care medicine, anaesthesiology, nephrology and pharmacology — from Europe, North and South America, and Australia, to discuss SA-AKI. The conference was held over 2.5 days in Vicenza, Italy, on 17–19 June 2022. This consensus meeting followed the established ADQI process and used a modified Delphi method to achieve consensus, as previously described 12 , 13 . Briefly, the ADQI approach uses methods that involve a combination of both expert panel and evidence appraisal, and this approach was chosen to achieve the best of both options. Each ADQI conference is divided into three phases: pre-conference, conference, and post-conference. In the pre-conference phase, the groups that are assigned to specific topics identify a list of key questions, conduct a systematic literature search, and generate a bibliography of key studies. Studies are identified via Medline search and bibliographies of review articles; searches are generally limited to articles written in English. The conference itself is divided into breakout sessions, where workgroups address the issues in their assigned topic area, and plenary sessions, where their findings are presented, debated and refined. This approach has led to important practice guidelines with wide acceptance and adoption into clinical practice. If further research is needed, the ADQI group proposes research questions that should be addressed in the future to facilitate advances in the field. Conference participants were divided into five working groups to discuss the epidemiology and definition of SA-AKI; the pathophysiology of SA-AKI and novel underlying mechanisms; the use of fluids and resuscitative strategies to treat SA-AKI; the use of biomarkers for aiding diagnosis and guiding therapy, and in the design of clinical trials; and the use of extracorporeal treatments and novel therapies. Members of the five workgroups reviewed the literature systematically and, where possible, developed a consensus that was backed by evidence, and proposed a research agenda to address important unanswered questions. In addition, the members were asked to note the level of evidence for all consensus statements using the Grades of Recommendation Assessment, Development and Evaluation system 14 . In several cycles of presentations, feedback and adjustments, all of the individual workgroups presented their output to conference participants. The final output was then assessed and aggregated in a session attended by all attendees, who formally voted and approved the consensus recommendations.

Definition and epidemiology of SA-AKI

Definition of sa-aki and sepsis-induced aki.

Currently, no universally accepted definition of SA-AKI exists 15 . To support clinical guidelines, quality improvement initiatives, and future research, we propose that the presence of both sepsis (as currently defined in adults by the Sepsis-3 criteria) and AKI (as presently defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria) should define SA-AKI 1 , 16 (Box  1 ). SA-AKI is a heterogeneous syndrome that occurs as the consequence of either direct mechanisms related to infection or the host response to infection, or indirect mechanisms driven by unwanted sequelae of sepsis or sepsis therapies 17 . As such, the term SA-AKI operationally unifies the presence of AKI (according to clinical, biochemical and functional criteria) in the context of sepsis as a specific disease phenotype that is characterized by a specific trajectory and outcome 18 , 19 .

Sepsis-induced AKI (SI-AKI) can be considered to be a subphenotype of SA-AKI, in which sepsis-induced mechanisms drive kidney damage directly. Thus, by definition, SI-AKI excludes injury that primarily develops as the indirect consequence of sepsis or sepsis therapies (for example, AKI caused by antimicrobial agent-induced nephrotoxicity or abdominal compartment syndrome) 20 , 21 . Importantly, mechanisms that underlie cellular and organ injury in ischaemic AKI or nephrotoxic AKI, such as microcirculation failure, inflammation and mitochondrial injury, might also contribute to SI-AKI. The limited availability of clinical tools such as biomarkers that can aid early identification complicate the distinction between SI-AKI and other causes of SA-AKI. Of note, although the development of AKI is associated with an increased risk of infection, this definition intentionally excludes sepsis following an AKI event, as the aetiology is likely different from that of SA-AKI.

To capture the temporal relationship between the two conditions, SA-AKI should be considered when AKI occurs within 7 days of sepsis diagnosis, and can be further differentiated into early (AKI occurs up to 48 h after sepsis diagnosis) or late SA-AKI (AKI occurs between 48 h and 7 days of sepsis diagnosis), to align with current AKI criteria (Box  1 ). The rationale for the proposed 7-day window in the definition of SA-AKI is based on the observation that, in most cases of sepsis, AKI occurs within a few days of sepsis onset and consensus was that AKI occurring after this timeframe was probably not directly related to the initial septic insult. The rationale for establishing a separation between early and late presentation is based on the observation that the development of AKI late in the course of sepsis is associated with worse clinical outcomes and increased mortality compared with early AKI development 22 . Distinguishing early versus late SA-AKI might improve phenotyping for targeted assessments and management, as patients with sepsis that is untreated or early in the course of treatment are more likely to have SI-AKI, whereas in patients who have received sepsis-related interventions, other factors might have also contributed to AKI development.

Box 1 Definition and epidemiology of SA-AKI

Consensus statement 1a

We propose that sepsis-associated acute kidney injury (SA-AKI) be characterized by the presence of both consensus sepsis criteria (as defined by Sepsis-3 recommendations) and AKI criteria (as defined by Kidney Disease: Improving Global Outcomes recommendations) when AKI occurs within 7 days from diagnosis of sepsis (not graded).

Consensus statement 1b

We suggest that sepsis-induced AKI should be considered a subphenotype of SA-AKI in which sepsis is the predominant driver of tissue damage (not graded).

Consensus statement 1c

We suggest that AKI diagnosed within 48 h of the diagnosis of sepsis be defined as early SA-AKI, whereas AKI occurring between 48 h and 7 days of sepsis diagnosis be classified as late SA-AKI (not graded).

Consensus statement 1d

The epidemiology of SA-AKI varies and depends on the patient population and the criteria used to define AKI and sepsis (not graded).

Epidemiology of SA-AKI

Sepsis and AKI are common in the setting of critical illness, with 25–75% of all AKI being associated with sepsis or septic shock globally 23 , 24 , 25 , 26 , 27 . The epidemiology of SA-AKI is highly variable owing to the lack of a standardized definition for SA-AKI, the loose implementation of standardized nomenclature for sepsis and AKI, the diversity of clinical settings and patient populations, and the inconsistent reporting of relevant outcomes (Supplementary Table  1 ). A 2020 systematic review of observational studies in SA-AKI illustrates these challenges in describing SA-AKI epidemiology 15 . Of the 47 studies identified, four definitions of sepsis and three definitions of AKI were used. Several studies did not report sepsis criteria, and only a few included the urine output criteria to define AKI or reported the timing of AKI relative to the onset of sepsis. Moreover, the patient populations were considerably heterogeneous, with varying incidence of sepsis, severe sepsis and/or septic shock, as well as differences in the clinical settings, which included the emergency department, medical, surgical and general ICUs, and medical wards (Box  1 ). The study also identified several risk factors for SA-AKI 15 which included the presence of septic shock, the use of vasopressors and mechanical ventilation, Gram-negative bacteraemia, use of renin–angiotensin–aldosterone system inhibitors, presence of chronic liver disease and chronic kidney disease (CKD), pre-existent hypertension and diabetes, and smoking. The reported incidence of SA-AKI ranged from 14–87% and the association with mortality (including ICU mortality, hospital mortality, 28-day and 90-day mortality) was also highly variable, ranging from 11 to 77%.

Research questions

What is the epidemiology of SA-AKI based on the proposed definition?

What is the epidemiology and the clinically relevant time frame for early versus late SA-AKI?

What are the aetiology, incidence and severity, risk factors, and renal and non-renal outcomes of both SA-AKI and SI-AKI?

How can the proposed definition of SA-AKI be operationalized in electronic health records?

Pathophysiology of SA-AKI and novel mechanisms

Mechanisms underlying the development of sa-aki.

Depending on the interaction between genotype and exposures, SA-AKI can lead to a variety of clinical phenotypes (that is, observable disease characteristics) and sub-phenotypes. Moreover, multiple pathophysiological mechanisms of injury (that is, the disease endotype) might underlie the same disease phenotype 18 , 19 (Box  2 ). This heterogeneity complicates the assessment of therapeutic efficacy in clinical trials of sepsis interventions, as different therapies might only be beneficial in the treatment of specific disease endotypes. Importantly, multiple pathophysiological mechanisms might simultaneously lead to AKI in an individual patient with sepsis. Therefore, the ability to identify the specific SA-AKI endotypes will be crucial to the development of effective therapies. Multiple mechanisms can contribute to injury in SA-AKI (Box  2 ), including systemic and renal inflammation, complement activation, RAAS dysregulation, mitochondrial dysfunction, metabolic reprogramming, microcirculatory dysfunction and macrocirculatory abnormalities (Fig.  1 ). Several additional processes might indirectly contribute to SA-AKI, such as exposure to nephrotoxic drugs, hyperchloraemia and abdominal compartment syndrome. Of note, some of these mechanisms might have temporal association with the onset and treatment of sepsis. The ability to recognize and link endotypes, subphenotypes and phenotypes therefore represents a major future research focus 10 , 28 , 29 . The biological and clinical characterization of endotypes and of the interactions between endotypes and sepsis-related treatments will be the key to refining the definitions of SI-AKI and SA-AKI set forth in this manuscript.

The release of pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide, and of damage-associated molecular patterns (DAMPs) from injured cells and tissues can lead to the dysregulated activation of the immune system that characterizes sepsis. Background susceptibility to tissue and organ injury varies across individuals, according to non-modifiable factors such as comorbidities, current lifestyle choices (for example, smoking), genetic variants (for example, single nucleotide polymorphisms), premorbid comorbidities and medication use (for example, the use of renin–angiotensin–aldosterone system (RAAS) inhibitors for blood pressure control), and modifiable factors such as the use of vasopressors, mechanical ventilation or the presence of bacteraemia. The pathways induced in response to sepsis (or sepsis therapies) are modulated by background susceptibility and determine the endotype-defining pathophysiological mechanisms that underlie acute kidney injury (AKI) in patients with sepsis. The combination of different disease mechanisms can therefore result in a variety of disease endotypes. Sepsis-associated AKI (SA-AKI) includes cases of sepsis-induced AKI, whereby the response to sepsis causes kidney injury directly, as well as cases in which other sepsis-associated factors (such as therapeutic interventions) indirectly contribute to AKI. For example, very high doses of norepinephrine can decrease microvascular blood flow and exacerbate the microvascular dysfunction induced by sepsis. Several tissue tolerance mechanisms, such as the activation of haem-oxygenase 1 or mitochondrial autophagy (that is, mitophagy), can protect cells and tissues from injury caused by PAMPs and DAMPs. Importantly, the disease phenotypes observed in the clinic (for example, sub-phenotypes 1–3) reflect a complex interplay between background susceptibility, disease endotypes and tolerance capacity. Consequently, phenotypes cannot be directly traced to a specific disease mechanism or endotype, and therefore clinical subphenotyping of patients with sepsis might not be sufficient to identify relevant therapeutic targets. The figure is a simplified representation of these complex interactions but also illustrates a roadmap for investigating mechanism-specific biomarkers that can identify whether specific endotypes and tolerance mechanisms are operational, thereby enabling the development and assessment of mechanism-specific therapies. BM, biomarker; AKD, acute kidney disease; CKD, chronic kidney disease; GFR, glomerular filtration rate; KDIGO, Kidney Disease Improving Global Outcomes.

Box 2 Pathophysiology of SA-AKI

Consensus statement 2a

Sepsis-associated acute kidney injury (SA-AKI) is a heterogeneous syndrome as multiple mechanisms contribute to injury with varying intensity between and within patients across the course of sepsis (not graded).

Consensus statement 2b

The relative contribution of one or more specific mechanisms that lead to injury defines distinct sepsis-induced AKI endotypes (not graded).

Consensus statement 2c

Modifiable and non-modifiable factors confer susceptibility to SA-AKI and determine the severity of AKI as well as the trajectory of recovery (not graded).

Consensus statement 2d

Integrating mechanism-specific biomarkers with clinical information will enable the identification of specific endotypes of SA-AKI (not graded).

Consensus statement 2e

Identifying distinct endotypes of SA-AKI might provide crucial prognostic information, help to define treatment responsiveness and enrich clinical trial populations (not graded).

Determinants of susceptibility and recovery trajectory

Several modifiable and non-modifiable factors affect susceptibility to AKI and disease severity in patients with sepsis. As discussed earlier, a 2020 meta-analysis identified ten clinical risk factors with prognostic value 15 . Although useful for risk stratification, such clinical factors only partly explain an individual’s susceptibility to developing SA-AKI and do not consider susceptibility within the conceptual framework of different SA-AKI endotypes.

Genetic and epigenetic variability, as well as the interplay between resistance and tolerance mechanisms during sepsis, have been recognized as potential key factors underlying individual susceptibility (Box  2 ). In patients with sepsis, single nucleotide polymorphisms (SNPs) in genes involved in both inflammatory ( TNF , IL6 and IL10 ) 30 , 31 , 32 , 33 and vascular ( VEGF ) 34 pathways have been implicated in the development of AKI 35 , 36 . However, study results have been inconsistent and three independent systematic reviews did not find a clear link between specific genetic variants and AKI risk in patients with sepsis 37 , 38 , 39 . Epigenetic control of gene expression is mediated by enzymatic DNA methylation or histone modification without changes in the genetic code. This type of control has been implicated in the induction of cross-tolerance in immune cells and kidney tubular epithelial cells, whereby innate and adaptive immune responses to a subsequent insult are attenuated 40 , 41 , 42 , 43 . However, exposure to sublethal ischaemic or toxic AKI can also be followed by a local hyper-inflammatory response in animals subsequently challenged with lipopolysaccharide or lipoteichoic acid 44 , 45 . This ‘biological memory’ and the capacity to reprogram future responses is probably induced by epigenetic mechanisms, whereby histone-modifying enzymes enhance the expression rate of inflammatory genes 45 , 46 , 47 . The influence of a previous insult on the response to a second insult are likely dependent on both the extent of the initial insult and the timing in relation to the initial event. Resistance and tolerance capacity (not to be confused with cross-tolerance described above) might explain an individual’s susceptibility to SA-AKI. Resistance capacity refers to the ability of the immune system to control or eliminate the microbial burden, whereas tolerance capacity has a critical role in sepsis because it reflects the ability of a cell, tissue, or organ to attenuate its susceptibility to injury during infection 48 , 49 . Tolerance mechanisms protect the host from the potential harm associated with resistance mechanisms. Several protective tolerance mechanisms against AKI have been identified including in preclinical models of malaria 50 , 51 , viral and bacterial sepsis 52 , 53 , 54 , ischaemia–reperfusion injury, and nephrotoxicity 50 , 51 , 52 , 53 , 54 . Tolerance mechanisms seem to be specific to the type of insult or infection and are thus not entirely generalizable. For instance, starvation protects from tissue injury and death in rodents with bacterial sepsis but worsens outcomes in viral sepsis 55 .

Similar to individual susceptibility to AKI, the trajectory of post-AKI recovery — determined by adaptive or maladaptive repair processes — is influenced not only by genetic variation, but also injury severity, recurrent insults, and the presence of underlying CKD. Within the nephron, adaptive repair involves the proliferation and re-differentiation of tubular epithelial cells, as well as the repair and regeneration of endothelial cells. By contrast, maladaptive repair manifests as tubular atrophy and dilation 56 , expansion of interstitial fibroblasts and myofibroblasts 57 , endothelial-to-mesenchymal transition and a reduction in peritubular capillary density 58 , 59 . Together, these maladaptive processes culminate in interstitial fibrosis, tissue hypoxia, increased oxidative stress and accelerated senescence 56 . Progressive fibrosis is followed by loss of functional renal reserve, glomerular hypertension and the development of CKD 60 .

SA-AKI mechanisms and novel therapeutic targets

As mentioned above, many clinical studies have attempted to investigate the benefit of therapeutic interventions in unselected patient populations, which might have reduced therapeutic efficacy signals and led to negative results. The framework proposed in this consensus statement advocates for a strategic shift in randomized controlled trial (RCT) design, whereby the deployment of any therapeutic strategy is targeted to subgroups of patients defined according to disease likelihood endotypes or therapy-responsive subphenotypes to enhance the possibility of discovering effective therapies. In addition, endotyping and subphenotyping will provide a platform to better understand the interaction between pathogenic mechanisms induced by sepsis directly or by sepsis-related factors (for example, nephrotoxins or complications such as abdominal compartment syndrome). Moreover, this granular approach will help to define the relationship between pathogenic mechanisms and time, and the therapeutic potential of different interventions in early and late SA-AKI or SI-AKI (Box  2 ).

Several interventions that modulate pathogenic processes involved in SA-AKI have been tested. For example, anti-inflammatory agents were not found to be beneficial but post hoc analyses demonstrated that dexamethasone was associated with a reduced need for kidney replacement therapy (KRT) in patients with sepsis 61 . A phase II trial showed long-term kidney benefit and lower mortality in patients who received the anti-inflammatory recombinant alkaline phosphatase ( NCT04411472 ) 62 . With regard to haemodynamics and oxygen delivery, studies using angiotensin 2 (ref. 63 ) (ASK-IT trial, NCT00711789 ) and levosimendan 64 , 65 suggest that these agents might protect the kidneys. Of note, although mitochondrial dysfunction is a feature of SA-AKI, no compounds targeting this impairment are in the clinical development phase thus far. Interventions related to cellular repair and fibrosis, including mesenchymal stem cell therapy 66 , protein-7 agonist 67 and mimetics of hepatocyte growth factor 68 , have been studied but not yet found to decrease the incidence or severity of AKI.

How can we validate mechanisms recognized in preclinical models in the clinical setting?

How can we identify distinct endotypes of SA-AKI?

How can we leverage molecular diagnostic technologies to identify novel therapeutic targets?

How can we match distinct endotypes of SI-AKI to targeted therapies?

How can we optimize the delivery of novel therapies to maximize efficacy within the kidney while minimizing remote toxicity?

What is the role of damage and systemic markers of sepsis in defining the mechanism and time course of SA-AKI and its endotypes?

Fluid and resuscitation therapy

Goals of fluid management in sa-aki.

Restoring intravascular volume through redistribution of fluid is a therapeutic target in sepsis to sustain adequate perfusion and tissue oxygen delivery. Together with source control and treatment with antimicrobials, the administration of fluids and vasopressors are key management strategies in SA-AKI. The main goal of fluid administration is to increase preload and cardiac output to maintain adequate oxygen delivery to vital organs. The haemodynamic targets for SA-AKI should be consistent with those outlined in the Surviving Sepsis Campaign Guidelines 2021 and our previous report on haemodynamics for monitoring fluid therapy from the 12th ADQI Consensus Conference 69 , 70 (Box  3 ). The utility of central venous pressure (CVP) as a haemodynamic indicator in SA-AKI is unclear and, although a high CVP might reflect congestion in the capacitance vessels 71 , 72 , CVP correlates only moderately with overall volume status, given that CVP is also influenced by right ventricular function 73 . Assessment of fluid status and response to fluid administration (that is, fluid responsiveness) should be undertaken to prevent under- or over-hydration. Urine output should be closely monitored but should not be used to guide fluid therapy in patients with SA-AKI. Measurement of intra-abdominal pressure can be useful in patients at risk of AKI. Daily and cumulative fluid balance should inform fluid management in patients with SA-AKI, as many studies have shown that fluid overload in critically ill patients is associated with excess mortality 74 , 75 . Assessment of fluid responsiveness should include clinical perfusion markers, and advanced haemodynamic monitoring, invasive or non-invasive, where available, should be considered 76 . Of note, the rate and duration of intravascular volume expansion following fluid administration are crucial given the role of the endothelial glycocalyx layer in vascular permeability where injury to this layer might lead to increased rates of fluid loss from the intravascular into the extravascular space and further fluid administration could cause fluid overload 77 , 78 , 79 .

Box 3 Fluid management in SA-AKI

Consensus statement 3a

In patients with sepsis-associated acute kidney injury (SA-AKI), haemodynamic management should be similar to that recommended by the Surviving Sepsis Guidelines 69 (grade 2C).

Consensus statement 3b

The significance of central venous pressure as a marker of congestion in SA-AKI is uncertain, although a high central venous pressure has been associated with AKI. Therefore, we suggest using measures of fluid status assessment and fluid responsiveness to assess the need for fluid administration (grade 1C).

Consensus statement 3c

We recommend daily and cumulative fluid balance monitoring (grade 1C) with concurrent, non-kidney organ dysfunction to inform fluid management strategy in SA-AKI (grade 2C).

Consensus statement 3d

We recommend that the amount of fluid administered in SA-AKI be targeted to specific endpoints (grade 1B).

Consensus statement 3e

We recommend that fluid protocols and frequency of monitoring urine output and kidney function consider the severity and rate of progression of AKI (grade 1C).

Consensus statement 3f

We recommend that the choice of fluids be informed by the need to correct patient acid–base and electrolyte imbalances (grade 1C).

Consensus statement 3g

We suggest that balanced solutions and 0.9% saline be used for resuscitation based on the biochemical profile of individual patients while their biochemical effects are closely monitored (grade 2B).

Consensus statement 3h

Albumin and bicarbonate might be of benefit in SA-AKI (grade 1C), but we recommend against the use of starch, gelatin and dextran (grade 1A).

Consensus statement 3i

We recommend the administration of vasopressors, inotropes, and diuretics based on haemodynamic assessments, phase of sepsis, and the severity of AKI (grade 1B).

Consensus statement 3j

We recommend that norepinephrine be used as the first-line vasopressor for sepsis with organ dysfunction (grade 1A).

Consensus statement 3k

We suggest that combining vasopressors with volume administration might have a net fluid-sparing effect (grade 1C).

Consensus statement 3l

We recommend the use of diuretics in patients with fluid overload (grade 1C).

Consensus statement 3m

We suggest that some subtypes of SA-AKI might benefit from the use of specific vasopressors (for example, vasopressin or angiotensin 2) (grade 2B).

Role of fluid protocols for the treatment of SA-AKI

Given the need to manage fluid volume, composition and distribution concurrently with AKI and sepsis of varying severity, the potential for toxicity from fluid therapy is substantial. The fluid management goals can be protocolized, utilizing the type, rate and duration of fluid delivery to target the interdependent relationship between sepsis and AKI (Box  3 ). Early and late SA-AKI might require different treatment protocols. Whereas haemodynamic stabilization is a priority in early SA-AKI, targeting fluid overload might be more relevant in late SA-AKI. The ongoing CLOVERS trial and ARISE FLUIDS observational study are expected to provide additional evidence in this field 80 , 81 . The use of fluid-restrictive protocols is feasible in SA-AKI, but a beneficial effect has not yet been demonstrated. The REVERSE-AKI trial, suggested that restricted daily fluid intake, aiming for a negative daily fluid balance with unrestricted use of diuretics was associated with reduced use of KRT compared with usual care. However, only ~50% of participants with AKI also had sepsis 82 . The recently published CLASSIC trial found that intravenous fluid restriction after initial fluid resuscitation was not superior to liberal fluid management with regard to kidney outcomes in adult patients with septic shock in the ICU 83 . As described previously at the 12th ADQI conference, the four phases of intravenous fluid therapy — resuscitation, optimization, stabilization and de-escalation — form an appropriate conceptual framework for tailoring fluid therapy to the individual patient context 70 . Although (balanced) crystalloids are often used, the recent BaSICS and PLUS trials and meta-analysis found no clinical benefit of balanced solutions over the use of 0.9% saline solutions 84 , 85 , 86 , 87 . The SMART trial reported that the use of balanced crystalloids significantly decreased major adverse kidney events at day 90 (MAKE 90 ) and a composite end point (death, KRT, or persistent kidney dysfunction) compared saline; however, only ~15% of the patient population had sepsis at baseline 88 . Similarly, the SALT-ED trial noted a significant decrease in MAKE 90 with the use of balanced crystalloids versus saline, but the study cohort comprised a heterogenous population of patients receiving treatment in the emergency department 89 .

Colloids of high molecular weight theoretically cause selective expansion of the intravascular space but this effect is impaired when vascular permeability is altered and the endothelial glycocalyx is damaged in inflammation. Supplemental albumin administration, as a preferred colloid over synthetic colloids, might be considered if substantial fluid replacement is required; however, to date, no data support its routine use for volume resuscitation in sepsis and data to inform a suggested cut-off value for crystalloid infusion above which albumin should be considered as part of resuscitation fluid are limited 69 , 85 , 90 , 91 . According to the subgroup analyses of patients with severe sepsis or septic shock in the SAFE and ALBIOS trials, the administration of albumin, either as a primary resuscitation fluid or as a supplement to crystalloid resuscitation, might be associated with a lower mortality trend 85 , 90 . However, these were post hoc analyses and must be interpreted with caution. We await the results of the ongoing ALBumin Italian Outcome Septic Shock-BALANCED trial (ALBIOSS-BALANCED) to provide evidence as to whether albumin, as a primary or supplemental resuscitation fluid, improves outcomes in patients with septic shock 92 . Of note, the use of hydroxyethyl starch (HES) has been associated with increased mortality risk and other adverse outcomes compared with crystalloids, including the need for KRT in patients with severe sepsis; accordingly, the FDA has mandated changes to safety labelling in HES products and its use was suspended in the European Union 93 . Hence, we recommend against the use of HES for fluid resuscitation in patients with SA-AKI. Similarly, compared with crystalloids or albumin, use of gelatin was associated with an increased risk of anaphylaxis, mortality, AKI and bleeding in a 2016 meta-analysis of 30 RCTs, 8 non-randomized studies and 22 animal studies 94 . Dextrans have also been associated with anaphylaxis, coagulation disorders, osmotic nephrosis and AKI in observational studies 95 , 96 . The BICAR-ICU study found that treatment with intravenous 4.2% sodium bicarbonate for severe metabolic acidaemia (pH <7.20) and moderate-to-severe AKI in the ICU reduced the primary composite outcome (death from any cause by day 28 and the presence of at least one organ failure at day 7) and 28-day mortality 97 . However, only ~60% of the trial population in each study arm had sepsis at the time of randomization, so the results cannot be fully extrapolated to patients with SA-AKI, particularly as these findings are specific to patients with severe acidaemia in the presence of AKI.

Combination of adjunctive therapies with fluid management

Adjunctive therapies should be used to optimize haemodynamic status and enhance fluid management, and should be adjusted based on the clinical condition of the patient (Box  3 ). Vasoactive agents are also key to haemodynamic optimization, and their use should not be limited by the presence or absence of central venous access. If clinically required, peripheral use of vasoactive agents should be initiated with careful monitoring for extravasation. Norepinephrine remains the first-line vasopressor for sepsis and SA-AKI 69 , 98 . The early use of vasopressors might have a volume-sparing effect. Conversely, diuretics have an essential role in the treatment of volume overload, potentially reducing mortality 99 . In the FFAKI, REVERSE-AKI and RADAR-2 RCTs, forced fluid removal prevented and treated fluid overload effectively in critically ill patients 82 , 100 , 101 . However, depending on the severity of AKI, significant increases in diuretic therapy dosage might be required to achieve a sufficient effect 100 , 102 . Moreover, specific phenotypes of SA-AKI might benefit from specific vasopressors. A secondary analysis of the VASST trial 29 showed improved survival compared with norepinephrine in patients with a subphenotype of SA-AKI that was characterized by a low severity of disease and low levels of angiotensin 1, angiotensin 2 and IL-8. A posthoc analysis of the ATHOS-3 trial found that patients with vasodilatory shock and AKI requiring KRT had significantly greater 28-day survival with a higher mean arterial pressure response and a higher rate of KRT discontinuation when treated with intravenous angiotensin II compared with placebo 103 . In the case of impaired cardiac function, inotropes should be considered to optimize oxygen delivery.

What is the utility of haemodynamic monitoring in SA-AKI?

What is the role of the assessment of renal perfusion using ultrasound, measurement of intra-abdominal pressure and assessment of mean perfusion pressure in managing SA-AKI?

What is the effect of 0.9% saline versus balanced crystalloids on outcomes for patients with SA-AKI, particularly with regard to hyperchloraemia and hyper- and hyponatraemia in patients with SA-AKI?

Is there an indication for using albumin for fluid resuscitation in patients with SA-AKI?

What is the clinical utility of markers of glycocalyx damage during fluid therapy and their correlation with markers of kidney dysfunction?

Does the choice of vasopressor agent affect the course of SA-AKI?

What is the role of diuretics in treating fluid overload in SA-AKI?

Biomarkers for diagnosis and guiding treatment

Measures for sa-aki prediction and diagnosis.

The ADQI 23 Consensus Conference statement 104 proposed combining damage and functional biomarkers to increase the sensitivity of AKI definitions. For example, stage 1S (‘subclinical AKI’), could be defined by biomarker-positive evidence of kidney injury that does not meet the KDIGO criteria (that is, AKI stage 1 defined by creatinine and urine output criteria are not achieved). Data from the Protocolized Care for Early Septic Shock (ProCESS) cohort reported in 2022, demonstrate that, for a given stage of KDIGO-defined AKI, higher biomarker values (stages 1B, 2B and 3B) were associated with a higher risk of 30-day mortality than stages 1A, 2A and 3A 105 . However, 30-day survival did not differ between biomarker-positive (stage 1S) and biomarker-negative cases in the absence of KDIGO AKI criteria.

Emerging data demonstrate that plasma proenkephalin (penKid) identifies patients with sepsis who are at an increased risk of developing KDIGO-defined functional AKI and MAKE; patients with stage 1S AKI (defined by plasma penKid increases) had higher 28-day mortality than those with KDIGO-defined functional AKI 106 , 107 . Similarly, plasma cystatin C has been proposed as an alternative to serum creatinine as a functional marker of glomerular filtration rate changes to identify AKI in patients with critical illnesses, including those with SA-AKI 108 . Whether these functional markers, which have shorter half-lives than serum creatinine, provide a swifter diagnosis of decreasing kidney function, can assist in appropriate drug dosing, and/or if other biological and analytical features improve the diagnosis and prognostication of AKI in sepsis, remains unclear 109 , 110 . Functional biomarkers (for example, cystatin C and penKid) and damage or stress biomarkers (for example, neutrophil gelatinase-associated lipocalin (NGAL) and (TIMP2) × (IGFBP7)) predict SA-AKI with high accuracy 104 , 106 , 111 , 112 , 113 , 114 , 115 . Additionally, several non-biochemical tools can forecast SA-AKI, including logistic or artificial intelligence-driven prediction models based on available clinical information 116 , 117 , 118 , 119 . The clinical information used for these models includes clinical and physiological data, volume assessment and other laboratory information. These forecasting models and biomarkers could be used in combination to assign patients with SA-AKI to specific phenotypes and subphenotypes 117 , 120 , 121 (Box  4 ). Several investigations have demonstrated the clinical potential for using biological, genetic and machine-learning multidimensional models for assessing AKI risk and improving outcomes 29 , 118 , 119 . Further research is needed to distinguish SA-AKI from other AKI aetiologies using validated measures, including biomarkers, and to characterize and differentiate SA-AKI endotypes or sub-phenotypes (Fig.  2 ).

At the top are the characteristics of an individual’s acute kidney injury (AKI) journey — severity, duration and trajectory. Each episode of AKI will have unique biological characteristics. In addition to pre-sepsis comorbidities, several tests will be performed, including standard laboratory measures, advanced biomarker assessment and genetic, proteomic and metabolic tests. When combining these tests with clinical and environmental factors, distinct sepsis-associated AKI (SA-AKI) phenotypes will be characterized, each with its distinct course and response to treatment plans. In the near future, biomarkers and machine-learning algorithms might be used to characterize patients by phenotype and endotype more rapidly to optimize their care or expedite enrolment into clinical trials. Adapted from Maslove et al. 193 , Springer Nature Limited.

Box 4 Biomarkers for diagnosis and guiding treatment in SA-AKI

Consensus statement 4a

We suggest the complementary use of validated measures — including functional, stress and tissue damage-related biomarkers — be considered in combination with the consensus Kidney Disease Improving Global Outcomes (KDIGO) definition to diagnose sepsis-associated acute kidney injury (SA-AKI) (grade 2C).

Consensus statement 4b

We recommend that measures validated to predict an episode of AKI in patients with sepsis be used in combination with available clinical information (grade 1B).

Consensus statement 4c

We suggest that selected functional and stress- or injury-related biomarkers should be used for clinical assessment to identify and discriminate patients with sepsis at risk of transient or persistent SA-AKI. These biomarkers can also enhance the risk assessment of the severity, duration, trajectory of recovery and occurrence of non-renal outcomes in patients with established SA-AKI (grade 1B).

Consensus statement 4d

We suggest that sepsis biomarkers be used to complement functional and tubular injury-related biomarkers for the prognosis of early or late SA-AKI (grade 2C).

Measures for SA-AKI course and outcome prediction

The duration of AKI has gained relevance as an additional dimension in AKI phenotyping 122 , given that a pattern of persistent, non-resolving AKI is associated with poorer short-term 20 and long-term outcomes 123 , 124 , 125 than transient AKI, regardless of disease severity. Early patient risk identification could aid the development of personalized in-hospital 126 and outpatient 127 care strategies to reduce AKI progression, the development of AKI-related complications and the risk of sequelae of SA-AKI, as well as enabling predictive enrichment in randomized trials of potential therapeutic targets. Various markers, including clinical risk scores, functional, stress- and injury-related biomarkers, and imaging tests, have been described in patients admitted to the ICU (Tables  1 and 2 ). Notably, many markers were tested in heterogeneous cohorts of critically ill patients; thus, their generalizability to patients with sepsis might require further investigation. Scoring systems (for example, the renal angina index) and imaging tests, such as the renal resistive index, can be considered complementary to direct AKI biomarker testing to optimize their use for the prediction of persistent AKI and other outcomes 128 , 129 (Box  4 ).

Various sepsis-associated biomarkers have been evaluated to assess the prognosis of SA-AKI (Supplementary Table  2 ). However, the timing of SA-AKI diagnosis relative to the timing of biomarker assessment is often highly variable, thus complicating the differentiation of early versus late SA-AKI and indeed, most sepsis-associated biomarker monitoring is anchored at the time of admission to the ICU. Of note, prognosis determination could be influenced by the introduction of a confounding variable after SA-AKI diagnosis but before the outcome measure. Many studies evaluating the association between biomarkers and AKI considered single or multiple biomarkers (Supplementary Table  3 ), but few directly compared or measured the additive impact of combining sepsis and kidney biomarkers to determine prognosis. Of note, AKI biomarkers predicting acute kidney disease (that is, 7 to 90 days post-insult) in patients with sepsis are less well-defined 130 .

Do kidney injury biomarkers add prognostic discrimination in patients with SA-AKI, and can they identify a high-risk 1S subgroup in the absence of KDIGO-defined functional AKI (subclinical AKI)?

What is the impact of individual biomarkers on SA-AKI clinical trajectories, including severity, duration, recovery and non-kidney-related outcomes?

What are the best methods for integrating clinical information, identification of phenotypes and single or serial use of validated measures to predict clinical course and the likelihood of response to interventions?

What is the role of the measurement of sepsis and kidney markers for targeted intervention in different subphenotypes and endotypes of SA-AKI?

Extracorporeal therapies for SA-AKI

Extracorporeal blood purification in sa-aki.

Extracorporeal blood purification (EBP) can be performed using various techniques (Supplementary Fig.  1 ); the most common techniques involve systems that are mainly employed for KRT with the aim of re-establishing homeostasis (Table  3 ). These techniques affect the molecular and electrolyte composition of blood directly, which might enable the correction, replacement and maintenance of homeostasis in multi-organ dysfunction through the control of acid–base, electrolyte and fluid balances. EBP techniques might also facilitate the control of immune dysregulation in sepsis by removing endotoxins, cytokines, pathogens and inflammatory factors 131 , 132 , 133 , 134 , 135 . The selection of a specific EBP modality or combination of selected modalities should be based on the patient’s needs (Table  3 ). Global practice is very heterogeneous owing to the lack of consensus guidelines and high-grade evidence, and the limited availability and approval of specific devices and therapies.

Accepted indications for commencing KRT to support kidney function during SA-AKI are consistent with those in place for other causes of AKI 16 . Although early KRT initiation for SA-AKI has been used for fluid and solute control and to prevent multi-organ dysfunction, no clear benefit has been demonstrated for earlier initiation 136 . Of the latest RCTs focused on the timing of initiation of KRT in critically ill AKI patients 137 , 138 , 139 , the IDEAL-ICU study 140 is the only one that focused on SA-AKI and demonstrated that earlier initiation of KRT had no significant survival benefit compared with ‘standard’ initiation, although a significant number of patients in the ‘delayed’ group were not treated with KRT, owing to spontaneous kidney recovery. Of note, a further study on the initiation of KRT in SA-AKI is currently underway 141 . Initiation of KRT in both septic and non-septic conditions should be based on clinical assessment and goals of EBP for kidney support, not just on creatinine levels and oliguria 69 . In patients with SA-AKI for whom KRT is indicated and with explicit clinical (for example, shock) and/or biological (for example, the detection of damage-associated molecular patterns and pathogen-associated molecular patterns) criteria are recognized, EBP for immunomodulatory support might be considered in combination with KRT, either concurrently (for example, hybrid treatments) or following KRT (Box  5 ). EBP for immunomodulatory support can be considered in patients with sepsis as a stand-alone treatment if kidney support is not required 142 . Despite the biological rationale for using EBP approaches in SA-AKI, namely their potential to limit the pathophysiology of organ damage, mitigate homeostatic derangements and prevent multi-organ dysfunction in sepsis, the lack of robust data precludes definitive recommendations with regard to its use in patients with sepsis or SA-AKI, including its timing in the clinical course of the disease.

Box 5 Extracorporeal and novel therapies for SA-AKI

Consensus statement 5a

Extracorporeal blood purification (EBP) techniques can be used to remove pathogens, microbial toxins, inflammatory mediators and toxic metabolites from the blood as well as replenish solutes (grade 1A).

Consensus statement 5b

Kidney replacement therapy provides organ support through solute control, blood detoxification, and fluid balance via diffusion, convection and adsorption. Peritoneal dialysis can be used for kidney support when extracorporeal techniques are unavailable (grade 1A).

Consensus statement 5c

Emergent indications for initiating kidney replacement therapy do not differ between SA-AKI and other types of acute kidney injury (grade 1A).

Consensus statement 5d

Initiation of EBP in sepsis might be considered for immunomodulatory support in patients who meet explicit and timely clinical and/or biological criteria, such as high concentrations of damage-associated molecular patterns and pathogen-associated molecular patterns, as well as other targets of systemic inflammation (not graded).

Consensus statement 5e

Optimal delivery of extracorporeal therapies is determined by factors such as timely and safe initiation, treatment duration, appropriate vascular access placement and maintenance, individualized patient dose, safe and effective anticoagulation protocols, appropriate adjustments of medications (for example, antimicrobials or vasopressors) and nutrients, and a dynamic prescription of fluid removal (not graded).

Consensus statement 5f

Safe and effective therapy requires objective indicators of treatment response, which must be evaluated throughout the therapy course with a focus on patient-centred care goals (grade 1B).

Delivery and monitoring of extracorporeal blood purification therapies

For haemoadsorption therapies, anticoagulation is recommended, and the indications for venous access are similar to those of KRT 143 . Haemoadsorption cartridges can be combined with the KRT circuit with variable blood flow rates 144 , 145 , 146 . Initiation of haemoadsorption to remove endotoxins has been based on the result of the endotoxin activity assay, which compares the activation of neutrophils caused by endotoxin to the theoretical maximum response when exogenous endotoxin is added to the blood sample 147 , 148 , 149 , 150 , 151 . Polymyxin B haemoadsorption has been used in sepsis with variable results. When Polymyxin B haemoadsorption was applied for 2-h sessions for 2 consecutive days, it was found to be safe but without a survival benefit. However, a potential survival benefit was observed in patients with an endotoxin activity assay of 0.6–0.9 EAA units, indicative of a high but measurable endotoxin burden 151 , 152 , 153 . These effects are being investigated in an ongoing trial (the TIGRIS trial, ClinicalTrials.gov Identifier: NCT03901807 ).

New synthetic polymeric resins enable highly biocompatible haemoadsorption designed for the non-specific adsorption of damage-associated molecular patterns and other mediators. The rationale for their use is based on the peak concentration hypothesis, which postulates that haemoadsorption might enable removal of the solutes with the highest concentration in blood (either pro- or anti-inflammatory mediators), helping to restore immunohomeostasis by mitigating the uncontrolled response of the innate and/or the adaptive immunity of the patient 154 , 155 . Additional research on clinical benefits is warranted. Notably, the unselective nature of such EBP interventions might result in unrecognized losses of electrolytes, nutrients and drugs. As significant losses of amino acids and several micronutrients, such as vitamins B1 and C, copper and selenium can occur, careful monitoring in prolonged KRT should be considered 156 . Importantly, discrepancies exist in the observed and predicted removal of antimicrobials with haemoadsorption in critically ill patients 157 , 158 , 159 , 160 , 161 , 162 , 163 . In patients undergoing continuous KRT, antimicrobial clearance depends on the effluent fluid rate and therapeutic drug monitoring should therefore be considered where available 157 . The identification of subphenotypes of patients and the delivery of EBP should be assessed and supported by a multidisciplinary team of trained personnel to improve patient selection and safety 164 . Optimal EBP delivery demands timely communication between stakeholders, iterative adjustment of therapy and quality assurance systems 165 , 166 . Patient selection, timing, duration and appropriate primary clinical endpoints are crucial elements for well-conducted clinical studies in this area. Moreover, given the phenotypic variability of SA-AKI, one extracorporeal therapy might be effective in a specific phenotype, while having no effect, or even causing harm, in others. Investigators should refrain from choosing mortality as the primary end point because of the well-known variation in mortality across centres, sepsis and AKI phenotypes 167 . RCTs examining the effects of EBP, in which patient heterogeneity is reduced through specific inclusion criteria with clinically relevant endpoints, including haemodynamic and organ improvement, as well as ICU stay rather than only mortality, should be performed.

How do the EBP therapies affect the pathophysiology of SA-AKI?

In which subgroup of patients, and when in the clinical course of the disease, might EBP therapies be beneficial?

Are EBP therapies safe, efficacious and cost-effective?

What meaningful target molecules can guide EBP therapy, and can their kinetics be employed to assess response to treatment?

What is the effect of EBP therapies on other organ systems during sepsis?

SA-AKI: the paediatric perspective

This Consensus statement has thus far been based on a systematic review of the literature as it pertains to adult medicine, especially with the use of Sepsis-3 as the definition of sepsis in adult patients. Although there is undoubtedly much overlap in the pathophysiology of SA-AKI throughout the lifespan, neonates and children do merit particular attention. SA-AKI is a common cause of AKI in critically ill children 168 but the definition of SA-AKI in paediatrics is currently limited by the reliance on adult sepsis criteria. The 26th ADQI recently published consensus recommendations for the advancement in paediatric AKI with particular attention to the role of development as a biological variable that modulates the development of and recovery from AKI 169 . AKI prediction in paediatric patients continues to progress. The renal angina index has been modified for paediatric patients with sepsis and shown to reliably predict SA-AKI, particularly when platelet count is incorporated within the scoring system 170 . Another study demonstrated the use of prognostic biomarkers for diagnostic and predictive enrichment in paediatric SA-AKI 171 . However, notable differences remain between current recommendations of management of SA-AKI for adult and paediatric patients, particularly with regard to fluid management and the type of fluid, with a preference for the use of balanced crystalloids in children. The aforementioned fluid recommendations in this manuscript apply to adults specifically 172 . Of note, a 2021 study reported the inclusion of paediatric populations in the study of EBP therapies to treat SA-AKI via a selective cytopheretic device 173 . Future work should align paediatric-specific sepsis definitions with SA-AKI management and research agendas (Box  6 ). A Society of Critical Care Medicine (SCCM) task force is currently working to streamline a definition of paediatric sepsis, but, for now, a precise definition of paediatric SA-AKI remains unavailable.

Box 6 SA-AKI in paediatric patients

Consensus statement 6a

Development, as a biological variable, might affect the pathophysiology and management of SA-AKI across the lifespan (not graded).

Consensus statement 6b

Neonates and children merit consideration and inclusion in SA-AKI research (not graded).

How should SA-AKI be defined in the paediatric population?

Are there differences in the pathophysiology of SA-AKI across the lifespan?

How can the proposed research agenda incorporate the concept of development as a biological variable in the diagnosis and management of SA-AKI?

Conclusions

The presence of AKI in patients with sepsis is common and SA-AKI is best defined by both consensus sepsis criteria and AKI criteria, with early SA-AKI occurring within 48 h of diagnosis of sepsis and late SA-AKI occurring between 48 h and 7 days of diagnosis of sepsis. Multiple mechanisms can contribute to the development of SA-AKI and their relative contributions might define distinct SA-AKI endotypes. These endotypes might be identified through the use of biomarkers, including functional, stress and tissue damage-related biomarkers, as well as clinical information. Prognostic information should help to determine treatment, which should follow currently accepted guidelines, but the use of specific therapies might be influenced by the endotype. For example, the SA-AKI endotype might affect the choice of vasopressor or dictate whether EBP techniques might be used for immunomodulatory support in patients who meet explicit criteria.

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Acknowledgements

The authors wish to acknowledge Ms. Gioia Vencato and Annamaria Saccardo, for their help in organizing this ADQI meeting. This conference was kindly supported by unrestricted educational grants from AM Pharma, Baxter, Biomerieux, Cytosorbants, Exthera Medical, Jafron, Ortho Clinical Diagnostics, Paion, Spectral and Sphingotec GmbH.

Author information

These authors contributed equally: Alexander Zarbock, Mitra K. Nadim.

Authors and Affiliations

Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital of Münster, Münster, Germany

Alexander Zarbock & Melanie Meersch

Outcomes Research Consortium, Cleveland, OH, USA

Alexander Zarbock

Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Mitra K. Nadim

Dept Intensive Care Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands

Peter Pickkers

Program for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA

Hernando Gomez

Division of Population Health and Genomics, University of Dundee, Dundee, UK

Samira Bell

Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria

Michael Joannidis

Division of Nephrology and Hypertension, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA

Kianoush Kashani

Department of Medicine, University of Chicago, Chicago, IL, USA

Jay L. Koyner

Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

Neesh Pannu

D’Or Institute for Research and Education (IDOR), Division of Kidney Transplantation, DF Star Hospital, SGAS 914, Asa Sul, 70390-140, Brasília, Brazil

Thiago Reis

Laboratory of Molecular Pharmacology, Faculty of Health Sciences, University of Brasília, Asa Norte, Campus Darcy Ribeiro, 70910-900, Brasília, Brazil

Anaesthesiology and Critical Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France

Thomas Rimmelé

Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta and Alberta Health Services, Edmonton, Alberta, Canada

• Sean M. Bagshaw

Department of Critical Care, University of Melbourne, Parkville, Australia

Rinaldo Bellomo & Emily J. See

Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia

Rinaldo Bellomo

Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia

Department of Intensive Care, Royal Melbourne Hospital, Melbourne, Australia

Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), “Maggiore della Carità” University Hospital, Novara, Italy

Vicenzo Cantaluppi

Paediatric Intensive Care Unit, King’s College Hospital NHS Foundation Trust, London, UK

Centre for Medical Sciences - CISMed, University of Trento, Trento, Italy

Silvia De Rosa

Anaesthesia and Intensive Care, Santa Chiara Regional Hospital, APSS, Trento, Italy

Servei de Medicina Intensiva, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain

Xose Perez-Fernandez

Department of Internal Medicine II, University Hospital Giessen and Marburg, Justus-Liebig-University Giessen, Giessen, Germany

Faeq Husain-Syed

Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

Sandra L. Kane-Gill

Department of Critical Care, Tallaght University Hospital, Tallaght, Dublin, Ireland

Yvelynne Kelly

School of Medicine, Trinity College Dublin, Dublin, Ireland

Department of Medicine, University of California San Diego, La Jolla, CA, USA

Ravindra L. Mehta

School of Medicine, University College Dublin, Dublin, Ireland

Patrick T. Murray

Department of Intensive Care, King’s College London, Guy’s & St Thomas’ Hospital, London, UK

• Marlies Ostermann

William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK

John Prowle

Department of Anaesthesia and Critical Care, Meyer Children’s University Hospital, Florence, Italy

Zaccaria Ricci

Department of Health Sciences, Section of Anaesthesiology and Intensive Care, University of Florence, Florence, Italy

Department of Nephrology, Royal Melbourne Hospital, Melbourne, Victoria, Australia

Emily J. See

Adult Intensive Care Unit, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

Antoine Schneider

Department of Paediatrics, Indiana University School of Medicine, Indianapolis, IN, USA

Danielle E. Soranno

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

Ashita Tolwani

Department of Health Sciences, Section of Anaesthesiology, Intensive Care and Pain Medicine. University of Florence. Azienda Ospedaliero Universitaria Careggi, Florence, Italy

Gianluca Villa

Department of Medicine, University of Padova, Padua, Italy

Claudio Ronco

International Renal Research Institute of Vicenza (IRRV), Vicenza, Italy

Department of Nephrology, San Bortolo Hospital, Vicenza, Italy

Department of Critical Care, Royal Surrey Hospital Foundation Trust, Guildford, Surrey, UK

Lui G. Forni

Faculty of Health Sciences, University of Surrey, Guildford, Surrey, UK

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All authors made equal contributions to the discussion of the content and researching data for the article. Members of each group contributed equally to writing their sections. L.G.F., A.Z. and M.K.N. combined the workgroup drafts and edited for style and length. All authors reviewed the final manuscript before submission.

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A.Z. has received consulting fees from Astute-bioMérieux, Baxter, Bayer, Novartis, Guard Therapeutics, AM Pharma, Paion, Fresenius, research funding from Astute-bioMérieux, Fresenius, Baxter, and speakers fees from Astute-bioMérieux, Fresenius, Baxter; P.P. has received speaker’s honoraria/travel/consultancy reimbursements as a member of an advisory board or steering committee from Baxter, EBI, AM-Pharma, Sphingotec, Adrenomed, 4Teen4, and Paion; H.G. serves as scientific adviser for Novartis and Trilinear bioventures, and has received research grants from bioMérieux, Baxter and TES Pharma; M.J. has received honoraria and research support from Baxter Healthcare Corp, AM-Pharma, CLS Behring, Fresenius and Novartis; K.K. has received research grants from Philips Research North America and Google, speaker’s honorarium from Nikkiso Critical Care Medical Supplies (Shanghai) Co., Ltd, funding from National Institute of Diabetes and Digestive and Kidney Diseases grant (R01DK131586) and consulting fees from Baxter Inc. to Mayo Clinic; J.L.K. has received consulting fees from Astute-bioMérieux, Sphingotec, Pfizer, Baxter, Mallinckrodt, Novartis, Guard Therapeutics, research funding from Astute-bioMérieux Medical, Bioporto, NxStage, Fresenius, Satellite Healthcare, and speakers fees from NxStage medical; M.M. received lecture fees from bioMérieux, Fresenius Medical Care and Baxter; T. Reis has received funding for lectures, been consultant or advisory board member for AstraZeneca, B. Braun, Baxter, bioMérieux, Boehringer Ingelheim, Contatti Medical (CytoSorbents), Eurofarma, Fresenius Medical Care, Jafron, Lifepharma and Nova Biomedical; T. Rimmelé serves as a scientific adviser for Jafron and Exthera, has received funding for lectures from B. Braun, Baxter, bioMérieux, Exthera, Fresenius Medical Care, Estor and Jafron, and has received research grants from Baxter and Fresenius Medical Care; S.M.B. is supported by a Canada Research Chair in Critical Care Outcomes and Systems Evaluation; R.B. has received grant money, speaker’s fees and advisory board fees from Baxter Acute Care, Jafron Biomedical, CSL Behring, AM Pharma and Paion; V.C. has received lecture fees from Baxter, Estor-Toray and Aferetica-Cytosorbents; S.L.K.-G. is an elected member of the Executive Committee (or Council) of the Society of Critical Care Medicine (SCCM) (the views presented are those of the author and do not represent the views of SCCM); R.L.M. has consulting/advisory relationships with Baxter, AM Pharma, bioMérieux, Intercept, Mallinckrodt, GE Healthcare, Medtronic, CHF Solutions, Sphingotec, Abiomed, Nova Biomed, Sanofi, Renasym, Alexion, Fresenius, Abbott and Renibus; P.T.M. serves as a scientific adviser for AM-Pharma, Novartis, and Renibus Therapeutics; M.O. has received speaker honoraria from Fresenius Medical, Baxter and bioMérieux, and research funding from Fresenius Medical, Baxter and bioMérieux; J.P. has received research support from Jafron Biomedical Co Ltd and bioMérieux SA, and consultancy or lecture fees from Baxter Inc, Nikkiso Europe GmbH, Mission Therapeutics Ltd and Paion UK Ltd; A.S. has received speaker and/or consulting honoraria from Fresenius Medical Care, CytoSorbents SA, Jafron, Medtronics and B. Braun Avitum, and has received grants from the Leenaards foundation and B Braun Melsungen; A.T. has received consulting fees from Baxter and royalties from 0.5% citrate patent from Baxter; G.V. received lecture fees from Baxter; C.R. has been on the advisory boards or speaker’s bureau for Asahi, Aferetica, Baxter, bioMérieux, Cytosorbents, B. Braun, GE, Medica, Medtronic, Jafron and AstraZeneca; L.G.F. has received research support and lecture fees from Ortho Clinical Diagnostics, Baxter, Exthera and bioMérieux, and consulting fees from La Jolla Pharmaceuticals and Paion; the remaining authors declare no competing interests.

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Zarbock, A., Nadim, M.K., Pickkers, P. et al. Sepsis-associated acute kidney injury: consensus report of the 28th Acute Disease Quality Initiative workgroup. Nat Rev Nephrol 19 , 401–417 (2023). https://doi.org/10.1038/s41581-023-00683-3

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Acute kidney injury in diabetic patients: A narrative review

Amninder kaur.

a Senior Resident, Department of Nephrology, All India Institute of Medical Sciences Rishikesh, Uttarakhand, India

Gaurav Shekhar Sharma

b Assistant Professor, Department of Nephrology, All India Institute of Medical Sciences Rishikesh, Uttrakhand, India

Damodar R Kumbala

c Diagnostic and Interventional Nephrologist, Renal Associates of Baton Rogue, Baton Rogue, LA.

Diabetes mellitus (DM) is the most common cause of chronic kidney disease, which leads to end-stage renal failure worldwide. Glomerular damage, renal arteriosclerosis, and atherosclerosis are the contributing factors in diabetic patients, leading to the progression of kidney damage. Diabetes is a distinct risk factor for acute kidney injury (AKI) and AKI is associated with faster advancement of renal disease in patients with diabetes. The long-term consequences of AKI include the development of end-stage renal disease, higher cardiovascular and cerebral events, poor quality of life, and high morbidity and mortality. In general, not many studies discussed extensively “AKI in DM.” Moreover, articles addressing this topic are scarce. It is also important to know the cause of AKI in diabetic patients so that timely intervention and preventive strategies can be implemented to decrease kidney injury. Aim of this review article is to address the epidemiology of AKI, its risk factors, different pathophysiological mechanisms, how AKI differs between diabetic and nondiabetic patients and its preventive and therapeutic implications in diabetics. The increasing occurrence and prevalence of AKI and DM, as well as other pertinent issues, motivated us to address this topic.

1. Introduction

Type 2 diabetes is one of the primary causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. [ 1 ] Over the past 2 decades, diabetes mellitus incidence and prevalence have steadily increased, from an estimated 30 million in 1985 to 537 million in 2021 and it is anticipated that the number will increase to 643 million by 2030 and 783 million by 2045. [ 2 ] Considering recent trends, microvascular and macrovascular disorders are associated with long-term diabetes-related complications. One significant microvascular sequelae of diabetes are diabetic nephropathy (DN) or diabetic kidney disease (DKD). [ 3 ] Around 20% to 40% of diabetic patients are thought to suffer from DKD, and approximately 40% will need renal replacement therapy at some point in their lifetime. [ 4 , 5 ] Risk factors for the progression of CKD include gender, racial disparities, hereditary factors, concurrent comorbid illnesses, for example, diabetes mellitus (DM), metabolic abnormalities, and previous episodes of acute kidney injury (AKI), etc. [ 6 ]

AKI, which affects up to 1% of the general population and 15% of all hospitalized patients, is a worldwide health issue. [ 7 – 9 ] Diabetes is a distinct risk factor for AKI. [ 10 ] Although baseline DM is also an independent risk factor for AKI in multivariate analyses adjusted for estimated glomerular filtration rate (eGFR). [ 11 ] There have been other studies that showed that patients with diabetes may be more prone to AKI. [ 12 , 13 ] Acute tubular injury caused by renal insults may have an impact on kidney function, leading to chronic functional impairment and later maladaptive recovery and failure to entirely undo the insults. [ 14 , 15 ] Generally, there is a significant correlation between AKI and the emergence of CKD and ESRD. [ 16 , 17 ] In a cohort of 4082 patients with diabetes, Thakar et al [ 18 ] showed that AKI episodes were related to a cumulative likelihood of developing progressive CKD, regardless of the presence of any other significant risk factors for progression. Subsequently, a large prospective study provided additional evidence that AKI is a strong indicator of unfavorable outcomes (doubling of serum creatinine or ESRD) and mortality in diabetes. [ 19 ]

2. Epidemiology of AKI in diabetes mellitus

Girman et al [ 20 ] compared 119,966 diabetic patients with 1794,516 nondiabetic patients and showed that the incidence of AKI was significantly higher in diabetic patients (198 per 100,000 person-years vs 27 per 100,000 patient-years; crude hazard ratio, 8.0; 95% confidence interval, 7.4–8.7). Despite accounting for additional known comorbidities and AKI risk factors, the differences remained statistically significant. However, in their study, a clinical coding system rather than a biochemical definition of AKI was employed, which could result in significant under-ascertainment. Additionally, a meta-analysis by James et al revealed that participants with diabetes had higher AKI hazard ratios than participants without diabetes, regardless of their eGFR levels. Again, the AKI definition in these studies was based on administrative codes, which underestimated mild forms of AKI. [ 21 ]

In a retrospective cohort study by Prabhu et al [ 22 ] , an annual AKI incidence was 12.6%. There was a substantial deviation from previously published studies by Thakar et al [ 18 ] and Monseu et al [ 19 ] , who reported AKI incidence of 2.8% and 5.2%, respectively.

In their retrospective cohort of 16,700 participants (9417 with type 2 diabetes and 7283 nondiabetic controls), Hapca et al [ 23 ] found that diabetic patients had higher rates of AKI than controls (48.6% vs 17.2%, respectively). The AKI risk among diabetic patients was 5 times higher than that of controls, even in the absence of CKD (121.5 vs 24.6 per 1000 person-years). AKI rates in diabetic patients with CKD were twice as high as in controls (384.8 vs 180.0 per 1000 person-years after the onset of CKD, and 109.3 vs 47.4 per 1000 person-years before the onset of CKD).

Recently, Venot et al [ 24 ] in their prospective case-control study, which included patients with severe sepsis and septic shock with or without diabetes, found that the incidence of AKI did not differ between the 2 groups however, diabetic patients requiring dialysis more often, had higher mean serum creatinine levels, and less recovery than nondiabetic patients. However, this study has several limitations, as the diagnosis was made based on the medical history, long-term diabetic complications, and HBA1C levels were not incorporated, initial renal function status was missing, and for the diagnosis of AKI, urine output criteria were not used. Finally, the requirement for dialysis was not assessed using defined criteria. This absence of differences between these 2 groups may be explained by these confounding factors.

Very few studies have examined concurrent AKI, CKD, and recurrent AKI in this group of patients. [ 18 ] Table ​ Table1 1 summarizes studies related to this topic.

Few studies assessed AKI incidences and outcomes in diabetic patients.

AKI = acute kidney injury, DM = diabetes mellitus.

3. Risk factors for AKI

3.1. diabetes and non-modifiable factors.

Girman et al [ 20 ] reported that diabetes alone was still associated with a higher risk of acute kidney failure, even after accounting for other risk factors, such as chronic kidney disease. Additional risk factors for AKI were increasing age, chronic kidney disease, systemic hypertension, previous history of AKI, and congestive cardiac failure. The combination of type 2 diabetes with congestive cardiac failure or systemic hypertension further increases the risk of AKI. In a previous study, elderly patients with heart failure had a 3.37-fold higher risk of AKI than those without heart failure, whereas hypertension was linked to a 1.94-fold higher risk of acute kidney injury. [ 30 ] Acute kidney injury occurred in 21% of patients in a cohort study admitted with congestive heart failure as their primary diagnosis. [ 31 ] preexisting proteinuria, hypertension, and diabetes mellitus were all independent AKI risk variables revealed in the study by Hsu et al [ 11 ]

3.2. Proteinuria and lower eGFR

According to Prabhu et al [ 22 ] , there was a correlation between AKI incidence and lower baseline eGFR, and higher proteinuria. With every 1 g rise in proteinuria, they have revealed that AKI risk was increased by 15.8%. Moseu et al came to the same conclusion regarding the correlation of AKI incidence with lower eGFR and albuminuria. [ 19 ] A large cohort study showed moderate to high proteinuria was a risk factor for AKI among all eGFR groups in hospitalized patients with AKI. [ 32 ]

3.3. Hypoglycemic agents

In comparison, nondiabetic patients, surgical patients with diabetes, and those taking oral antidiabetic medications had a 30% higher chance of developing acute renal failure following surgery, while those taking insulin had a 70% higher risk. [ 33 ]

Drug-induced AKI represents 20% of all etiologies. [ 34 ] Patho physiological mechanism depends on the type of drug involved. [ 34 ] ACE/ARB (angiotensin-converting enzyme/angiotensin receptor blocker) were the main causes of AKI contributing to 35% of cases due to their increased use in diabetic patients. This risk was even higher in patients with congestive heart failure, volume depletion, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), and bilateral renal artery stenosis. Aminoglycoside (gentamicin) and NSAIDs contributed to 16% followed by statins (10%), antitubercular agents (rifampicin), and ifosfamide 6% and 3% respectively. Glomerular filtration rate and renal blood flow are decreased as a result of the suppression of prostaglandin production due to NSAIDs. They also reported dehydration and intravenous rehydration as prognostic factors in their study. [ 35 ]

The histological lesion of AKI caused by diuretics may primarily manifest as tubular epithelial cell vacuolation. Risk is even higher in a combination of other drugs that is, NSAIDs, antibiotics, ACEi, and contrast. [ 36 ] Diabetic patients who used hydrochlorothiazide (HCT) frequently experienced renal events (decline in eGFR > 30%), which affected about 20% of individuals as shown in a retrospective study. [ 37 ] Similarly, another study showed that diuretic-associated AKI patients had a higher rate of comorbidities (DM, CVD, CKD, hypertension) as compared to the non-diuretic AKI group. In the diuretic-induced AKI group, 27.5% was caused by diuretics only and 29.8% was caused by the combination of diuretics with other drugs. [ 36 ]

AKI hospitalizations in the US have recently increased considerably, from 35,000 in 1979 to 650,000 in 2002. This increase was attributed to the increasing drug consumption by the elderly, and various comorbidities. [ 38 ] Similarly, from 1992 to 2001, AKI incidence among Medicare beneficiaries increased by 11% annually, with higher rates seen in the elderly, men, and African-Americans. [ 39 ]

Although it is believed that the use of ACE/ARB is linked to acute renal failure, it can be challenging to interpret published studies because those who are most at risk for AKI may also be the ones who are most likely to receive treatment with angiotensin-converting enzyme/ARBs. [ 40 ]

3.5. Dehydration

Extracellular volume depletion due to glycosuria because of uncontrolled diabetes especially in pediatric patients leads to prerenal AKI. [ 41 ] The combined effect of uncontrolled diabetes along with prerenal AKI may cause intrinsic renal AKI, characterized by renal parenchymal damage and tubular necrosis. [ 42 ]

3.6. Sepsis

Along with dysfunctional immune systems both humoral and cell-mediated, increase neutrophil dysfunction also contributes to an increased risk of sepsis. [ 22 ] Sepsis was the primary cause of AKI in a retrospective study done by Prabhu et al [ 22 ] In addition, they showed that there was a higher eGFR decline secondary to sepsis-related AKI as compared to other etiologies. Diabetes mellitus has been demonstrated to be an independent risk factor in a recent meta-analysis of sepsis-related AKI. [ 43 ]

3.7. Contrast

Diabetic patients, particularly those who developed DN, are more prone to contrast-induced injury. Diabetes and contrast-induced acute kidney injury (CI-AKI) are mutually causative, causing kidney function to deteriorate further. Renal hypoxia, generation of reactive oxygen species, and increased oxidative stress in diabetic patients lead to vascular constriction due to vasoactive substances. Immunological changes in diabetic patients also contribute to contrast-induced AKI. Signaling pathways that is, inflammation, reactive oxygen species production, and apoptosis related to both diabetes and contrast-induced AKI. [ 44 ] Due to impaired nitro vasodilation, increased endothelin synthesis, and hyperresponsiveness to adenosine-related vasoconstriction, peritubular blood flow may also be affected. [ 45 ] According to data, the incidence of Contrast-induced AKI ranges from 5.7% to 29.4% in diabetes patients and is approximately 13% in nondiabetic patients. [ 46 ] A recent meta-analysis showed that diabetes is associated with a higher risk of CI-AKI. Moreover, the subgroup of DM patients with CKD had a greater predictive effect of elevated CI-AKI but this correlation was not significant in the subgroup of patients without CKD. [ 47 ]

Table ​ Table2 2 summarizes the causes of AKI in diabetic patients.

Risk factors of AKI in diabetic patients.

AKI = acute kidney injury, NSAIDs = nonsteroidal anti-inflammatory drugs.

4. Pathophysiologic mechanisms of AKI in patients with diabetes

The pathophysiologic mechanisms causing diabetes-related kidney damage are multifactorial. (Fig. ​ (Fig.1) 1 ) It has been hypothesized that structural and functional alterations in the renal vasculature and the tubular epithelial cells increase the cytokines and chemokines generation, which produce inflammation, ischemia, and isolated proximal tubulopathy. [ 48 , 49 ]

Pathophysiological mechanism of diabetes-induced kidney damage.

Endothelial cell dysfunction is one of the main mechanisms underlying DN. Diabetic kidneys are known to produce less nitric oxide (NO), which is produced by the enzyme endothelial nitric oxide synthase (eNOS). Because of diabetes’s distorted NO metabolism, the renal vasculature is more vulnerable to stimuli that cause vasoconstriction. [ 3 ]

It is believed that in uncontrolled diabetes, renal vasculature dysregulation is the primary factor contributing to glomerular hyperfiltration. [ 50 , 51 ] Persistent glomerular hyperfiltration causes intraglomerular hypertension, followed by glomerulosclerosis, which causes a progressive decline in kidney function and eventually DKD. [ 50 , 51 ]

In the case of prerenal AKI, when the body depends on variations in renal vascular resistance to maintain blood pressure, a dysregulation in normal renal vascular tone may hasten the kidney damage. [ 52 , 53 ] The absence of a suitable vascular counterregulatory response to sustain kidney blood flow can also significantly worsen kidney hypoperfusion. [ 50 , 51 ]

Chronic and acute renal damage related to diabetes may be exacerbated by hyperuricemia. [ 54 ] It has been demonstrated that hyperuricemia can cause crystal-mediated and crystal-independent nephropathy, glomerular injury, and tubulointerstitial involvement. [ 55 ] It is crucial to remember that hyperuricemia could signify dehydration, which can directly cause renal injury.

Persistent hyperglycemia, which is related to prolonged ICU stays and an increased risk of AKI is another pathophysiologic pathway that results in CKD and eventually ESRD. [ 3 ] Apoptosis of endothelial cells, vascular rarefaction and hypoxia, mitochondrial dysfunction, proximal tubular disorder, podocyte disorder, podocyte apoptosis, and autophagy due to diabetes have all been shown in laboratory studies. [ 3 ]

5. AKI in diabetic versus nondiabetic patients

Diabetic patients are at higher risk of AKI than nondiabetic patients, which can be attributed to diabetes, chronic kidney disease, hyperglycemic crisis, drugs that is, ACE inhibitors and sodium-glucose cotransporter-2 (SGLT2) inhibitors, associated cardiovascular disease and heart failure, and previous AKI episodes. [ 56 ] Girman et al [ 20 ] in a retrospective cohort showed that diabetic patients were 8 times more likely to have incident acute renal failure than nondiabetic patients. There have been 2 retrospective analyses, both of which had conflicting findings. [ 10 , 57 ] Diabetic patients had less severe AKI, recovery to baseline renal function and the proportion of patients developing progressive CKD was lower in the diabetic group as shown by Johns et al [ 10 ] However, the 10-year retrospective analysis done by Xin S et al showed that the recurrence rate of AKI was higher in the diabetic group than in the nondiabetic group. [ 57 ] Between diabetes and nondiabetic groups, mortality was comparable in both retrospective analyses.

6. Diabetes and cardiorenal syndrome

Cardiorenal syndrome (CRS) is a disease affecting the heart and kidneys simultaneously. T2DM is a significant risk factor for the development of CRS; the National Health and Nutrition Examination Survey in the USA found a strong association between type 2 CRS and T2DM. [ 58 ] Moreover, being a systemic disorder affecting the heart and kidneys, and it is also associated with type 4 and type 5 CRS. [ 59 ] SGLT 2 inhibitors were implicated in CRS due to both renal and cardioprotective effects. Reno protective effects of SGLT2 inhibitors in AKI contributed by increased vascular endothelial growth factor A expression, increase vasodilatation due to NO, and decrease renal fibrosis. [ 60 ] Regardless of the presence of atherosclerotic CVD or a history of heart failure, these drugs decrease the hospitalization rate for heart failure and the progression of renal illness. [ 61 ] EMPA-REG OUTCOME (Empagliflozin cardiovascular outcome event trial in type 2 diabetes mellitus), DECLARE-TIMI 58, CANVAS (Canagliflozin Cardiovascular Assessment Study), and CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy) are the 4 major trials in diabetic patients showed positive cardiovascular and renal outcomes. [ 62 – 65 ] In December 2016 there was an FDA alert regarding the use of canagliflozin and dapagliflozin. [ 66 ] However, this increased risk of AKI with SGLT2 inhibitors was not supported by studies. [ 67 ] Meta-analysis showed the protective effect of SGLT2 inhibitors with AKI, primarily driven by empagliflozin. [ 68 ]

These drugs should not be started in CRS 1 and 3 but may be continued with close hemodynamic and renal function monitoring. SGLT2 inhibitors are preferred drugs in CRS types 2, 4, and 5 for glycaemic, as well as metabolic, control. [ 69 ]

7. Preventive strategies and implications

In AKI, there is no universal therapy for AKI. The primary goals of treatment are to address underlying causes, such as dehydration, avoiding nephrotoxic drugs, fluid, and electrolyte management, and renal replacement therapy. [ 70 ]

Obese patients have glomerulomegaly, increase renal blood flow, hyperfiltration, and higher albuminuria despite the absence of hypertension. [ 71 ] Moreover, sleep apnea in obese patients causes hypoxic episodes contributing to renal impairment. [ 72 ] Hence weight control is an important preventive aspect in terms of decreasing renal injury.

Renin-angiotensin-aldosterone system inhibitors have been shown to attenuate proteinuria and continue to be the cornerstone of current therapeutic methods. [ 73 , 74 ] As patients with T2DM has more significantly greater urinary albumin-to-creatinine ratios than patients with T1DM even after adjustment for all known risk factors for diabetic kidney disease, as shown in the SEARCH study, hence RASS inhibitors are indicated in diabetic patients treatment frequently. [ 75 ] However, these drugs have nephrotoxic effects directly or indirectly by affecting renal hemodynamic function. [ 72 , 74 ]

Many antihyperglycemic agents, including metformin, thiazolidinediones, dipeptidyl peptidase inhibitors, Glucagon-like peptide agonists, and SGLT2 (Sodium-glucose Cotransporter-2) inhibitors, also have nephroprotective properties in addition to glucose-lowering effects. [ 76 – 78 ] However, accumulation of metformin in case of impaired eGFR (e.g., 30–60 mL/minutes/1.73 m2) causes type B lactic acidosis and toxicity by impairing mitochondrial function. Thiazolidinediones, such as pioglitazone, have been shown to decrease proteinuria in a large meta-analysis. [ 46 ] However, no randomized controlled trials showed renal protective effects of thiazolidinediones. [ 79 ] Role of dipeptidyl peptidase inhibitors and glucagon-like peptide 1 receptor agonist as nephroprotective agents are controversial. These have been shown to have nephroprotective effects in some studies. [ 76 , 80 ] However their effects on eGFR were uncertain as shown in a recent Cochrane review. [ 80 ] SGLT2 inhibitors were found to have a nephroprotective effect as shown in DECLARE-TIMI 58 and EMPA-REG OUTCOME trials, but in the Cochrane review, it did not show any effect on AKI risk. [ 80 – 82 ]

Some drugs have been evaluated in animal models and may represent future therapeutic options for AKI prevention, such as mineralocorticoid receptor antagonists, endothelin receptor antagonists, peroxisome proliferator-activated receptors agonists, and phosphodiesterase inhibitors. In animal models, finerenone also decreases the progression of AKI to CKD, and hence it can be an excellent therapeutic option in AKI to prevent long-term complications. [ 83 ]

8. Conclusion

In summary, AKI is a complication of diabetes mellitus. It increases the risk of further episodes of AKI, progression to chronic kidney disease, end-stage renal disease, cardiac and cerebrovascular events, and all-cause morbidity and mortality. Additionally, diabetes is the risk factor for AKI irrespective of underlying CKD. Current strategies should focus on its identification and mitigation, reducing proteinuria, weight control, fluid management, removal of precipitant factors (drugs, sepsis, contrast), and other supportive measures to improve AKI outcomes. Many glucose-lowering drugs (SGLT2 inhibitors) have nephroprotective against AKI in patients with diabetes in addition to their antidiabetic effects. A promising new approach to treating AKI and CKD using novel classes of medications that target renal hemodynamic dysfunction in diabetic patients. In the interim, healthcare professionals need to be aware of the risks and effects of AKI in patients with diabetes.

Author contributions

Conceptualization: Amninder Kaur, Gaurav Shekhar Sharma, Damodar Kumbala.

Supervision: Gaurav Shekhar Sharma.

Validation: Gaurav Shekhar Sharma, Damodar Kumbala.

Visualization: Amninder Kaur, Damodar Kumbala.

Writing – original draft: Amninder Kaur.

Writing – review & editing: Amninder Kaur, Gaurav Shekhar Sharma.s

Abbreviations:

The authors have no funding and conflicts of interest to disclose.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

How to cite this article: Kaur A, Sharma GS, Kumbala DR. Acute kidney injury in diabetic patients: A narrative review. Medicine 2023;102:21(e33888).

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Use of progestogens and the risk of intracranial meningioma: national case-control study

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• Use of progestogens and the risk of intracranial meningioma: national case-control study - March 28, 2024
• Noémie Roland , general practitioner and epidemiologist 1 ,
• Anke Neumann , senior statistician 1 ,
• Léa Hoisnard , epidemiologist 2 ,
• Lise Duranteau , endocrinologist and gynaecologist 3 ,
• Sébastien Froelich , professor of neurosurgery 4 ,
• Mahmoud Zureik , professor of epidemiology and head of department 1 5 ,
• Alain Weill , senior epidemiologist and deputy director 1
• 1 EPI-PHARE Scientific Interest Group, French National Agency for Medicines and Health Products Safety, French National Health Insurance, Saint-Denis, France
• 2 EpiDermE Epidemiology in Dermatology and Evaluation of Therapeutics, EA7379, Paris Est Créteil University UPEC, Créteil, France
• 3 Department of Medical Gynaecology, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Paris Saclay University, 94270, Le Kremlin-Bicêtre, France
• 4 Department of Neurosurgery, Lariboisière University Hospital, Paris-Cité University, Assistance Publique-Hôpitaux de Paris, Paris, France
• 5 University Versailles St-Quentin-en-Yvelines, Montigny le Bretonneux, France
• Correspondence to: N Roland noemie.roland{at}assurance-maladie.fr (@NoemieRoland11 @EPIPHARE on X)
• Accepted 22 February 2024

Objective To assess the risk of intracranial meningioma associated with the use of selected progestogens.

Design National case-control study.

Setting French National Health Data System (ie, Système National des Données de Santé ).

Participants Of 108 366 women overall, 18 061 women living in France who had intracranial surgery for meningioma between 1 January 2009 and 31 December 2018 (restricted inclusion periods for intrauterine systems) were deemed to be in the case group. Each case was matched to five controls for year of birth and area of residence (90 305 controls).

Main outcome measures Selected progestogens were used: progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and intrauterine levonorgestrel. For each progestogen, use was defined by at least one dispensation within the year before the index date (within three years for 13.5 mg levonorgestrel intrauterine systems and five years for 52 mg). Conditional logistic regression was used to calculate odds ratio for each progestogen meningioma association.

Results Mean age was 57.6 years (standard deviation 12.8). Analyses showed excess risk of meningioma with use of medrogestone (42 exposed cases/18 061 cases (0.2%) v 79 exposed controls/90 305 controls (0.1%), odds ratio 3.49 (95% confidence interval 2.38 to 5.10)), medroxyprogesterone acetate (injectable, 9/18 061 (0.05%) v 11/90 305 (0.01%), 5.55 (2.27 to 13.56)), and promegestone (83/18 061 (0.5%) v 225/90 305 (0.2 %), 2.39 (1.85 to 3.09)). This excess risk was driven by prolonged use (≥one year). Results showed no excess risk of intracranial meningioma for progesterone, dydrogesterone, or levonorgestrel intrauterine systems. No conclusions could be drawn concerning dienogest or hydroxyprogesterone because of the small number of individuals who received these drugs. A highly increased risk of meningioma was observed for cyproterone acetate (891/18 061 (4.9%) v 256/90 305 (0.3%), odds ratio 19.21 (95% confidence interval 16.61 to 22.22)), nomegestrol acetate (925/18 061 (5.1%) v 1121/90 305 (1.2%), 4.93 (4.50 to 5.41)), and chlormadinone acetate (628/18 061 (3.5%) v 946/90 305 (1.0%), 3.87 (3.48 to 4.30)), which were used as positive controls for use.

Conclusions Prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone was found to increase the risk of intracranial meningioma. The increased risk associated with the use of injectable medroxyprogesterone acetate, a widely used contraceptive, and the safety of levonorgestrel intrauterine systems are important new findings.

Introduction

Meningiomas account for 40% of primary tumours of the central nervous system. 1 2 The incidence of meningioma in the United States is 9.5 per 100 000 person years. 2 Meningiomas are mostly slow growing, histologically benign tumours but can nevertheless compress adjacent brain tissue and thus patients may require surgical decompression. 3 The incidence of meningiomas increases with age, rising sharply after the age of 65 years. Conversely, meningiomas are rare before the age of 35. Other recognised risk factors for meningioma are being female, intracranial exposure to ionising radiation, neurofibromatosis type 2 2 , and, as shown only recently, prolonged use (≥one year) to high doses of three potent progestogens: cyproterone acetate, 4 5 chlormadinone acetate, 4 and nomegestrol acetate. 4

The link between female sexual hormones, in particular progesterone, and intracranial meningioma is biologically plausible. 6 Progesterone receptors are present in more than 60% of meningiomas 7 and the volume of these tumours has been observed to increase during pregnancy and to decrease post partum. 8 However, previous pregnancy does not appear to be an unequivocal risk factor for meningioma. 9 Studies have also shown a link, albeit a weak one, between breast cancer and meningiomas. 10

No significant association between exogenous female hormones and risk of meningioma has been shown to date for hormonal contraceptives (either combined or progestogen only pills). 11 12 Additionally, data for hormone replacement treatment for menopause are contradictory. Several studies have shown a slight excess risk of meningioma associated with the use of hormone replacement treatment for menopause, 11 13 whereas others have reported no deleterious effects of these molecules. 14 By contrast, the excess risk of meningioma observed with the use of high doses of cyproterone acetate among cis women, men, and trans women has been shown to be very high 5 15 16 and somewhat lower, but still substantial, for chlormadinone acetate and nomegestrol acetate. 4 Discontinuation of each of these three progestogens generally leads to a reduction in meningioma volume, 17 18 which avoids the need for surgery and its associated risk of complications for most patients.

Whether progestogens other than these three oral progestogens at high doses have a similar effect depending on their route of administration is still unknown. Our study aimed to assess the real-life risk of intracranial meningioma associated with the use of progestogens from an extensive list (progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and levonorgestrel intrauterine systems) with different routes of administration (oral, percutaneous, intravaginal, intramuscular, and intrauterine). Although some of the progestogens studied are used in France (promegestone) or in only a few countries (medrogestone), others are widely used worldwide in various doses and for various indications (progesterone, levonorgestrel, hydroxyprogesterone, medroxyprogesterone) (supplementary table A). Certain progestogens may also be risky at some doses when used over a long period of time, but not at lower doses or when used for a short period of time. Our secondary objectives were to describe the characteristics of the women who were in the cases group (age, grade, and anatomical location of the meningiomas) and to approximate the number of surgically treated meningiomas attributable to the use of the concerned progestogens.

Study design and data source

This observational population based study used data derived from the French national health data system ( Système National des Données de Santé (SNDS)). Given the analysis of multiple exposure situations (different exposure definitions and lookback periods) in our study, we opted for a case-control design rather than a cohort study, thus including long term users of the considered medications. 19

The SNDS database contains information on all health spending reimbursements for over 99% of the population residing in France and is linked to the French hospital discharge database. 20 SNDS is currently one of the largest healthcare databases in the world and is widely used in pharmacoepidemiological studies. 4 5 21 22 23 24

Definition of cases and selection of controls

The eligible cases in this study were women residing in France of all ages who underwent surgery for intracranial meningioma between 1 January 2009, and 31 December 2018. For each case, the start date of the corresponding admission to hospital marked the index date. Women with a pregnancy beginning in the two years before the index date were excluded from the study (pregnancies were defined as those that had resulted in childbirth or medical termination of the pregnancy after 22 weeks of amenorrhoea).

Surgery for intracranial meningioma was defined by the simultaneous combination of the following diagnoses and procedures recorded for the same hospital stay: a meningeal tumour (codes D32, D42, or C70 according to the 10 th revision of the International Classification of Diseases (ICD-10)) coded as the main diagnosis of the admission to hospital and an intracranial surgery act (supplementary table B). These codes have already been used in our previous studies. 4 5

Five women in the control group were randomly matched to each woman in the case group for the year of birth and area of residence (“ département ”, a French geographical subdivision, n=101). Matching was based on the risk set sampling approach. 25 The traceability of the controls in the SNDS was ensured by selecting only women who had had at least one service reimbursed in the calendar year before the index date and the two to three calendar years preceding the index date. This criterion was also applied to the selection of cases.

For analyses relating to intrauterine systems, subsets of these cases and the matched controls were considered to ensure sufficiently long lookback periods. For the hormonal intrauterine systems containing 52 mg levonorgestrel and copper intrauterine devices, the cases and controls from the years 2011 to 2018 were retained. For the hormonal intrauterine systems containing 13.5 mg levonorgestrel, the inclusion period was restricted to 2017 to 2018 (start of commercialisation in France in 2013).

Definition of exposure

Exposure to the progestogen of interest was defined according to WHO’s anatomical, therapeutic, and chemical (ATC) classification. The list included progesterone (oral and intravaginal: 100, 200 mg (ATC code G03DA04); percutaneous: 25 mg per bar (G03DA04)), dydrogesterone (10 mg, or in association with oestrogen: 5 or 10 mg (G03DB01, G03FA14, G03FB08)), hydroxyprogesterone (500 mg (G03DA03)), medrogestone (5 mg (G03DB03)), promegestone (0.125, 0.25, or 0.5 mg (G03DB07)), medroxyprogesterone acetate (injectable contraceptive, 150 mg/3 mL (G03AC06, L02AB02 partially)), dienogest (in association with oestrogen, 2 mg (G03FA15)), levonorgestrel (52 mg intrauterine systems (G02BA03); 13.5 mg intrauterine systems (G02BA03)) (supplementary tables C and D). As drospirenone, which is a spironolactone derivative, is not reimbursed in France, we were unable to access data concerning its use. We therefore chose to study the use of spironolactone (25, 50, and 75 mg), even though its indications may be very different. The code used to identify spironolactone was C03DA01. The indications for these various progestogens in France are available in table 1 .

Main indications (marked as x), in France, for the progestogens under study

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For oral, intravaginal, percutaneous, or intramuscular progestogens, exposure was defined as at least one dispensation of the progestogen of interest in the 365 days before the index date. For intrauterine progestogens, a dispensation was sought within three years before the index date for levonorgestrel 13.5 mg (as the duration of efficacy of this intrauterine system is three years before any change or withdrawal of the device) and within five years before the index date for levonorgestrel 52 mg intrauterine systems (duration of contraceptive efficacy of five to six years according to current recommendations during the study period).

Exposure was described by three modes for each progestogen as follows: 1) exposure to the progestogen concerned, 2) exposure during the three years preceding the index date to at least one of the three high dose progestogens known to increase the risk of meningioma (ie, chlormadinone acetate, nomegestrol acetate, and cyproterone acetate), and 3) absence of exposure to the progestogen considered or to the three high dose progestogens (the reference for the analyses).

Definition of covariates

The description of sociodemographic and medical characteristics included age, area of residence, existence of neurofibromatosis type 2 (ICD-10 code Q85.1), and, for cases only, the year of surgery, anatomical site (anterior, middle, or posterior base of the skull, convexity, falx and tentorium, others; supplementary table C), and grade of severity of the meningioma (according to WHO’s classification 1 : benign, malignant, or atypical, supplementary table E).

Adjuvant radiotherapy was also sought from three months before the index date to six months after (supplementary table F). Additionally, all causes mortality at two and five years after the index date was assessed in cases, as well as the use of antiepileptic drugs in the third year after the index date (supplementary table G).

Statistical analysis

Logistic regression models conditioned on matched pairs were used to estimate odds ratios and their 95% confidence intervals (CIs) for the association between exposure to the progestogens of interest and meningioma (odds ratio of exposure relative to non-exposure). Additionally, the effect of history of neurofibromatosis type 2 on the risk of meningioma was estimated, as well as the effect of chlormadinone acetate, nomegestrol acetate, and cyproterone acetate exposure, all serving as positive controls for exposure to validate our results. In parallel, exposure to a copper intrauterine device was used as a negative control for exposure (codes in supplementary table H).

The risk of meningioma associated with progestogen use was also estimated for each oral, percutaneous, intravaginal, and intramuscular progestogen according to the duration of use: short term (at least one dispensation in the year before the index date but no dispensation in the second year before the index date) and prolonged use (at least one dispensation in the year before the index date and at least one dispensation in the second year before the index date).

The population attributable fraction was approximated from the odds ratio obtained for each progestogen. The formula used was as follows: population attributable fraction=p c (1-1/odds ratio), where p c is the prevalence of the use of the progestogen concerned (isolated exposure) among the cases. 26 Lastly, sensitivity analyses were performed. Analyses were stratified for age (<35 years, 35-44 years, 45-54 years, 55-64 years, and ≥65 years) and for the location and grade of severity of the tumours whenever a positive association was found between exposure to the considered progestogen and meningioma surgery.

Data were analysed using SAS software version 9.4 (SAS Institute Inc). A P value of less than 0.05 was considered statistically significant (two tailed tests).

The present study was authorised by decree 2016–1871 on 26 December 2016. 27 As an authorised permanent user of the SNDS, the author’s team was exempt from approval from the institutional review board. This work was declared, before implementation, on the register of studies of the EPI-PHARE Scientific Interest Group with register reference T-2023-01-437.

Patient and public involvement

The list of progestogens of interest (supplementary table B) was drawn up in consultation with a temporary scientific advisory board comprised of representatives of the French National Agency for Medicines and Health Products Safety, patient organisations, and healthcare professionals (neurosurgery, endocrinology, gynaecology, and general medicine).

Description of cases and controls

In total, 108 366 women were included in the study during the inclusion period of 2009 to 2018, consisting of 18 061 women in the case group were matched with 90 305 in the control group ( fig 1 ).

Flowchart for the analyses of oral, percutaneous, intravaginal, and intramuscular progestogens. Index date is defined as the date of hospital admission

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Among them, 15 162 cases and 75 810 controls were retained for the analyses of intrauterine systems and copper intrauterine devices using 52 mg of levonorgestrel (restricted inclusion period: 2011 to 2018) (supplementary figure A) and 4048 cases and their 20 240 controls for the analysis of intrauterine systems of 13.5 mg of levonorgestrel (2017-18) (supplementary figure B). Descriptions of cases and controls for the analyses of intrauterine devices are detailed in supplementary I and J.

The mean age of all women was 57.6 years (standard deviation 12.8 years). The most highly represented age groups were 45-54 (26.7%), 55-64 (26.4%), and 65-74 (21.5%) years ( table 2 ).

Description of the cases and controls (overall inclusion period 2009-18). Data are number of individuals (percentage), unless otherwise specified

The number of cases steadily increased from 1329 in 2009 to 2069 in 2018. Meningiomas requiring surgery were most frequently located at the base of the skull (a total of 10 046/18 061 cases (55.6%); anterior skull base: 3979/18 061 (22.0%), middle: 3911/18 061 (21.7%), posterior: 2156/18 061 (11.9%)), followed by the convexity (6468/18 061 (35.8%)). Concerning tumour grade, most meningioma cases were benign (16 662/18 061, 92.3%) and 1047/18 061 (5.8%) were classified as atypical and 352/18 061 (1.9%) as malignant. Among cases, 28.8% (5202/18 061) of women used antiepileptic drugs three years after the index date of surgery. Mortality was also higher among cases than controls: 502 cases/18 061 (2.8%) died within two years ( v 1.2% of controls) and 951/18 061 (5.3%) within five years ( v 3.4% of controls). Mortality was higher for the cases with malignant tumours, 12.5% of whom died within two years and 20.7% within five.

The comparison of the cases and controls in the subsets used to analyse hormonal intrauterine systems is included the supplementary data (supplementary tables I and J).

Progestogens (others than intrauterine)

Exposure among cases.

Among the 18 061 women admitted to hospital for meningioma surgery between 2009 and 2018, 329 (1.8%) had used oral or intravaginal progesterone, 90 (0.5%) percutaneous progesterone, zero hydroxyprogesterone, 156 (0.9%) dydrogesterone, 42 (0.2%) medrogestone, nine (<0.1%) medroxyprogesterone acetate, 83 (0.5%) promegestone, three (<0.1%) dienogest, and 264 (1.5%) spironolactone ( table 3 , supplementary figure C). These numbers excluded 2999 women who had been exposed to cyproterone acetate, nomegestrol acetate, or chlormadinone acetate, or a combination, within the previous three years (among these 2999 women, 68 had also been exposed to oral progesterone, 47 to percutaneous progesterone, 0 to hydroxyprogesterone, 43 to dydrogesterone, 10 to medrogestone, 0 to medroxyprogesterone acetate, 17 to promegestone, 1 to dienogest, and 56 to spironolactone). The median cumulative doses of progestogens for cases and exposed controls are shown in supplementary table K.

Associations between use of oral, percutaneous, intravaginal, and intramuscular progestogen and risk of surgically treated intracranial meningioma. Data are number of individuals (percentage), unless otherwise specified

Effect on meningioma risk

No significant association with an increased risk of intracranial meningioma surgery was noted with exposure to oral or intravaginal progesterone (odds ratio of 0.88 (95% CI 0.78 to 0.99)) or percutaneous progesterone (1.11 (0.89 to 1.40)), dydrogesterone (0.96 (0.81 to 1.14)), or spironolactone (0.95 (0.84 to 1.09)) ( table 3 , supplementary figure C). Exposure to dienogest was rare, with only 14 women who were exposed (3/18 061 among cases and 11/90 305 among controls) and, consequently, the estimated odds ratio had a very large confidence interval (1.48 (0.41 to 5.35)). Additionally, we could not assess the odds ratio concerning hydroxyprogesterone because no exposed cases were found ( fig 2 ).

Associations between various progestogens and risk of intracranial meningioma requiring surgery (case control design, 2009-18). Odds ratio in logarithmic scale. CI=confidential interval; LNG=levonorgestrel; SNDS=French National Health Data System ( Système National des Données de Santé ). *LNG had different denominators due to restricted inclusion periods (10/4048 cases, 48/20 240 controls; 566/15 162 cases, 3888/75 810 controls)

By contrast, an excess risk of meningioma was associated with the use of medrogestone (3.49 (2.38 to 5.10)), medroxyprogesterone acetate (5.55 (2.27 to 13.56)), and promegestone (2.39 (1.85 to 3.09)). As expected, an excess risk of meningioma for women with positive control exposure neurofibromatosis type 2 (18.93 (10.50 to 34.11)), as well as those exposed to chlormadinone acetate (3.87 (3.48 to 4.30)), nomegestrol acetate (4.93 (4.50 to 5.41)), and cyproterone acetate (19.21 (16.61 to 22.22)) was also noted ( fig 2 ).

The duration of exposure to medrogestone, medroxyprogesterone acetate, promegestone, chlormadinone, nomegestrol, and cyproterone acetate for exposed cases and controls is presented in supplementary table L. The results show that three quarters of the women in the cases group who had been exposed for more than a year had been exposed for more than three years. As for medrogestone, medroxyprogesterone acetate, and promegestone, the excess risk associated with prolonged use was higher than that measured for short term and prolonged exposure combined. Specifically, prolonged use of promegestone had an odds ratio of 2.74 (2.04 to 3.67) (versus 2.39 for all durations of exposure) and short term use an odds ratio of 1.62 (0.95 to 2.76). For prolonged use of medrogestone, the odds ratio was 4.08 (2.72 to 6.10) (versus 3.49 for all durations of exposure combined), and for medroxyprogesterone acetate, the odds ratio was 5.62 (2.19 to 14.42). No significant association was reported for either short or prolonged periods of use for any of the other progestogens studied.

Meningiomas before age 45 years were rare in cases of exposure to medrogestone (n=3/42), medroxyprogesterone acetate (n=3/9), or promegestone (n=10/83), and only one (medroxyprogesterone) was observed before the age of 35.

Concerning medrogestone, the most frequent locations of meningiomas in exposed cases were the base of the skull (n=21/42; 13 in the middle) and the convexity (n=19/42) (supplementary tables M, N and O). The excess risk of meningioma for the middle of the base of the skull was particularly high (odds ratio 8.30 (95% CI 3.70 to 18.63)). Additionally, the estimated excess risk among women aged 45-54 years was slightly higher than that in the main analysis (4.53 (2.73 to 7.53) v 3.49 (2.38 to 5.10)).

In women in the cases group who were exposed to promegestone, meningiomas were preferentially located at the front of the base of the skull (n=25/83), the convexity (n=25/83), and the middle of the base of the skull (n=22/83). The excess risk of meningioma linked to promegestone use was slightly higher in the group who were older than 65 years (odds ratio 3.21 (95% CI 1.39 to 7.43)) and for meningiomas located at the front or middle of the base of the skull (3.15 (1.95 to 5.10) and 3.03 (1.82 to 5.02), respectively).

We found no malignant grade tumours among cases exposed to medrogestone, medroxyprogesterone acetate, or promegestone (for information, the same analyses were carried out for chlormadinone acetate, nomegestrol acetate, and cyproterone acetate in supplementary table N).

Levonorgestrel intrauterine systems

In total, 566/15 162 users of hormonal levonorgestrel 52 mg were among the cases with meningioma surgery between 2011 and 2018 (3.7%) ( table 3 ). For the intrauterine systems with 13.5 mg of levonorgestrel, 10 of 4048 users were reported among the cases from 2017 and 2018 (0.2% of all cases). Again, women who had been exposed to cyproterone acetate, nomegestrol acetate, or cyproterone acetate, or a combination, within the previous three years were not counted (among them, 95 were exposed to the intrauterine systems of 52 mg levonorgestrel and three to intrauterine systems of 13.5 mg levonorgestrel).

No excess risk of meningioma was reported with the use of hormonal intrauterine systems containing 52 mg (odds ratio 0.94 (95% CI 0.86 to 1.04)) or 13.5 mg (1.39 (0.70 to 2.77)) of levonorgestrel ( fig 2).

Exposure to copper intrauterine devices, used as a negative control for exposure in this study, had an odds ratio of 1.13 (1.01 to 1.25).

Attributable cases

The population attributable fractions, which are relative to the observed overall number of surgically treated intracranial meningiomas, were 0.17% for exposure to medrogestone, 0.04% for medroxyprogesterone acetate, and 0.27% for promegestone. For comparison, they were calculated as 2.58% for chlormadinone acetate, 4.08% for nomegestrol acetate, and 4.68% for cyproterone acetate. The numbers for the attributable cases are presented in supplementary figure D.

Principal findings

Although the risk of meningioma was already known for three progestogens, this study is the first to assess the risk associated with progestogens that are much more widely used for multiple indications, such as contraception.

This population based study shows an association between the prolonged use of medrogestone (5 mg), medroxyprogesterone acetate injection (150 mg), and promegestone (0.125, 0.25, 0.5 mg) and a risk of intracranial meningioma requiring surgery. No such risk was reported for less than one year of use of these progestogens. However, we found no excess risk of meningioma with the use of progesterone (25, 100, 200 mg; oral, intravaginal, percutaneous), dydrogesterone (10 mg, combined with oestrogen: 5, 10 mg), or spironolactone (25, 50, 75 mg), neither with short term nor prolonged use, and with the use of levonorgestrel intrauterine systems (13.5, 52 mg). A small number of women were exposed to dienogest (2 mg, in association with oestrogen) and hydroxyprogesterone (500 mg), therefore we cannot draw any conclusions concerning the association between use of these progestogens and the risk of meningioma.

No malignant meningiomas were noted for women exposed to medrogestone, medroxyprogesterone acetate, or promegestone. Moreover, the number of cases of surgically treated intracranial meningioma attributable to use of these progestogens was much lower than the number of cases attributable to the intake of chlormadinone acetate, nomegestrol acetate, and, in particular, cyproterone acetate. This finding is explained by both a lower excess risk of meningioma (for medrogestone and promegestone) and lower rates of use in France (particularly low for medroxyprogesterone acetate, with less than 5000 women exposed each quarter during the inclusion period of the study of 2009-18).

Specific considerations on meningiomas

Meningioma is a predominantly benign tumour. Between 2011 and 2015, 80.5% of the meningiomas diagnosed in the United States were grade 1, 17.7% grade 2, and 1.7% grade 3. 1 Even in the absence of malignancy, meningiomas can cause potentially disabling symptoms. In such cases, first line treatment is surgery, even for the oldest patients, entailing a risk of complications and morbidity. 28 29

Age is an important factor both for the indication of progestogens and for considering intracranial surgery. In our study, the mean age of women in the cases group was 57.6 years. Medrogestone, medroxyprogesterone acetate, and promegestone can be used both by women of childbearing age and by premenopausal and postmenopausal women. In our study, only one user of these progestogens who had undergone meningioma surgery was younger than 35 years (medroxyprogesterone).

Postoperative complications are not uncommon for meningioma surgery. Depending on the exact location of meningiomas, the surgical risk varies but surgery may have severe neurological consequences due to the immediate proximity of highly functional cortical area and critical neurovascular structures. Cognitive function tends to improve after surgery for meningioma, 30 31 but several studies have suggested a potential for postoperative anxiety and depression and a high intake of antidepressants and sedatives in the medium term, 32 33 although other studies have reported conflicting findings for depression. 34 Seizures are also a possible short term complication of surgery, 35 leading to a need to take antiepileptic drugs in the years following the operation. In our study, almost three in 10 women (28.8% of cases) were using antiepileptic drugs three years after the operation, which was consistent with previously published findings. 36 Additionally, results showed that progestin related meningiomas tend to occur more frequently at the skull base and that surgery for lesions in this location is much more challenging. The recent evidence supporting stabilisation or regression of meningiomas after stopping chlormadinone acetate, nomegestrol acetate, and cyproterone acetate has reduced the surgical indications for these patients, thus avoiding potential complications. 17 18 A recent report showed that although the tissue portion of the meningioma most often regresses in size, the hyperostosis associated with meningiomas further increases, which may require surgical intervention, not for oncological purposes but only for decompression of the structures nerves and relief of symptoms. 37

Use of the studied progestogens in France and worldwide

Medrogestone is indicated in France for the treatment of menstrual cycle disorders and luteal insufficiency (eg, dysmenorrhea, functional menorrhagia or fibroid-related menorrhagia, premenstrual syndrome, and irregular cycles), endometriosis, mastodynia, and hormone replacement therapy for menopause. In the United States, medrogestone has never been approved by the US Food and Drug Administration. Outside of France, this molecule is also used in Germany, in combination with oestrogen (0.3 mg/5 mg, 0.6 mg/2 mg, 0.6 mg/5 mg). 38 The use of medrogestone increased significantly in France in 2019, notably as a result of postponements in the prescription of chlormadinone acetate, nomegestrol acetate, and cyproterone acetate, following the French and European recommendations to reduce the risk of meningioma attributable to these progestogens in 2018 and 2019. 39 40 As therapeutic alternatives have not shown an increased risk of meningioma, switching from products that notoriously increase this risk to medrogestone should be reconsidered.

Worldwide, in 2019, 3.9% of women of childbearing age were using injectable contraception (medroxyprogesterone), that is, 74 million users, but figures vary widely between world regions (from 1.8% in high income countries to 8.7% in low income countries). 41 This method of contraception is the most widely used in Indonesia (13 million women), 42 Ethiopia (4.6 million women), and South Africa (3.6 million women). 41 In the USA, medroxyprogesterone acetate is used in more than 2 million prescriptions in 2020 and more than one of five sexually active American women report having used injected medroxyprogesterone acetate (150 mg/3 mL) in their lifetime. 43 44 Injectable contraceptives are much less widely used in Europe (3.1% of women of childbearing age in the UK and 0.2% in France 41 ). Our results support preliminary findings from studies of meningioma cases exposed to chronic use of medroxyprogesterone acetate or cases of high dose administration. 45 46 47 48 49 In particular, our results show similarities with those of a retrospective review of 25 patients diagnosed with meningioma who had a history of chronic medroxyprogesterone acetate use and were treated at the University of Pittsburgh Medical Center between 2014 and 2021 concerning the characteristics of cases exposed to medroxyprogesterone acetate (women (mean age of 46 years) with meningiomas commonly located at the base of the skull). 48 In addition, medroxyprogesterone acetate used as an injected contraceptive is known to be prescribed to specific populations, especially people with mental illnesses. 50 The protection of these vulnerable populations from additional drug risks is particularly important. Depot medroxyprogesterone acetate (150 mg) is registered for use as a form of birth control in more than 100 countries worldwide. 41 In countries that have high numbers of people using medroxyprogesterone acetate, the number of meningiomas attributable to this progestogen may be potentially high. Furthermore, medroxyprogesterone (non-acetate) is also used orally, at lower doses, in some countries other than France (notably in the US), for which no data exists on a risk of meningioma so far.

Promegestone was only available in France (not marketed in any other country) and was withdrawn from the market in 2020. This drug was indicated for the relief of premenopausal symptoms and hormone replacement therapy for menopause. With the discontinuation of its marketing, some users could have switched to medrogestone in 2020, a molecule also implicated in the risk of meningioma in our results. Clinicians therefore must remain vigilant because meningioma risk could last beyond market withdrawal and a potential switch to another progestogen.

The FDA defines a therapeutic class as “all products (…) assumed to be closely related in chemical structure, pharmacology, therapeutic activity, and adverse reactions”. 51 52 Various subtypes of progestogens exist depending on the molecule from which the progestogen is derived (ie, progesterone, testosterone, and spironolactone) (supplementary table B). 53 Their chemical structures and pharmacological properties differ according to this classification, which explains why no class effect is reported for certain benefits and risks associated with their use (eg, breast cancer and cardiovascular risk). 54 55 56 57 Progestogens have distinct affinities for different target organ steroid receptors, which may vary even within a subclass, determining their activity.

Our study suggests that 17-OH-hydroprogesterone and 19-norprogesterone derivatives, both progesterone derivatives, have a class effect on meningioma risk. Four of five progestogens belonging to the 17-OH-hydroprogesterone group have shown an increase in the risk of meningioma (supplementary table R). However, the fact that we found different sizes of risk appears to be more a question of duration and cumulative dose than that of belonging to a progestogen class. We could not draw any conclusions about hydroxyprogesterone (due to a lack of power), the fifth progestogen in the subclass, but its main indication (assisted reproductive technology) corresponded to fewer women exposed and very short exposure (approximately 15 days), which could explain why this drug differs from the others. Finally, to date, at the doses considered in the study, no excess risk of meningioma associated with testosterone derivatives has been shown. However, the risk of meningioma associated with the use of these derivatives at other doses and in other regimens needs to be investigated.

Strengths and limitations

To our knowledge, this study of meningioma risk is the first to expand the list of progestogens of interest beyond chlormadinone acetate, nomegestrol acetate, and cyproterone acetate, detailing the risk associated with each progestogen, with different modes of administration. This study was conducted on a national scale for women of all ages for both the cases and their controls. The SNDS database allowed the use of exhaustive real-world data from over a period of 12 years (2006-18; postoperative information was searched even up to 2022), thus preventing recall bias.

The exclusion of women with a pregnancy beginning in the two years preceding the index date ensured that estimates of the risks associated with progestogen use were reliable. Pregnancy is a unique state, affecting exposure to progestogens (of endogenous or exogenous origin), the likelihood of a meningioma appearing or increasing in volume, 9 58 59 and the likelihood of admission to hospital for surgery (possibly with a lower surgery rate, depending on the symptoms, maternal and foetal health, and tumour characteristics). 59

Another potentially important confounding factor, use of chlormadinone acetate, nomegestrol acetate, or cyproterone acetate, was considered in the analyses by modelling exposure to each progestogen of interest with a separate mode of prior or simultaneous exposure to these drugs. Furthermore, the results obtained for the negative and positive control exposure, including exposure to chlormadinone acetate, nomegestrol acetate, and cyproterone acetate, support the appropriateness of the method chosen for this study.

However, this study also had several limitations. As a result of the scarcity of historical data in the SNDS (which began in 2006, and did not have information for some reimbursement schemes during the first few years), we have only three years of lookback period for the oldest meningioma cases (2009-06), and 12 years for the most recent. The SNDS does not provide information on non-reimbursed drugs, which obliged us to study dienogest in association with oestrogen rather than dienogest alone. Further studies will therefore be necessary. Similarly, we were unable to study other progestogens, such as norgestimate, gestodene, and norethisterone, contained in non-reimbursed products (supplementary table B). Conversely, desogestrel is available and reimbursed in France. Its dosage is much lower and, thus, we chose not to study the drug. Further study to assess a dose-response association in the event of prolonged use would be needed. The progestogen implants (etonogestrel) are also rarely used in France, and concern young women, for whom the risk of meningioma is probably very low. 60 61 We have also not studied the risk associated with the use of hormonal intrauterine systems containing 19.5 mg levonorgestrel because its marketing in France was too recent (2018). However, any excess risk associated with the use of the levonorgestrel 19.5 mg intrauterine systems is unlikely because this dose of levonorgestrel is lower than that of the levonorgestrel 52 mg intrauterine systems, for which we observed no risk.

Moreover, the SNDS does not provide information on all the clinical details and medical indications for which progestogens are prescribed. These missing data mean assessing the risk-benefit ratio of prescriptions is not possible, which could be favourable in the absence of an effective alternative, for example, in the case of relief of endometriosis symptoms. We only have some indirect idea of the indication, depending on the age of the user, and the molecule used (progesterone is not indicated for endometriosis, for example, and dydrogesterone is indicated for endometriosis but is rarely used in this indication). Nevertheless, a risk-benefit assessment was not the aim of our study and will require further studies using other sources of data for product efficacy. Furthermore, no evidence suggests that an increase in meningioma risk depends on the medical indication for the progestogen prescription. In the study of Weill and colleagues in 2021, the excess risk of meningioma associated with the use of cyproterone acetate was equivalent for men and women, who, nevertheless, use cyproterone acetate for radically different indications. 5

In this study, only admission to hospital for meningioma surgery was used as the outcome of interest. However, meningiomas can also be treated with radiotherapy (in rare cases) or simply monitored. Therefore, this study is highly likely to have underestimated the prevalence of meningiomas attributable to the use of progestogens by limiting itself solely to symptomatic tumours that require surgery. However, using admission to hospital for surgery as the outcome ensured diagnostic specificity and thus limited classification bias. The SNDS does not specify the histological characteristics of the meningiomas or the isolated or multiple nature of the tumour, both of which are important criteria in determining severity and the choice of appropriate treatment. Nevertheless, for the cases selected for this study, WHO’s severity grade of the meningioma is coded via the main diagnosis, which is entered according to the ICD-10 code at the end of the hospital stay after a reading of the pathology report. As such, we had indirect information about the histology of the tumours.

Our study has several confounding factors. The two main risk factors identified for meningioma, in addition to age (which was considered in this study) and being female (only women were included in this study), are genetic predisposition, attributed, in particular, to hereditary mutations of the neurofibromatosis type 2 gene, and medical or environmental exposure to high doses of ionising radiation. Radiotherapy for brain cancer (especially during childhood) is probably the most important of the possible medical reasons for intracranial radiation exposure, but only a small proportion of individuals in the general population had cerebral radiotherapy or a malignant brain tumour during childhood.

The progestogens investigated in our study that did not result in an increase to risk of meningioma should be considered under the specific conditions of use in France. These results may not be generalised to the use of these progestogens for other indications, increased doses, or increased duration of use. Similarly, the use of one or more of these progestogens might increase the meningioma risk, when the patient had previously received another type of progestogen.

Prescribers need to be aware of previous progestogen use of any kind and any changes in type of progestogen prescribed that may have occurred and should consider the cumulative dose of progestogens for each patient. The list of progestogens we studied is wide ranging, covering a variety of indications (summarised in table 1 ) for women of all ages (childbearing, premenopausal, and menopausal). As in hormone replacement therapy for menopause, progestogens can be easily substituted for each other, and thus progesterone appears to be the safest alternative. For endometriosis, however, therapeutic alternatives are much more limited, and each indication must be discussed on the basis of the personal benefit to risk ratio. If a high risk progestogen is to be continued, clinical and radiological monitoring and compliance with recommendations are essential.

Finally, we did not estimate the effect of concomitant oestrogen use on the risk of meningioma. In a previous report, having a concomitant oestrogen prescription was weakly but significantly associated with meningioma risk, with an age adjusted hazard ratio of 1.6 (95% CI 1.1 to 2.4) for use of cyproterone acetate. In our previous studies, the simultaneous prescription of oestrogen with chlormadinone acetate (hazard ratio 0.8 (0.5 to 1.3)) and nomegestrol acetate (1.0 (0.7 to 1.7)) was not significantly associated with a risk of meningioma. 28 62 In addition, in these two studies, which were cohort studies of women initiating treatment with the progestogen considered, the proportion of women with a simultaneous prescription of oestrogen at the initiation of progestogen treatment was relatively low (6.8%, and 5.0%, respectively per study).

Conclusions

Prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone was found to be associated with an increased risk of meningioma. Future studies should further clarify the association between the duration of use and risk for the progestogens studied, and extend the discussion of meningioma risk to dienogest and hydroxyprogesterone. Finally, no excess risk of meningioma was associated with the use of progesterone, dydrogesterone, or spironolactone, or the hormonal intrauterine systems used worldwide, regardless of the dose of levonorgestrel they contained.

Further studies are also needed to assess the meningioma risk with the use of medroxyprogesterone acetate, which, in this study, was considered at a dose of 150 mg and corresponded to a second line injectable contraceptive that is rarely used in France. Studies from countries with a broader use of this product, which, furthermore, is often administered to vulnerable populations, are urgently needed to gain a better understanding of its dose-response association.

What is already known on this topic

Known risk factors for intracranial meningioma include age, female sex, neurofibromatosis type 2, exposure to ionising radiation, and use of high dose progestogens: nomegestrol, chlormadinone, and cyproterone acetate

Many other progestogens are widely used for multiple indications for which the risk of meningioma associated with their use has not been estimated individually

What this study adds

Prolonged use of medrogestone (5 mg, oral), medroxyprogesterone acetate (150 mg, injectable), and promegestone (0.125/0.5 mg, oral) was found to be associated with an excess risk of intracranial meningioma

In countries for which the use of medroxyprogesterone acetate for birth control is frequent (74 million users worldwide), the number of attributable meningiomas may be potentially high

The results for oral, intravaginal, and percutaneous progesterone, as well as dydrogesterone and levonorgestrel intrauterine systems, are reassuring, supporting the absence of excess meningioma risk

Ethics statements

Ethical approval.

The present study was authorised by decree 2016–1871 on December 26, 2016. 27 As a permanent user of the SNDS, the author’s team was exempt from approval from the institutional review board. This work was declared, before implementation, on the register of studies of the EPI-PHARE Scientific Interest Group requiring use of the SNDS (register reference: EP-0437).

Data availability statement

Under the terms of the SNDS data use agreement, the complete study data cannot be shared with other investigators ( https://www.snds.gouv.fr ). However, the authors try to share publication related data as much as possible: algorithms and other additional information are provided in the supplemental data; aggregated data can be supplied upon request by contacting the corresponding author at noemie.roland{at}assurance-maladie.fr .

Acknowledgments

We thank Bérangère Baricault and Pauline Dayani for their help in responding to the reviewers, and Sylvie Fontanel and Emmanuelle Mignaton for reviewing the manuscript. We also thank Alex Edelman and Associates for proofreading the English version.

Contributors: AW had the idea for the study. NR, AN, LH, and AW conceived and planned the study. NR and AN drafted the manuscript. AN and LH performed the data management. AN, LH, and NR performed the statistical analyses. AW and MZ ensured project and study management. All authors approved the final manuscript. The corresponding author (NR) attests that all listed authors meet the authorship criteria and that no others meeting the criteria have been omitted. AW is the guarantor.

Funding: This research was funded by the French National Health Insurance Fund (Cnam) and the French National Agency for Medicines and Health Products Safety (ANSM) via the Health Product Epidemiology Scientific Interest Group (ANSM-Cnam EPI-PHARE Scientific Interest Group). NR, AN, and AW are employees of the French National Health Insurance Fund, MZ is an employee of the French National Agency for Medicines and Health Products Safety. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from French National Health Insurance Fund (Cnam) and the Health Product Epidemiology Scientific Interest Group (ANSM-Cnam EPI-PHARE Scientific Interest Group) for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work.

Transparency: The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported, that no important aspects of the study have been omitted, and that any discrepancies from the study as originally planned (and, if relevant, registered) have been explained.

Dissemination to participants and related patient and public communities: The results were presented for the first time on 12 June 2023, at a meeting organised by the French National Agency for Medicines and Health Products Safety to invited patient association representatives, gynaecologists, endocrinologists, neurosurgeons, and general practitioners. The report on this study (in French) was than published on 26 June 2023, on the EPI-PHARE, ANSM (Agence nationale de sécurité du médicament et des produits de santé), and Cnam (Caisse nationale de l’assurance maladie) websites and was sent to the European Medicine Agency.

Provenance and peer review: Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

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Abortions outside medical system increased sharply after Roe fell, study finds

Researchers report that volunteer-led networks distributing abortion pills helped drive a rise in ‘self-managed’ abortions.

The number of women using abortion pills to end their pregnancies on their own without the direct involvement of a U.S.-based medical provider rose sharply in the months after the Supreme Court eliminated a constitutional right to abortion, according to the most comprehensive examination to date of how many people have ended their pregnancies outside of the formal medical system since the ruling.

Nearly 28,000 additional doses of pills intended for “self-managed” abortions were provided in the six months after the fall of Roe v. Wade — more than quadrupling the average number of abortion pills provided that way per month before the decision and suggesting that many women have turned to medication abortion to circumvent state bans.

The research — published in JAMA on Monday , the day before the highly anticipated Supreme Court arguments on a challenge to a key abortion drug — highlights the importance of abortion pills in post- Roe America. Before the ruling legalized abortion nationwide in 1973, women seeking abortions were forced to find someone to perform an illegal surgical procedure, leading to thousands of deaths . Today, the process for accessing abortion is far easier and safer, with a rapidly expanding online and community-based network of pill suppliers sending pills through the mail into states with strict bans.

Other studies have estimated that approximately 32,000 fewer abortions occurred at licensed brick-and-mortar and telehealth clinics in the six months following the fall of Roe . But the jump in self-managed abortions offsets nearly that whole figure.

Supply of abortion pills for

self-managed abortions

The supply of abortion pills outside of the formal health-care setting increased sharply in the six months after Dobbs v. Jackson Women’s Health Organization , a landmark ruling that eliminated the constitutional right to abortion. A major factor in the increase was the rise of community-based, volunteer-led networks that organized to help women in states with abortion bans.

Online vendors

Telemedicine

Community networks

Source: Provision of Medications for Self-managed Abortion

Before and After the Dobbs v Jackson Women’s Health

Organization decision. JAMA (2024)

Source: Provision of Medications for Self-managed Abortion Before and After

the Dobbs v Jackson Women’s Health Organization decision. JAMA (2024)

Supply of abortion pills for self-managed abortions

“The numbers we’re looking at seem to suggest that [self-managed abortion] is more mainstream than perhaps we thought,” said Abigail Aiken, a professor at the University of Texas at Austin and the lead author of the study. “This is something people are doing on a larger scale.”

Women in states with bans are also using the traditional health-care system to access abortion, traveling out of state to pick up pills or to have a procedure at a clinic in a state where abortion remains legal. A different study published last week by the Guttmacher Institute, which supports abortion rights, revealed that the overall number of abortions facilitated within the formal health-care system increased last year despite the bans, with medication abortions accounting for 63 percent of the more than 1 million abortions performed in 2023.

Taken together, the flurry of new data points to a perhaps surprising result of the fall of Roe : While the ruling has made abortion more difficult to access for people in antiabortion states, a large portion of those women have been able to navigate around the laws and end their pregnancies.

Self-managed abortions with pills are facilitated in a legal gray area. Women obtaining abortions by mail are not breaking the law themselves; abortion bans are designed to penalize only doctors and others involved in facilitating an abortion. Those involved with distributing the pills could potentially be charged. In many states, abortion bans carry penalties of at least several years in prison.

The landscape of self-managed abortion is sprawling and difficult to quantify, Aiken said. According to Plan C, an abortion rights organization that tests pills and publishes a list of verified sources online, at least 25 websites now mail abortion medication into states that ban the procedure, along with several telehealth clinics and community-based networks.

Aiken identified 15 distinct sources for abortion pills that were operating outside of the formal health-care setting in the first six months after Roe fell, most of which shared with the researchers month-by-month data on the number of pills they distributed to U.S. patients during that period. Some sources relayed the numbers without providing internal documentation, Aiken said, because they do not keep formal records.

Rebecca Gomperts, the founder of Aid Access, the largest telehealth clinic mailing pills into states with abortion bans, and Elisa Wells, a founder of Plan C, are co-authors of the study.

The various sources that mail pills for self-managed abortions operate with very different models, offering a range of medical and emotional support through the process of passing a pregnancy at home, according to the new study.

In the first six months after the Supreme Court decision, the JAMA study shows that most women who chose to self-manage their abortions obtained pills through networks of volunteers that quickly mobilized and expanded after the ruling. These networks — one of the largest of which is based in Mexico — buy pills from international pharmacies, then mail them to people for free without a prescription, offering peer support but typically no direct access to a doctor. The pills often arrive unsealed, according to Plan C.

Along with community-based networks, people are also obtaining pills through internationally based telehealth clinics, which provide a prescription from a doctor, or other websites that sell pills typically without offering any kind of built-in support for women taking them.

Abortion pills have become even easier to get since the immediate aftermath of Dobbs v. Jackson Women’s Health Organization , with new suppliers appearing regularly and existing suppliers expanding to absorb more demand.

In the year since the research in the study was compiled, Aiken said, telehealth clinics in particular have significantly expanded their reach in antiabortion states, leading to far more abortions provided than are reflected in her study. While Europe-based Aid Access, the largest of these groups, initially relied on pharmacies in India to mail pills to patients in states with bans, the organization has now started allowing U.S.-based doctors to prescribe and mail the pills themselves, making use of “shield laws” recently passed in several Democratic-led states to protect the providers from prosecution. That change has reduced Aid Access’s shipping time from several weeks to a few days.

The organization now mails approximately 6,000 doses of medication abortion into states with abortion bans each month, according to Gomperts. She expects that number will continue to grow.

“What we know from other countries is the more this [becomes] mainstreamed, the more people will feel comfortable doing it by themselves,” she said.

Struggling to come up with a way to crack down on self-managed abortions, antiabortion advocates have taken aim at abortion pills more broadly. At Tuesday’s Supreme Court arguments, antiabortion advocates will argue that the U.S. Food and Drug Administration rushed its 2000 approval of mifepristone, the first drug in the two-step medication abortion regimen, as well as subsequent decisions to lift restrictions on the pill. Perhaps most significantly, antiabortion advocates are seeking to reinstate the requirement for people taking medication abortion to see a medical provider in person — a change that could halt the mailing of abortion pills.

“When the FDA is recklessly saying that this is safe and women don’t need or deserve ongoing care — that’s dangerous,” Christina Francis, chief executive of the American Association of Pro-Life Obstetricians and Gynecologists, said in an interview last month.

Leading studies show that medication abortions conducted via telehealth are safe. Major adverse events, such as infections or a hemorrhage, occur in less than 1 percent of cases, a figure that remains the same whether or not a patient has an ultrasound and an in-person consultation.

The upcoming Supreme Court case could have significant implications for people taking abortion pills in states with bans, potentially preventing U.S. providers from utilizing shield laws.

Abortion rights leaders say they will continue to mail pills into antiabortion states, regardless of whether it’s legal.

“The reality is that medication abortion and telemedicine will continue — but whether it continues from licensed providers, aboveboard, without stigma … is something we have to really be aware of and fighting for,” said Julie Kay, the executive director of the Abortion Coalition for Telemedicine, an abortion rights group.

U.S. abortion access, reproductive rights

Tracking abortion access in the United States: Since the Supreme Court struck down Roe v. Wade , the legality of abortion has been left to individual states. The Washington Post is tracking states where abortion is legal, banned or under threat.

Abortion and the 2024 election: Voters in a dozen states in 2024 could decide the fate of abortion rights with constitutional amendments on the ballot in a pivotal election year. One of the country’s strictest abortion bans will take effect in Florida on May 1 , but the state Supreme Court also ruled that an amendment to enshrine abortion rights in the state’s constitution can go on the November ballot .

New study: The number of women using abortion pills to end their pregnancies on their own without the direct involvement of a U.S.-based medical provider rose sharply in the months after the Supreme Court eliminated a constitutional right to abortion , according to new research.

Abortion pills: The Supreme Court seemed unlikely to limit access to the abortion pill mifepristone . Here’s what’s at stake in the case and some key moments from oral arguments . For now, full access to mifepristone will remain in place . Here’s how mifepristone is used and where you can legally access the abortion pill .

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