literature review on kidney disease

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• Published: 23 November 2017
• Chronic kidney disease
• Paola Romagnani 1 ,
• Giuseppe Remuzzi 2 , 3 , 4 ,
• Richard Glassock 5 ,
• Adeera Levin 6 ,
• Kitty J. Jager 7 ,
• Marcello Tonelli 8 ,
• Ziad Massy 9 , 10 ,
• Christoph Wanner 11 &
• Hans-Joachim Anders 12  

Nature Reviews Disease Primers volume  3 , Article number:  17088 ( 2017 ) Cite this article

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• Diabetes complications
• End-stage renal disease
• Public health
• Renal replacement therapy

Chronic kidney disease (CKD) is defined by persistent urine abnormalities, structural abnormalities or impaired excretory renal function suggestive of a loss of functional nephrons. The majority of patients with CKD are at risk of accelerated cardiovascular disease and death. For those who progress to end-stage renal disease, the limited accessibility to renal replacement therapy is a problem in many parts of the world. Risk factors for the development and progression of CKD include low nephron number at birth, nephron loss due to increasing age and acute or chronic kidney injuries caused by toxic exposures or diseases (for example, obesity and type 2 diabetes mellitus). The management of patients with CKD is focused on early detection or prevention, treatment of the underlying cause (if possible) to curb progression and attention to secondary processes that contribute to ongoing nephron loss. Blood pressure control, inhibition of the renin–angiotensin system and disease-specific interventions are the cornerstones of therapy. CKD complications such as anaemia, metabolic acidosis and secondary hyperparathyroidism affect cardiovascular health and quality of life, and require diagnosis and treatment.

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Acknowledgements

P.R. is supported by the European Research Council under the Consolidator Grant RENOIR (ERC-2014-CoG), grant number 648274. G.R. and H.-J.A. have received support from the European Union's research and innovation programme (under grant agreement Horizon 2020, NEPHSTROM No. 634086). Z.M. has received research grants from the French government (the Investisssement d'Avenir programme). H.-J.A. has received support from the Deutsche Forschungsgemeinschaft (AN372/16-2, 23–1 and 24–1). The views expressed here are the responsibility of the authors only. The EU Commission takes no responsibility for any use made of the information set out.

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Romagnani, P., Remuzzi, G., Glassock, R. et al. Chronic kidney disease. Nat Rev Dis Primers 3 , 17088 (2017). https://doi.org/10.1038/nrdp.2017.88

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Chronic Kidney Disease Diagnosis and Management : A Review

• 1 Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
• 2 Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland

Importance   Chronic kidney disease (CKD) is the 16th leading cause of years of life lost worldwide. Appropriate screening, diagnosis, and management by primary care clinicians are necessary to prevent adverse CKD-associated outcomes, including cardiovascular disease, end-stage kidney disease, and death.

Observations   Defined as a persistent abnormality in kidney structure or function (eg, glomerular filtration rate [GFR] <60 mL/min/1.73 m 2 or albuminuria ≥30 mg per 24 hours) for more than 3 months, CKD affects 8% to 16% of the population worldwide. In developed countries, CKD is most commonly attributed to diabetes and hypertension. However, less than 5% of patients with early CKD report awareness of their disease. Among individuals diagnosed as having CKD, staging and new risk assessment tools that incorporate GFR and albuminuria can help guide treatment, monitoring, and referral strategies. Optimal management of CKD includes cardiovascular risk reduction (eg, statins and blood pressure management), treatment of albuminuria (eg, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers), avoidance of potential nephrotoxins (eg, nonsteroidal anti-inflammatory drugs), and adjustments to drug dosing (eg, many antibiotics and oral hypoglycemic agents). Patients also require monitoring for complications of CKD, such as hyperkalemia, metabolic acidosis, hyperphosphatemia, vitamin D deficiency, secondary hyperparathyroidism, and anemia. Those at high risk of CKD progression (eg, estimated GFR <30 mL/min/1.73 m 2 , albuminuria ≥300 mg per 24 hours, or rapid decline in estimated GFR) should be promptly referred to a nephrologist.

Conclusions and Relevance   Diagnosis, staging, and appropriate referral of CKD by primary care clinicians are important in reducing the burden of CKD worldwide.

Read More About

Chen TK , Knicely DH , Grams ME. Chronic Kidney Disease Diagnosis and Management : A Review . JAMA. 2019;322(13):1294–1304. doi:10.1001/jama.2019.14745

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• Published: 22 April 2024

A loss-of-function AGTR1 variant in a critically-ill infant with renal tubular dysgenesis: case presentation and literature review

• Aljazi Al-Maraghi 1 ,
• Waleed Aamer 1 ,
• Mubarak Ziab 2 ,
• Elbay Aliyev 1 ,
• Najwa Elbashir 1 ,
• Sura Hussein 1 ,
• Sasirekha Palaniswamy 1 ,
• Dhullipala Anand 3 ,
• Donald R. Love 4 ,
• Adrian Charles 5 ,
• Ammira A.S.Akil 2 &
• Khalid A. Fakhro 1 , 2 , 6 , 7  

BMC Nephrology volume  25 , Article number:  139 ( 2024 ) Cite this article

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Renal tubular dysgenesis (RTD) is a severe disorder with poor prognosis significantly impacting the proximal tubules of the kidney while maintaining an anatomically normal gross structure. The genetic origin of RTD, involving variants in the ACE, REN, AGT, and AGTR1 genes , affects various enzymes or receptors within the Renin angiotensin system (RAS). This condition manifests prenatally with oligohydramninos and postnatally with persistent anuria, severe refractory hypotension, and defects in skull ossification.

Case presentation

In this report, we describe a case of a female patient who, despite receiving multi vasopressor treatment, experienced persistent hypotension, ultimately resulting in early death at five days of age. While there was a history of parental consanguinity, no reported family history of renal disease existed. Blood samples from the parents and the remaining DNA sample of the patient underwent Whole Genome Sequencing (WGS). The genetic analysis revealed a rare homozygous loss of function variant (NM_000685.5; c.415C > T; p.Arg139*) in the Angiotensin II Receptor Type 1 ( AGTR1 ) gene.

This case highlights the consequence of loss-of-function variants in AGTR1 gene leading to RTD, which is characterized by high mortality rate at birth or during the neonatal period. Furthermore, we provide a comprehensive review of previously reported variants in the AGTR1 gene, which is the least encountered genetic cause of RTD, along with their associated clinical features.

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Renal tubular dysgenesis (RTD) (MIM# 267,430) is a rare autosomal recessive disorder of renal tubular development that was first characterized in two stillborn siblings in 1983 [ 1 ]. The disease carries a poor prognosis and a high mortality rate due to the severity of the disease where patients may die in utero or soon after birth, despite the availability of high-quality clinical care. Although the exact prevalence of RTD is unknown, there are multiple reports of RTD cases [ 2 , 3 ].

The underlying pathophysiology of RTD involves reduced intrauterine renal perfusion leading to dysgenesis of proximal tubule formation in the kidneys, with preservation of grossly normal kidney structure [ 4 ].The clinical manifestations of RTD include persistent fetal anuria with subsequent oligohydramnios in pregnancy, pulmonary hypoplasia, and skull ossification defects of the bone due to persistent hypotension [ 5 ]. In addition, typical pathological changes seen on kidney sections taken from affected patients show the incomplete development of renal proximal tubules. These changes are attributed to the consequences of hypoperfusion and renal ischemia in the absence of Angiotensin II (ANG II) production or function, a defect responsible for the severe refractory hypotension observed at birth [ 6 ].

Previous studies have demonstrated the fundamental role of Renin Angiotensin System (RAS) during fetal development of the kidneys. Physiologically, the RAS pathway regulates extracellular fluid volume and maintains blood pressure levels in the body [ 7 ]. Several variants in four different genes encoding RAS signaling proteins ( AGT , REN , ACE , and AGTR1 ) have been described to cause RTD [ 8 ]. Variants in the AGTR1 gene constitute approximately 8% of the reported mutations causing RTD [ 9 ].

The Angiotensin II Receptor Type 1 ( AGTR1 ) gene encodes a receptor protein of the ligand angiotensin II, which is a potent vasopressor hormone in the RAS pathway [ 10 ]. The binding of ANG II to the Angiotensin II Type 1 receptor (AT1 receptor) promotes its activation, leading to vasoconstriction, sympathetic activity and aldosterone release from adrenals, ultimately increasing blood pressure [ 11 ]. Angiotensin II also regulates renal growth during fetal development [ 12 ].

Herein, we report a rare nonsense variant in the AGTR1 gene detected through whole genome sequencing (WGS) in a neonate exhibiting persistent anuria and resistant refractory pulmonary hypoplasia, ultimately resulting in early lethality.

The female patient, born to consanguineous parents (first degree cousins) with a family history of Oculocutaneous Albinism in the mother. This was the mother’s first pregnancy and antental ultrasound scans revealed oligohydramnios and Intra-Uterine Growth Retardation (IUGR). The patient was born prematurely at 36 weeks through an emergency cesarean section due to reduced fetal movement and failed induction. The baby was born weighing 2.0 kg with meconium stained liquor and Apgar scores were 6 and 9 at one and five minutes, respectively. The baby required minimal resuscitation and she was managed on continuous positive airway pressure (CPAP) in the first hour of life; however, within a few hours she deteriorated with bilateral pneumothoraces requiring chest drains, intubation, and ventilation. The patient was started on inhaled nitric oxide for hypoxic respiratory failure, and inotropes due to low blood pressure including dopamine, dobutamine, and epinephrine. The patient remained hypotensive with a mean blood pressure of 15–20 mmHg, which required the addition of hydrocortisone followed by vasopressin to improve her blood pressure. Her oxygen saturation measurements were 35%—45% in 100% FiO 2 . Supportive measures, including sedation, antibiotics, and fluids were administered. The patient didn’t have any urine output and she developed persistent hypoxia and hypotension, necessitating veno-arterial Extra Corporeal Membrane Oxygenation (ECMO) support on the second day of life, which led to an improvement in her oxygen saturation. However, the patients blood pressure remained low despite the ECMO and continuous inotropic support. While on ECMO, renal replacement therapy (CRRT) was initiated, effectively normalzing the creatinine levels, however the CRRT was discontinued due to the development of hypotension, resulting in progressive edema and fluid overload. Subsequently, the decision was made to decannulate and remove the ECMO support due to a substantial right-sided parenchymal hemorrhage and extra-axial hemorrhage observed on head ultrasound. The patient experienced coagulopathy, manifesting as oozing from the skin and chest tubes requiring multiple Fresh Frozen Plasma (FFP), cryoprecipitate, and red cell transfusions due to low hemoglobin, persistent thrombocytopenia and coagulopathy. On the fourth day, a multi-disciplinary team meeting, with the patient’s parents present, concluded to transition the patient from intensive care to comfort care with no further resuscitation. The patient was extubated the following day and passed away a few hours later.

Imaging studies that were done on the baby included: (1) Echocardiography, which showed a structurally normal heart but was associated with severe persistent pulmonary hypertension of newborn (PPHN) and complete right to left shunting across the ductus arteriosus; (2) Abdominal ultrasound, which showed non-specific bilateral echogenic kidneys; (3) Head ultrasound, which showed large left intra-parenchymal and extra-axial acute bleeding associated with mass effect.

The post-mortem examination revealed mildly hypoplastic kidneys, moderate pulmonary hypoplasia, solid and poorly aerated lungs with diffuse alveolar damage, significantly reduced skull vault mineralization and bony development, indicative features of oligohydramnios sequence. Limbs exhibited some flexion changes, and there were characterestics findings of of Potters’ facies, marked edema, and a structurally normal heart. Histopathology showed changes of renal tubular dysgenesis with the renal cortex containing crowded glomeruli separated by small tubules with distal tubular morphology and absence of proximal tubules (Fig.  1 ). The proximal tubules should be as numerous as the glomeruli and have plump lining cells with abundant cytoplasm. The medulla appeared largely unremarkable. The family history of parental consanguinity and the severity of symptoms prompted enrolling the family in the Mendelian disease program at Sidra Medicine (Fig.  2 a) [ 13 ]. Genome sequencing was performed on all family members, and following our in-house analysis pipeline [ 14 ], the patient was, initially, found to carry six de novo and nine homozygous rare protein-altering variants, including two that were predicted to lead to loss-of-function (LoF) (Additional file 1 ). These two include a variant in OR1J4 (c.221C > G, p.Ser74*), an olfactory receptor gene not known to be associated with Mendelian disease, and a nonsense previously unreported variant (NM_000685.5; c.415C > T; p.Arg139*) was identified in the Angiotensin II Receptor Type 1 (AGTR1) gene (Table  1 ). Importantly, LoF variants in this gene have been associated with renal tubular dysgenesis (MIM# 267,430) [ 8 ]. Both parents were heterozygous carriers of the variant (Fig.  2 b) and in-silico pathogenicity scores predicted it to be highly damaging (CADD of 39 and GERP of 5.8).

Renal histological characteristics. a H&E renal cortex, showing crowding of the glomeruli, with intervening tubules mainly of distal tubule type, and lack of proximal tubules. b CD10 highlighting the glomeruli and the Bowmans capsule, but normal proximal tubules are not seen, only weak staining of the ureteric buds

Patient characteristics and genetic findings. a Family pedigree of the patient along with genotypes of the nonesense AGTR1 variant (c.415C > T; p.Arg139*). b Chromatogram of Sanger sequencing showing the variant position and genotypes of the 3 family members. c Schematic of AGTR1 gene body with highlights of protein domains and reported ClinVar variants. The yellow stars refer to the staring system of ClinVar which indicate the review status of the variant

Discussion and conclusion

The molecular mechanisms underlying the genetic basis of RTD pathogenesis are still not fully elucidated; however, LoF/structural variants in genes encoding components of the RAS pathway are a major cause of the disease [ 8 ]. Disruption of the RAS leads to defects in the differentiation of proximal tubules during fetal development resulting in severe symptoms during pre- and postnatal periods including fetal anuria and oligohydramnios [ 15 ].

In this report, we present a case of a newborn female patient who suffered from congenital RTD and several severe complications, ultimately resulting in perinatal death at five days of life. Genetic analysis of the child and her parents identified a pathogenic nonsense variant in exon 3 of the AGTR1 gene. The predicted effects of this variant are protein truncation and possibly nonsense-mediated mRNA decay. To date, only eight RTD patients, including ours, have been reported with five different AGTR1 gene variants (Table  1 , Fig.  2 c), reflecting the rare nature of RTD and the significance of RAS signaling pathway in early development.

The genetic association of AGTR1 variants with an RTD phenotype is supported by the literature in which patients suffer severe symptoms during pre-and/or postnatal life [ 8 , 9 ]. In addition, recent evidence has pointed to the possibility of a milder form of the RTD depending on the variant position in the AGTR1 gene [ 16 ]. A male carrier of a homozygous LoF variant (p.Arg216*) in AGTR1 has been described who lived to 28 years of age under management with high doses of fludrocortisone which, along with vasopressin, have proved effective in managing RTD [ 16 ]. Overall, although the severity of symptoms in patients who carry AGTR1 mutations is consistent across all reported cases, it has been suggested that, similar to other genetic renal diseases, the phenotype is more severe when the affected protein is located more distally along the RAS pathway [ 17 ].

Reaching a final diagnosis of RTD prenatally has been challenging because all prenatal symptoms of oligohydramnios, and IUGR are not specific. This challenge leaves genetic testing as the only viable diagnostic option after none genetic causes have been excluded [ 18 ], particularly when offered in the context of prenatal diagnosis through chorionic villus sampling. Even when early symptoms began to emerge postnatally, the patient's instability did not indicate a specific diagnosis. The genetic finding complemented by the histopathology confirmed the diagnosis of RTD. Although the treatment remained supportive, providing prompt answers to healthcare providers and families is immensely valuable.

Given the severity of the condition, improved outcomes for RTD patients can be realized through early detection, facilitating clinical decision making and enhancing neonatal care, particularly in cases of severe congenital diseases with prenatal indications and symptoms. Genetic testing empowers carrier parents to make informed decisions regarding their future family plans. In the case of the newborn discussed here, the parents received appropriate counselling and were informed about the genetic results, and the disease risk in subsequent pregnancies. Early identification of recessive pathogenic variants, particularly in such highly consanguineous population, plays a pivotal role in the success of population screening programs and contributes to lowering the long-term burden of Mendelian diseases.

Availability of data and materials

The datasets analysed during the current study are available in the Genome Sequence Archive in Sidra Medicine, Qatar. Variant submitted in ClinVar under accession number VCV002430252.2.

Abbreviations

Angiotensin-converting enzyme

Angiotensin II Receptor Type 1

Continuous positive airway pressure

Renal replacement therapy

Extra Corporeal Membrane Oxygenation

Intra-uterine growth retardation

Persistent pulmonary hypertension of newborn

Renin angiotensin system

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Acknowledgements

We are grateful to the families and individuals who participated in this study.

This work was supported by Qatar Foundation, National Priorities Research Program (NPRP11S-0110–180250).

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Laboratory of Genomic Medicine, Sidra Medicine, P.O. Box 26999, Doha, Qatar

Aljazi Al-Maraghi, Waleed Aamer, Elbay Aliyev, Najwa Elbashir, Sura Hussein, Sasirekha Palaniswamy & Khalid A. Fakhro

Department of Human Genetics-Precision Medicine in Diabetes Prevention, Sidra Medicine, P.O. Box 26999, Doha, Qatar

Mubarak Ziab, Ammira A.S.Akil & Khalid A. Fakhro

Neonatology Division, Sidra Medicine, P.O. Box 26999, Doha, Qatar

Dhullipala Anand

Genetic Pathology, Sidra Medicine, P.O. Box 26999, Doha, Qatar

Donald R. Love

Anatomical Pathology, Sidra Medicine, P.O. Box 26999, Doha, Qatar

Adrian Charles

College of Health and Life Sciences, Hamad Bin Khalifa University, P.O. Box 34110, Doha, Qatar

Khalid A. Fakhro

Department of Genetic Medicine, Weill Cornell Medical College, P.O. Box 24144, Doha, Qatar

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Contributions

A. A. conducted genetic analysis and literature searches, taking the lead in writing the manuscript. W. A. played a key role in Whole Genome Sequence acquisition and manuscript drafting. A. D. contributed to clinical data collection and provided support to the patient. M. Z. and D. R. L. performed variant validation, while J. L. and S. H. were involved in patient enrollment and sample processing. E. A. performed structural variant analysis and reviewed the manuscript. D. R. L. offered clinical interpretation of genetic findings, and S. P. managed follow-up and reporting. A. C. provided images and description of renal histopathology. A. A. K. oversaw the original study, supervised patient recruitment, and handled manuscript review, editing, and regulatory requirements. K. A. F. secured funding, designed the study, coordinated the overall process, and conducted final proofreading and critical manuscript review. All authors participated in reading and approving the final manuscript.

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Correspondence to Khalid A. Fakhro .

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The institutional review board approval of this study was obtained from Sidra Medicine, Qatar (IRB 1636872). Furthermore, the family members signed informed consent and assent forms to participate in the proposed research study.

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We obtained written informed consent from the patient’s father to publish this potentially identifiable information from all of the family members included in this case report.

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Al-Maraghi, A., Aamer, W., Ziab, M. et al. A loss-of-function AGTR1 variant in a critically-ill infant with renal tubular dysgenesis: case presentation and literature review. BMC Nephrol 25 , 139 (2024). https://doi.org/10.1186/s12882-024-03569-z

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Efficacy and safety of direct oral anticoagulants in patients with atrial fibrillation combined with chronic kidney disease: a systematic review and meta-analysis

• Yaodi Li 1   na1 ,
• Shuyi Wu 1   na1 ,
• Jintuo Zhou 1   na1 &
• Jinhua Zhang   ORCID: orcid.org/0000-0002-5629-0348 1  

Thrombosis Journal volume  22 , Article number:  40 ( 2024 ) Cite this article

Metrics details

Currently published studies have not observed consistent results on the efficacy and safety of direct oral anticoagulants (DOACs) use in patients with chronic kidney disease (CKD) combined with atrial fibrillation (AF). Therefore, this study conducted a meta-analysis of the efficacy and safety of DOACs for patients with AF complicated with CKD.

Database literature was searched up to May 30, 2023, to include randomized controlled trials (RCT) involving patients with AF complicated with CKD DOACs and vitamin K antagonists (VKAs). Stroke, systemic embolism (SE), and all-cause mortality were used as effectiveness indicators, and major bleeding, intracranial hemorrhage (ICH), fatal bleeding, gastrointestinal bleeding (GIB), and clinically relevant non-major bleeding (CRNMB) were used as safety outcomes.

Nine RCT studies were included for analysis according to the inclusion criteria. Results of the efficacy analysis showed that compared with VKAs, DOACs reduced the incidence of stroke/SE (OR = 0.75, 95% CI 0.67–0.84) and all-cause deaths (OR = 0.84, 95% CI 0.75–0.93) in patients with AF who had comorbid CKD. Safety analyses showed that compared with VKAs, DOACs improved safety by reducing the risk of major bleeding (OR = 0.76, 95%CI 0.65–0.90), ICH (OR = 0.46, 95%CI 0.38–0.56), and fatal bleeding (OR = 0.75, 95%CI 0.65–0.87), but did not reduce the incidence of GIB and CRNMB.

Compared with VKAs, DOACs may increase efficacy and improve safety in AF patients with CKD (90 ml/min> Crcl≥15 ml/min), and shows at least similar efficacy and safety in AF patients with Kidney failure (Crcl<15 ml/min).

Introduction

Published studies have yielded inconsistent findings regarding the effectiveness and safety of DOACs in patients with AF and CKD. Patients with atrial fibrillation (AF) are susceptible to stroke or thromboembolic events due to increased heart rate, enlarged atria, and the special structure of the left atrium, which can lead to stagnation of blood flow [ 1 ]. To prevent thromboembolism, oral anticoagulants (OACs), including VKAs and direct oral anticoagulants (DOACs), are one of the preferred treatments for patients at risk of thromboembolism [ 2 ]. Compared with warfarin, DOACs is gradually being widely used in the clinic because of its fixed-dose, shorter half-life, and rapid elimination after discontinuation [ 3 ]. In addition, it has been shown that compared with warfarin, DOACs used in patients with atrial fibrillation with normal renal function can lead to a significant reduction in the risk of thrombosis and hemorrhage [ 4 , 5 ], and the efficacy and safety have been clinically proven to be superior to that of warfarin [ 6 , 7 ].

VKAs are metabolized by the liver and no dose adjustment is required in renal insufficiency. In contrast, DOACs has varying degrees of renal clearance, with approximately 80% of dabigatran, 50% of edoxaban, 35% of rivaroxaban, and 27% of apixaban excreted [ 8 ]. Owing to the exclusion of patients with advanced-stage CKD from phase 3 clinical trials of DOACs, the utilization of DOACs has lagged behind in this specific population. In dialysis patients, the utilization of VKAs poses heightened risks such as renal calcification and diminished platelet production due to renal failure, thus increasing the likelihood of bleeding within the typical INR range compared to the general population. Patients undergoing hemodialysis are subject to systemic heparin anticoagulant therapy during the treatment period. However, studies assessing bleeding complications in hemodialysis patients treated with AVKs or DOACs have not taken into consideration the extent of heparinization during hemodialysis treatment. Therefore, the efficacy and safety of DOACs in AF patients combined with CKD, particularly in cases involving kidney failurehas been controversial. The current literature review indicates that, in patients with moderate CKD, dabigatran and apixaban exhibit superior efficacy over VKAs in reducing the incidence of stroke and systemic embolism. However, no statistically significant differences emerge between apixaban, rivaroxaban, and VKAs in this regard. In terms of major bleeding risk reduction, edoxaban, apixaban, and VKAs demonstrate more favorable outcomes compared to VKAs alone. Conversely, no notable distinction is observed between rivaroxaban and dabigatran etexilate in this aspect [ 9 ]. A meta-analysis conducted by T. Ha et al. found insufficient evidence to determine the superiority of VKAs or DOACs in AF patients with advanced CKD [ 10 ]. Another study showed that DOACs were not associated with a reduced risk of thromboembolism in AF patients on long-term dialysis, whereas VKAs, dabigatran, and rivaroxaban were associated with a significantly higher risk of bleeding compared with apixaban and no anticoagulants [ 11 ]. However, one study showed that DOACs was significantly more effective and safer than VKAs in patients with CKD or ESRD combined with AF [ 12 ]. In addition, a meta-analysis of the use of DOACs and VKAs in end-stage dialysis patients showed at least similar efficacy and safety [ 13 ].

Therefore, to better investigate the efficacy and safety of DOACs use in patients with CKD combined with AF, the present study conducted a systematic review and meta-analysis of the available evidence from randomized controlled trials (RCTs) to inform clinical medication decisions.

We conducted a systematic review and meta-analysis of DOACs and VKAs for patients with AF comorbid CKD. CKD is defined as abnormalities of kidney structure or function, present for > 3 months, with implications for health. CKD is classified based on Cause, GFR category (G1–G5), and Albuminuria category (A1–A3) [ 14 ]. Renal insufficiency was defined as patients with CrCl < 95 ml/min, and patients with CrCl < 15 ml/min were defined as patients with kidney failure [ 15 ]. This study was conducted under the Preferred Reporting Initiative (PRISMA), registration number: CRD42023451323 [ 16 ].

Search strategies

The PubMed and Web of Science databases were searched and the time frame was from the creation of the database to May 31, 2023. To ensure a comprehensive literature search, we also identified additional studies by searching the reference lists of the literature. Search words: (“dabigatran” or “rivaroxaban” or “apixaban” or “edoxaban” or “NOAC” or “DOAC” or “non-vitamin K antagonist oral anticoagulantacting” or “novel oral anticoagulant” and “warfarin” or “coumadin” or “vitamin K antagonist”) and (“renal insufficient” or “kidney disease” or “chronic renal insufficiency” or “end-stage renal disease” or “renal dialysis or hemodialysis” and “atrial fibrillation” or “kidney failure”). Detailed search strategies for each database are provided in Table S 1 .

Study selection

Inclusion criteria: (1) RCT; (2) The study was conducted in AF patients with CKD; (3) DOACs, including comparative studies of apixaban, rivaroxaban, edoxaban, and dabigatran with VKAs. Both control and experimental groups reported at least one bleeding or thrombosis occurrence data; (4) Full text was available and relevant data could be extracted.

Exclusion criteria: (1) Patients with AF not comorbid with CKD; (2) Duplicate studies or incomplete experimental data.

Data extraction and study outcomes

Data extraction was done independently by two researchers (YL and SW). If there was a dispute, it will be discussed and resolved by a third researcher (JZ) to reach a consensus. Regarding missing data, we endeavor to communicate with the authors of the primary studies in an effort to obtain any unavailable data. If this proves unfeasible, we resort to the exclusion of studies with missing data. It is crucial to note, however, that this exclusionary approach may introduce selection bias if the missing data not missing completely at random. Furthermore, to ensure the reliability and robustness of our findings, we undertake a sensitivity analysis, scrutinizing the impact of varying scenarios on our results.

The following data were extracted from each study: study information (authors, year of publication), study characteristics (study population, sample size, duration of follow-up), intervention, and outcome indicators. Efficacy indicators were stroke, SE, and all-cause deaths. Safety indicators were major bleeding, intracranial hemorrhage (ICH), fatal bleeding, gastrointestinal bleeding (GIB), clinically relevant nonmajor bleeding (CRNMB), and minor bleeding.

Quality assessment

Using the Cochrane Collaboration Risk Assessment Tool [ 17 ], two authors independently evaluated each paper for bias in seven areas: generation of randomized sequences, allocation concealment, blinding of subjects and investigators, blinding of outcome evaluations, completeness of outcome data, selective reporting of outcomes, and other biases. The level of risk of bias was evaluated as “high”, “low”, and “unclear”. If there is a dispute, another researcher (JZ) will evaluate it and help to solve the problem.

Statistical analysis

Data on the incidence of all-cause death, stroke, SE, major bleeding, ICH, fatal bleeding, GIB, CRNMB, and minor bleeding were extracted for the inclusion of the experimental group and the control group. Forest plots were made using Review Manager 5.3 software. P -value, odds ratio (OR), and 95% confidence interval (Cl) were used as indicators of statistical differences in the comparison of the two groups. P -value < 0.05 and 95% Cl not containing 1 were considered as statistically significant differences. Statistical heterogeneity of the included studies was assessed using the Cochrane q-test p -value and I ² statistic, where a Cochrane q-test p -value < 0.1 or I ² value > 50% indicated significant heterogeneity. Fixed-effected model was used to calculate the pooled ORs and its 95% confidence interval (CI) if q-test p -value > 0.10 and I 2  < 50%. Otherwise, the random-effect model was applied.

Sensitivity analyses and subgroup analyses were also performed to look for sources of heterogeneity. In secondary analyses, data on dabigatran were excluded and the meta-analysis was re-run considering that the direct thrombin inhibitor dabigatran has the highest rate of renal excretion and renal function has a greater impact on it. In addition, to analyze whether DOACs and renal function levels affect the study indexes, subgroup analyses were performed according to the type of DOACs and the level of renal function of the patients. Since less than ten papers were included in this study, publication bias detection was not performed.

Literature search

According to the search strategy, a total of 2997 papers were included, 695 duplicates were removed, and 500 papers of special types (review, case, letter, guideline, comment, animal) were removed. After reading the titles and abstracts and removing uncontrolled studies, reviews, and literature that could not be accessed in full text, the remaining 55 could be downloaded in full text for reading. After removing 25 of the cohort studies, as well as 21 of the literature with incomplete data that could not be extracted as relevant, and 1 of the literature with data that could not be transformed [ 18 ], the remaining 9 randomized controlled studies were included in the meta-analysis [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ] The flow chart for inclusion in the study is shown in Fig. 1 .

Flow chart for inclusion of studies

Baseline characteristics of included studies

The baseline characteristics of the included studies are shown in Table 1 . Nine randomized controlled studies with 15 subgroups were included in this study. The experimental group drugs DOACs included apixaban [ 19 , 25 , 26 , 27 ], rivaroxaban [ 20 , 22 , 24 ], dabigatran [ 21 ], and edoxaban [ 23 ]. The control drugs were dose-adjusted VKAs with INR values controlling between 2 and 3 except in literature where the control drug was warfarin (or matching placebo) [ 19 ] or phenprocoumon [ 27 ]. A total of 47,298 people were included, including 26,245 in the DOACs group and 21,053 in the VKAs group Table 2 .

Nine articles were at low risk for randomized sequence generation, completeness of outcome data, selective reporting of results, and other biases. Three articles were at high risk for allocation concealment and two were unclear. Three articles were at high risk for blinding of subjects and investigators, and one article was unclear about blinding of results (Fig. 2 ).

Risk of bias in each study. Green, low risk of bias; yellow, unclear risk of bias; and red, high risk of bias

Trial sequential analysis

Trial Sequential Analysis (TSA) was conducted in this study for various outcome indicators. A two-sided type I error probability (α) of 0.05 and type II error probability (β) of 0.20 were established, along with the definition of the Required Information Size (RIS). The control group’s incidence was computed using the data from the included studies. The TSA results showed the cumulative Z curves for stroke or SE, ICH and fetal bleeding crossed both the conventional and TSA boundaries and reached the the required information size (RIS), indicating that the meta-analysis results were stable and statistically significant (Fig. 3 C, F, J). The cumulative Z curves for all-cause death and major bleeding crossed the traditional threshold and TSA threshold, further confirming the credibility of the synthesized data (Fig. 3 D, E). The cumulative Z curves for stroke, minor bleeding, GIB crossed conventional test boundary; however, they did not cross Alpha-spending boundary, nor did it reach the required information size (Fig. 3 A, I, G). And the cumulative Z curves for SE and CRNMB did not cross trial sequential monitoring boundaries, and the sample size did not reach the RIS, suggesting no conclusive evidence to support a statistically significant difference in reducing SE and CRNMB, and larger randomized controlled trials are warranted to further investigate these outcomes (Fig. 3 B, H).

TSA results for various outcome measures in AF patients with CKD treated with DOACs versus VKAs. A stroke, B SE, C stroke or SE, D all-cause deaths, E major bleeding, F ICH, G GIB, H CRNMB, I minor bleeding, J fetal bleeding

Efficacy analysis

Comparison of efficacy metrics for stroke, SE, and all-cause death between DOACs and VKAs groups.

4 studies with a total of 6 data sets compared stoke, resulting in a 21% reduction in incidence with DOACs, although there was no statistically significant difference ( P  = 0.008, OR = 0.79, 95% CI 0.67–0.94) and no significant heterogeneity between groups ( P  = 0.35, I 2  = 10%) (Fig. 4 ).

Three studies with a total of 5 data sets compared SE, resulting in a 33% reduction in the incidence of DOACs, although there was no statistically significant difference in the results ( P  = 0.25, OR = 0.67, 95%CI 0.34–1.32), and there was no significant heterogeneity between the groups ( P  = 0.63, I 2  = 0%) (Fig. 5 ).

Forest plot for stroke in AF patients with CKD treated with DOACs versus VKAs. c1: CrCl 30-50 ml/min, edoxaban 30 mg daily; c2: CrCl 50-95 ml/min, edoxaban 60 mg daily; d1: CrCl＜15 ml/min, rivaroxaban 10mg daily; d2: CrCl＜15 ml/min, rivaroxaban and vitamin K2

There were 4 studies with a total of 8 data sets comparing stroke or SE. DOACs reduced the incidence by 25% compared with VKAs, a statistically different result ( P  < 0.001, OR = 0.75, 95% CI 0.67–0.84), with no heterogeneity between groups ( P  = 0.07, I 2  = 46%) (Fig. 6 ).

Forest plot for SE in AF patients with CKD treated with DOACs versus VKAs. c1: CrCl 30-50 ml/min, edoxaban 30 mg daily; c2: CrCl 50-95 ml/min, edoxaban 60 mg daily; d1: CrCl＜15 ml/min, rivaroxaban 10mg daily; d2: CrCl＜15ml/min, rivaroxaban and vitamin K2

Forest plot for stroke or SE in AF patients with CKD treated with DOACs versus VKAs. a1: CrCl 51-80 ml/min, apixaban 5 mg twice daily or 2.5 mg twice daily; a2: CrCl≤50 ml/min, apixaban 5 mg twice daily or 2.5 mg twice daily; b1: CrCl 50-80 ml/min, dabigatran 110 mg twice daily; b2: CrCl 50-80 ml/min, dabigatran 150 mg twice daily; b3: CrCl 30-49 ml/min, dabigatran 110 mg twice daily; b4: CrCl 30-49 ml/min, dabigatran 150 mg twice daily

A total of 13 data sets from 7 studies compared all-cause deaths. The results were statistically significant when comparing the DOACs group to the VKAs group, with a 16% reduction in incidence with DOACs ( P  = 0.0007, OR = 0.84, 95% CI 0.75–0.93), with heterogeneity between groups ( P  = 0.01, I 2  = 53%) (Fig.  7 ).

Forest plot for all-cause deaths in AF patients with CKD treated with DOACs versus VKAs. a1: CrCl 51–80 ml/min, apixaban 5 mg twice daily or 2.5 mg twice daily; a2: CrCl ≤ 50 ml/min, apixaban 5 mg twice daily or 2.5 mg twice daily; b1: CrCl 50–80 ml/min, dabigatran 110 mg twice daily; b2: CrCl 50–80 ml/min, dabigatran 150 mg twice daily; b3: CrCl 30–49 ml/min, dabigatran 110 mg twice daily; b4: CrCl 30–49 ml/min, dabigatran 150 mg twice daily; c1: CrCl 30–50 ml/min, edoxaban 30 mg daily; c2: CrCl 50–95 ml/min, edoxaban 60 mg daily; d1: CrCl<15 ml/min, rivaroxaban 10 mg daily; d2: CrCl<15 ml/min, rivaroxaban and vitamin K2

Safety analysis

Safety metrics such as major bleeding, ICH, and fatal bleeding were compared between the DOACs and VKAs groups.

A total of 9 studies with 15 data sets compared the incidence of major bleeding and the results were statistically different. DOACs compared with VKAs reduced the incidence by 24% ( P  = 0.001, OR = 0.76, 95%CI 0.65–0.90), and there was heterogeneity between the groups ( P  < 0.001, I 2  = 73%) (Fig. 8 ).

Forest plot for major bleeding in AF patients with CKD treated with DOACs versus VKAs. a1: CrCl 51–80 ml/min, apixaban 5 mg twice daily or 2.5 mg twice daily; a2: CrCl ≤ 50 ml/min, apixaban 5 mg twice daily or 2.5 mg twice daily; b1: CrCl 50–80 ml/min, dabigatran 110 mg twice daily. b2: CrCl 50–80 ml/min, dabigatran 150 mg twice daily. b3: CrCl 30–49 ml/min, dabigatran 110 mg twice daily; b4: CrCl 30–49 ml/min, dabigatran 150 mg twice daily; c1: CrCl 30–50 ml/min, edoxaban 30 mg daily; c2: CrCl 50–95 ml/min, edoxaban 60 mg daily; d1: CrCl<15 ml/min, rivaroxaban 10 mg daily; d2: CrCl<15 ml/min, rivaroxaban and Vitamin K2

A total of 6 studies with 10 data sets compared ICH incidence. There was a significant difference between the two groups, with DOACs reducing the incidence by 54% ( P <0.001, OR = 0.46, 95%CI 0.38–0.56) and no heterogeneity between groups ( P  = 0.25, I 2  = 20%) (Fig. 9 ).

Forest plot for ICH in AF patients with CKD treated with DOACs versus VKAs. b1: CrCl 50–80 ml/min, dabigatran 110 mg twice daily. b2: CrCl 50–80 ml/min, dabigatran 150 mg twice daily. b3: CrCl 30–49 ml/min, dabigatran 110 mg twice daily; b4: CrCl 30–49 ml/min, dabigatran 150 mg twice daily; c1: CrCl 30–50 ml/min, edoxaban 30 mg daily; c2: CrCl 50–95 ml/min, edoxaban 60 mg daily

A total of 5 studies with 10 datasets compared the incidence of fatal bleeding and there was a significant difference between the two groups, with DOACs reducing the incidence by 25% ( P  < 0.001, OR = 0.75, 95%CI 0.65–0.87). There was no heterogeneity between the groups ( P  = 0.44, I 2  = 0%) (Fig. 10 ).

Forest plot for fetal bleeding in AF patients with CKD treated with DOACs versus VKAs. b1: CrCl 50–80 ml/min, dabigatran 110 mg twice daily. b2: CrCl 50–80 ml/min, dabigatran 150 mg twice daily. b3: CrCl 30–49 ml/min, dabigatran 110 mg twice daily; b4: CrCl 30–49 ml/min, dabigatran 150 mg twice daily; c1: CrCl 30–50 ml/min, edoxaban 30 mg daily; c2: CrCl 50–95 ml/min, edoxaban 60 mg daily; d1: CrCl<15 ml/min, rivaroxaban 10 mg daily; d2: CrCl<15 ml/min, rivaroxaban and Vitamin K2

A total of 4 studies with 6 data sets compared GIB, with no significant difference between the two groups ( P  = 0.01, OR = 1.30, 95% CI 1.07–1.58) and no heterogeneity between the groups ( P  = 0.35, I 2  = 10%) (Fig. 11 ).

Forest plot for GIB AF patients with CKD treated with DOACs versus VKAs. c1: CrCl 30–50 ml/min, edoxaban 30 mg daily; c2: CrCl 50–95 ml/min, edoxaban 60 mg daily; d1: CrCl<15 ml/min, rivaroxaban 10 mg daily; d2: CrCl<15 ml/min, rivaroxaban and Vitamin K2

A total of 3 studies with 3 data sets compared CRNMB. There was no significant difference between the two groups ( P  = 0.83, OR = 0.99, 95% CI 0.88–1.11) and no heterogeneity between groups ( P  = 0.80, I 2  = 0%). Forest plot results (Fig. 12 ).

Forest plot for CRNMB in AF patients with CKD treated with DOACs versus VKAs

A total of 2 studies with 4 sets of data compared minor bleeding. DOACs reduced the incidence by 13%, statistically different between the two groups ( P  = 0.03, OR = 0.87, 95% CI 0.77–0.99), with no heterogeneity between the groups ( P  = 0.39, I 2  = 0%) (Fig. 13 ).

Forest plot for minor bleeding in AF patients with CKD treated with DOACs versus VKAs. c1: CrCl 30-50 ml/min, edoxaban 30 mg daily; c2: CrCl 50-95 ml/min, edoxaban 60 mg daily; d1: CrCl＜15 ml/min, rivaroxaban 10mg daily; d2: CrCl＜15 ml/min, rivaroxaban and Vitamin K2

Sensitivity analysis

There was heterogeneity in all-cause deaths. Further sensitivity analyses showed a decrease in I 2 from 53 to 32% after the removal of the Hijazi et al. 2014c group [ 21 ], indicating that the CrCl 30–50 ml/min dabigatran 110 mg group was a possible source of heterogeneity in the all-cause deaths.

There was heterogeneity in the incidence of major bleeding. Further sensitivity analyses showed a decrease in I 2 from 73 to 55% after removal in the Hohnloser et al. 2012, a1 group [ 19 ], from 73 to 68% after removal in the Hohnloser et al. 2012, a2 group [ 19 ], and from 73 to 19% after simultaneous removal in both groups, which suggests that there is a possible source of heterogeneity in major bleeding in the apixaban group.

Subgroup analysis

For AF patients with CKD, subgroup analyses performed differently for DOACs showed that rivaroxaban and apixaban were superior in reducing all-cause deaths compared with VKAs, with rivaroxaban reducing the incidence by 25% ( P  = 0.01, OR = 0.75, 95% CI 0.60–0.93) and apixaban reducing the incidence by 29% ( P  < 0.001, OR = 0.71, 95% CI 0.62–0.81). There was no statistical difference between edoxaban and dabigatran ( P  = 0.09; P  = 0.44). There was heterogeneity between groups ( P  = 0.1, I 2  = 51.7%), suggesting that different DOACs may be a source of heterogeneity (Figure S 1 ).

Subgroup analyses of AF patients with kidney failure differing for DOACs showed that neither rivaroxaban nor apixaban reduced the incidence of all-cause deaths compared with VKAs (Figure S 2 ).

Subgroup analysis showed that DOACs reduced all-cause deaths in patients with CrCl 50–95 ml/min with heterogeneity between groups ( P <0.001, OR = 0.82, 95% CI 0.75–0.90, I 2  = 51%), and did not reduce all-cause deaths in patients with CrCl < 30 ml/min. There was no heterogeneity between groups ( P  = 0.69, I 2  = 0%) (Figure S 3 ).

For AF patients with CKD, subgroup analyses differing according to DOACs showed that apixaban significantly reduced the incidence of major bleeding compared with VKAs ( P  < 0.001, OR = 0.47, 95% CI 0.34–0.64); edoxaban reduced the incidence of major bleeding by 18% ( P  = 0.02, OR = 0.82, 95% CI 0.70–0.97), and no significant difference between rivaroxaban and dabigatran ( P  = 0.95; P  = 0.14). Heterogeneity existed between the different DOACs study groups ( P  = 0.0004, I 2  = 83.7%), suggesting that the different DOACs may be the source of the heterogeneity in major bleeding (Figure S 4 ).

Subgroup analysis of AF patients with Kidney failure with different DOACs showed that neither rivaroxaban nor apixaban reduced the incidence of major bleeding compared with VKAs (Figure S 5 ).

Subgroup analyses based on renal function levels showed that, in terms of major bleeding, compared with VKAs, DOACs reduced the incidence by 21% in patients with CrCl 50–95 ml/min ( P  = 0.02, OR = 0.79, 95% CI 0.64–0.96); by 67% in patients with CrCl 15–29 ml/min (OR 0.33, 95% CI 0.13–0.80). There was no significant difference in patients with CrCl 30–49 ml/min and CrCl < 15 ml/min ( P  = 0.28; P  = 0.18). There was no heterogeneity between groups for different renal function subgroups ( P  = 0.20, I 2  = 34.8%) (Figure S 6 ).

The current study shows that in patients with AF combined with CKD, DOACs may be able to reduce the incidence of stroke and SE as well as all-cause deaths compared with VKAs in terms of efficacy. In terms of safety, it may reduce the incidence of major bleeding, ICH, fatal bleeding, and minor bleeding, and may not reduce the incidence of GIB and CRNMB. Subgroup analyses showed that [ 1 ] in AF patients with comorbid CKD (90 ml/min> Crcl≥15 ml/min), apixaban and rivaroxaban reduced all-cause deaths, apixaban and dabigatran reduced the incidence of stroke or SE, apixaban and edoxaban reduced the incidence of major bleeding, and edoxaban and dabigatran reduced ICH and fatal bleeding, compared to VKAs [ 2 ]. In AF patients with comorbid kidney failure, there were no significant differences in the efficacy and safety of rivaroxaban compared with VKAs, except for an advantage in reducing stroke and fatal bleeding, while there were no significant differences in the efficacy and safety of apixaban. Upon excluding direct thrombin inhibitors, specifically dabigatran, the analysis revealed that inhibitors targeting thrombin and factor X can further diminish the occurrence of stroke or systemic embolism, all-cause mortality, massive bleeding, and fatal bleeding in patients with CKD.

In this study, we found that apixaban and dabigatran were superior to VKAs in reducing stroke and SE in patients with CKD and that there was no significant difference between rivaroxaban and edoxaban compared with VKAs. Apixaban and edoxaban reduced the risk of major bleeding significantly compared to VKAs, which is similar to the findings of Feldberg et al. [ 9 ], but when compared to VKAs, edoxaban and dabigatran had a significant advantage in reducing ICH and fatal bleeding, and rivaroxaban and apixaban had a significant advantage in reducing all-cause deaths, which was not reported by Feldberg et al. The study conducted by Feldberg et al. included only six RCTs, evaluated only stroke, SE, and hemorrhage, and included aspirin in addition to VKAs in the control group. In contrast, this paper uses 9 RCTs, all of which were conducted in patients with AF, and all of which had VKAs including warfarin as the control drug, making the results more comparable. Comparison with the analysis of Kuno et al. [ 11 ] in terms of efficacy. In terms of safety, Kuno et al. concluded that the use of anticoagulants increased the risk of bleeding in dialysis patients, whereas our study showed a similar risk of bleeding. The reason for this may be that Kuno et al. included 16 observational studies, which considered dialysis patients excluded from RCT trials, only 2 studies out of 16 combined AF, and there was a high degree of heterogeneity in the studies. In contrast, 3 RTC trials were included in our study of dialysis patients. RCT trials have strict nadir criteria and the level of evidence for their results is higher than that of observational studies. A study by Chen et al. showed that DOACs was significantly more effective and safer than warfarin in patients with CKD combined with AF [ 12 ]. The study by Chen et al. included 6 RCTs and 19 observational studies; there were no RCTs for Kidney failure, and 2 of these studies reported on venous thromboembolism populations non-AF populations. Whereas our article used all RCT studies with a high level of evidence, including 3 RCTs with a CrCl < 15 ml/min. Secondly, Chen et al. analyzed stroke, SE, and VTE together as the same efficacy outcome, which may introduce bias due to the differences in pathomechanisms of SE and VTE. Chen et al. did not conduct further subgroup analysis based on renal function staging and failed to analyze the effectiveness and safety of kidney failure combined with AF patients. The preceding meta-analysis, concentrating on end-stage patients, aligns with our study’s findings [ 13 ]. Li et al.‘s investigation encompassed one randomized controlled trial and five observational studies. Despite our inclusion of three randomized controlled trials, it is noteworthy that due to recruitment challenges in some of these trials, the level of evidence in our study did not surpass that of Li et al.‘s. Both investigations illustrated that the use of DOACs, namely rivaroxaban or apixaban, in patients with kidney failure combined with AF yielded comparable efficacy and safety outcomes to those observed with VKAs. A meta-analysis concerning AF patients with kidney failure, comparing DOACs and warfarin, utilized three RCTs [ 28 ]; however, one study had missing data [ 24 ]. Their outcome measures focused solely on major bleeding, systemic embolism, and cardiovascular death, lacking the depth of analysis found in our article. Additionally, our study included a subgroup analysis of patients with CrCl between 15 ml/min and 90 ml/min, augmenting overall comprehensiveness and persuasiveness. Another meta-analysis on DOACs and warfarin in AF patients with CKD did not specifically explore kidney failure patients with distinct physiological and functional changes [ 29 ]. This analysis relied on five pre-2016 RCTs and 14 observational studies. In contrast, a network meta-analysis concluded that DOACs out performed warfarin in preventing thromboembolic events and reducing bleeding risk in AF patients with mild to moderate kidney disease [ 30 ]. However, the study acknowledged a limitation in the strength of evidence, precluding a definitive preference for a particular DOACs. Conversely, our study suggests an elevated risk of bleeding without significant benefits from OACs in dialysis patients with AF. In comparison to previous meta-analyses on the efficacy and safety of DOACs and VKAs in AF patients with CKD. This article incorporates nine RCTs with robust evidence levels, encompassing all DOACs. Among these, three RCTs were specifically scrutinized concerning patients with kidney failure, with two employing apixaban and one utilizing rivaroxaban. The use of warfarin in dialysis patients is associated with an increased risk of bleeding, even when maintaining an INR within the normal range, posing challenges to its practical application. Hemodialysis patients typically undergo systemic heparin anticoagulation during their sessions, a variable inconsistently considered in studies examining bleeding complications related to both VKAs and DOACs in this population. As a result, research in this domain has consistently lagged behind. This investigation disclosed no significant disparity in efficacy and safety between VKAs and DOACs for patients with kidney failure and concurrent AF. This finding introduces a novel and more convenient option for anticoagulant therapy in this patient demographic.Our study showed that increased DOACs efficacy and reduced side effects were associated with renal clearance of the drug. Dabigatran has the greatest dependence on renal function due to renal excretion as a prototype [ 31 ], apixaban has the lowest renal clearance renal impairment has less effect on its excretion [ 32 ], and renal function is moderately affected by rivaroxaban [ 33 ]. Compared with warfarin, DOACs has a protective effect on renal function [ 34 ]. Our study shows that apixaban may be the best choice when compared to VKAs in the case of an adjusted degree of renal impairment.

Fordyce et al.’s study revealed that the incidence of major bleeding attributed to rivaroxaban at doses of 10 mg daily and 15–20 mg daily in patients with a Crcl of 30–49 ml/min was 6.38% and 4.12%, respectively, with no statistically significant difference observed. In individuals with kidney failure, the incidence of major bleeding increased to 13.04% for those receiving rivaroxaban at a daily dose of 10 mg, and when combined with vitamin K2, the incidence was 9.52%. This underscores the heightened bleeding risk associated with kidney failure. Among patients with a Crcl of 25–30 ml/min receiving apixaban, the incidence of major bleeding for doses of 2.5 mg bid compared to 5 mg bid was 3.42% and 4.39%, respectively, while the incidence of major or clinically relevant non-major bleeding was 4.28% and 7.35%, respectively. The study conducted by A. Mavrakanas et al. concluded that a dosage of apixaban at 2.5 mg bid is the appropriate choice for patients with kidney failure. This suggests a correlation between reduced renal function levels and the necessity for dose reduction.

VKAs is metabolized in the liver by cytochrome P450s and excreted as a metabolite via the kidneys, whereas all DOACs have varying degrees of prototypic drug excretion via the kidneys, and moderate-to-severe renal insufficiency has a significant effect on their pharmacokinetics. Therefore, dose adjustment is required for use in patients with CKD. However VKAs leads to the risk of calcification of the renal arteries, calcification of the aortic valve, and decreased bone calcium [ 35 ]. Calcification of small arteries may lead to an increased incidence of ischemic stroke [ 36 ]. There is no specific treatment for the defense of calcification due to warfarin anticoagulation, which has a poor prognosis and high morbidity and mortality once it occurs. Warfarin anticoagulation therapy is a risk factor for the development of calcification defense [ 37 ]. The US guidelines recommend anticoagulation with warfarin in kidney failure patients with CrCl < 15 ml/min [ 38 ]. The nephrology guidelines also recommend warfarin as the drug of choice for anticoagulation in kidney failure patients [ 39 ]. However, European guidelines do not recommend DOACs anticoagulation in kidney failure patients with CrCl < 15 ml/min [ 40 ]. Previous meta-studies also showed that warfarin for AF patients undergoing dialysis did not show significant benefits or harms [ 13 , 41 ]. In contrast, our study showed at least similar efficacy and safety when comparing DOACs and warfarin in patients with CrCl < 15 ml/min.

For AF patients with comorbid CKD, since thrombopoietin mRNA can be expressed in the kidneys, decreased renal function can lead to impaired platelet production and an increased risk of bleeding [ 42 ]. Inadequate anticoagulation therapy exists for this group of patients, especially dialysis patients, due to the concern that anticoagulant use may lead to an increased incidence of bleeding [ 43 ].

This study demonstrates that the use of DOACs improves safety and reduces the incidence of major bleeding, fatal bleeding, and ICH in patients with CKD and concurrent AF, as compared to VKAs therapy. For patients with kidney failure combined with AF, rivaroxaban and apixaban showed at least similar effectiveness and safety when compared to warfarin. This may inform drug selection for oral anticoagulation in patients with CKD combined with AF. Moreover, this article employed nine randomized controlled trials (RCTs), providing a higher level of evidence compared to alternative meta-analyses. Notably, three RCT studies were specifically dedicated to patients with kidney failure, thereby addressing a gap in prior research.

This study also has some limitations: (1) The method of CrCl calculation was not consistent across studies, with 6 studies using the Cockcroft-Gault formula and two using Hemodialysis. (2) Lack of data on the DOACs dose-adjustment regimen, in addition to the level of renal function, the dose of drug use may be affected by factors such as body weight, age, etc., so further studies are needed to investigate the pharmacokinetics of DOACs use in this population. (3) Failure to perform subgroup analysis based on DOACs high and low dose groups.

Compared with VKAs, DOACs improves the efficacy and safety of anticoagulation in patients with CKD combined with AF. In patients with atrial fibrillation combined with Kidney failure DOACs has at least similar effectiveness and safety when compared with VKAs.

Availability of data and materials

All data relevant to the study are included in the article or uploaded as supplementary information.

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Yaodi Li, Shuyi Wu and Jintuo Zhou contributed equally to this work.

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Department of Pharmacy, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, #18 Daoshan Road, Fuzhou, 350001, China

Yaodi Li, Shuyi Wu, Jintuo Zhou & Jinhua Zhang

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JHZ initiated the study. YDL and SYW performed data extraction and analyses. YDL drafted the first version of the manuscript. YDL, JTZ and SYW critically reviewed the manuscript and revised it. YDL, JTZ and SYW contributed to the analysis of data and provided critical revisions. JHZ, YDL, and SYW contributed to the conception and design, and they provided critical revisions of the paper for crucial intellectual content. All authors read and approved the final manuscript.

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Li, Y., Wu, S., Zhou, J. et al. Efficacy and safety of direct oral anticoagulants in patients with atrial fibrillation combined with chronic kidney disease: a systematic review and meta-analysis. Thrombosis J 22 , 40 (2024). https://doi.org/10.1186/s12959-024-00608-5

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Diet and Kidney Function: a Literature Review

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• Published: 03 February 2020
• Volume 22 , article number  14 , ( 2020 )

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Purpose of Review

The burden of chronic kidney disease (CKD) is increasing worldwide. For CKD prevention, it is important to gain insight in commonly consumed foods and beverages in relation to kidney function.

Recent Findings

We included 21 papers of prospective cohort studies with 3–24 years of follow-up. We focused on meat, fish, dairy, vegetables, fruit, coffee, tea, soft drinks, and dietary patterns. There was convincing evidence that a healthy dietary pattern may lower CKD risk. Plant-based foods, coffee, and dairy may be beneficial. Unhealthy diets and their components, such as red (processed) meat and sugar-sweetened beverages, may promote kidney function loss. For other foods and beverages, associations with CKD were neutral and/or the number of studies was too limited to draw conclusions.

Healthy dietary patterns are associated with a lower risk of CKD. More research is needed into the effects of specific food groups and beverages on kidney function.

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Introduction

Chronic kidney disease (CKD) is a major public health burden [ 1 , 2 ], with a global prevalence of ~ 11% in the general adult population [ 1 ]. If left untreated, CKD slowly progresses to end-stage renal disease, which requires dialysis or kidney transplant [ 2 , 3 ]. CKD is bidirectionally associated with cardiovascular diseases (CVD) [ 4 , 5 ]. Hypertension [ 6 ] and type 2 diabetes mellitus (T2DM) [ 7 , 8 ] are independent risk factors for CKD [ 6 , 7 ], and their global prevalences are increasing [ 9 , 10 ], which will likely impact CKD. Worldwide, a 31.7% increase of CKD mortality was observed over the last decade [ 11 ].

Lifestyle factors, including smoking [ 12 ], alcohol use [ 13 ], and physical inactivity [ 14 ], could promote CKD. Apart from that, there is increasing scientific interest in the potential role of diet [ 15 , 16 ]. High salt intake is an established risk factor for kidney function decline [ 17 , 18 ], mainly through its adverse effect on blood pressure and vascular health [ 19 , 20 , 21 ]. Less is known about other dietary factors. Therefore, we reviewed the current evidence on foods, beverages, and overall dietary quality in relation to the risk of incident CKD using data from prospective cohort studies.

We performed a comprehensive search in PubMed of papers published until August 2019 describing prospective cohort studies, supplemented by manual searches of reference lists from appropriate studies. The review is based on prospective cohort studies with at least 3 years of follow-up that reported on the relation between food groups, beverages, and dietary patterns and kidney function in populations free from CKD (defined as mean estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73 m 2 ).

Foods of interest were red (processed) meat, poultry, fish, dairy, vegetables, legumes, nuts, and fruits. Beverages included coffee, tea, sugar-sweetened beverages (SSBs), and diet beverages. Dietary patterns included adherence to the Dietary Approach to Stop Hypertension (DASH) diet, Mediterranean diet, and other healthy dietary patterns. Unhealthy diets were high fat, high sugar diets, and diets with a high acid load.

Concerning kidney function, we selected studies with data on the eGFR, derived from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [ 22 , 23 ] and Modification of Diet in Renal Disease (MDRD) [ 24 ].

Reasons for exclusion of articles were studies with (1) follow-up less than 3 years, (2) study design other than prospective cohort study, (3) study population with T2DM and analgesic use, (4) no full-text available, and (5) focus on end-stage renal disease. The selection process is shown in eFig. 1 .

From selected papers, we extracted data on population characteristics, study design, intakes of foods and/or beverages, kidney function outcomes, risk estimates for diet-kidney function associations, and potential confounders.

The primary outcome for this review was “incident CKD” based on eGFR cutoff criteria, described in eTable 1 . Associations between foods, beverages, and incident CKD in different studies were expressed as odds ratios (OR), obtained from logistic regression analysis, or hazard ratios (HR), obtained from Cox proportional hazard analysis with corresponding 95% confidence intervals (CI). In this review, OR and HR are both denoted as relative risks (RRs). Continuous associations between food groups, beverages, and change in eGFR are expressed as beta regression coefficients, obtained from multivariable linear regression.

RRs and betas from fully adjusted models are reported in tables with potential confounders. When these models included possible intermediates (i.e., factors could play a role in the biological pathway), risk estimates from less adjusted models are given. Two-sided P values < 0.05 for risk estimates were considered statistically significant.

An overview of studies of foods, beverages, and dietary patterns and their associations with incident CKD is presented in eTable 1 . Studies that focused on eGFR change, albuminuria, or hyperuricemia are described in eTable 2 and eTable 3 . Graphical displays of the point estimates with 95% CI related to incident CKD using forest plots are presented in Figs.  1 , 2 , and 3 .

Forest plot for associations between commonly consumed foods and incident chronic kidney disease

Forest plot for associations between commonly consumed beverages and incident chronic kidney disease. SSB, sugar-sweetened beverages

Forest plot for associations between dietary patterns and incident chronic kidney disease. DASH, Dietary Approach to Stop Hypertension

Two studies evaluated the consumption of red (processed) meat and poultry in relation to incident CKD (Fig.  1 ) [ 25 ••, 26 ••]. Red meat intake in these studies varied between 0.17 to 0.34 servings per day (low intake) and 1.15 to 2.52 servings per day (high intake). In the Atherosclerosis Risk in Communities (ARIC) study of ~ 12,000 US participants with 23 years of follow-up, a total of 2632 participants developed CKD [ 25 ••]. In this population, the HR for high versus low intake of red meat and CKD risk was 1.19 (95% CI, 1.03; 1.36; Fig.  1 ) [ 25 ••]. In a study of 4881 Iranian participants followed for 3 years, 613 participants developed CKD with an OR of 1.73 (95% CI, 1.33; 2.24) for high versus low red meat intake (Fig.  1 ) [ 26 ••]. Findings for processed meat were similar to those for red meat in both studies, and no significant associations with kidney function were found for poultry (Fig.  1 ) [ 25 ••].

Two studies evaluated the association between fish consumption and incident CKD (Fig.  1 ) [ 25 ••, 27 ]. The Strong Heart Study among American Indians followed 2261 participants for 5.4 years of whom 4% developed CKD. Fish intake was analyzed in four categories ranging from 0 to > 15 g per day [ 27 ]. No significant associations were found with an OR of 1.46 (95% CI, 0.65; 3.26) for high versus zero fish intake [ 27 ]. In the ARIC study [ 25 ••], fish intake was analyzed in quintiles ranging from 0.07 to 0.64 servings per day. A borderline significant HR of 0.89 (95% CI, 0.78; 1.01) was found in the upper versus lower quintile of intake (Fig.  1 ) [ 25 ••].

Dairy consumption and incident CKD were examined in the ARIC study among US individuals (Fig.  1 ) [ 25 ••]. Intake of low-fat dairy ranged from 0.00 to 2.04 servings per day and intake of high-fat dairy from 0.13 to 1.61 servings per day [ 25 ••]. A significantly lower risk of CKD was found for low-fat dairy intake, with a HR of 0.75 (95% CI, 0.65; 0.85) for high versus low intake. High-fat dairy intake was also inversely associated with CKD, albeit non-significant (Fig.  1 ) [ 25 ••].

We found 3 studies of vegetable intake and CKD risk (Fig.  1 ) [ 28 •, 29 ••, 30 ]. In a study of 1780 Iranians from the Tehran Lipid Glucose Study (TLGS), followed for 6 years, 319 participants developed CKD [ 28 •]. Allium vegetable intake was analyzed in tertiles ranging from 1 to 39 g per week [ 28 •]. A significant inverse association with CKD risk was found, with a HR of 0.68 (95% CI, 0.48; 0.98) in the upper versus lower tertiles of intake [ 28 •]. In 9229 participants from the Korean Genome and Epidemiology Study, 1741 incident CKD cases were reported during 8.2 years [ 29 ••]. Intake of non-fermented vegetables ranged from 49 to 222 g per day, and intake of fermented vegetables from 164 to 227 g per day [ 29 ••]. Non-fermented vegetables were inversely related to CKD risk, with a HR of 0.86 (95% CI, 0.76; 0.98) for high versus low intake (Fig.  1 ) [ 29 ••]. For fermented vegetables, an inverse but non-significant association was found (Fig.  1 ) [ 29 ••]. In the abovementioned TLGS, nitrate-containing vegetable intake ranged from 146 to 428 g per day [ 30 ]. No significant association with CKD risk was found after 3 years of follow-up (Fig.  1 ) [ 30 ].

Legumes and Nuts

In the ARIC study with 23 years of follow-up, legume intake ranged from 0.07 to 0.68 servings per day and nut intake ranged from 0.03 to 0.86 servings per day [ 25 ••]. Both legumes and nuts were significantly associated with lower risks of CKD, with HRs of 0.83 (95% CI, 0.72; 0.95) and 0.81 (95% CI, 0.72; 0.92) for high versus low intakes, respectively (Fig.  1 ) [ 25 ••].

One study in 9229 South Koreans, followed for 8.2 years, reported on fruit consumption and incident CKD [ 29 ••]. Fruit intake ranged from 143 to 345 g per day and showed no association with incident CKD (HR of 1.00) (Fig.  1 ) [ 29 ••].

Three studies examined coffee consumption and incident CKD (Fig.  2 ) [ 31 , 32 , 33 ]. The Iranian TLGS compared coffee drinkers (median intake 8.3 ml per day) to non-drinkers [ 31 ]. In the ARIC study in the USA [ 32 ] and the Korean Genome and Epidemiology Study in South Korea [ 33 ], those drinking at least 3 cups [ 32 ] or at least 2 cups [ 33 ] were compared with non-coffee drinkers. In the Iranian study, a non-significant direct association between coffee and CKD was found [ 31 ], whereas in the US and Korean studies, significant inverse associations were observed in those with higher coffee intakes, with HR of 0.84 [ 32 ] and 0.80 [ 33 ], respectively (Fig.  2 ).

The Iranian TLGS also reported on tea consumption, ranging from < 250 ml (low intake) to > 750 ml per day (high intake) (Fig.  2 ) [ 31 ]. Unfortunately, data on the type of tea and its preparation method was not collected [ 31 ]. However, a previous study reported that in Iran, black tea is often consumed [ 34 ] with added sweets and sugar, including a variety of additives [ 31 ]. No significant association with incident CKD was found (Fig.  2 ) [ 31 ].

Soft Drinks

Three studies reported on SSBs and incident CKD (Fig.  2 ) [ 35 , 36 , 37 ], of which one American study also reported on diet beverages (Fig.  2 ) [ 36 ]. In the ARIC study with 9 years of follow-up, consumption of SSB (cutoff 1 drink per day) was not significantly associated with CKD risk [ 35 ]. In the Jackson Heart Study (3003 participants, 185 CKD cases) with 8 years of follow-up, a direct, non-significant association of SSB with CKD risk was found [ 36 ]. In the Iranian TLGS, SSB consumption ranged from < 0.5 to > 4 servings per week [ 37 ]. A significantly elevated risk of CKD was found when comparing high with low intakes, with an OR (95% CI) of 1.92 (1.05; 3.48) (Fig.  2 ) [ 37 ]. Diet beverages were studied in the Jackson Heart Study and showed no significant association with CKD risk (Fig.  2 ) [ 36 ].

Dietary Patterns

Healthy diets.

A number of studies examined healthy dietary patterns and incident CKD [ 38 , 39 , 40 •, 41 , 42 ••, 43 , 44 ], including the DASH diet [ 39 , 40 •, 41 ], Mediterranean diet [ 38 , 42 ••], and other healthy dietary patterns [ 42 ••, 43 , 44 ], for which findings are shown in Fig.  3 . The DASH diet was examined in the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort with 5 years of follow-up [ 40 •], in the ARIC study with 23 years of follow-up [ 41 ] and in the Iranian TLGS with 6.1 years of follow-up [ 39 ]. All studies suggested a beneficial effect of the DASH diet, with RRs between 0.41 and 0.86 for high versus low adherence (Fig.  3 ). The association was statistically significant for 2 studies [ 39 , 41 ].

Mediterranean diet scores were examined in the Northern Manhattan Study [ 38 ] and ARIC study [ 42 ••], with 6.9 years [ 38 ] and 24 years [ 42 ••] of follow-up, respectively. Reduced RRs of 0.50 [ 38 ] and 0.89 [ 42 ••] were found for high versus low adherence, which were significant for both studies (Fig.  3 ).

The ARIC study also examined [ 42 ••] adherence to healthy dietary patterns assessed using the Healthy Eating Index-2015 (HEI-2015) and the alternative HEI-2010 [ 42 ••]. The HEI-2015 was designed to assess adherence to US Dietary Guidelines for Americans [ 45 ], while the alternative HEI-2010 was designed to identify key components associated with chronic diseases [ 46 ]. For both diet quality scores, significantly lower risks of CKD were found for higher adherence, with RRs of 0.86 and 0.81, respectively (Fig.  3 ) [ 42 ••].

In the ARIC study with 22 years of follow-up, the Healthy Diet Score based on American Heart Association’s Life’s Simple 7 was studied, which appeared not to be associated with incident CKD [ 43 ]. In the Framingham Offspring cohort followed for 6.6 years (1802 participants, 171 CKD cases), the Dietary Guidelines Adherence Index was borderline significantly inversely associated with CKD risk [ 44 ].

Healthy dietary patterns were also beneficially associated with other renal function outcomes, such as rapid eGFR decline [ 40 •, 44 ] and ≥ 25% eGFR decline [ 40 •] (Supplementary material; eTable 1 ).

Unhealthy Diets

Two studies reported on unhealthy dietary patterns and incident CKD (Fig.  3 ) [ 47 , 48 ]. In the TLGS, a high-fat, high-sugar diet was related to a significantly higher risk of CKD, with OR of 1.46 [ 47 ]. In participants of the ARIC study, an increased HR of 1.13 was found for a diet with a high acid load (12.2 to 100.7 mEq per day), which is characterized by high levels of salt, animal protein, and phosphorus, compared with a low acid load (− 119.1 to − 3.2 mEq per day).

This review of 21 prospective cohort studies among individuals with (relatively) normal kidney function shows a consistently lower risk of CKD in those adhering to a healthy dietary pattern [ 38 , 39 , 40 •, 41 , 42 ••, 43 , 44 ]. For individual food groups and beverages, the observed associations were more variable and weaker. We found adverse associations for red (processed) meat and SSBs in some studies and beneficial associations for dairy, vegetables, legumes, and nuts.

Two recent reviews have indicated that healthy dietary patterns may prevent incident CKD [ 15 , 16 ]. Ajjarapu et al. included 26 prospective cohort studies and found that adherence to a DASH or Mediterranean diet may be useful to prevent CKD [ 16 ]. Similar results were found in a meta-analysis of 15 prospective and retrospective cohort studies performed by Bach et al. [ 15 ]. A low animal/vegetable protein ratio is often considered an indicator of a healthy dietary pattern. In this regard, the ARIC study [ 25 ••] showed that after 23 years of follow-up, high (> 22.8 g per day) versus low (< 12.1 g per day) intake of vegetable protein was significantly associated with lower risk of CKD, whereas no association was found for high (> 69.6 g per day) versus low (< 36.4 g per day) intake of animal protein [ 25 ••]. Similar results on animal protein intake were found in 1135 participants with normal renal function (defined as eGFR > 80 ml/min/1.73 m 2 ) from the Nurses’ Health Study [ 49 ].

A lower risk of incident CKD for those consuming more vegetables and legumes may partly be attributable to fiber, as shown in a study among Iranian TLGS participants, with 6.1 years of follow-up [ 50 ]. Consumption of whole grains has also been linked to less kidney function decline in the Doetinchem Study in The Netherlands, with 15 years of follow-up [ 51 ]. In a study of vegetables and fruit intake in relation to kidney function decline, assessed by the annual change in eGFR, inverse associations were found [ 51 ] (Supplementary material; eTable 2 ), which strengthens our findings on healthy dietary patterns.

We found no association of CKD with fish intake, which is often considered part of a healthy diet. This was confirmed in another study among American Indians with 5.4 years of follow-up, where fish intake was not related to change in kidney function [ 27 ] (Supplementary material; eTable 2 ). For poultry, we could only include one study, and more research is needed.

Our results for coffee, indicating a potentially protective effect, are also in line with the results from a study on kidney function change [ 52 ] (Supplementary material; eTable 2 ). In this study, the coffee was mainly caffeinated [ 52 ] and likely to be filtered. The Iranian study suggested an increased, albeit non-significant, risk of CKD, which could be attributable to the regularly consumed unfiltered type of coffee in this country [ 31 ]. However, more information regarding the type of coffee and its preparation methods is needed, including amounts of added sugar and other condiments, before results can be correctly interpreted. We found no beneficial associations for tea and incident CKD, which was in line with the results from a Dutch study on kidney function decline [ 52 ] (Supplementary material; eTable 2 ). However, our review included only one study on incident CKD from Iran [ 31 ]. More information about the types of tea in relation to kidney function, including amounts of added sugar, is needed before drawing conclusions.

For low-fat dairy products and incident CKD, we found some evidence for a potentially protective effect on kidney function, though based on only one study [ 25 ••]. This is in line with a study in Dutch participants in which less kidney function loss was found during 15 years of follow-up who consumed more milk and low-fat dairy [ 53 ] (Supplementary material; eTable 2 ).

With regard to other kidney function outcomes (Supplementary material; eTable 3 ), studies on the risk of albuminuria [ 27 , 35 , 54 , 55 ] and hyperuricemia [ 35 ] were in accordance with those for CKD. A higher, albeit non-significant risk of hyperuricemia was found for high versus low SSB consumption [ 35 ]. Also, a good versus poor diet quality, based on eight fundamental DASH diet components, was associated with a lower risk of incident microalbuminuria [ 55 ], and fruit intake was related to a lower risk of albuminuria [ 54 ]. Fish intake was not associated with albuminuria [ 27 , 56 ].

To summarize, this review shows that a healthy dietary pattern may help prevent kidney function decline and lower the risk of CKD. The number of studies of individual foods and beverages in this field, however, is limited and most of the evidence comes from a limited number of cohorts. More research on the components of healthy (and unhealthy) diets and indicators of kidney health in different populations is needed to fill these knowledge gaps.

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van Westing, A.C., Küpers, L.K. & Geleijnse, J.M. Diet and Kidney Function: a Literature Review. Curr Hypertens Rep 22 , 14 (2020). https://doi.org/10.1007/s11906-020-1020-1

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Surgical management of renal cell carcinoma with subhepatic inferior vena cava tumor thrombus: a case report and review of the literature

• Bekim Ademi 1 ,
• Luan Jaha 1 ,
• Isa Haxhiu 2 ,
• Xhevdet Çuni 2 ,
• Afrim Tahiri 3 ,
• Jetmir Gashi 1 ,
• Adhurim Koshi 1 &
• Art Jaha 1  

Journal of Medical Case Reports volume  18 , Article number:  201 ( 2024 ) Cite this article

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Renal cell carcinomas are the most common form of kidney cancer in adults. In addition to metastasizing in lungs, soft tissues, bones, and the liver, it also spreads locally. In 2–10% of patients, it causes a thrombus in the renal or inferior vena cava vein; in 1% of patients thrombus reaches the right atrium. Surgery is the only curative option, particularly for locally advanced disease. Despite the advancements in laparoscopic, robotic and endovascular techniques, for this group of patients, open surgery continues to be among the best options.

Here we present a case of successful tumor thrombectomy from the infrahepatic inferior vena cava combined with renal vein amputation and nephrectomy. Our patient, a 58 year old Albanian woman presented to the doctors office with flank pain, weight loss, fever, high blood pressure, night sweats, and malaise. After a comprehensive assessment, which included urine analysis, complete blood count, electrolytes, renal and hepatic function tests, as well as ultrasonography and computed tomography, she was diagnosed with left kidney renal cell carcinoma involving the left renal vein and subhepatic inferior vena cava. After obtaining informed consent from the patient we scheduled her for surgery, which went well and without complications. She was discharged one week after to continue treatment with radiotherapy, chemotherapy, and immunotherapy.

Open surgery is a safe and efficient way to treat renal cell carcinoma involving the renal vein and inferior vena cava. It is superior to other therapeutic modalities. When properly done it provides acceptable long time survival and good quality of life to patients.

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Renal cell carcinomas (RCCs) in adults account for around 85% of kidney neoplasms [ 1 , 2 ] and may be linked to various risk factors, such as genetics, smoking, obesity, and exposure to certain chemicals. Other potential risk factors include hypertension, exposure during work to trichloroethylene, benzene or herbicides, the use of nonsteroidal anti-inflammatory drugs, dialysis, hepatitis C infection, and kidney stones [ 3 , 4 ].

RCC can remain clinically undetected throughout much of its progression. In around 90% of cases, RCC does not present with the hallmark symptoms of flank mass, hematuria, and flank pain until the disease has progressed significantly. Other signs and symptoms are weight loss, malaise, fever, night sweats, hypercalcemia, and hypertension. Male patients may also experience varicoceles on their left side as a result of obstruction of the testicular vein. However, almost one third of patients show no symptoms and end up discovering the carcinoma incidentally [ 5 ].

Around one third of RCC patients develop metastatic disease, with metastases being present either at the time of diagnosis or, in up to half of cases, later after a nephrectomy. The most common sites for metastatic disease are the lungs, soft tissues, bones, and liver, although the skin and central nervous system are also frequently affected [ 6 ].

A comprehensive diagnostic approach typically involves urinalysis, blood tests, renal and hepatic profiles, and imaging techniques, such as PET scans and angiotomography. Percutaneous core biopsy may also be performed to determine malignancy status.

RCC is staged using tumor, node, metastasis (TNM) classification and the American Joint Committee on Cancer (AJCC) staging system. Higher grade tumors are associated with poorer prognosis; inferior cava vein involvement is classified as stage III within these staging systems [ 6 ].

Surgical intervention is currently the only effective treatment for localized RCC, although it may also be utilized to relieve symptoms in cases of metastatic disease. The specific surgical approach depends on the location of the tumor thrombus. Several surgical staging systems have been proposed, including the Neves, Novick, and Hinman systems. In the Novick system, which we have used in this case report, a tumor thrombus found in the renal vein that extends less than 2 cm within the inferior vena cava (IVC) is classified as a level I thrombus. An infrahepatic thrombus is classified as a level II thrombus. A level III classification is given to an intrahepatic IVC thrombus below the diaphragm, while a level IV classification is reserved for an IVC tumor thrombus that extends above the diaphragm, as illustrated in Fig.  1 [ 7 , 8 , 9 ].

Preoperative computed tomography angiography, coronary view

We are pleased to present a successful tumor thrombectomy from the infrahepatic inferior vena cava (class II) in patients with renal cell carcinoma. Our patient was a 58-year-old Albanian housewife who presented at the doctors office with a range of symptoms, including flank pain, hematuria, weight loss, fever, hypertension, night sweats, and malaise.

Despite these symptoms, she remained well-oriented to person, place, and time. Her vital signs were slightly altered, with a blood pressure of 150/95 mmHg, heart rate of 90 beats per minute, respiratory rate of 20 breaths per minute, and temperature of 38 °C. The skin appeared reddened, warm, and moist, without any lesions or rashes observed. The head was normocephalic and the neck was supple with no masses or lymphadenopathy. No visual deficits, ptosis, or facial asymmetry indicating cranial nerve pathology were noted. Muscle strength was 5/5 bilaterally, and sensations were intact to light touch and pinprick throughout. Reflexes were 2 and symmetric in all extremities, with no pathological reflexes present. Gait was steady and coordinated, without any observed abnormalities. Palpation over the left flank elicited tenderness, pain, and guarding, as did percussion. No abnormalities were heard on auscultation of the abdomen.

After a comprehensive assessment, which included urine analysis, complete blood count, electrolytes, renal and hepatic function tests, as well as ultrasonography and computed tomography, she was diagnosed with left kidney renal cell carcinoma involving the left renal vein and subhepatic inferior vena cava (Figs.  1 , 2 ). All tests came back normal, except for microhematuria and slight hypoalbuminemia. A minor increase in C-reactive protein was also noted (Table  1 ).

Preoperative computed tomography angiography, sagittal view

Apart from for a beta blocker (carvedilol 6.25 mg, twice a day orally) that she was taking for hypertension, she was on no other medications. The patient was a nonsmoker and did not consume alcohol. There was no history of kidney or other malignancy in the family.

The cancer extension into the left renal vein and subhepatic inferior vena cava corresponded to Neves II stage disease. After careful consideration, we decided to perform a nephrectomy, renal vein amputation and thrombectomy of the subhepatic vena cava.

A team composed of vascular surgeons, urologists, a hepatobiliary surgeon, and an anesthesiologist came together to form a multidisciplinary team. Adequate amounts of blood products, such as packed red blood cells, platelets, cryoprecipitate, fresh frozen plasma, and clotting factors, were made available for surgery. The surgical procedure was carried out under general endotracheal anesthesia. To monitor and resuscitate the patient during surgery, a large bore central venous catheter, a 15 F catheter in the right internal jugular vein, and a right radial arterial catheter were inserted.

A midline incision was made to approach the abdomen as it was thought to provide optimal exposure of the inferior vena cava and contralateral kidney, enable thorough metastatic evaluation, and minimize postoperative pain. Since we decided to remove the kidney first and cancer thrombus after, we mobilized the colon medially, brought the kidney outside of Gerota’s fascia, and tied the ureter. After tying the renal artery and leaving the kidney attached only by the renal vein, the kidney was removed (Fig.  3 ).

Nephrectomy

Afterwards, liver was separated from its connections and tourniquets were positioned around the suprahepatic IVC, which was then mobilized together with the contralateral renal vein. To manage and identify lumbar veins, vascular clamps were placed above and below the tumor thrombus (Fig.  4 ). Patient response was monitored with a 1 minute test clamp, during which no hemodynamic changes were observed, allowing the clamps to remain in place as we performed cavotomy. A precise incision was created around the ostium of the renal vein into the IVC, followed by placement of a Fogarty catheter to facilitate thrombus removal (Fig.  5 ). The tumor itself was successfully removed without any issues and the cavotomy incision was closed using a 3–0 polypropylene suture (Figs.  6 , 7 ). After ensuring meticulous hemostasis, the abdominal cavity was closed using multiple layers.

Vascular control of the inferior vena cava, right renal vein, and ovarian vein

Tumor thrombus removal

Suturing of the inferior vena cava

Overall, the patient received 10 units of packed red blood cells, 10 units of fresh frozen plasma, 10 units of platelets, and 10 units of cryoprecipitate. The surgery proceeded without complications. The patient was then referred for further treatment in the ICU, where she stayed for a day for postoperative care. She received an additional two units of red blood cells and one unit of plasma to achieve a hematocrit value of 38% and hemoglobin level of 115 g/L. Blood urea nitrogen (BUN) and creatinine levels were within the normal range, as were the electrolyte levels. Liver enzyme levels were also normal. Hemodynamically, she remained stable, and her oxygen saturation consistently stayed above 98%. At 6 hours later, she was successfully extubated. On the second day after surgery, she was transferred to the ward, and 1 week later, she was discharged to continue treatment with radiotherapy, chemotherapy, and immunotherapy. During her ward stay, she received intravenous antibiotics (1 g of ceftriaxone twice daily and metronidazole 500 mg three times daily), subcutaneous low molecular weight heparin (enoxaparin 4000 IU/day), intravenous proton pump inhibitor (pantoprazole 40 mg once daily), and analgesics (diclofenac 50 mg intravenously twice daily for the first two days and as needed for pain thereafter). No additional blood transfusions were required (Fig. 8 ).

Postoperative computed tomography

The ICV is free of thrombus, but there are already developed regional and liver metastases.

On the follow-up computed tomography (CT) scan performed one month after surgery, the inferior vena cava was free of tumor, but unfortunately, the tumor had already spread to the liver and retroperitoneum (Fig.  7 ). The patient’s condition deteriorated 3 months after surgery and despite aggressive chemotherapy, she passed away 6 months later. Owing to religious reasons, no autopsy was performed.

In the midst of the ongoing debate concerning the role of open surgery in the treatment of renal cell carcinoma involving the renal vein and inferior vena cava, especially when compared with less invasive surgical approaches, our case presentation aims to align with those who consider open surgical thrombectomy from the infrahepatic inferior vena cava combined with renal vein amputation and the removal of the affected kidney, a viable treatment option.

However, it requires extensive preoperative management, a multidisciplinary team, precise technical expertise during the procedure, exceptional anesthesia management, and diligent postoperative care. The surgical team must be well-prepared for any unexpected situations that may arise during the procedure while also having a clear understanding of the procedure at hand. When dealing with cases above the liver, the team should include vascular, urology, hepatobiliary, and cardiac surgeons. Additionally, strategies, such as kidney immobilization and tyrosine inhibitors, are recommended to decrease the size of the tumor before surgery.

The first routine preoperative arterial embolization of the kidney to decrease the tumor size and facilitated the surgical procedure was advocated by Pouliot and coworkers [ 10 ], but was found to have no significant advantage over no embolization. Preoperative arterial embolization of the kidney has not shown significant advantages and is only recommended in specific situations, as it is associated with complications, such as angioinfarction syndrome and inflammation around the kidney and surgical field [ 11 ]. The usefulness of tyrosine kinase inhibitors is still debated and remains to be confirmed through randomized trials despite its effectiveness in treating metastatic RCC [ 12 , 13 , 14 ].

There have been reports of surgeons placing IVC Greenfield Filters during surgery to prevent pulmonary embolism, but studies have found this practice to be ineffective and potentially dangerous. The filter may become clogged with thrombus, requiring complete removal and IVC reconstruction [ 15 ].

When dealing with a patient with RCC and IVC tumor thrombus, the surgical approach must be personalized on the basis of the level of the thrombus and characteristics of the tumor. Precise preoperative imaging plays a critical role in effective planning [ 16 ]. It is imperative to ascertain the location of the tumor thrombus—whether it is infrahepatic, intrahepatic, or suprahepatic—as this will dictate the appropriate surgical approach, methodology for controlling the inferior vena cava, and potential requirement for vascular bypass [ 6 ].

In patients with RCC and IVC tumor thrombus, general endotracheal anesthesia is favored over regional epidural anesthesia owing to the risk of significant blood loss and coagulopathy, which increases the potential for epidural hematomas.

Various modes of surgical treatment have been described for patients with RCC involving renal vein and IVC, including laparoscopic, robotic, and endovascular surgery [ 17 , 18 , 19 , 20 ]. In certain exceptional situations of renal cell carcinoma (RCC) and tumor thrombus in level I of the inferior vena cava (IVC), a laparoscopic method might be feasible. However, recorded cases have indicated an elevated possibility of intraoperative complications with minimal proof regarding its cancer-fighting efficacy and safety. Moreover, robotic radical nephrectomy has proven to be effective in certain instances of low-level thrombi, but thorough research remains inadequate, and these minimally invasive procedures are not commonly recommended [ 6 ].

Open surgery, specifically nephrectomy and IVC thrombectomy, remains the preferred option and has shown usefulness even in metastatic disease, provided the patient is a candidate for surgery and has local symptoms [ 21 ]. In patients with metastatic RCC, the most reliable indicators of their prognosis are their response to systemic therapy and the burden of their metastatic disease [ 22 , 23 , 24 ].

The factors that could affect the survival of patients in this cohort are related to pathological TNM stage, nuclear grade, histological tumor subtype, regional lymph node status, and perinephritic fat invasion. It is worth noting, however, that there is little or no correlation between the level of IVC tumor thrombus and overall survival (OS). According to a recent study, the recurrence rate might be influenced by the extent of IVC tumor thrombus, however, there does not seem to be any correlation with OS [ 25 ]. Additionally, research on the results of surgery in patients with RCC who underwent nephrectomy and IVC thrombectomy revealed that the existence of fragile venous thrombus could augment the probability of synchronous nodal or distant metastases [41]. According to reports, the 5-year OS rate following surgical approach ranges from 32 to 69% in patients with IVC tumor thrombus wall invasion [ 25 , 26 , 27 , 28 ].

As for the procedure itself, radical nephrectomy with concomitant IVC thrombectomy has a reported perioperative mortality rate of 5–10%. However, it has been associated with significant morbidity, resulting in an overall complication rate of 38% [50]. As such complex surgeries require extensive vascular, hepatobiliary, cardiothoracic, and anesthesia support, it is recommended that only centers of excellence with the necessary resources undertake these procedures. Specifically, they should be reserved for patients with more advanced level III and IV IVC tumor thrombi [ 29 , 30 , 31 , 32 ].

The effective management of renal cell carcinoma and inferior vena cava tumor thrombus relies heavily on a skilled multidisciplinary surgical team. Adequate preoperative imaging is crucial for the planning and facilitation of surgical procedures for such cases. The surgical strategy should be customized to suit the specific characteristics and extent of the tumor thrombus situated in the inferior vena cava. While minimally invasive surgical techniques (including robotics) may have a role in this matter, their use should be limited to specific cases, particularly level I IVC tumor thrombus cases with favorable anatomic and tumor characteristics. For smaller lesions in patients who are not candidates for surgery, thermal ablation may provide a viable alternative. Metastatic disease in RCC can be treated with targeted therapy and immunotherapy, whereas chemotherapy and hormonal therapy have generally been unsuccessful.

Availability of data and materials

The data are available under consideration of the corresponding author upon reasonable request.

Abbreviations

• Renal cell carcinoma

Inferior vena cava

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Department of Vascular Surgery, University Clinical Center of Kosovo, Prishtina, Kosovo

Bekim Ademi, Luan Jaha, Jetmir Gashi, Adhurim Koshi & Art Jaha

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Isa Haxhiu & Xhevdet Çuni

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The surgical procedure was carried out by BA, LJ, IH, XC, AK, and AT. LJ and AJ conducted extensive research on medical literature, gathered relevant data, and were the main contributors to writing the manuscript. All authors read and approved final manuscript.

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Correspondence to Luan Jaha .

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Ademi, B., Jaha, L., Haxhiu, I. et al. Surgical management of renal cell carcinoma with subhepatic inferior vena cava tumor thrombus: a case report and review of the literature. J Med Case Reports 18 , 201 (2024). https://doi.org/10.1186/s13256-024-04517-z

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Received : 05 September 2023

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DOI : https://doi.org/10.1186/s13256-024-04517-z

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Single-Center Experience of Pediatric Cystic Kidney Disease and Literature Review

Affiliations.

• 1 Department of Pediatrics, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia.
• 2 Department of Pediatrics, University Hospital Center Zagreb, 10000 Zagreb, Croatia.
• 3 Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, 10000 Zagreb, Croatia.
• 4 Department of Internal Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia.
• PMID: 38671609
• PMCID: PMC11048964
• DOI: 10.3390/children11040392

Introduction: Pediatric cystic kidney disease (CyKD) includes conditions characterized by renal cysts. Despite extensive research in this field, there are no reliable genetics or other biomarkers to estimate the phenotypic consequences. Therefore, CyKD in children heavily relies on clinical and diagnostic testing to predict the long-term outcomes.

Aim: A retrospective study aimed to provide a concise overview of this condition and analyze real-life data from a single-center pediatric CyKD cohort followed during a 12-year period.

Methods and materials: Medical records were reviewed for extensive clinical, laboratory, and radiological data, treatment approaches, and long-term outcomes.

Results: During the study period, 112 patients received a diagnosis of pediatric CyKD. Male patients were more involved than female (1:0.93). Fifty-six patients had a multicystic dysplastic kidney; twenty-one of them had an autosomal dominant disorder; fifteen had an isolated renal cyst; ten had been diagnosed with autosomal recessive polycystic kidney disease; three had the tuberous sclerosis complex; two patients each had Bardet-Biedl, Joubert syndrome, and nephronophthisis; and one had been diagnosed with the trisomy 13 condition. Genetic testing was performed in 17.9% of the patients, revealing disease-causing mutations in three-quarters (75.0%) of the tested patients. The most commonly presenting symptoms were abdominal distension (21.4%), abdominal pain (15.2%), and oligohydramnios (12.5%). Recurrent urinary tract infections (UTI) were documented in one-quarter of the patients, while 20.5% of them developed hypertension during the long-term follow-up. Antibiotic prophylaxis and antihypertensive treatment were the most employed therapeutic modalities. Seventeen patients progressed to chronic kidney disease (CKD), with thirteen of them eventually reaching end-stage renal disease (ESRD). The time from the initial detection of cysts on an ultrasound (US) to the onset of CKD across the entire cohort was 59.0 (7.0-31124.0) months, whereas the duration from the detection of cysts on an US to the onset of ESRD across the whole cohort was 127.0 (33.0-141.0) months. The median follow-up duration in the cohort was 3.0 (1.0-7.0) years. The patients who progressed to ESRD had clinical symptoms at the time of initial clinical presentation.

Conclusion: This study is the first large cohort of patients reported from Croatia. The most common CyKD was the multicystic dysplastic kidney disease. The most common clinical presentation was abdominal distention, abdominal pain, and oliguria. The most common long-term complications were recurrent UTIs, hypertension, CKD, and ESRD.

Keywords: ADPKD; ARPKD; Bardet–Biedl syndrome; Joubert syndrome; cystic kidney disease; multicystic dysplastic kidney; nephronophthisis complex; tuberous sclerosis complex.

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