research studies related to dialysis

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The current and future landscape of dialysis

Jonathan himmelfarb.

1 Kidney Research Institute, Seattle, WA USA

2 Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA USA

Raymond Vanholder

3 Nephrology Section, Department of Internal Medicine and Pediatrics, University Hospital, Ghent, Belgium and European Kidney Health Alliance (EKHA), Brussels, Belgium

Rajnish Mehrotra

Marcello tonelli.

4 Division of Nephrology, Department of Medicine, University of Calgary, Calgary, Alberta Canada

The development of dialysis by early pioneers such as Willem Kolff and Belding Scribner set in motion several dramatic changes in the epidemiology, economics and ethical frameworks for the treatment of kidney failure. However, despite a rapid expansion in the provision of dialysis — particularly haemodialysis and most notably in high-income countries (HICs) — the rate of true patient-centred innovation has slowed. Current trends are particularly concerning from a global perspective: current costs are not sustainable, even for HICs, and globally, most people who develop kidney failure forego treatment, resulting in millions of deaths every year. Thus, there is an urgent need to develop new approaches and dialysis modalities that are cost-effective, accessible and offer improved patient outcomes. Nephrology researchers are increasingly engaging with patients to determine their priorities for meaningful outcomes that should be used to measure progress. The overarching message from this engagement is that while patients value longevity, reducing symptom burden and achieving maximal functional and social rehabilitation are prioritized more highly. In response, patients, payors, regulators and health-care systems are increasingly demanding improved value, which can only come about through true patient-centred innovation that supports high-quality, high-value care. Substantial efforts are now underway to support requisite transformative changes. These efforts need to be catalysed, promoted and fostered through international collaboration and harmonization.

Dialysis is a life-saving therapy; however, costs of dialysis are high, access is inequitable and outcomes are inadequate. This Review describes the current landscape of dialysis therapy from an epidemiological, economic, ethical and patient-centred framework, and describes initiatives that are aimed at stimulating innovations in the field to one that supports high-quality, high-value care.

• The global dialysis population is growing rapidly, especially in low-income and middle-income countries; however, worldwide, a substantial number of people lack access to kidney replacement therapy, and millions of people die of kidney failure each year, often without supportive care.
• The costs of dialysis care are high and will likely continue to rise as a result of increased life expectancy and improved therapies for causes of kidney failure such as diabetes mellitus and cardiovascular disease.
• Patients on dialysis continue to bear a high burden of disease, shortened life expectancy and report a high symptom burden and a low health-related quality of life.
• Patient-focused research has identified fatigue, insomnia, cramps, depression, anxiety and frustration as key symptoms contributing to unsatisfactory outcomes for patients on dialysis.
• Initiatives to transform dialysis outcomes for patients require both top-down efforts (that is, efforts that promote incentives based on systems level policy, regulations, macroeconomic and organizational changes) and bottom-up efforts (that is, patient-led and patient-centred advocacy efforts as well as efforts led by individual teams of innovators).
• Patients, payors, regulators and health-care systems increasingly demand improved value in dialysis care, which can only come about through true patient-centred innovation that supports high-quality, high-value care.

Introduction

Haemodialysis as a treatment for irreversible kidney failure arose from the pioneering efforts of Willem Kolff and Belding Scribner, who together received the 2002 Albert Lasker Clinical Medical Research Award for this accomplishment. Kolff treated his first patient with an artificial kidney in 1943 — a young woman who was dialysed 12 times successfully but ultimately died because of vascular access failure. By 1945, Kolff had dialysed 15 more patients who did not survive, when Sofia Schafstadt — a 67-year-old woman who had developed acute kidney injury — recovered, becoming the first long-term survivor after receipt of dialysis. In 1960, Belding Scribner, Wayne Quinton and colleagues at the University of Washington, WA, USA, designed shunted cannulas, which prevented the destruction of blood vessels and enabled repeated haemodialysis sessions. The first patient who received long-term treatment (named Clyde Shields) lived a further 11 years on haemodialysis. In their writings, both Kolff and Scribner eloquently described being motivated by their perception of helplessness as physicians who had little to offer for the care of young patients who were dying of uraemia and stated that the goal of dialysis was to achieve full rehabilitation to an enjoyable life 1 .

The potential to scale the use of dialysis to treat large numbers of patients with kidney failure created great excitement. At the 1960 meeting of the American Society for Artificial Internal Organs (ASAIO), Scribner introduced Clyde Shields to physicians interested in dialysis, and Quinton demonstrated fabrication of the shunt. The following decade saw rapid gains in our understanding of kidney failure, including the discovery of uraemia-associated atherogenesis and metabolic bone disease, and in virtually every aspect of haemodialysis, including improvements in dialyser technology, dialysate composition, materials for haemocompatibility and water purification systems. The Scribner–Quinton shunt rapidly became an historical artefact once Brescia and colleagues developed the endogenous arteriovenous fistula in 1966 (ref. 2 ), and prosthetic subcutaneous interpositional ‘bridge’ grafts were developed shortly thereafter. Concomitant with these pioneering efforts, in 1959, peritoneal dialysis (PD) was first used successfully to sustain life for 6 months. Within 2 years a long-term PD programme was established in Seattle, WA, USA, and within 3 years the first automated PD cycler was developed 3 .

In 1964, Scribner’s presidential address to the ASAIO described emerging ethical issues related to dialysis, including considerations for patient selection, patient self-termination of treatment as a form of suicide, approaches to ensure death with dignity and selection criteria for transplantation 4 . Indeed, the process of selecting who would receive dialysis contributed to the emergence of the field of bioethics. The early success of dialysis paradoxically created social tensions, as access to this life-sustaining therapy was rationed by its availability and the ‘suitability’ of patients. In the early 1970s, haemodialysis remained a highly specialized therapy, available to ~10,000 individuals, almost exclusively in North America and Europe, with a high frequency of patients on home haemodialysis. In a portentous moment, Shep Glazer, an unemployed salesman, was dialysed in a live demonstration in front of the US Congress House Ways and Means Committee. Soon thereafter, in October 1972, an amendment to the Social Security Act creating Medicare entitlement for end-stage renal disease (now known as kidney failure), for both dialysis and kidney transplantation, was passed by Congress and signed into law by President Nixon.

The resulting expansion of dialysis, previously described as “from miracle to mainstream” 5 , set in motion dramatic changes 6 , including the development of a for-profit outpatient dialysis provider industry; relaxation of stringent patient selection for dialysis eligibility in most HICs; a move away from home towards in-centre dialysis; efforts on the part of single payors such as Medicare in the USA to restrain per-patient costs through the introduction of bundled payments and the setting of composite rates; the development of quality indicators — such as adequate urea clearance per treatment — that were readily achievable but are primarily process rather than outcome measures; consolidation of the dialysis industry, particularly in the USA owing to economies of scale, eventually resulting in a duopoly of dialysis providers; the development of joint ventures and other forms of partnerships between dialysis providers and nephrologists; the globalization of dialysis, which is now available, albeit not necessarily accessible or affordable in many low-income and middle-income countries (LMICs); and finally, a dramatic slowing in the rate of true patient-centred innovation, with incremental gains in dialysis safety and efficiency replacing the pioneering spirit of the early innovators.

The population of patients receiving dialysis continues to grow rapidly, especially in LMICs, as a result of an increase in the availability of dialysis, population ageing, increased prevalence of hypertension and diabetes mellitus, and toxic environmental exposures. However, despite the global expansion of dialysis, notable regional differences exist in the prevalence of different dialysis modalities and in its accessibility. Worldwide, a substantial number of people do not have access to kidney replacement therapy (KRT), resulting in millions of deaths from kidney failure each year. Among populations with access to dialysis, mortality remains high and outcomes suboptimal, with high rates of comorbidities and poor health-related quality of life. These shortcomings highlight the urgent need for innovations in the dialysis space to increase accessibility and improve outcomes, with a focus on those that are a priority to patients. This Review describes the current landscape of dialysis therapy from an epidemiological, economic, ethical and patient-centred framework, and provides examples of initiatives that are aimed at stimulating innovations in dialysis and transform the field to one that supports high-quality, high-value care.

Epidemiology of dialysis

Kidney failure is defined by a glomerular filtration rate <15 ml/min/1.73 m 2 (ref. 7 ) and may be treated using KRT (which refers to either dialysis or transplantation) or with supportive care 8 . The global prevalence of kidney failure is uncertain, but was estimated to be 0.07%, or approximately 5.3 million people in 2017 (ref. 9 ), with other estimates ranging as high as 9.7 million. Worldwide, millions of people die of kidney failure each year owing to a lack of access to KRT 10 , often without supportive care. Haemodialysis is costly, and current recommendations therefore suggest that haemodialysis should be the lowest priority for LMICs seeking to establish kidney care programmes. Rather, these programmes should prioritize other approaches, including treatments to prevent or delay kidney failure, conservative care, living donor kidney transplantation and PD 11 . Nonetheless, haemodialysis is the most commonly offered form of KRT in LMICs, as well as in high-income countries (HICs) 12 , and continued increases in the uptake of haemodialysis are expected worldwide in the coming decades. Here, we review the basic epidemiology of kidney failure treated with long-term dialysis and discuss some of the key epidemiological challenges of the future (Fig.  1a ).

Growth is continuously outpacing the capacity of kidney replacement therapy (KRT), defined as maintenance dialysis or kidney transplant, especially in low-income and middle-income countries. a | Global prevalence of chronic dialysis. b | Estimated worldwide need and projected capacity for KRT by 2030. pmp, per million population. Adapted with permission from the ISN Global Kidney Health Atlas 2019.

Prevalence of dialysis use

Prevalence of haemodialysis.

Worldwide, approximately 89% of patients on dialysis receive haemodialysis; the majority (>90%) of patients on haemodialysis live in HICs or the so-called upper middle-income countries such as Brazil and South Africa 12 , 13 . The apparent prevalence of long-term dialysis varies widely by region but correlates strongly with national income 14 . This variation in prevalence in part reflects true differences in dialysis use 12 , 15 but also reflects the fact that wealthier countries are more likely than lower income countries to have comprehensive dialysis registries. Of note, the prevalence of haemodialysis is increasing more rapidly in Latin America (at a rate of ~4% per year) than in Europe or the USA (both ~2% per year), although considerable variation between territories exists in all three of these regions, which again correlates primarily (but not exclusively) with wealth 16 , 17 . The prevalence of haemodialysis varies widely across South Asia, with relatively high prevalence (and rapid growth) in India and lower prevalence in Afghanistan and Bangladesh 18 . Limited data are available on the prevalence of dialysis therapies in sub-Saharan Africa 19 . A 2017 report suggests that haemodialysis services were available in at least 34 African countries as of 2017, although haemodialysis was not affordable or accessible to the large majority of resident candidates 13 .

Prevalence of peritoneal dialysis

Worldwide, PD is less widely available than haemodialysis. In a 2017 survey of 125 countries, PD was reportedly available in 75% of countries whereas haemodialysis was available in 96% 20 . In 2018, an estimated 11% of patients receiving long-term dialysis worldwide were treated with PD; a little over half of these patients were living in China, Mexico, the USA and Thailand 21 .

Large variation exists between territories in the relative use of PD for treating kidney failure; in Hong Kong for example, >80% of patients on dialysis receive PD, whereas in Japan this proportion is <5% 22 . This variation is, in part, determined by governmental policies and the density of haemodialysis facilities 23 . In some countries such as the USA, rates of PD utilization also vary by ethnicity with African Americans and Hispanics being much less likely than white Americans to receive PD 24 . Disparate secular trends in PD use are also evident, with rapid growth in the use of PD in some regions such as the USA, China and Thailand and declining or unchanging levels of PD use in other regions, for example, within Western Europe 22 . As for haemodialysis, access to PD is poor in many LMICs for a variety of reasons, as comprehensively discussed elsewhere 25 .

Incidence of dialysis use

Following a rapid increase in dialysis use over a period of approximately two decades, the incidence of dialysis initiation in most HICs reached a peak in the early 2000s and has remained stable or slightly decreased since then 22 , 26 , 27 . Extrapolation of prevalence data from LMICs suggests that the incidence of dialysis initiation seems to be steadily increasing in LMICs 10 , 28 – 30 , with further increases expected over the coming decades. However, incidence data in LMICs are less robust than prevalence data, although neither reflect the true demand for KRT given the lack of reporting.

Of note, the incidence of dialysis initiation in HICs is consistently 1.2-fold to 1.4-fold higher for men than for women, despite an apparently higher risk of chronic kidney disease (CKD) in women 31 . Whether this finding reflects physician or health system bias, different preferences with regard to KRT, disparities in the competing risk of death, variation in rates of kidney function loss in women versus men, or other reasons is unknown and requires further study. Few data describe the incidence of haemodialysis by sex in LMICs.

Dialysis outcomes

Mortality is very high among patients on dialysis, especially in the first 3 months following initiation of haemodialysis treatment. Approximately one-quarter of patients on haemodialysis die within a year of initiating therapy in HICs, and this proportion is even higher in LMICs 32 – 34 . Over the past two decades, reductions in the relative and absolute risk of mortality have seemingly been achieved for patients on haemodialysis. Data suggest that relative gains in survival may be greater for younger than for older individuals; however, absolute gains seem to be similar across age groups 35 . Although controversial, improvements in mortality risk seem to have been more rapid among patients on dialysis than for the general population 36 , suggesting that better care of patients receiving dialysis treatments rather than overall health gains might be at least partially responsible for these secular trends. The factors responsible for these apparent trends have not been confirmed, but could include better management of comorbidities, improvements in the prevention or treatment of dialysis-related complications such as infection, and/or better care prior to the initiation of dialysis (which may translate into better health following dialysis initiation). Historically, although short-term mortality was lower for patients treated with PD than for those treated with haemodialysis, the long-term mortality risk was higher with PD 37 , 38 . In the past two decades, the reduction in mortality risk has been greater for patients treated with PD than with haemodialysis, such that in most regions the long-term survival of patients treated with PD and haemodialysis are now similar 39 – 41 .

Despite these improvements, mortality remains unacceptably high among patients on dialysis and is driven by cardiovascular events and infection. For example, a 2019 study showed that cardiovascular mortality among young adults aged 22–29 years with incident kidney failure was 143–500-fold higher than that of otherwise comparable individuals without kidney failure, owing to a very high burden of cardiovascular risk factors 42 . The risk of infection is also markedly greater among patients on dialysis than in the general population, in part driven by access-related infections in patients on haemodialysis with central venous catheters and peritonitis-related infections in patients on PD 43 – 47 . Hence, strategies to reduce the risk of infection associated with dialysis access should continue to be a high clinical priority.

The risk of mortality among patients on dialysis seems to be influenced by race. In the USA, adjusted mortality is lower for African American patients than for white patients on dialysis, although there is a significant interaction with age such that this observation held only among older adults, and the converse is actually true among younger African American patients aged 18 to 30 years 48 . A similar survival advantage is observed among Black patients compared with white patients or patients of Asian heritage on haemodialysis in the Netherlands 49 . In Canada, dialysis patients of indigenous descent have higher adjusted mortality, and patients of South Asian or East Asian ethnicity have lower adjusted mortality than that of white patients. In addition, between-region comparisons indicate that mortality among incident dialysis patients is substantially lower for Japan than for other HICs. Whether this difference is due to ethnic origin, differences in health system practices, a combination of these factors or other, unrelated factors is unknown 30 . No consistent evidence exists to suggest that mortality among incident adult dialysis patients varies significantly by sex 50 – 52 .

Other outcomes

Hospitalization, inability to work and loss of independent living are all markedly more common among patients on dialysis than in the general population 53 – 55 . In contrast to the modest secular improvements in mortality achieved for patients on dialysis, health-related quality of life has remained unchanged for the past two decades and is substantially lower than that of the general population, due in part to high symptom burden 56 – 59 . Depression is also frequent among patients on dialysis 60 , and factors such as high pill burden 61 , the need to travel to dialysis sessions and pain associated with vascular access puncture all affect quality of life 62 .

Future epidemiological challenges

The changing epidemiology of kidney failure is likely to present several challenges for the optimal management of these patients. For example, the ageing global population together with continuing increases in the prevalence of key risk factors for the development of kidney disease, such as diabetes mellitus and hypertension, mean that the incidence, prevalence and costs of kidney failure will continue to rise for the foreseeable future. This increased demand for KRT will undoubtedly lead to an increase in the uptake of haemodialysis, which will pose substantial economic challenges for health systems worldwide. Moreover, as growth in demand seems to be outpacing increases in KRT capacity, the number of deaths as a result of kidney failure is expected to rise dramatically (Fig.  1b ).

The same risk factors that drive the development of kidney disease will also increase the prevalence of multimorbidities within the dialysis population. These comorbidities will in turn require effective management in addition to the management of kidney failure per se 63 and will require technical innovations of dialysis procedures, as well as better evidence to guide the management of comorbidities in the dialysis population.

Finally, the particularly rapid increases in the incidence and prevalence of kidney failure among populations in LMICs will place considerable strain on the health systems of these countries. The associated increases in mortality resulting from a lack of access to KRT will create difficult choices for decision makers. Although LMIC should prioritize forms of KRT other than haemodialysis, some haemodialysis capacity will be required 11 , for example, to manage patients with hypercatabolic acute kidney injury or refractory PD-associated peritonitis, which, once available, will inevitably increase the use of this modality.

Health economy-related considerations

The cost of dialysis (especially in-centre or in-hospital dialysis) is high 64 , and the cost per quality-adjusted life-year associated with haemodialysis treatment is often considered to be the threshold value that differentiates whether a particular medical intervention is cost-effective or not 65 . Total dialysis costs across the population will probably continue to rise, owing to increases in life expectancy of the general population and the availability of improved therapeutics for causes of kidney failure such as diabetes mellitus, which have increased the lifespan of these patients and probably will also increase their lifespan on dialysis. KRT absorbs up to 5–7% of total health-care budgets, despite the fact that kidney failure affects only 0.1–0.2% of the general population in most regions 66 . Although societal costs for out-of-centre dialysis (for example, home or self-care haemodialysis, or PD) are in general lower than that of in-centre haemodialysis in many HICs, these options are often underutilized 67 , adding to the rising costs of dialysis.

Reimbursement for haemodialysis correlates with the economic strength of each region 68 , but in part also reflects willingness to pay . In most regions, the correlation curve for PD or reimbursement with respect to gross domestic product projects below that of in-centre haemodialysis, which in part reflects the lower labour costs associated with PD 68 . Unfortunately, little clarity exists with regard to the aggregated cost of single items that are required to produce dialysis equipment for both PD and haemodialysis and the labour costs involved in delivering haemodialysis 69 , which makes it difficult for governments to reimburse the real costs of haemodialysis.

Although increasing reimbursement of home dialysis strategies would seem to be an appropriate strategy to stimulate uptake of these modalities, evidence from regions that offer high reimbursement rates for PD suggests that the success of this strategy is variable 23 , 68 . However, financial incentives may work. In the USA, reimbursement for in-centre and home dialysis (PD or home haemodialysis) has for a long time been identical. The introduction of the expanded prospective payment system in 2011 further enhanced the financial incentives for PD for dialysis providers, which led to a doubling in both the absolute number of patients and the proportion of patients with kidney failure treated with PD 70 – 73 .

Although in countries with a low gross domestic product, dialysis consumes less in absolute amounts, it absorbs a higher fraction of the global health budget 68 , likely at the expense of other, potentially more cost-effective interventions, such as prevention or transplantation. Although society carries most of the costs associated with KRT in most HICs, some costs such as co-payment for drugs or consultations are borne by the individual, and these often increase as CKD progresses. In other regions, costs are covered largely or entirely by the patient’s family, leading to premature death when resources are exhausted 74 . In addition, costs are not limited to KRT but also include the costs of medication, hospitalizations and interventions linked to kidney disease or its complications (that is, indirect costs), as well as non-health-care-related costs such as those linked to transportation or loss of productivity.

Dialysis also has an intrinsic economic impact. Patients on dialysis are often unemployed. In the USA, >75% of patients are unemployed at the start of dialysis, compared with <20% in the general population 53 . Unemployment affects purchasing power but also lifestyle, self-image and mental health. Moreover, loss of productivity owing to unemployment and/or the premature death of workers with kidney failure also has economic consequences for society 75 . Therefore, continued efforts to prevent kidney failure and develop KRT strategies that are less time consuming for the patient and allow more flexibility should be an urgent priority. Concomitantly, employers must also provide the resources needed to support employees with kidney failure.

Hence, a pressing need exists to rethink the current economic model of dialysis and the policies that direct the choice of different treatment options. The cost of dialysis (especially that of in-centre haemodialysis) is considerable and will continue to rise as the dialysis population increases. Maintaining the status quo will prevent timely access to optimal treatment for many patients, especially for those living in extreme poverty and with a low level of education and for patients living in LMICs.

Ethical aspects

A 2020 review by a panel of nephrologists and ethicists appointed by three large nephrology societies outlined the main ethical concerns associated with kidney care 76 . With regard to management of kidney failure (Box  1 ), equitable access to appropriate treatment is probably the most important ethical issue and is relevant not only in the context of haemodialysis but also for the other modalities of kidney care (including transplantation, PD and comprehensive conservative care) 76 . Of note, conservative care is not equivalent to the withdrawal of treatment, but rather implies active management excluding KRT.

As mentioned previously, access to such care is limited in many countries 10 , 77 . Inequities in access to dialysis at the individual level are largely dependent on factors such as health literacy, education and socio-economic status, but also on the wealth and organization of the region in which the individual lives. Even when dialysis itself is reimbursed, a lack of individual financial resources can limit access to care. Moreover, elements such as gender, race or ethnicity and citizenship status 78 , 79 can influence an individual’s ability to access dialysis 80 . These factors impose a risk that patients who are most vulnerable are subject to further discrimination. In addition, without necessarily being perceived as such, dialysis delivery may be biased by the financial interests of dialysis providers or nephrologists, for example, by influencing whether a patient receives in-centre versus home dialysis, or resulting in the non-referral of patients on dialysis for transplantation or conservative care 81 , 82 .

A potential reason for the high utilization of in-centre haemodialysis worldwide is a lack of patient awareness regarding the alternatives. When surveyed, a considerable proportion of patients with kidney failure reported that information about options for KRT was inadequate 83 , 84 . Patient education and decision support could be strengthened and its quality benchmarked, with specific attention to low health literacy, which is frequent among patients on dialysis 85 . Inadequate patient education might result from a lack of familiarity with home dialysis (including PD) and candidacy bias among treating physicians and nurses. Appropriate education and training of medical professionals could help to solve this problem. However, the first step to increase uptake of home dialysis modalities is likely policy action undertaken by administrations, but stimulated by advocacy by patients and the nephrology community, as suggested by the higher prevalence of PD at a lower societal cost of regions that already have a PD-first policy in place 68 .

Although the provision of appropriate dialysis at the lowest possible cost to the individual is essential if access is to be improved 86 , approaches that unduly compromise the quality of care should be minimized or avoided. General frameworks to deal with this challenge can be provided by the nephrology community, but trade-offs between cost and quality may be necessary and will require consultation between authorities, medical professionals and patient representatives. Consideration must also be given to whether the societal and individual impact of providing dialysis would be greater than managing other societal health priorities (for example, malaria or tuberculosis) or investing in other sectors to improve health (for example, access to clean drinking water or improving road safety).

The most favourable approach in deciding the most appropriate course of action for an individual is shared decision-making 87 , which provides evidence-based information to patients and families about all available therapeutic options in the context of the local situation. Providing accurate and unbiased information to support such decision-making is especially relevant for conservative care, to avoid the perception that this approach is being recommended to save resources rather than to pursue optimal patient comfort. Properly done, shared decision-making should avoid coercion, manipulation, conflicts of interest and the provision of ‘futile dialysis’ to a patient for whom the harm outweighs the benefits, life expectancy is low or the financial burden is high 88 . However, the views of care providers do not always necessarily align with those of patients and their families, especially in multicultural environments 89 . Medical professionals are often not well prepared for shared decision-making, and thus proper training is essential 90 . Policy action is also required to create the proper ethical consensus and evidence-based frameworks at institutional and government levels 91 to guide decision-making in the context of dialysis care that can be adapted to meet local needs.

Box 1 Main ethical issues in dialysis

Equity in access to long-term dialysis

• Inequities in the ability to access kidney replacement therapy exist worldwide; however, if dialysis is available, the ability to transition between different dialysis modalities should be facilitated as much as possible. Specific attention should be paid to the factors that most prominently influence access to dialysis, such as gender, ethnicity, citizenship status and socio-economic status

Impact of financial interests on dialysis delivery

• Financial interests of dialysis providers or nephrologists should in no way influence the choice of dialysis modality and/or result in the non-referral of patients for transplantation or conservative care

Cost considerations

• Local adaptations are needed to ensure that the costs of dialysis provision are as low as possible without compromising quality of care
• The high cost of dialysis means that consideration must be given to whether the benefits obtained by dialysis outweigh those obtained by addressing other health-care priorities, such as malaria or tuberculosis

Shared decision-making

• Shared decision-making, involving the patient and their family, is recommended as an approach to allow an informed choice of the most appropriate course to follow
• Approaches to shared decision-making must be evidence based and adapted to local circumstances
• Futile dialysis should be avoided
• Proper training is required to prepare physicians for shared decision-making

Clinical outcomes to measure progress

Over the past six decades, the availability of long-term dialysis has prolonged the lives of millions of people worldwide, often by serving as a bridge to kidney transplantation. Yet, patients on dialysis continue to bear a high burden of disease, both from multimorbidity and owing to the fact that current dialysis modalities only partially replace the function of the native kidney, resulting in continued uraemia and its consequences. Thus, although dialysis prevents death from kidney failure, life expectancy is often poor, hospitalizations (particularly for cardiovascular events and infection) are frequent, symptom burden is high and health-related quality of life is low 22 , 92 , 93 .

Given the multitude of health challenges faced by patients on dialysis, it is necessary to develop a priority list of issues. For much of the past three decades, most of this prioritization was performed by nephrology researchers with the most effort to date focusing on approaches to reducing all-cause mortality and the risk of fatal and non-fatal cardiovascular events. However, despite the many interventions that have been tested, including increasing the dose of dialysis (in the HEMO and ADEMEX trials 94 , 95 ), increasing dialyser flux (in the HEMO trial and MPO trial 94 , 96 ), increasing haemodialysis frequency (for example, the FHN Daily and FHN Nocturnal trials 97 , 98 ), use of haemodiafiltration (the CONTRAST 99 , ESHOL 100 and TURKISH-OL-HDF trials 101 ), increasing the haemoglobin target (for example, the Normal Haematocrit Trial 102 ), use of non-calcium-based phosphate binders (for example, the DCOR trial 103 ), or lowering of the serum cholesterol level (for example, the 4D, AURORA and SHARP trials 104 – 106 ), none of these or other interventions has clearly reduced all-cause or cardiovascular mortality for patients on dialysis. These disappointments notwithstanding, it is important that the nephrology community perseveres in finding ways to improve patient outcomes.

In the past 5 years, nephrology researchers have increasingly engaged with patients to understand their priorities for meaningful outcomes that should be used to measure progress. The overarching message from this engagement is that although longevity is valued, many patients would prefer to reduce symptom burden and achieve maximal functional and social rehabilitation. This insight highlights the high symptom burden experienced by patients receiving long-term dialysis 92 , 93 , 96 , 107 . These symptoms arise as a consequence of the uraemic syndrome. Some of these symptoms, such as anorexia, nausea, vomiting, shortness of breath and confusion or encephalopathy, improve with dialysis initiation 108 – 110 , but many other symptoms, such as depression, anxiety and insomnia do not. Moreover, other symptoms, such as post-dialysis fatigue, appear after initiation of haemodialysis.

Of note, many symptoms of uraemic syndrome might relate to the persistence of protein-bound uraemic toxins and small peptides (so-called middle molecules) that are not effectively removed by the current dialysis modalities. The development of methods to improve the removal of those compounds is one promising approach to improving outcomes and quality of life for patients on dialysis, as discussed by other articles in this issue.

Patients on dialysis report an average of 9–12 symptoms at any given time 92 , 93 , 107 . To determine which of these should be prioritized for intervention, the Kidney Health Initiative used a two-step patient-focused process involving focus groups and an online survey to identify six symptoms that should be prioritized by the research community for intervention. These include three physical symptoms (fatigue, insomnia and cramps) and three mood symptoms (depression, anxiety and frustration) 111 . Parallel to these efforts, the Standardizing Outcomes in Nephrology Group (SONG) workgroup for haemodialysis ( SONG-HD ) has identified several tiers of outcomes that are important to patients, caregivers and health-care providers. Fatigue was identified as one of the four core outcomes, whereas depression, pain and feeling washed out after haemodialysis were identified as middle-tier outcomes 112 – 114 . Along these same lines, the SONG workgroup for PD ( SONG-PD ) identified the symptoms of fatigue, PD pain and sleep as important middle-tier outcomes 115 , 116 . Despite the importance of these symptoms to patients on dialysis, only a few studies have assessed the efficacy of behavioural and pharmacological treatments on depression 117 – 121 . Even more sobering is the observation that very few, if any, published studies have rigorously tested interventions for fatigue or any of the other symptoms. The nephrology community must now develop standardized and psychometrically robust measures that accurately capture symptoms and outcomes that are important to patients and ensure that these are captured in future clinical trials 122 , 123 .

Approaches to maximizing functional and social rehabilitation are also important to patients with kidney failure. In addition to the above-mentioned symptoms, SONG-HD identified ability to travel, ability to work, dialysis-free time, impact of dialysis on family and/or friends and mobility as important middle-tier outcomes 112 – 114 . SONG-PD identified life participation as one of five core outcomes, and impact on family and/or friends and mobility as other outcomes that are important to patients 115 , 116 . Given the importance of these outcomes to stakeholders, including patients, it is imperative that nephrology researchers develop tools to enable valid and consistent measurement of these outcomes and identify interventions that favourably modify these outcomes.

Fostering innovation

As described above, the status quo of dialysis care is suboptimal. Residual symptom burden, morbidity and mortality, and economic cost are all unacceptable, which begs the question of what steps are needed to change the established patterns of care. Patients are currently unable to live full and productive lives owing to the emotional and physical toll of dialysis, its intermittent treatment schedule, the dietary and fluid limitations, and their highly restricted mobility during treatment. Current technology requires most patients to travel to a dialysis centre, and current modalities are non-physiological, resulting in ‘washout’, which is defined as extensive fatigue, nausea and other adverse effects, caused by the build-up of uraemic toxins between treatments and the rapid removal of these solutes and fluids over 4-h sessions in the context of haemodialysis. LMICs face additional difficulties in the provision of dialysis owing to infrastructural requirements, the high cost of this treatment, the need for a constant power supply and the requirement for high volumes of purified water. For LMICs, innovations that focus on home-based, low-cost therapies that promote rehabilitation would be especially beneficial.

We contend that initiatives to transform dialysis outcomes for patients require both top-down efforts (for example, those that involve systems changes at the policy, regulatory, macroeconomic and organizational levels) and bottom-up efforts (for example, patient-led and patient-centred advocacy and individual teams of innovators). Top-down efforts are required to support, facilitate and de-risk the work of innovators. Conversely, patient-led advocacy is essential for influencing governmental and organizational policy change. Here, by considering how selected programmes are attempting to transform dialysis outcomes through innovation in support of high-value, high-quality care, we describe how top-down and bottom-up efforts can work synergistically to change the existing ecosystem of dialysis care (Fig.  2 ). The efforts described below are not an exhaustive list; rather, this discussion is intended to provide a representative overview of how the dialysis landscape is changing. Additional articles in this issue describe in more detail some of the bottom-up efforts of innovators to create wearable 124 , portable 125 , more environmentally friendly 126 and more physiological dialysis systems 127 , 128 , priorities from the patients’ perspective 129 , and the role of regulators in supporting innovation in the dialysis space 130 .

Initiatives to transform dialysis outcomes for patients require both top-down efforts (for example, those that involve systems-level changes at the policy, regulatory, macroeconomic and organizational level) and bottom-up efforts (for example, patient-led and patient-centred advocacy efforts and efforts from individual teams of innovators). Both of these efforts need to be guided by priorities identified by patients. Such an approach, focused on patient-centred innovation, has the potential to result in meaningful innovations that support high-quality, high-value care. NGOs, non-governmental organizations.

The Kidney Health Initiative

In 2012, the American Society of Nephrology (ASN) and the FDA established the KHI as an umbrella organization through which the kidney community can work collaboratively to remove barriers to the development of innovative drugs, devices, biologics and food products, in order to improve outcomes for people living with kidney diseases. To advance its mission, KHI has initiated a number of projects composed of multidisciplinary workgroups. A major accomplishment for the KHI was the establishment of a precompetitive environment to promote innovation while ensuring patient safety.

The KHI is the largest consortium in the kidney community, with over 100 member organizations including patient groups, health professional organizations, dialysis organizations, pharmaceutical and device companies, and government agencies. During the first 7 years of its existence, the KHI has launched and in many cases completed projects that have facilitated the development of new therapeutic options for dialysis patients (Box  2 ), as well as published position papers on topics relevant to innovation in haemodialysis care, including innovations in fluid management 131 and symptom management 132 in patients on haemodialysis, recommendations for clinical trial end points for vascular access 133 , perspectives on pragmatic trials in the haemodialysis population 134 and regulatory considerations for the use of haemodiafiltration 135 .

Box 2 Kidney Heath Initiative Projects that Support Dialysis Innovation

Patient and Family Partnership Council

Since 2015, the Kidney Health Initiative (KHI) Patient and Family Partnership Council (PFPC) has helped KHI stakeholders to engage and network with patients and patient organizations. The PFPC also advises industry and research partners of patient needs and preferences as new products are planned and developed. The PFPC continually emphasizes that innovation will only be successful if built around the needs of people with kidney disease and focused on improving their quality of life.

ESRD Data Standard Project

The aim of this project is to create a harmonized common data standard for kidney failure. The availability of a uniform data standard could accelerate the pace of scientific discovery, facilitate the creation of scientific registries for epidemiological surveillance and allow the development of common metrics for value-based health care.

Building Capacity to Incorporate Patient Preferences into the Development of Innovative Alternatives to kidney replacement therapy (KRT)

This project, which is supported by a 3-year contract with the FDA, is based on the premise that access to scientifically valid patient preference information could positively inform the decisions of industry and regulators as they design and review new devices for individuals with kidney failure. This project will collect patients’ preference information and also address a stated goal of the Advancing American Kidney Health (AAKH) initiative, which instructs the FDA to “develop a new survey to gain insight into patient preferences for new kidney failure treatments” 137 .

Clinical Trial Design to Support Innovative Approaches to KRT

This project is intended to facilitate coordinated efforts between regulators and the nephrology community to streamline the clinical development pathway. The primary objectives of the project are to define terminology for future KRT products (for example, wearable, portable, implantable and artificial kidney) and identify the most appropriate trial designs and end points for a variety of KRT products.

Advancing American Kidney Health

In July 2019, President Donald Trump signed an Executive Order on Advancing American Kidney Health (AAKH) 136 , which promises to fundamentally change the clinical care of kidney disease in general and kidney failure in particular. Components of the AAKH that are relevant to dialysis care include a directive for education and support programmes to promote awareness of kidney disease; a shift in the focus of reimbursement initiatives from in-centre haemodialysis to home therapies, transplantation and upstream CKD care; a system that rewards clinicians and dialysis facilities for providing a range of treatments for kidney failure, with the aim of increasing uptake of home dialysis and transplantation; and incentives for nephrology care teams to focus on reducing costs and improving outcomes by providing longitudinal care of patients with kidney disease.

Finally, and perhaps most radically, the AAKH calls on the US Department of Health and Human Services to support premarket approval of wearable and implantable artificial kidneys and welcomes other strategies to facilitate transformative innovation in dialysis devices. The AAKH directive specifically identifies the KidneyX programme (described below) as the vehicle with which to drive this innovation. The AAKH is the most ambitious US policy initiative ever undertaken to transform the care of patients with advanced kidney disease. Its agenda is still being shaped by the federal governmental agencies, with input from professional societies and other kidney community stakeholders, but this initiative provides a framework and support for transformative innovation in dialysis care.

The KHI Technology Roadmap and KidneyX

The KHI Technology Roadmap for Innovative Approaches to KRT, published in 2019 (ref. 137 ), is aimed at supporting the development of innovative dialysis devices by providing guidance on technical criteria, patient preferences, assessment of patient risk tolerances and regulatory, reimbursement and marketing considerations. Key strengths of the Roadmap include its patient-centred focus and the description of multiple solution pathways for different technologies (for example, portable, wearable and implantable devices that may be purely mechanical, cell-based or hybrid systems), each with appropriate timeline projections.

The KRT Roadmap was designed to be complementary to the Kidney Innovation Accelerator (also known as KidneyX). KidneyX is a public–private partnership between the Department of Health and Human Services and the ASN, and is aimed at accelerating the development of drugs, devices, biologics and other therapies across the spectrum of kidney care. The current major focus of KidneyX is to catalyse the fundamental redesign of dialysis, supported by a series of competitions. Phase I prizes focused on innovations in biomaterials, novel biosensors and safety monitors used for haemodialysis, as well as approaches for improved vascular access and the development of novel technologies that replicate kidney function more precisely than conventional dialysis. Phase II focuses on strategies to build and test prototype solutions or components of solutions that can replicate normal kidney function or improve haemodialysis access. KidneyX has also awarded a series of Patient Innovator Challenge prizes to patients who have proposed innovative solutions to problems emanating from their everyday experiences with kidney disease, including approaches to monitoring blood electrolyte levels and increasing the accessibility of patient education resources.

Dutch Kidney Foundation and Neokidney

The Dutch Kidney Foundation (DKF; or Nierstichting Nederland ) was founded in 1968. It supports research into the causes, prevention and treatment of kidney failure. Furthermore, it works to improve the quality of dialysis treatment and increase the number of kidney transplants. All projects are planned and organized with considerable patient involvement. The DKF also offers financial support to kidney research projects by large Dutch multi-centric consortia. These projects not only promote innovation in the Netherlands but also support trans-national European Union (EU)-supported projects with Dutch participation or leadership, such as Horizon 2020 and Horizon Europe.

Neokidney is a partnership between the DKF and several companies that specialize in miniaturization of dialysis equipment (including dialysis pumps) and sorbent technology for dialysate regeneration. This partnership is aimed at developing a small, portable haemodialysis device that will enable more frequent dialysis sessions, permit more flexibility for patients and improve patient quality of life, as well as reduce health-care costs. The first prototype is currently undergoing preclinical testing and is expected to be tested in humans soon, with the aim of demonstrating proof-of-concept for the first portable haemodialysis machine for daily use, requiring only a limited volume of dialysate. In addition to the development of miniaturization technologies, the partnership is also investigating the use of polymer membranes that permit combined filtration and absorption to achieve more effective haemodialysis 138 .

Nephrologists Transforming Hemodialysis Safety

Nephrologists Transforming Hemodialysis Safety (NTDS) is a collaborative initiative of the ASN and Centers for Disease Control and Prevention (CDC) that is aimed at addressing a specific complication inherent to contemporary dialysis — infection. In 2016, the CDC observed that 10% of dialysis patients in the USA died each year as the result of infections — most of which were preventable. The aim of NTDS is to develop and deploy innovations to achieve zero preventable infections in dialysis facilities across the USA. To reach this goal, NTDS uses a multi-pronged approach. For example, education strategies via publications 139 – 143 and webinars that address various aspects of infection prevention and standards of care, use of social media, development of an interactive chapter for trainees and clinicians, and invited lectures are aimed at ensuring that nephrologists, nurses, dialysis administrators and other professionals understand the risk of dialysis-related infections and evidence-based best working practices.

NTDS also interacts with experts in infection detection, prevention and treatment within federal, state and local health departments who can provide advice and assistance that is independent of the regulatory and potentially punitive arms of health departments. NTDS promotes the appropriate use of these experts in settings where expert advice is needed.

To promote leadership among physicians and nurses, NTDS is sponsoring a leadership academy to ensure that knowledge pertaining to evidence-based best working practices is applied to improve workflows in clinical practice. Effective leadership is a requirement, particularly in complex settings, to ensure that patient safety is prioritized and to motivate staff to use best practices.

NTDS are also collaborating with human factors engineers to study the workflows used in haemodialysis facilities and help to define ways of avoiding errors that lead to infection. As a first step in this process, NTDS and human factors engineers have spent time in various haemodialysis facilities to obtain information about the complex processes of care within those facilities, particularly with regard to the use of haemodialysis catheters and approaches to hand hygiene, injection safety and disinfection. Better understanding of current processes may lead to better workflow design.

Finally, based on lessons learned during the Ebola Crisis of 2014, an NTDS work group has designed processes to anticipate and respond to unexpected health-care crises. At the time of writing this Review, the NTDS team is working with CDC and haemodialysis organizations to anticipate and respond to the COVID-19 epidemic and its effect on dialysis care.

The Affordable Dialysis Prize

As discussed earlier, kidney failure remains a death sentence for many residents of LMICs owing to a lack of access to dialysis. In response to the pressing need for cost-effective dialysis options, the International Society of Nephrology in collaboration with the George Institute for Global Health and the Asian Pacific Society of Nephrology launched the Affordable Dialysis Prize in 2017 with the objective of facilitating the design of a dialysis system that would cost less than US $1,000, and provide treatment for less than $5 a day, yet be as safe and effective as existing dialysis systems. The prize was awarded to an engineer for a system that runs off solar power and includes a miniature distiller for producing pure water from any source via steam distillation. The purified water can then be mixed with electrolytes in empty PD bags to produce cheap, homemade dialysis solutions. This strategy identifies the lack of cheap, high-quality water as a major impediment to dialysis in LMICs and LICs. The system will ideally fit into a small suitcase 144 . This device remains under development with the goal of initiating clinical trials and ultimately commercializing the technology.

Empowered in-centre haemodialysis

For some patients with kidney failure, maintenance in-centre haemodialysis will always be the preferred treatment, and despite incentivizing policy levers, they will not be interested in pursuing home dialysis or kidney transplantation. In-centre self-dialysis (also referred to as empowered haemodialysis) originated in Sweden, when a young engineer named Christian Farman returned to haemodialysis in 2010 after a failed transplant. Farman began negotiating with his nurses to perform his own dialysis treatments with staff supervision and caught the attention of other patients 145 . Eventually, the process of self-dialysis within this centre — whereby coaches in the dialysis unit train people to take over control of their own treatments and health — grew so popular that a new unit was built at the hospital for self-dialysis patients only, with patient input into the design of the unit. Since then, self-care units were installed in several haemodialysis units in Europe and the USA, offering patients the autonomy and flexibility of home haemodialysis within the safety of a controlled environment. This approach to empowering patients has not been widely used to date, but deserves rigorous study and evaluation 146 .

Remote monitoring to support self-care

Telemedicine is defined as the electronic exchange of medical information between sites with the aim of improving a patient’s health. Telehealth encompasses a broader set of services such as the provision of educational content. New technologies have broadened the scope of telemedicine and telehealth applications and services, making these tools more accessible and useful in the care of patients who live remotely or have difficulty visiting a clinic. The range of services that can be delivered by telehealth now includes two-way interactive video, device data programming, asynchronous messaging , sensors for remote monitoring and portals to enable patients to access electronic health records. Although relatively understudied in haemodialysis patients to date, telehealth has the potential to increase the acceptance of home dialysis and improve patient satisfaction, while potentially decreasing costs and improving outcomes.

Telehealth and the remote monitoring of dialysis patients has become more commonplace in the past decade, particularly in Australia, where telehealth is used widely for patients receiving home dialysis. Telemedicine is also considered a support tool for kidney care in disaster situations such as earthquakes where many individuals in remote locations can be affected. Telemedicine has also been used for distance monitoring of patients receiving PD 147 , 148 . In the USA, the Bipartisan Budget Act of 2018 included provisions to expand telehealth coverage to include patients on home dialysis. This legislation allows patients on home dialysis to choose to have their monthly care-provider visits take place via telehealth, without geographic restrictions. The ongoing COVID-19 pandemic has also resulted in an unprecedented and rapid expansion in the use of telemedicine for providing health care in many regions worldwide, including for the care of patients undergoing in-centre haemodialysis. The experience gained during this pandemic has the potential to permanently embed telemedicine in health-care delivery in many health-care systems.

Although telehealth has considerable promise for the care of dialysis patients, the implementation of telehealth in clinical practice can be challenging 149 . Telehealth-guided digital interactions have the potential to improve outcomes through the provision of activities such as individualized patient-centred education, remote communication and data exchange, in-home clinical guidance and monitoring, assessment of prescription and/or treatment efficacy and adherence, real-time modification of treatments and early alerts for problems that require intervention, although all of these interventions need to be rigorously tested 150 .

The European Kidney Health Alliance

The European Kidney Health Alliance (EKHA) is a non-governmental organization based in Brussels, Belgium, which advocates for kidney patients and the nephrology community at relevant bodies of the EU and also at European national organizations. The EKHA represents all of the major stakeholders in kidney care, including physicians, patients, nurses and foundations. The actions of the EKHA are supported by a dedicated group of Members of European Parliament. Of note, according to the treaty of Lisbon 151 , health-care systems are the responsibility of the national authorities of EU countries, which limits the role of the European Commission to one of complementing national policies and fostering cooperation. The EKHA has undertaken several initiatives in the area of kidney care, mainly focusing on measures to decrease the costs of kidney care while maintaining quality of care and access for all appropriate candidates, and to reduce demand for dialysis by promoting efforts to prevent the progression of kidney disease, and encouraging kidney transplantation as the KRT of choice 66 , 152 . In 2021, the EKHA will focus on reimbursement strategies and access to KRT, especially home haemodialysis.

The Nephrology and Public Policy Committee is a similar initiative created by the European Renal Association–European Dialysis and Transplant Association (ERA–EDTA). This committee aims to translate important kidney-related clinical topics into public policy, including the search for novel biomarkers of CKD, improving transition between paediatric and adult nephrology, and improving collaboration between the ERA-EDTA Registry and the guidance body of the ERA-EDTA, European Renal Best Practice 153 .

Beating Kidney Disease

Together with the Dutch Federation for Nephrology and the Dutch Kidney Patients Association, the DKF has initiated a strategic agenda for research and innovation in the Netherlands. This initiative, called Beating Kidney Disease (Nierziekte de Baas) will promote four specific research areas 154 : prevention of kidney failure, including root causes such as other chronic diseases; personalized medicine including genome and big data analyses, and studies of rare diseases; patient-centred outcomes and quality of life, transplantation and home haemodialysis; and regenerative medicine including bio-artificial kidneys. In collaboration with the EKHA, the Beating Kidney Disease initiative will be proposed as a framework for future initiatives at the Directorate General for Health and Food Safety of the European Commission, and the European Commissioner of Health. Similar to European initiatives that have promoted transplantation 152 , 155 , 156 , these efforts will emphasize shifts in policy action to strengthen institutional frameworks, improve education, training and information, optimize registries, and ensure appropriate benchmarking in nephrology.

Conclusions

The past 50 years have seen rapid changes in how and to whom dialysis is provided. From a global perspective, the escalating numbers of patients who require dialysis mean that even current costs are not sustainable, and yet most people who develop kidney failure forego treatment owing to a lack of access, with millions of lives lost every year as a consequence. Also important, the limitations of current dialysis treatment in alleviating patient suffering, morbidity and mortality are now viewed as unacceptable. Consequently, patients, payors, regulators and health-care systems are increasingly demanding improved value, which can only come about through true patient-centred innovation that supports high-quality, high-value care. Substantial efforts are now underway to support requisite transformative changes. These efforts need to be catalysed, promoted and fostered through international collaboration and harmonization to ensure that in the future, people living with kidney failure have more and better treatment options than exist today.

Author contributions

The authors contributed equally to all aspects of the article.

Competing interests

J.H. declares that The Kidney Research Institute and the Center for Dialysis Innovation at the University of Washington, which he directs, has received gift and grant support from the Northwest Kidney Centers, a not-for-profit dialysis provider. The Center for Dialysis Innovation has also received a Phase I prize from KidneyX, and a grant from the Veterans Administration. J.H. is also a founder and holds equity in AKTIV-X Technologies, Inc. R.V. has consulted for Baxter Healthcare, B. Braun and Neokidney. R.M. has received an honorarium from Baxter Healthcare and serves as a member of the Board of Trustees of the Northwest Kidney Centers. M.T. has received a lecture fee from B. Braun, which was donated to charity.

Peer review information

Nature Reviews Nephrology thanks M. Verhaar, who co-reviewed with M. van Gelder, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Affordable Dialysis Prize: https://www.dialysisprize.org/

Dutch Kidney Foundation: https://www.narcis.nl/organisation/RecordID/ORG1238896/Language/en

ESRD Data Standard Project: https://khi.asn-online.org/projects/project.aspx?ID=78

European Kidney Health Alliance: http://ekha.eu/

Kidney Health Initiative: https://khi.asn-online.org/

KidneyX: https://www.kidneyx.org/

Neokidney: https://www.nextkidney.com/

Nephrologists Transforming Hemodialysis Safety: https://www.asn-online.org/ntds/

Nephrology and Public Policy Committee: https://www.era-edta.org/en/nppc/

Nierstichting Nederland: https://nierstichting.nl/

Patient and Family Partnership Council: https://khi.asn-online.org/pages/?ID=1

SONG-HD: https://songinitiative.org/projects/song-hd/

SONG-PD : https://songinitiative.org/projects/song-pd/

Standardizing Outcomes in Nephrology Group (SONG): https://songinitiative.org/

• Open access
• Published: 27 June 2023

Factors predicting post-dialysis fatigue of maintenance hemodialysis patients

• Huiwen Li 1   na1 ,
• Jinmei Yin 1   na1 ,
• Yi Dong 1 &
• Zhiwu Tian 1  

Renal Replacement Therapy volume  9 , Article number:  30 ( 2023 ) Cite this article

1667 Accesses

1 Citations

Metrics details

Post-dialysis fatigue is a common complication in maintenance hemodialysis patients. This study aims to evaluate post-dialysis fatigue and discover related risk factors.

Design and methods

In this cross-sectional study, we used the specific scale to measure post-dialysis fatigue of maintenance hemodialysis patients from June to September 2021, and looked for risk factors from sociodemographic and clinical data.

The post-dialysis fatigue score for 147 maintenance hemodialysis patients was 14.75 ± 8.24. The post-dialysis fatigue was associated with increasing age ( b  = 2.00, p  = 0.016), fewer dialytic vintages ( b  =  − 1.91, p  = 0.001), increasing inter-dialysis weight gain ( b  = 5.79, p  < 0.01), decreasing hemoglobin ( b  =  − 3.30, p  = 0.011) and Kt/V ( b  =  − 2.74, p  = 0.035).

Conclusions

Patients with old age, dialytic vintage less than 36 months, poor control of inter-dialysis weight gain, anemia, and inadequate dialysis are more likely to suffer from post-dialysis fatigue.

Introduction

For patients with end-stage renal disease (ESRD), kidney transplantation, peritoneal dialysis and hemodialysis are the main methods to prolong their lives and improve their quality of life [ 1 ]. As the most commonly used technique in renal replacement therapy, hemodialysis has played an important role in prolonging the life expectancy of ESRD patients [ 2 ]. For maintenance hemodialysis (MHD) patients, while enjoying the prolonged life, they are also bearing the undesirable symptoms that accompany hemodialysis, such as fatigue, especially post-dialysis fatigue (PDF) [ 3 ].

MHD patients should be able to return to society in a better condition after hemodialysis, but the appearance of PDF has made it more difficult [ 4 ]. Different from the persistent fatigue caused by chronic diseases, PDF is a kind of discomfort after hemodialysis. It is often described as MHD patients feeling tired or exhausted and requiring rest or sleep after the dialysis session [ 5 ]. PDF is regarded as one of the indicators of debilitating MHD patients, and it is usually the main reason for patients' unwillingness to comply with the best dialysis prescriptions [ 3 ]. Therefore, we should attach sufficient attention to PDF to ensure the effectiveness of treatment.

There are not many studies on PDF, and the measurement tools and evaluation criteria are different. Some studies used open-ended questions to understand the degree of fatigue of patients [ 5 , 6 ], some studies used the time to recover from dialysis (TIRD) to indirectly measure the degree of fatigue of patients [ 3 , 7 , 8 , 9 ], some studies focused on using the fatigue-specific PROM (patient-reported outcome measure) as a measure of fatigue in the dialysis population [ 10 , 11 ]. It is difficult to truly grasp the current status of PDF in MHD patients through existing studies, but we can still use the existing results as a reference to get a preliminary understanding of the relevant information about PDF. A multi-center study on PDF found that 60.5% of MHD patients had PDF, of which 22.1% were moderate PDF and 38.4% were severe PDF [ 8 ]. Among MHD patients who have been on hemodialysis for more than 1 year, 74% of patients have PDF, and nearly 50% of patients have a recovery time of more than 2 h after dialysis [ 7 ]. The prevalence and severity of PDF in MHD patients should be given enough attention.

According to the existing studies, we can think that the appearance of PDF is associated with higher mortality, higher hospitalization and worse mental state of MHD patients [ 9 , 12 ]. But it is still not clear for us to understand the causes of PDF. Some studies have found that lactic acid level and interleukin-10 (IL-10) are related to PDF from the perspective of biochemistry [ 6 , 7 ], some studies have found that sedentary behavior and daily activity ability are related to PDF from the perspective of lifestyle [ 8 , 13 , 14 ], and some studies have found that the ultrafiltration rate and inter-dialysis weight gain (IDWG) are related to PDF from the perspective of dialysis [ 5 , 9 ].

Therefore, this study aims to use a dedicated rating scale to evaluate PDF in MHD patients and discover related risk factors to deepen the understanding of PDF among researchers and clinicians and provide a theoretical basis for future interventions.

Materials and methods

This was a single-center cross-sectional study in the Blood Purification Center from June 2021 to September 2021. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies. All participants signed informed consent. This study has been approved by the ethics committee of our hospital.

Participants

In this study, we recruited ESRD patients with stable clinical characteristics and receiving hemodialysis for more than 6 months. All patients were able to go to the center for hemodialysis on their own. Considering other disease-related factors that may have an impact on the patient's fatigue, we excluded patients with the following conditions: severe cardiovascular and cerebrovascular diseases, mental illness that is difficult to diagnose and treat, surgery within the past month, and acute infections. All patients received hemodialysis 3 times a week for 4 h each time, using standard bicarbonate dialysate. The dialysate flow was 500 mL/min and the blood flow was 200–300 mL/min. All dialyzers used biocompatible membranes. This study adopted convenient sampling method. In this study, 14 predictors were selected. According to the empirical formula, the sample size should be 5–10 times of the number of predictors. Considering 20% unqualified questionnaires, the minimum sample size of this study is 14*5*(1 + 20%) = 84. All participants signed informed consent forms. This study has been approved by the ethics committee of our hospital.

Data collection and measurements

Electronic information systems are used to extract relevant information about patients, including gender, age, occupation, primary diseases of ESRD, dialytic vintage, height, dry weight, body mass index (BMI), weight before and after dialysis, hemodialysis mode (Hemodialysis = HD, Hemodiafiltration = HDF, Hemodialysis and Hemoperfusion = HD + HP), ultrafiltration volume, systolic blood pressure before and after dialysis, and blood biochemical results (including hemoglobin, serum albumin, predialysis potassium and predialysis phosphorus), Kt/V, etc.

We have integrated some of the original data and converted it into another variable for statistical analysis, such as inter-dialysis weight gain. The difference in systolic blood pressure before and after dialysis is used to judge the patient's blood pressure stability (If the absolute value of the difference is within 20 mmHg, we believe that the patient’s blood pressure is stable in this dialysis session).

Regarding the collection of blood samples, according to the requirements of Blood Purification Standard Operating Procedure [ 15 ], the hemodialysis specialist nurse collected blood from the patient's arteriovenous fistula (AVF) or central venous catheter (CVC) before and after dialysis and sent it to the laboratory for evaluation of hemoglobin, serum albumin, potassium and phosphorus in the blood. The evaluation of all laboratory data was based on the recommendations of the Chinese Hemodialysis Adequacy Clinical Practice Guidelines [ 16 ].

PDF measurement

There are three methods that have been used to assess PDF. The first is to use the simple visual analogue scale (VAS), which is, in general, used as a measure of the level of fatigue experienced by individuals after undergoing hemodialysis. The second is to use TIRD to evaluate the PDF indirectly. TIRD is an open-ended question asked by the investigator to the patients: how long will it take for you to recover to a healthy state after dialysis treatment [ 17 ]. This question was easily understood by patients and widely used by researchers and clinicians. The third, and innovative aspect of this study, is to use the PDF scale developed by Kodama [ 18 ] to directly evaluate PDF. Previous studies on PDF extracted some questions from a complete scale to measure PDF, which undoubtedly destroyed the integrity of the scale. Unlike these scales, the PDF scale is a complete scale specifically developed to evaluate post-dialysis fatigue in MHD patients. This was a self-rating scale containing 13 items. The content of the scale is the adverse symptoms of the patients after dialysis, including fatigue, general malaise, feeling exhausted and weak, lightheadedness, need to lie down and take a nap or rest, difficulty moving without taking a nap or rest, no appetite, headache, thoracic discomfort, toothache, not wanting to move, not being motivated to do anything and feeling pain after dialysis and eventually doing nothing for the whole day. These symptoms are evaluated on a 5-point scale, ranging from “very severe” or “strongly agree” to “not at all” or “absolutely not applicable”. The higher the patient's self-score, the more severe the PDF. The cumulative variance contribution rate of the scale in the hemodialysis population was 51.08%, and the Cronbach's alpha was 0.924 [ 18 ].

Our center conducted blood sampling for patients on a regular basis to facilitate timely adjustment of the dialysis program. Blood was collected before and after dialysis to evaluate the effect of the dialysis. The PDF measured in this study was exactly the patients' fatigue after this dialysis. Because the patients were on regular dialysis, we administrated the questionnaire face-to-face to the patients at the next dialysis treatment. Therefore, the time interval between blood collection and questionnaire administration was 2–3 days.

Statistical analysis

Continuous variables with normal distributions were presented as mean ± standard deviation (SD), and those without normal distributions as the median (interquartile range), categorical variables as number (percentage). Differences between groups were analyzed with independent-samples t test or one-way ANOVA, and the LSD (Least—Significant Difference) method was used to make multiple comparisons between groups. Pearson correlation coefficient was used to test the relationship between TIRD and PDF scores. We use multivariate regression to analyze the risk factors of PDF. P value < 0.05 was considered statistically significant. All statistical analysis was completed in SPSS 25.0 software.

Relationship between VAS, PDF score and TIRD

In this study, we evaluated the internal consistency reliability of the PDF scale and the correlation between the items using the Cronbach’s α and corrected item-total correlation (CITC). The results showed that the Cronbach’s α was 0.851 and the CITC value ranged from 0.284 to 0.691 (Table 1 ), indicating that the scale had good reliability and reasonable correlation among the items.

In this study, the VAS was 4.55 ± 2.09 and the TIRD was 2.64 ± 2.42 h. The PDF was 14.75 ± 8.24 (0–33), and no patients showed particularly high PDF. The results of the correlation analysis showed that the PDF and its items had r -value between 0.283 and 0.836 with the VAS and between 0.229 and 0.682 with the TIRD (Table 2 ), further confirming the reliability and stability of the PDF scale. The next statistical analysis used PDF score as the dependent variable instead of TIRD.

Participants characteristics

A total of 147 MHD patients were included in this study. Their demographic characteristics, clinical characteristics were shown in Table 3 . The mean age was 51.63 ± 12.14 years (range from 20 to 83 years), and male patients accounted for 59.9%. The PDF score of patients over 60 years old was significantly higher than that of patients younger than 60 years old ( p  < 0.01), but there was no difference in PDF score between male and female patients ( p  = 0.069). Patients employed accounted for 74.1%, and their PDF score was significantly higher than those unemployed ( p  = 0.011). The median (interquartile range) for dialytic vintage (months) was 52 (33, 98). Glomerulonephritis accounted for 63.9% of all primary causes of ESRD. According to the recommendations of the guidelines, the IDWG within a reasonable range (less than 5% dry weight) of patients accounted for 69.4%. In the clinical characteristics, except for the dialysis vintage and IDWG ( p  = 0.027 and p  < 0.01, respectively), other factors, including primary causes of ESRD, BMI, change in SBP and hemodialysis mode, were not associated with PDF ( p  > 0.05).

Table 4 showed the differences in the laboratory parameters of the PDF score in MHD patients. Sixty-eight percent of patients had hemoglobin levels above 100 g/L, and their PDF score was significantly lower than those of patients with hemoglobin levels below 100 g/L ( p  < 0.01). The Kt/V levels of 70.1% of patients reached the range recommended by the guidelines (≥ 1.2). Compared with patients with Kt/V levels less than 1.2, the PDF score of the former was significantly lower ( p  = 0.042). As for serum albumin, predialysis K and predialysis P, there was no statistically significant difference between the groups in their PDF scores.

Risk factors of PDF

We performed multiple linear regression analysis on the statistically significant related factors in the above results to determine the influencing factors of PDF in MHD patients. The results showed that the risk factors of PDF were age ( b  = 2.00, p  = 0.016), dialysis vintage ( b  =  − 1.91, p  = 0.001), IDWG ( b  = 5.79, p  < 0.01), hemoglobin ( b  =  − 3.30, p  = 0.011) and Kt/V ( b  =  − 2.74, p  = 0.035) ( R 2  = 0.315, F  = 10.724, p  < 0.01; Table 5 ).

This study was one of the few to directly measure the PDF of MHD patients in the form of a scale, and used TIRD to measure the PDF indirectly. TIRD could be used as a simple tool to quickly evaluate the PDF of MHD patients. The primary finding of this study was that the PDF of MHD patients was 14.75 ± 8.24, and no patients showed particularly high PDF. The PDF of MHD patients was associated with age more than 60 years, dialytic vintage less than 36 months, increasing IDWG, decreasing hemoglobin and insufficient dialysis.

Among the demographic factors, this study found that the age over 60 was an independent risk factor for PDF in MHD patients. Compared with other studies that have found that there was no age difference in PDF of MHD patients, this finding was novel and worthy of reflection [ 5 , 7 ]. One possible explanation was that compared with younger people, older people have more chronic disease symptoms, slower recovery of body functions, and poor tolerance [ 1 ]. For example, most elderly patients with MHD were accompanied by blood pressure instability, whether it was hypotension or hypertension. During dialysis, as antihypertensive drugs were partially removed or the ultrafiltration volume increased, the adverse effects of blood pressure changes on such patients appeared, and this result was often considered to be caused by dialysis. Therefore, the PDF of elderly patients with MHD appeared to be severe. As for the relationship between employment and PDF, the results of this study were inconsistent with previous results. The reason for this result may be related to occupational type and work intensity, and the exact conclusion needs further research to verify.

From the perspective of dialysis factors, dialytic vintage and IDWG were independent risk factors for PDF in MHD patients, and IDWG was an important risk factor. Our study found that the PDF of MHD patients within 36 months of dialytic vintage was relatively severer, which was contrary to the results of previous studies that found that PDF increased with the increase of dialytic vintage [ 7 ]. This phenomenon may be related to the following reasons. First, although patients have been on hemodialysis for more than 6 months, there are still some patients who are in the vascular access selection phase for vascular reasons or for fear of pain, especially arteriovenous fistula (AVF) and central venous catheter (CVC). Second, most patients are expected to work, and due to hemodialysis 2–3 times a week, they have difficulty coordinating or finding a suitable job in a short period of time, and they have to meet their work demands by reducing their dialysis time, which undoubtedly increases the PDF. Third, as patients' old habits are broken and new habits have not yet been formed, the dry weight, water intake, and urine output are constantly changing. Failure to assess and adjust for these changes in a timely manner can also result in poorly set dialysis prescriptions and increased patients' fatigue. Given that most of the above reasons are specific realities of dialysis treatment in our centre, we cannot exclude the possibility that high PDF cases tend to die within 36 months, and this result may not apply to other areas as well. Despite this, we can still take the following measures to face these situations. On the one hand, patients need to adjust their living conditions and habits to adapt to their future dialysis life; on the other hand, we should improve management measures, dynamically adjust dialysis prescriptions, and improve dialysis quality to reduce PDF.

In addition, unlike previous negative results that IDWG and PDF were not related, this study found that PDF in MHD patients was significantly correlated with increased IDWG [ 8 ]. As a reference indicator of the ultrafiltration volume during a dialysis session, IDWG affected the quality of dialysis of MHD patients [ 19 ]. The increasing IDWG meant that the water in the patient's body increased, which caused a burden on the body and the heart, which could easily lead to symptoms such as heart failure and high blood pressure [ 20 ]. The primary purpose of hemodialysis in patients with MHD was to remove excess water from the body, but in order to ensure the reperfusion balance of various organs and reduce complications such as cramps and hypotension, the ultrafiltration volume of a single dialysis was generally not more than 5% of dry weight [ 15 ]. With the increase of IDWG, the ultrafiltration volume was increasing, the hemodynamics of patients during dialysis became unstable, and it was more likely to cause dialysis complications such as acute cardiac ischemia and abnormal regional wall motion and caused PDF [ 21 , 22 ]. If the IDWG of MHD patients increased too much, the effective way was to increase the number of dialysis instead of increasing the ultrafiltration volume in a single dialysis, which could not only ensure the quality of dialysis, but also reduce PDF.

The results of the relationship between laboratory indicators and PDF for MHD patients were unexpected but reasonable. After all, the findings of previous studies on the relationship between the two were not consistent [ 6 , 8 ]. This study found that the PDF of MHD patients increased with the decrease of hemoglobin and Kt/V. As one of the most powerful indicators of anemia, the reduction of hemoglobin could easily induce fatigue in MHD patients [ 23 ]. However, the hemoglobin of MHD patients was often stable because of erythropoietin and iron. Therefore, the increase of fatigue caused by the decrease of hemoglobin would not only appear after dialysis, but also before dialysis, even on non-dialysis days, which could be the reason for the inconsistent results of related studies. Kt/V represented the adequacy of dialysis, and its increase represented an increase in the clearance rate of small molecule toxins such as urea by dialysis, the body burden of MHD patients was reduced, and the PDF was reduced.

This study used a newly developed PDF-specific scale to evaluate the PDF of MHD patients, with the expectation of standardizing the evaluation of PDF and providing new directions for future research on PDF. In addition, the participants in this study were all patients undergoing long-term hemodialysis in our center, and the investigators were all their nurses in charge, who had a considerable understanding of their basic information and disease status, thus ensuring the validity of the questionnaire data.

Some limitations of this study need to be noted. First of all, the scale used in this study were developed recently, and the scope of use was relatively small. On the one hand, this study may have benefited more by the use of value graded scaling like from 1 to 10 for each symptom rather than a 5-point scale. On the other hand, there may be some differences when comparing the results of other studies. Future studies can compare the objective results evaluated using the scale with the results subjectively felt by patients in order to complete the measurement of PDF from multiple perspectives and improve the PDF scale. In addition, this study used the face-to-face questionnaire method, in which the investigator asked the patients about their fatigue after the last dialysis. Due to the frequency of dialysis in MHD patients, the time of questionnaire administration will be 2–3 days away from the last dialysis time. Therefore, patients may have recall bias, and we cannot accurately determine whether their responses were about fatigue after the last dialysis or chronic fatigue throughout the dialysis period. Telephone follow-up on the second day of dialysis for MHD patients may be a better way to investigate. Moreover, this study was a single-center, cross-sectional study with a small sample size and slightly underrepresented, which also contributed to the suboptimal Cronbach's coefficient alpha of the PDF scale in this study. Finally, the time span we set for the analysis vintage is too large, resulting in too many confounding factors, so the impact of the dialysis vintage on the PDF may be unstable. In future studies, we will consider collaborating with other centers to expand the sample size, increase sample diversity, control for confounding factors, and perform the necessary stratified analysis to improve the stability of the results.

In conclusion, PDF was ubiquitous in MHD patients and should be given enough attention. In this study, PDF was more serious in MHD patients with old age, dialytic vintage less than 36 months, poor control of IDWG, anemia, and inadequate dialysis.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Huiwen Li and Jinmei Yin contributed equally to this work and should be considered as co-first authors.

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Blood Purification Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China

Huiwen Li, Jinmei Yin, Yi Dong & Zhiwu Tian

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HL conceived of the study, and participated in its design and drafted the manuscript. JY carried out the investigation and data curation, participated in formal analysis and drafted the manuscript. YD carried out the investigation and data curation. ZT carried out the supervision and project administration, and participated in its design and coordination and helped to revise the manuscript. All authors read and approved the final manuscript.

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Li, H., Yin, J., Dong, Y. et al. Factors predicting post-dialysis fatigue of maintenance hemodialysis patients. Ren Replace Ther 9 , 30 (2023). https://doi.org/10.1186/s41100-023-00486-z

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The effect of ascending- descending ultrafiltration and sodium profiles on blood pressure in hemodialysis patients: a randomized cross-over study

• Morteza Arasnezhad 1 ,
• Mohammad Namazinia 2 ,
• Seyyed Reza Mazlum 3 &
• Kheizaran Miri 2  

BMC Nephrology volume  25 , Article number:  128 ( 2024 ) Cite this article

Metrics details

Considering no previous research into the utilization of ascending/descending ultrafiltration and linear sodium profiles in improving blood pressure among hemodialysis patients, the present study aimed to explore the effect of the A/D-UF along with linear sodium profiles on HD patients with hypotension.

Applying a crossover design, this clinical trial was fulfilled between December 2022 and June 2023 on 20 patients undergoing HD, randomized into two groups, each one receiving two intervention protocols, viz., (a) an intervention protocol in which the liquid sodium in the dialysis solution was linear and the UF profiling was A/D, and (b) a routine protocol or HD, wherein both liquid sodium and UF in the dialysis solution remained constant. The HD patients’ BP was then checked and recorded at six intervals, namely, before HD, one, two, three, and four hours after it, and following its completion, within each session. The data were further statistically analyzed using the IBM SPSS Statistics 20 and the related tests.

In total, 20 patients, including 12 men (60%) and 8 women (40%), with the mean age of 58.00 ± 14.54 on HD for an average of 54 months, were recruited in this study. No statistically significant difference was observed in the mean systolic and diastolic BP levels in the group receiving the A/D-UF profile all through the desired hours ( p  > 0.05), indicating that the patients did not face many changes in these two numbers during HD. Our cross-over clinical trial demonstrated a statistically significant reduction in symptomatic IDH episodes from 55 to 15% with the application of the A/D-UF profile ( p  < 0.05).

The study demonstrated that the A/D-UF profile could contribute to the stability of blood pressure levels among HD patients, with no significant fluctuations observed during treatment sessions.

Trial Registration

This study was registered in the Iranian Registry of Clinical Trials (no. IRCT20180429039463N5) on 07/01/2023.

Peer Review reports

Introduction

Chronic kidney disease (CKD) is a growing long-term condition affecting around 2–3% of the global population [ 1 ]. The number of hemodialysis (HD) patients in Iran has shown a significant increase over the years, from 945 patients in 1997 to 30,882 cases in 2017 [ 2 ]. HD is the most common treatment for CKD and relies on the principles of diffusion and ultrafiltration (UF) [ 3 ]. Dialyzer machines help filter waste products, excess fluids, and toxins from the blood of individuals with kidney dysfunction [ 4 ]. During UF, fluids are typically removed from the extracellular space (ECF), allowing patients to achieve their dry weight and reduce total plasma volume [ 5 ]. However, this treatment can lead to hemodynamic instability, particularly in patients with fluid overload and hypotension prior to HD. These patients may experience hypotension and various symptoms such as headache, dizziness, nausea, vomiting, and decreased consciousness during the later stages of HD [ 6 ].

The reported incidence of Intradialytic hypotension ranges from 7.5 to 69% according to different definitions [ 7 , 8 ]. Of note, hypotension dramatically increases the total number of deaths in such patients, limits fluid withdrawal during HD, and even brings about severe vascular effects, such as a cerebral infarction, as well as cardiac or mesenteric ischemia. Furthermore, it calls for more nursing care services, and has various negative effects on the quality of life of HD patients [ 9 ]. The routine intervention protocols practiced at some stage in hypotension during HD correspondingly take account of making some changes in the patient’s position into the Trendelenburg one, moderating or halting the UF process, administering normal saline to restore intravascular volume, using high sodium concentrations, and lowering the dialysate temperature [ 10 , 11 , 12 ]. In spite of this, these interventions can result in more sodium and fluid retention in the patient’s body within certain circumstances, wherein they fail to reach dry weight [ 13 ]. Among the methods mainly exploited to improve blood pressure (BP) is UF profiling [ 14 ], described as a set of programs to change the UF speed at different time intervals based on patient’s condition, characterized by assorted types, i.e., linear, step-wise, ascending, descending, functional, etc [ 15 ]... In this context, the A/D-UF profile has been among those investigated in little research [ 6 ]. This type of profiling seems to help maintain the filling of the intravascular volume status in patients during HD, and further adjusts weighing intervals in keeping with the filling volume of the vessels. In addition, it prevents many complications for the duration of HD induced by hypotension, as well as insufficient interdialytic weight gain (IDWG), and failure to reach dry weight at the end of each session [ 16 ]. One other method for preventing and improving hypotension, utilized along with the UF profile, is sodium profiling [ 17 ]. Thus, the combination of the UF and sodium profiles makes HD patients’ BP more stable, so there is less decrease in the BP level [ 18 ]. Sodium profiling is not applied or manually increased or decreased at the bedside in most centers, which raises some problems, such as thirst and IDWG [ 13 ]. Upon adjusting sodium profile, the HD procedure starts with hypernatremic solution at the beginning of each session, and the amount of sodium solution is diminished during the treatment, so the excess sodium transferred for the hypernatremic period is removed from the patient’s blood. Besides, it prevents more hypotension during HD by maintaining intravascular volume [ 19 ]. Recent studies have advocated the combination of the UF and sodium profiles to reduce numerous complications arising in HD [ 19 , 20 ]. For example, the linear UF-sodium profiling had improved BP in the HD patients in one study by Borzou et al. (2015) [ 14 ]. The present study aims to investigate the combined effect of A/D-UF and sodium profiling on HD patients with hypotension, considering the lack of research in using these methods to improve blood pressure in Iran.

Trial design

Using a crossover design, this clinical trial was conducted on the HD patients referred to the Hemodialysis Center of 9-Day Hospital, Torbat-e Heydarieh, Iran, between December 2022 and June 2023 (Fig.  1 ).

CONSORT Flow Chart of participants

Participants

The inclusion criteria were being at the age range of 18–75, suffering from end-stage renal disease (ESRD), experiencing hypotension during HD in more than 20% of the sessions within one month before the study commencement, undergoing HD for over six months, having no shortness of breath and pulmonary edema, and receiving dialysis solution with sodium bicarbonate three times a week. If the patients had taken antihypertensive medications on the day of HD, the results of those sessions were excluded from the data analysis process. Likewise, BP following blood transfusion and the use of other blood volume expanders were not included.

Hypotension during HD was accordingly defined in this study as a condition wherein the systolic BP (SBP) in the patients dropped by more than 30% below 100 mmHg, compared with that before this procedure, or the diastolic BP (DBP) was below 60 mmHg.

Intervention .

Two HD protocols were implemented via a crossover design for both study groups. In this respect, 16 HD sessions were considered for each patient in each protocol. The protocols were (a) an intervention protocol in which the liquid sodium in the dialysis solution was linear and the UF profiling was A/D, and (b) a routine protocol or HD, wherein both liquid sodium and UF in the dialysis solution remained constant. Besides, four wash-out HD sessions were utilized between these two protocols.

The HD duration in the A/D-UF profiling was about four hours. In this HD protocol, UF was divided into three phases, viz., ascending, intermediate, and venular. At the ascending phase, 25.5% of the patient’s total weight was taken with a low UF rate. There was then an aggressive phase taking 51.2% of the patient’s weight at the intermediate phase, which was the maximum UF rate. At the descending phase, 23.6% of the total weight of the patient was further taken, and the UF rate was low. The UF rate refers to the rate at which a fluid or solution is filtered through a membrane using ultrafiltration. These phases were performed during ten steps using the B BRAUN Dialog plus Dialysis Machine, in profile one (Fig.  2 ) (Table  1 ).

Ultrafiltration ascending-descending profile

For the linear sodium profiling, the sodium concentration of the dialysis solution was 150 mmol/L at the onset of HD, which diminished linearly and reached 138 mmol/L at the end of the session. This HD protocol was further divided into three phases, within ten steps, each one lasting 24 min (Fig.  3 ) (Table  2 ).

Linear profile of sodium

During the routine HD protocol, UF remained constant. The same volume of the dialysis was further removed in every hour of this procedure. In this protocol, sodium in the dialysis fluid was constant (140 mmol/L) all through a four-hour session.

Patients’ BP was then checked and recorded at six intervals, namely, before HD, one, two, three, and four hours after it, and following this procedure, within each session.

A two-part questionnaire was also administered to collect the data, that is, the first part was associated with the demographic characteristics, viz., age, gender, education, income, place of residence, first HD date, and vascular access, and the second part was the BP measurement checklist.

To ensure the accuracy of the study, the B BRAUN Dialog plus Dialysis Machine (Germany) was used for all samples. The dialysis solution was sodium bicarbonate buffer and its temperature was set at 37 o C for all patients, the blood flow rate was between 200 and 350 ml/min, and the dialysis fluid flow rate was set at 500 ml/min.

To validate the credibility of the study findings, the patients’ BP was initially measured by the researcher and other colleagues, recruiting 10 samples, and the correlation coefficient of the measured BP levels was then determined. This value was equal to 0.93 and 0.89 as reported by the researcher and the first and second collaborators, respectively. To measure BP, the same standard mercury sphygmomanometer was used for all samples.

Sample size and randomization

Our intention is to enroll 20 patients in the study. The statistical calculations used to determine the required sample size were specifically tailored for cross-over studies, with a significance level (α) of 0.05 and a power (β) of 0.80 [ 21 ].

After extracting the baseline characteristics of the HD patients with reference to their records, those with hypotension in at least more than 20% of the sessions (that is, greater than three sessions) during the last one month, meeting the inclusion criteria in this study, were selected. The patients were then randomized into two groups of 10, benefiting the web-based randomization service ( http://randomozation.com ) to generate the random allocation sequence.

Statistical methods

The data were then analyzed using the IBM SPSS Statistics 20. To describe and categorize the data, descriptive statistics, viz., frequency distribution, mean, and standard deviation (SD) were exploited. Additionally, the repeated measures analysis of variance (RM-ANOVA), paired t-test, and independent samples t-test were employed to test the research hypothesis. The normality of the quantitative variables was further established via the Kolmogorov-Smirnov (K-S) test. Of note, the 95% confidence interval (CI) and the 0.05 significance level were applied in all tests.

In total, 20 patients, including 12 men (60%) and 8 women (40%), with the mean age of 58.00 ± 14.54 on HD for an average of 54 months, were recruited in this study. The vascular access in the majority of the patients (70%) was through a fistula. The modality of most patients was High Flux Hemodialysis (85%). In this study, each patient completed 16 HD sessions, and 320 sessions were totally analyzed (Table  3 ).

The study results demonstrated no statistically significant difference in the mean SBP in the group with the A/D-UF profiling at the intervals before HD, one, two, three, and four hours after it, and following this procedure, in each session ( p  > 0.05). This suggested that the patients did not experience some changes in the systolic and diastolic BP levels during HD. In contrast, there was a statistically significant difference in the mean SBP in the routine HD group before this procedure, one, two, three, and four hours after it, and following HD, in each session ( p  < 0.05). In addition, SBP in the patients in the routine HD group fell by 20 mmHg until the end of this procedure (Table  2 ). The mean DBP of the group receiving the A/D-UF profile at the times before HD, one, two, three, and four hours after it, and following this procedure in each session showed no statistically significant difference ( p  > 0.05). This denoted that the patients did not face changes in DBP during HD. However, there was a statistically significant difference in the mean DBP in the routine HD group before HD, one, two, three, and four hours after it, and following this procedure, in each session ( p  < 0.05), and the patients had been subjected to hypotension during HD (Table  4 ).

A statistically significant difference was further observed in the mean arterial pressure (MAP) in the A/D-UF profiling group before dialysis, one, two, three, and four hours after it, and after HD, in each session ( p  < 0.05). The MAP of the routine HD group before dialysis, one, two, three, and four hours after it, and following this procedure, in each session, also indicated a statistically significant difference ( p  < 0.05) (Table  4 ) (Fig.  4 ) (Fig.  5 ).

Blood pressure in Routine Profile

Blood pressure in ascending-descending profile

Table  5 presents a comparative analysis detailing the various aspects of treatment administered to two distinct groups: one following an ascending-descending profile approach and the other adhering to a routine or standard treatment protocol. This table aims to elucidate the differences in treatment characteristics between these methodologies. Our cross-over clinical trial demonstrated a statistically significant reduction in symptomatic IDH episodes from 55 to 15% with the application of the A/D-UF profile ( p  < 0.05) (Table  5 ).

Hypotension is among the major complications arising during HD, which has been further acknowledged as the leading cause of discomfort in the patients affected [ 19 ]. The results of the present study accordingly established that the patients’ BP in the group receiving the A/D-UF profiling did not drop during HD, but remained in the same range until the end. Nevertheless, the patients’ BP in the routine HD group gradually dropped, and this condition aggravated up until the session completed.

One of the main concerns related to the use of the UF profiling for HD has been thus the interdialytic increase in BP, which seems to be a rise in BP before this procedure. In the present study, no significant difference was further observed in the mean SBP among the patients before HD in the A/D-UF profiling group. Thus, it was concluded that the application of the A/D-UF profile did not produce a sudden increase in the interdialytic BP, and this alleviated the concerns about the growth in BP following this treatment method, which had been until that time brought up in some studies.

Upon the review of previous research into the effect of the A/D-UF profile on patients’ BP during HD, no similar study was found. Therefore, the results of other investigations in this domain were considered. As an example, Tang et al. (2016) assessed the effect of the linear sodium profiling on BP in 13 HD patients at a hospital in China, and presented that the mean SBP after HD was higher in the intervention group than the controls [ 22 ], which was consistent with the results of the present study. This type of profiling seemed to help maintain the filling of the intravascular volume status in patients during HD, and further adjusted weighing intervals in keeping with the filling volume of the vessels. In addition, it prevented many complications for the duration of HD induced by hypotension, as well as insufficient interdialytic weight gain (IDWG), and failure to reach dry weight at the end of each session [ 16 ]. Moreover, Ghafouri-Fard et al. (2010) reflected on the effect of the linear and step-wise sodium and UF profiles on hypotension and muscle cramps on 26 patients undergoing HD at a hospital in Isfahan, Iran, and showed that the use of both profiles as trouble-free and low-cost methods could stabilize the patient’s hemodynamic status during HD by adjusting the sodium concentration and the UF extraction rate [ 3 ].

As well, Borzou et al. (2015) questioned the effect of the linear sodium-UF profiling on tolerance in HD, and confirmed that hypotension was significantly lower in this method as compared with the conventional ones. Additionally, convenience was higher in the linear sodium-UF profiling [ 14 ]. Making some changes in the sodium concentration and the amount of fluid withdrawal enhancing vascular refilling in the linear sodium-UF profiling could thus fuel the patients’ tolerance in HD [ 23 ], which was in line with the results of the present study. Molaie et al. (2014) also investigated the effect of UF and sodium concentration of the dialysis solution in the prevention of BP and muscle cramps during this procedure, and indicated that the sodium and UF profiles as simple and inexpensive methods could reduce hypotension-related complications and muscle cramps [ 24 ].

In this context, Meira et al. (2010) compared two types of sodium profiles, namely, linear and stepwise, on complications during HD in 22 patients in Brazil, and showed that BP and muscle cramps in the linear and step-wise profile group were lower than those advocated in the conventional ones [ 25 ]. These findings were in harmony with the results of the present study. Coli et al. (2003) correspondingly deemed that the UF profiling could result in hemodynamic stability in patients and even prevent blood volume loss during HD as well as hypotension [ 26 ]. Moreover, Maksimov (2002) maintained that BP in HD patients could be kept at an optimal level if a combination of the sodium and UF profiles had been practiced [ 27 ].

Our study observed the trends in patients’ BP levels when subjected to the A/D-UF profiling as opposed to the routine HD protocol. The former group showed a stability in BP, which could suggest an indirect indication of the protocol’s potential in maintaining intravascular volume status. Nevertheless, it should be considered that the A/D-UF-Na group might have experienced lower IDWG and lower UF rates, which in turn may have contributed to the higher BP observed in the study. It is necessary to note that while our study did not directly measure changes in IDWG or precisely analyze the intravascular volume status, the findings related to BP stability imply a potentially beneficial profile that merits further investigation to elucidate this relationship. Future studies specifically designed to assess the impact of UF rate and IDWG on BP outcomes will provide the clarity required to affirm these findings definitively.

In light of the statistical significance in sodium concentration changes before and after dialysis in the A/D-UF group, we delve deeper into its physiological repercussions. Although the A/D-UF profile is not entirely sodium-neutral, the apparent stability it provides could be attributed in part to a vasopressin-mediated effect linked with higher plasma sodium concentration. Ettema’s research elucidates this association by demonstrating that increased plasma sodium levels can stimulate vasopressin release, enhancing vascular tone and volume status [ 28 ]. This osmotically-driven vasopressin release could be one of the underlying mechanisms contributing to the improved hemodynamic stability observed in our study with the A/D-UF protocol.

Overall, the utilization of the A/D UF and linear sodium profiles as undemanding and economical methods could stabilize the patients’ hemodynamic status during HD, and further reduce hypotension by adjusting the sodium concentration and the UF amount. Recent studies have accordingly proposed the combination of both profiles [ 29 ], but no previous research was found to investigate the effect of the A/D-UF profiling on BP among HD patients.

The limitations of this research include the unavailability of some patients (due to travel), the failure of dialysis machines, the small number of B-Brown machines in the hemodialysis center, as well as the need for further clinical investigation to assess the usefulness of the sodium-ultrafiltration profile in routine practice.

As evidenced in this study, the A/D-UF profile could prevent hypotension, as well as IDWG, and failure to reach dry weight at the end of each session. From this perspective, it was suggested to use the A/D-UF profiling, compared with the conventional treatment methods, in order to prevent hypotension for the duration of HD.

Data availability

The datasets generated in the current study are available from the corresponding author upon reasonable request.

Abbreviations

Ascending/Descending Ultrafiltration

• Hemodialysis

Chronic kidney disease

• Blood pressure

Extracellular space

Interdialytic weight gain

End-Stage Renal Disease

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Acknowledgements

We thank the supervisor, nurses working in the dialysis unit, patients and their family members for helping us in the current research.

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Mohammad Namazinia & Kheizaran Miri

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All authors have read and approved the manuscript. Study design: MN, KM, MA; data collection and analysis: MA; manuscript preparation: MN, KM, MS, SRM.

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Arasnezhad, M., Namazinia, M., Mazlum, S.R. et al. The effect of ascending- descending ultrafiltration and sodium profiles on blood pressure in hemodialysis patients: a randomized cross-over study. BMC Nephrol 25 , 128 (2024). https://doi.org/10.1186/s12882-024-03554-6

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