Evaluation of the effect of sodium zirconium cyclosilicate on arrhythmia-related cardiovascular outcomes in patients receiving chronic haemodialysis with hyperkalaemia: protocol for the multicentre, randomised, controlled DIALIZE-Outcomes study.

INTRODUCTION: Patients with kidney failure receiving chronic haemodialysis have elevated risk of arrhythmias potentially increasing the likelihood of sudden cardiac death, stroke and hospitalisation. The DIALIZE study (NCT03303521) demonstrated that sodium zirconium cyclosilicate (SZC) was an efficacious and well-tolerated treatment for predialysis hyperkalaemia in patients undergoing haemodialysis. The DIALIZE-Outcomes study evaluates the effect of SZC on sudden cardiac death and arrhythmia-related cardiovascular outcomes in patients receiving chronic haemodialysis with recurrent hyperkalaemia. METHODS AND ANALYSIS: International, multicentre, randomised, double-blind, placebo-controlled study conducted at 357 study sites across 25 countries. Adults (≥18 years) receiving chronic haemodialysis three times per week with recurrent predialysis serum potassium (K+) ≥5.5 mmol/L post long interdialytic interval (LIDI) are eligible. Patients (~2800) will be randomised 1:1 to SZC or placebo, starting at 5 g orally once daily on non-dialysis days and titrated weekly in 5 g increments (maximum 15 g) to target predialysis serum K+ 4.0-5.0 mmol/L post LIDI. The primary objective is to evaluate efficacy of SZC versus placebo in reducing occurrence of the primary composite endpoint of sudden cardiac death, stroke or arrhythmia-related hospitalisation, intervention or emergency department visit. Secondary endpoints include efficacy of SZC versus placebo in maintaining normokalaemia (serum K+ 4.0-5.5 mmol/L post LIDI) at the 12-month visit, preventing severe hyperkalaemia (serum K+ ≥6.5 mmol/L post LIDI) at the 12-month visit and reducing the incidence of individual cardiovascular outcomes. Safety of SZC will be evaluated. The study is event driven, with participants remaining in the study until 770 primary endpoint events have occurred. Average time in the study is expected to be ~25 months. ETHICS AND DISSEMINATION: Approval was obtained from the relevant institutional review board/independent ethics committee from each participating site (approving bodies in supplementary information). The results will be submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: EudraCT 2020-005561-14 and clinicaltrials.gov identifier NCT04847232.

The gut-kidney-heart axis in chronic kidney disease.

The recent explosion of scientific interest in the gut microbiota has dramatically advanced our understanding of the complex pathophysiological interactions between the gut and multiple organs in health and disease. Emerging evidence has revealed that the gut microbiota is significantly altered in patients with chronic kidney disease (CKD), along with impaired intestinal barrier function. These alterations allow translocation of various gut-derived products into the systemic circulation, contributing to the development and progression of CKD and cardiovascular disease (CVD), partly mediated by chronic inflammation. Among potentially toxic gut-derived products identifiable in the systemic circulation, bacterial endotoxin and gut metabolites (e.g., p-cresyl sulfate and trimethylamine-N-oxide) have been extensively studied for their immunostimulatory and atherogenic properties. Recent studies have also suggested similar biological properties of bacterial DNA fragments circulating in the blood of patients with CKD, even in the absence of overt infections. Despite the accumulating evidence of the gut microbiota in CKD and its therapeutic potential for CVD, the precise mechanisms for multidirectional interactions between the gut, kidney, and heart remain poorly understood. This review aims to provide recent evidence on the associations between the gut microbiota, CKD, and CVD, and summarize current understanding of the potential pathophysiological mechanisms underlying the "gut-kidney-heart" axis in CKD.

Association between malnutrition-inflammation score and risk of subsequent self-reported bone fractures in prevalent kidney transplant recipients.

Chronic inflammation and protein energy wasting (PEW) syndrome are common in kidney transplant recipients (KTR). The presence of inflammation and PEW syndrome can directly affect bone resorption and bone formation, leading to bone loss and fractures. We showed PEW is independently associated with new clinically detected bone fractures in prevalent KTR. INTRODUCTION: Kidney transplant recipients (KTR) have a 4-fold higher risk of fracture compared to the general population. Chronic inflammation and PEW syndrome are common in KTR and are associated with poor outcomes. We hypothesized that the Malnutrition-Inflammation Score (MIS), a validated measure of PEW, is associated with higher risk of bone fractures in KTR. METHODS: This prospective cohort study included 839 prevalent KTR from a Central European academic center. MIS, a semiquantitative instrument of PEW, was calculated at the study entry. Self-reported history of fractures was recorded during the 2-year follow-up period. The association between MIS and bone fractures was examined in logistic regression analyses with adjustment for age, gender, eGFR, smoking habits, history of pre-transplant bone fractures, and acute rejection. RESULTS: Mean age was 51 ± 13 years, and 56% of patients were males with median (interquartile range) transplant vintage 69 (38-112) months, estimated glomerular filtration rate 55 ± 21 ml/min/1.73 m2, and calculated MIS 3 (2-4) at enrollment. Fifty-five (7%) patients experienced self-reported bone fractures during the 2-year follow-up period. Higher MIS score showed linear association with increased risk of fracture. Each one-point higher MIS was associated with 23% higher risk of bone fractures (odds ratio (OR) and 95% CI 1.23, 1.12-1.34), which remained significant after multivariable adjustments (OR 1.17, 95% CI 1.06-1.29). CONCLUSION: The MIS is independently associated with new clinically detected bone fractures in prevalent KTR.

Differences in health outcomes associated with initial adherence to oral antidiabetes medications among veterans with uncomplicated Type 2 diabetes: a 5-year survival analysis.

AIM: To determine the association of adherence to oral antidiabetes medication with macrovascular and microvascular complications, time to insulin therapy, revascularization, admissions, and death among veterans with uncomplicated diabetes. METHODS: This was a retrospective cohort study using the Veterans Affairs Corporate Data Warehouse to examine 159 032 veterans diagnosed with uncomplicated diabetes during 2002-2014 and starting oral antidiabetes therapy for the first time. The first uncomplicated diabetes diagnosis was identified and confirmed by subsequent oral antidiabetes therapy initiation. Adherence was calculated from outpatient pharmacy records using the proportion of days covered over the first year of therapy. Health outcomes were observed up to 5 years beyond the first oral antidiabetes agent fill, and compared according to adherence status using Cox proportional hazards models adjusted for baseline demographic and clinical characteristics. RESULTS: During the first 5 years of oral antidiabetes treatment, people initially non-adherent to oral antidiabetes therapy were more likely to experience myocardial infarction (hazard ratio 1.14, 95% CI 1.03-1.27) and ischaemic stroke (hazard ratio 1.22, 95% CI 1.05-0.1.42), or to die (hazard ratio 1.21; 95% CI 1.15-1.28). Veterans with <20% adherence to oral antidiabetes therapy in the first year had particularly high hazards for ischaemic stroke (hazard ratio 1.78, 95% CI 1.27-2.49) and all-cause death (hazard ratio 1.33, 95% CI 1.17-151). Adherent people were more likely to be diagnosed with a microvascular complication or chronic kidney disease. CONCLUSIONS: People who are non-adherent to treatment were more likely to experience detrimental health outcomes within the first 5 years of antidiabetes therapy. Adherence is paramount to disease management and this should be stressed from the time at which treatment is initiated.

Estimated glomerular filtration rate and the risk-benefit profile of intensive blood pressure control amongst nondiabetic patients: a post hoc analysis of a randomized clinical trial.

BACKGROUND: The Systolic Blood Pressure Intervention Trial (SPRINT; ClinicalTrials.gov, NCT01206062) reported reduced cardiovascular events by intensive blood pressure (BP) control amongst hypertensive patients without diabetes. However, the risk-benefit profile of intensive BP control may differ across estimated glomerular filtration rate (eGFR) levels. METHODS: This is a post hoc analysis of the SPRINT. Nondiabetic hypertensive adults (n = 9361) with eGFR >20 mL per min per 1.73 m2 were enrolled from 102 US facilities between November 2010 and March 2013 and were followed up until August 2015 (median follow-up, 3.26 years). Patients were randomly assigned to either a systolic BP target of <120 or <140 mmHg (for intensive or standard treatment, respectively). The outcomes of interests were the development of (i) fatal and nonfatal major cardiovascular events and (ii) acute kidney injury (AKI). RESULTS: The cardiovascular benefit from intensive treatment was attenuated with lower eGFR (Pinteraction  = 0.019), whereas eGFR did not modify the adverse effect on AKI (Pinteraction  = 0.179). Amongst 891 participants with eGFR <45 mL per min per 1.73 m2 , intensive treatment did not reduce the cardiovascular outcome (54/446 vs. 54/445 events in the standard group, respectively; hazard ratio [HR], 0.92; 95% CI, 0.62-1.38) with an absolute rate difference (ARD) of -0.02 (95% CI, -0.07 to +0.03) per 100 patient-years, whereas it increased AKI (62/446 vs. 38/445 events in the standard group; HR, 1.73; 95% CI, 1.12-2.66) with an ARD of +1.93 (95% CI, +1.88 to +1.97) per 100 patient-years. CONCLUSIONS: Intensive BP control may provide little or no benefit and even be harmful for patients with moderate-to-advanced chronic kidney disease.

Obesity and kidney disease: Hidden consequences of the epidemic.

Obesity has become a worldwide epidemic, and its prevalence has been projected to grow by 40% in the next decade. This increasing prevalence has implications for the risk of diabetes, cardiovascular disease, and also for chronic kidney disease (CKD). A high body mass index is one of the strongest risk factors for new-onset CKD. In individuals affected by obesity, a compensatory hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight. The increase in intraglomerular pressure can damage the kidneys and raise the risk of developing CKD in the long-term. The incidence of obesity-related glomerulopathy has increased tenfold in recent years. Obesity has also been shown to be a risk factor for nephrolithiasis, and for a number of malignancies including kidney cancer. This year the World Kidney Day promotes education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle, and health policy measures that makes preventive behaviors an affordable option.

Obesity and kidney disease: hidden consequences of the epidemic.

Obesity has become a worldwide epidemic and its prevalence has been projected to grow by 40% in the next decade. This increasing prevalence has implications for the risk of diabetes, cardiovascular disease and also for chronic kidney disease (CKD). A high body mass index is one of the strongest risk factors for new-onset CKD. In individuals affected by obesity, a compensatory hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight. The increase in intraglomerular pressure can damage the kidneys and raise the risk of developing CKD in the long-term. The incidence of obesity-related glomerulopathy has increased ten-fold in recent years. Obesity has also been shown to be a risk factor for nephrolithiasis, and for a number of malignancies including kidney cancer. This year, the World Kidney Day will promote education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle and health policy measures that make preventive behaviors an affordable option.

[FGF23 and the heart]. / FGF23 e cuore.

The prevalence of chronic kidney disease (CKD) has now reached epidemic proportions and it is very likely that it will continue to rise with the increasing prevalence of juvenile diabetes mellitus, hypertension and aging population. CKD is a risk factor for cardiovascular disease (CVD) and cardiovascular disease can lead to CKD. It is also well known that patients with CKD have a higher risk of death from CVD than of progressing to end-stage renal disease that requires renal replacement therapy. In patients with CKD, there is a higher mortality from sudden cardiac death and congestive heart failure than coronary artery disease, which is not the case in the general population. The high prevalence of congestive heart failure in CKD is due to cardiac remodeling which progresses from concentric remodeling to concentric and eccentric hypertrophy, leading to left ventricular hypertrophy with both systolic and diastolic dysfunction. Recent studies have suggested that, in patients with chronic kidney disease, common traditional risk factors for cardiovascular disease such as hypertension, hyperlipidemia and obesity may not be the main determinants of cardiovascular disease. Among the various non-traditional cardiovascular risk factors present in patients with chronic kidney disease, abnormalities of CKD related mineral and bone disorder, which includes elevated fibroblast growth factor 23 (FGF23) have been one of the most extensively studied. However, after many years of research, the debate over the exact pathways by which FGF23 may lead to increased CVD still continues. FGF23 may have both direct and indirect effects on the cardiovascular system. Better understanding of the most relevant pathophysiologic pathways for FGF23 may lead to therapeutic interventions against cardiovascular disease in patients with CKD.

Clinical outcomes in kidney transplant recipients receiving long-term therapy with inhibitors of the mammalian target of rapamycin.

Inhibitors of the mammalian target of rapamycin (mTOR), sirolimus and everolimus, reduce the incidence of acute rejection following kidney transplantation, but their impact on clinical outcomes beyond 2 years after transplantation is unknown. We examined risks of mortality and allograft loss in a prospective observational study of 993 prevalent kidney transplant recipients who enrolled a median of 72 months after transplantation. During a median follow-up of 37 months, 87 patients died and 102 suffered allograft loss. In the overall population, use of mTOR inhibitors at enrollment was not associated with altered risk of allograft loss, and their association with increased mortality was of borderline significance. However, history of malignancy was the strongest predictor of both mortality and therapy with an mTOR inhibitor. Among patients without a history of malignancy, use of mTOR inhibitors was associated with significantly increased risk of mortality in propensity score-adjusted (hazard ratio [HR] 2.6; 95% CI, 1.2, 5.5; p = 0.01), multivariable-adjusted (HR 3.2; 95% CI, 1.5, 6.5; p = 0.002) and one-to-one propensity score-matched analyses (HR 5.6; 95% CI 1.2, 25.7; p = 0.03). Additional studies are needed to examine the long-term safety of mTOR inhibitors in kidney transplantation, especially among recipients without a history of malignancy.

Associations of pretransplant serum albumin with post-transplant outcomes in kidney transplant recipients.

The association between pretransplant serum albumin concentration and post-transplant outcomes in kidney transplant recipients is unclear. We hypothesized that in transplant-waitlisted hemodialysis patients, lower serum albumin concentrations are associated with worse post-transplant outcomes. Linking the 5-year patient data of a large dialysis organization (DaVita) to the Scientific Registry of Transplant Recipients, we identified 8961 hemodialysis patients who underwent first kidney transplantation. Mortality or graft failure and delayed graft function (DGF) risks were estimated by Cox regression (hazard ratio [HR]) and logistic regression (Odds ratio [OR]), respectively. Patients were 48 ± 13 years old and included 37% women and 27% diabetics. The higher pretransplant serum albumin was associated with lower mortality, graft failure and DGF risk even after multivariate adjustment for case-mix, malnutrition-inflammation complex and transplant related variable. Every 0.2 g/dL higher pretransplant serum albumin concentration was associated with 13% lower all-cause mortality (HR = 0.87 [95% confidence interval: 0.82-0.93]), 17% lower cardiovascular mortality (HR = 0.83[0.74-0.93]), 7% lower combined risk of death or graft failure (HR = 0.93[0.89-0.97]) and 4% lower DGF risk (OR = 0.96[0.93-0.99]). Hence, lower pretransplant serum albumin level is associated with worse post-transplant outcomes. Clinical trials to examine interventions to improve nutritional status in transplant-waitlisted hemodialysis patients and their impacts on post-transplant outcomes are indicated.

Associations of body mass index and weight loss with mortality in transplant-waitlisted maintenance hemodialysis patients.

A body mass index (BMI) below morbid obesity range is often a requirement for kidney transplant wait-listing, but data linking BMI changes to mortality during the waitlist period are lacking. By linking the 6-year (7/2001-6/2007) national databases of a large dialysis organization and the Scientific Registry of Transplant Recipients, we identified 14 632 waitlisted hemodialysis patients without kidney transplantation. Time-dependent survival models examined the mortality predictability of 13-week-averaged BMI, pretransplant serum creatinine as a muscle mass surrogate and their changes over time. The patients were on average 52 ± 13 years old, 40% women and had a BMI of 26.9 ± 6.3 kg/m². Each kg/m² increase of BMI was associated with a death hazard ratio (HR) of 0.96 (95%CI: 0.95-0.97). Compared to the lowest creatinine quintile, the 4th and 5th quintiles had death HRs of 0.75 (0.66-0.86) and 0.57 (0.49-0.66), respectively. Compared to minimal (< ± 1 kg) weight change over 6 months, those with 3 kg- < 5 kg and ≥ 5 kg weight loss had death HRs of 1.31 (1.14-1.52) and 1.51 (1.30-1.75), respectively. Similar associations were observed with creatinine changes over time. Transplant-waitlisted hemodialysis patients with lower BMI or muscle mass and/or unintentional weight or muscle loss have higher mortality in this observational study. Impact of intentional weight change remains unclear.

Body mass index, waist circumference and mortality in kidney transplant recipients.

Higher body mass index (BMI) appears paradoxically associated with better outcomes in patients with chronic kidney disease. Whereas higher BMI reflects both increased visceral and subcutaneous fat and/or muscle mass, a combined assessment of BMI and waist circumference may enable differentiation of visceral adiposity from muscle and/or nonvisceral fat mass. We examined the association of BMI and waist circumference with all-cause mortality in a prospective cohort of 993 kidney transplant recipients. Associations were examined in Cox models with adjustment for demographic and comorbid conditions and for inflammatory markers. Unadjusted death hazard ratios (95%CI) associated with one standard deviation higher BMI and waist circumference were 0.94 (0.78, 1.13), p = 0.5 and 1.20 (1.00, 1.45), p = 0.05, respectively. Higher BMI was associated with lower mortality after adjustment for waist circumference (0.48 [0.34, 0.69], p < 0.001), and higher waist circumference was more strongly associated with higher mortality after adjustment for BMI (2.18 [1.55-3.08], p < 0.001). The associations of waist circumference with mortality remained significant after additional multivariable adjustments. Higher BMI and waist circumference display opposite associations with mortality in kidney transplant recipients. Waist circumference appears to be a better prognostic marker for obesity than BMI.

Outcomes associated with serum phosphorus level in males with non-dialysis dependent chronic kidney disease.

BACKGROUND/AIMS: Hyperphosphatemia is associated with higher mortality and increased incidence of end-stage renal disease in patients with non-dialysis dependent CKD (NDD-CKD), but there has not been a concomitant assessment of mortality and progressive kidney disease that would also account for cumulative effects of hyperphosphatemia. METHODS: In order to account for the cumulative effects of abnormal serum phosphorus we examined associations of not only baseline, but also time-averaged serum phosphorus levels with all-cause mortality, the composite of mortality or ESRD and the slopes of estimated glomerular filtration rate (eGFR), by using Cox models and mixed effects models in a contemporary cohort of 713 males with moderate and advanced NDD-CKD. RESULTS: Higher baseline and time-averaged serum phosphorus were both associated with mortality and with the composite outcome. A 1 mg/dl higher time-averaged serum phosphorus was associated with a multivariable adjusted hazard ratio of all-cause mortality (95% CI) of 1.56 (1.19 - 2.05), p = 0.001. Higher serum phosphorus was associated with a steeper slope of eGFR in unadjusted analyses, but this association became non-significant after multivariable adjustments. CONCLUSION: The cumulative burden of hyperphosphatemia is associated with increased mortality in patients with moderate and advanced NDD-CKD. Clinical trials are needed to determine if lowering serum phosphorus can result in improved mortality in this population.

Secondary hyperparathyroidism is associated with higher mortality in men with moderate to severe chronic kidney disease.

Secondary hyperparathyroidism is associated with mortality in patients undergoing maintenance dialysis treatment. We studied 515 male US veterans with chronic kidney disease, who were not yet on dialysis, to see what outcomes were associated with secondary hyperparathyroidism in this population. Relationships between intact parathyroid hormone levels and all-cause mortality along with the composite of mortality or incidence of dialysis were measured in unadjusted and adjusted Cox models for case-mix and laboratory variables. Elevated parathyroid hormone levels above the upper limit compared to the lower limit of the normal range were significantly associated with mortality after adjustments. Higher intact parathyroid hormone levels in the upper limit of normal were significantly associated with higher mortality overall and showed similar trends in subgroups of patients with stage 3 and stage 4-5 chronic kidney disease and with higher and lower serum calcium and phosphorus levels. Similar associations were found with the composite outcome of mortality or dialysis. Our study shows that secondary hyperparathyroidism is independently associated with higher mortality in patients with chronic kidney disease but not yet on dialysis.

Vitamin D receptor activation and survival in chronic kidney disease.

Replacement of activated vitamin D has been the cornerstone of therapy for secondary hyperparathyroidism (SHPT). Recent findings from several large observational studies have suggested that the benefits of vitamin D receptor activators (VDRA) may extend beyond the traditional parathyroid hormone (PTH)-lowering effect, and could result in direct cardiovascular and metabolic benefits. The advent of several new analogs of the activated vitamin D molecule has widened our therapeutic armamentarium, but has also made therapeutic decisions more complicated. Treatment of SHPT has become even more complex with the arrival of the first calcium-sensing receptor (CSR) agonist (cinacalcet hydrochloride) and with the uncovering of novel mechanisms responsible for SHPT. We provide a brief overview of the physiology and pathophysiology of SHPT, with a focus on vitamin D metabolism, and discuss various practical aspects of VDRA therapy and its reported association with survival in recent observational studies. A detailed discussion of the available agents is aimed at providing the practicing physician with a clear understanding of the advantages or disadvantages of the individual medications. A number of open questions are also analyzed, including the present and future roles of CSR agonists and 25(OH) vitamin D replacement.

Regional mortality differences in end-stage renal disease: how far can observational studies take us?

The survival of patients with ESRD living in various geographic regions is strikingly different. Efforts to determine the reasons behind this observation have been hampered by difficulties in adjusting for many characteristics that are inherently different in patient populations living on different continents. The mortality rate for the general population in a given region could be used to adjust for risk factors that would be otherwise difficult to quantify.

Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients.

Although renal osteodystrophy and vitamin D analogs may be related to survival in maintenance hemodialysis (MHD) patients, most studies have examined associations between baseline values and survival without accounting for variations in clinical and laboratory measures over time. We examined associations between survival and quarterly laboratory values and administered paricalcitol in a 2-year (July 2001-June 2003) cohort of 58,058 MHD patients from all DaVita dialysis clinics in USA using both time-dependent Cox models with repeated measures and fixed-covariate Cox models with only baseline values. Whereas hypercalcemia and hyperphosphatemia were robust predictors of higher death risk in all models, the association between serum calcium and mortality was different in time-varying models. Changes in baseline calcium and phosphorus values beyond the Kidney Disease Outcome Quality Initiative recommended targets were associated with increased mortality. Associations between high serum parathyroid hormone and increased death risk were masked by case-mix characteristics of MHD patients. Time-varying serum alkaline phosphatase had an incremental association with mortality. Administration of any dose of paricalcitol was associated with improved survival in time-varying models. Controlling for nutritional markers may introduce overadjustment bias owing to their strong collinearity with osteodystrophy surrogates. Whereas both time-dependent and fixed-covariate Cox models result in similar associations between osteodystrophy indicators and survival, subtle but potentially clinically relevant differences between the two models exist, probably because fixed models do not account for variations of osteodystrophy indices and changes in medication dose over time.

Association of anemia with outcomes in men with moderate and severe chronic kidney disease.

Anemia is a common complication of chronic kidney disease (CKD), but the outcomes associated with lower hemoglobin (Hgb) levels in patients with CKD not yet on dialysis are not well characterized. Analyses exploring outcomes associated with a single baseline Hgb value also do not account for the longitudinal variation of this measure. After collecting all Hgb measurements (N=17 194, median (range): 12 (1-168)) over a median follow-up period of 2.1 years in a historical prospective cohort of 853 male US veterans with CKD Stages 3-5 not yet on dialysis, we examined the association of time-averaged Hgb levels with predialysis all-cause mortality, end-stage renal disease (ESRD), and a composite end point of both. Kaplan-Meier survival analysis and Cox models adjusted for age, race, body mass index, smoking status, blood pressure, diabetes mellitus, cardiovascular disease, categories of estimated glomerular filtration rate, serum concentrations of albumin and cholesterol, and proteinuria were examined. Lower time-averaged Hgb was associated with significantly higher hazard of the composite end point (hazard ratio (95% confidence interval) in the adjusted model for time-averaged Hgb of <110, 111-120 and 121-130, compared to >130 g/l: 2.57 (1.85-3.58), 1.97 (1.45-2.66), 1.19 (0.86-1.63), P(trend)<0.001). Lower time-averaged Hgb was associated with both significantly higher pre-dialysis mortality and higher risk of ESRD, when analyzed separately. Anemia (especially time-averaged Hgb <120 g/l) is associated with both higher mortality and increased risk of ESRD in male patients with CKD not yet on dialysis.