Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Incremental Initiation of Dialysis: One Center's Experience over a Two-Year Period

Objective This pilot study describes our center's experience with peritoneal dialysis (PD) over the past 2 years using a “healthy start” dialysis protocol with an incremental approach to prescription management. Design Nonrandomized, prospective pilot study. Setting Single PD unit of a university teaching hospital. Patients Thirteen PD patients who initiated dialysis at our center from April 1997 to June 1999. Methods Patients initiating PD with residual renal Kt/V of 1.0 – 2.0/week were invited to participate. They were given an initial dialysis prescription so that total (residual renal + dialysis) weekly Kt/V exceeded 2.0. The dialysis prescription was “incrementally” increased as residual renal function (RRF) declined. Data collected for all patients included monthly serum chemistries, residual renal weekly Kt/V and creatinine clearance (CCr) at 1- to 2-month intervals, and peritoneal weekly Kt/V and CCr at 3-month intervals and 1 month after each prescription change. Results To date, we have followed 13 patients on our incremental PD protocol for a total of 159.3 patient-months. Mean serum albumin concentration and mean normalized protein equivalent of nitrogen appearance (nPNA) were stable throughout the study. Mean total Kt/V and CCr remained above the recommended targets of 2.0/wk and 60 L/wk, respectively. Residual renal function declined rather slowly in our PD patients. One patient died from complications of aortic valve surgery and a second died from pneumonia. A third patient died from peritonitis. One patient required a new Tenckhoff catheter after catheter migration. Three patients were temporarily switched to hemodialysis after a hernia repair, a pleural leak, and elective native/transplant nephrectomies, respectively. Two patients were permanently switched to hemodialysis: one after an episode of peritonitis, the second after accidentally damaging his PD catheter. Conclusions Providing incremental dialysis to maintain adequate total small solute clearance has been technically feasible in our patient population. However, a larger than expected number of complications was seen in our study. Fortunately, complications were easier to manage due to the presence of RRF. Because this study was not designed to compare outcome with that observed after traditional initiation of dialysis, further large-scale studies are needed. </jats:sec

Genetic factors in end-stage renal disease

Genetic factors in end-stage renal disease. Despite more aggressive treatment of diabetes, hypertension, and hyperlipidemia, the incidence and prevalence rates of end-stage renal disease (ESRD) continue to increase worldwide. The likelihood of developing chronic kidney disease in an individual is determined by interactions between genes and the environment. Familial clustering of nephropathy has repeatedly been observed in all population groups studied and for multiple etiologies of kidney disease. A three- to nine-fold greater risk of ESRD is observed in individuals with a family history of ESRD. Marked racial variation in the familial aggregation of kidney disease exists, with high rates in African American, Native American, and Hispanic American families. Disparate etiologies of nephropathy aggregate within African American families, as well. These data have led several investigators to search for genes linked to diabetic and other forms of nephropathy. Evidence for linkage to kidney disease has been detected and replicated at several loci on chromosomes 3q (types 1 and 2 diabetic nephropathy), 10q (diabetic and nondiabetic kidney disease), and 18q (type 2 diabetic nephropathy). Multicenter consortia are currently recruiting large numbers of multiplex diabetic families with index cases having nephropathy for linkage and association analyses. In addition, large-scale screening studies are underway, with the goals of better defining the overall prevalence of chronic kidney disease, as well as educating the population about risk factors for nephropathy, including family history. Given the overwhelming burden of kidney disease worldwide, it is imperative that we develop a clearer understanding of the pathogenesis of nephropathy so that individuals at risk can be identified and treated at earlier, potentially reversible, stages of their illness

Sudden and cardiac death rates in hemodialysis patients

Sudden and cardiac death rates in hemodialysis patients.BackgroundSudden and cardiac death (including death from congestive heart failure, myocardial infarction, and sudden death) are common occurrences in hemodialysis patients. The intermittent nature of hemodialysis may lead to an uneven distribution of sudden and cardiac death throughout the week. The purpose of this study was to assess the septadian rhythm of sudden and cardiac death in hemodialysis patients.MethodsData from the United States Renal Data System (USRDS) were obtained to examine the day of death for United States hemodialysis and peritoneal dialysis patients from 1977 through 1997. The days of death were also determined for patients in the Case Mix Adequacy Study of the USRDS.ResultsThere was an even distribution of sudden and cardiac deaths for patients on peritoneal dialysis, and hemodialysis patients dying of noncardiac deaths also had an even distribution. For all hemodialysis patients, Monday and Tuesday were the most common days of sudden and cardiac death. For patients in the Case Mix Adequacy Study designated as Monday, Wednesday, and Friday dialysis patients, 20.8% of sudden deaths occurred on Monday compared with the 14.3% expected (P = 0.002). Similarly, 20.2% of cardiac deaths occurred on Monday compared with the 14.3% expected (P = 0.0005). Similar trends were found on Tuesday for Tuesday, Thursday, and Saturday dialysis patients.ConclusionsThe intermittent nature of hemodialysis may contribute to an increased sudden and cardiac death rate on Monday and Tuesday for patients enrolled in the USRDS

Frequency and Causes of Discrepancy between Kt/V and Creatinine Clearance

Objective This study examines the frequency of discrepancy between Kt/V urea and creatinine clearance (Ccr) measurements in patients on peritoneal dialysis (PD) and the reasons for this discrepancy. Design Nonrandomized, retrospective data analysis. Setting Single PD unit of a university teaching hospital. Patients All adult patients receiving PD at our center from January 1995 to December 1996. Methods Actual (a) and desired (d) body weight (BW) were used to calculate urea volume of distribution (V) and body surface area (BSA). Patients were divided into four groups based upon their total small solute clearances (Kt/V and Ccr, normalized by actual weight) and three additional groups based upon actual/desired (a/d) body weight ratio. An additional analysis was performed for the subset of anuric patients. Data collected for all patients included the following: total Kt, total Ccr, 4-hour dialysate/ plasma (D/P) creatinine, serum albumin concentration, duration of PD, actual body weight, age, and height. Results Twenty-three percent of the clearance measurements in our study were discrepant, defined as having values for either Kt/V or Ccr (but not both) above the accepted targets of Kt/V ≥ 2.0/wk and Ccr ≥ 60 L/wk/ 1.73 m2. Patients with both values above target are more likely to have higher residual renal function. Patients who are significantly less than BWd and patients on PD for a longer time are more likely to have adequate Kt/V but not Ccr. Furthermore, patients who are less than 90% or greater than 110% of BWd have markedly different values for Kt/V and Ccr when BWa versus BWd values are used. Conclusions Kt/V and Ccr values are frequently discrepant; a number of factors affect these two measurements to varying degrees, including weight, degree of residual renal function, and duration of PD. </jats:sec