Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers for Advanced Chronic Kidney Disease : A Systematic Review and Retrospective Individual Participant-Level Meta-analysis of Clinical Trials.

BACKGROUND: In patients with advanced chronic kidney disease (CKD), the effects of initiating treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) on the risk for kidney failure with replacement therapy (KFRT) and death remain unclear. PURPOSE: To examine the association of ACEi or ARB treatment initiation, relative to a non-ACEi or ARB comparator, with rates of KFRT and death. DATA SOURCES: Ovid Medline and the Chronic Kidney Disease Epidemiology Collaboration Clinical Trials Consortium from 1946 through 31 December 2023. STUDY SELECTION: Completed randomized controlled trials testing either an ACEi or an ARB versus a comparator (placebo or antihypertensive drugs other than ACEi or ARB) that included patients with a baseline estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. DATA EXTRACTION: The primary outcome was KFRT, and the secondary outcome was death before KFRT. Analyses were done using Cox proportional hazards models according to the intention-to-treat principle. Prespecified subgroup analyses were done according to baseline age (<65 vs. ≥65 years), eGFR (<20 vs. ≥20 mL/min/1.73 m2), albuminuria (urine albumin-creatinine ratio <300 vs. ≥300 mg/g), and history of diabetes. DATA SYNTHESIS: A total of 1739 participants from 18 trials were included, with a mean age of 54.9 years and mean eGFR of 22.2 mL/min/1.73 m2, of whom 624 (35.9%) developed KFRT and 133 (7.6%) died during a median follow-up of 34 months (IQR, 19 to 40 months). Overall, ACEi or ARB treatment initiation led to lower risk for KFRT (adjusted hazard ratio, 0.66 [95% CI, 0.55 to 0.79]) but not death (hazard ratio, 0.86 [CI, 0.58 to 1.28]). There was no statistically significant interaction between ACEi or ARB treatment and age, eGFR, albuminuria, or diabetes (P for interaction > 0.05 for all). LIMITATION: Individual participant-level data for hyperkalemia or acute kidney injury were not available. CONCLUSION: Initiation of ACEi or ARB therapy protects against KFRT, but not death, in people with advanced CKD. PRIMARY FUNDING SOURCE: National Institutes of Health. (PROSPERO: CRD42022307589).

Underrepresentation of black individuals in pivotal trials for novel anticancer drugs: Potential consequence of using estimated creatinine clearance to assess kidney function?

BACKGROUND: Black individuals are historically underrepresented in oncology clinical trials. One potential reason for this is the prevalence of kidney disease in Black individuals, utilization of estimated creatinine clearance as a surrogate for glomerular filtration rate (GFR) in oncology, and GFR-based trial eligibility criteria. We characterized the representation of racial minorities in anticancer agent pivotal trials and examined if GFR-based trial eligibility criteria impact the proportion of Black individuals in trial populations. METHODS: We constructed a data repository for anticancer drugs FDA-approved 2015-2019 and associated pivotal trials, from which we extracted trial population racial compositions and GFR-based trial eligibility criteria. We calculated the participation-to-incidence ratio (PIR) and participation-to-mortality ratio (PMR) for a variety of cancer sites, where PIR or PMR >1.2 and < 0.8 indicate overrepresentation and underrepresentation, respectively. We evaluated the relationship between GFR eligibility cutoffs and the proportion of Black enrollees with Spearman rank correlation coefficient. RESULTS: We assessed 24,698 patients in 74 trials. Black individuals were underrepresented in all trials (PIR ≤0.48, PMR ≤0.50). For trials with GFR-based eligibility criteria (n = 49), a lower GFR cutoff was modestly associated with a higher proportion of Black enrollees (r = -0.29, p = 0.039). This relationship was strengthened for trials that only used estimated creatinine clearance to estimate GFR (r = -0.43, p = 0.004). CONCLUSIONS: GFR-related eligibility, and specifically the use of estimated creatinine clearance, may contribute to Black individuals being disproportionately excluded from cancer clinical trials. This highlights the need for implementation of contemporary GFR equations and other interventions to boost racial minority trial enrollment.

A meta-analysis of randomized controlled clinical trials for implications of acute treatment effects on glomerular filtration rate for long-term kidney protection.

Pharmacologic interventions to slow chronic kidney disease progression, such as ACE-inhibitors, angiotensin receptor blockers, or sodium glucose co-transporter 2 inhibitors, often produce acute treatment effects on glomerular filtration rate (GFR) that differ from their long-term chronic treatment effects. Observational studies assessing the implications of acute effects cannot distinguish acute effects from GFR changes unrelated to the treatment. Here, we performed meta-regression analysis of multiple trials to isolate acute effects to determine their long-term implications. In 64 randomized controlled trials (RCTs), enrolling 154,045 participants, we estimated acute effects as the mean between-group difference in GFR slope from baseline to three months, effects on chronic GFR slope (starting at three months after randomization), and effects on three composite kidney endpoints defined by kidney failure (GFR 15 ml/min/1.73m2 or less, chronic dialysis, or kidney transplantation) or sustained GFR declines of 30%, 40% or 57% decline, respectively. We used Bayesian meta-regression to relate acute effects with treatment effects on chronic slope and the composite kidney endpoints. Overall, acute effects were not associated with treatment effects on chronic slope. Acute effects were associated with the treatment effects on composite kidney outcomes such that larger negative acute effects were associated with lesser beneficial effects on the composite kidney endpoints. Associations were stronger when the kidney composite endpoints were defined by smaller thresholds of GFR decline (30% or 40%). Results were similar in a subgroup of interventions with supposedly hemodynamic effects that acutely reduce GFR. For studies with GFR 60 mL/min/1.73m2 or under, negative acute effects were associated with larger beneficial effects on chronic GFR slope. Thus, our data from a large and diverse set of RCTs suggests that acute effects of interventions may influence the treatment effect on clinical kidney outcomes.

Assessment of Glomerular Filtration Rate in Patients with Cancer: A Statement from the American Society of Onco-Nephrology.

Accurate assessment of glomerular filtration rate (GFR) is crucial to guiding drug eligibility, dosing of systemic therapy, and minimizing the risks of both undertreatment and toxicity in patients with cancer. Up to 32% of cancer patients have baseline chronic kidney disease (CKD), and both malignancy and treatment may cause kidney injury and subsequent CKD. To date, there has been lack of guidance to standardize approaches to GFR estimation in the cancer population. In this two-part statement from the American Society of Onco-Nephrology, we present key messages for estimation of GFR in patients with cancer, including the choice of GFR estimating equation, use of race and body surface-area (BSA)-adjustment, and anticancer drug dose-adjustment in the setting of CKD. These key messages are based on a systematic review of studies assessing GFR estimating equations using serum creatinine and cystatin C in patients with cancer, against a measured GFR comparator. The preponderance of current data involving validated GFR estimating equations involves the CKD-EPI equations, with 2,508 patients in whom CKD-EPI using serum creatinine and cystatin C was assessed (8 studies) and 15,349 in whom CKD-EPI with serum creatinine was assessed (22 studies). The former may have improved performance metrics and be less susceptible to shortfalls of eGFR using serum creatinine alone. Since included studies were moderate quality or lower, the ASON Position Committee rated the certainty of evidence as low. Additional studies are needed to assess the accuracy of other validated eGFR equations in patients with cancer. Given the importance of accurate and timely eGFR assessment we advocate for the use of validated GFR estimating equations incorporating both serum creatinine and cystatin C in patients with cancer. Measurement of GFR via exogenous filtration markers should be considered in patients with cancer for whom eGFR results in borderline eligibility for therapies or clinical trials.

Consistency of metabolite associations with measured glomerular filtration rate in children and adults.

Background: There is interest in identifying novel filtration markers that lead to more accurate GFR estimates than current markers (creatinine and cystatin C) and are more consistent across demographic groups. We hypothesize that large-scale metabolomics can identify serum metabolites that are strongly influenced by glomerular filtration rate (GFR) and are more consistent across demographic variables than creatinine, which would be promising filtration markers for future investigation. Methods: We evaluated the consistency of associations between measured GFR (mGFR) and 887 common, known metabolites quantified by an untargeted chromatography- and spectroscopy-based metabolomics platform (Metabolon) performed on frozen blood samples from 580 participants in Chronic Kidney Disease in Children (CKiD), 674 participants in Modification of Diet in Renal Disease (MDRD) Study and 962 participants in African American Study of Kidney Disease and Hypertension (AASK). We evaluated metabolite-mGFR correlation association with metabolite class, molecular weight, assay platform and measurement coefficient of variation (CV). Among metabolites with strong negative correlations with mGFR (r < -0.5), we assessed additional variation by age (height in children), sex, race and body mass index (BMI). Results: A total of 561 metabolites (63%) were negatively correlated with mGFR. Correlations with mGFR were highly consistent across study, sex, race and BMI categories (correlation of metabolite-mGFR correlations between 0.88 and 0.95). Amino acids, carbohydrates and nucleotides were more often negatively correlated with mGFR compared with lipids, but there was no association with metabolite molecular weight, liquid chromatography/mass spectrometry platform and measurement CV. Among 114 metabolites with strong negative associations with mGFR (r < -0.5), 27 were consistently not associated with age (height in children), sex or race. Conclusions: The majority of metabolite-mGFR correlations were negative and consistent across sex, race, BMI and study. Metabolites with consistent strong negative correlations with mGFR and non-association with demographic variables may represent candidate markers to improve estimation of GFR.

Dihydropyridine Calcium Channel Blockers and Kidney Outcomes.

BACKGROUND: Early trials of dihydropyridine calcium channel blockers (DCCBs) suggest a detrimental effect on intraglomerular pressure and an association with albuminuria. OBJECTIVE: We sought to evaluate the associations of DCCB initiation with albuminuria and kidney failure with replacement therapy (KFRT) and to determine whether renin-angiotensin system (RAS) blockade modified these associations. DESIGN: We conducted a target trial emulation study using a new user, active comparator design and electronic health record data from Geisinger Health. PARTICIPANTS: We included patients without severe albuminuria or KFRT who were initiated on a DCCB or thiazide (active comparator) between January 1, 2004, and December 31, 2019. MAIN MEASURES: Using inverse probability of treatment weighting, we performed doubly robust Cox proportional hazards regression to estimate the association of DCCB initiation with incident severe albuminuria (urine albumin to creatinine ratio > 300 mg/g) and KFRT, overall and stratified by RAS blocker use. KEY RESULTS: There were 11,747 and 26,758 eligible patients initiating a DCCB and thiazide, respectively, with a weighted baseline mean age of 60 years, systolic blood pressure of 143 mm Hg, and eGFR of 86 mL/min/1.73 m2, and with a mean follow-up of 8 years. Compared with thiazides, DCCBs were significantly associated with the development of severe albuminuria (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.16-1.43), with attenuation of risk in the presence of RAS blockade (P for interaction < 0.001). The risk of KFRT was increased among patients without RAS blockade (HR, 1.66; 95% CI, 1.19-2.31), but not with RAS blockade (P for interaction = 0.005). CONCLUSIONS: DCCBs were associated with increased risk of albuminuria and, in the absence of RAS blockade, KFRT. These findings suggest coupling DCCB therapy with RAS blockade may mitigate adverse kidney outcomes.

Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknowns.

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD) updates the KDIGO 2012 guideline and has been developed with patient partners, clinicians, and researchers around the world, using robust methodology. This update, based on a substantially broader base of evidence than has previously been available, reflects an exciting time in nephrology. New therapies and strategies have been tested in large and diverse populations that help to inform care; however, this guideline is not intended for people receiving dialysis nor those who have a kidney transplant. The document is sensitive to international considerations, CKD across the lifespan, and discusses special considerations in implementation. The scope includes chapters dedicated to the evaluation and risk assessment of people with CKD, management to delay CKD progression and its complications, medication management and drug stewardship in CKD, and optimal models of CKD care. Treatment approaches and actionable guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence and the strength of recommendations which followed the "Grading of Recommendations Assessment, Development, and Evaluation" (GRADE) approach. The limitations of the evidence are discussed. The guideline also provides practice points, which serve to direct clinical care or activities for which a systematic review was not conducted, and it includes useful infographics and describes an important research agenda for the future. It targets a broad audience of people with CKD and their healthcare, while being mindful of implications for policy and payment.

Drug stewardship in chronic kidney disease to achieve effective and safe medication use.

People living with chronic kidney disease (CKD) often experience multimorbidity and require polypharmacy. Kidney dysfunction can also alter the pharmacokinetics and pharmacodynamics of medications, which can modify their risks and benefits; the extent of these changes is not well understood for all situations or medications. The principle of drug stewardship is aimed at maximizing medication safety and effectiveness in a population of patients through a variety of processes including medication reconciliation, medication selection, dose adjustment, monitoring for effectiveness and safety, and discontinuation (deprescribing) when no longer necessary. This Review is aimed at serving as a resource for achieving optimal drug stewardship for patients with CKD. We describe special considerations for medication use during pregnancy and lactation, during acute illness and in patients with cancer, as well as guidance for the responsible use of over-the-counter drugs, herbal remedies, supplements and sick-day rules. We also highlight inequities in medication access worldwide and suggest policies to improve access to quality and essential medications for all persons with CKD. Further strategies to promote drug stewardship include patient education and engagement, the use of digital health tools, shared decision-making and collaboration within interdisciplinary teams. Throughout, we position the person with CKD at the centre of all drug stewardship efforts.

Glomerular Filtration Rate Estimation Using ß2-Microglobulin and ß-Trace Protein in Adults With Solid Tumors: A Prospective Cross-Sectional Study.

RATIONALE & OBJECTIVE: ß2-Microglobulin (B2M) and ß-trace protein (BTP) are novel endogenous filtration markers that may improve the accuracy of estimated glomerular filtration rate (eGFR) beyond creatinine and cystatin C (eGFRcr-cys), but they have not been assessed in patients with cancer. STUDY DESIGN: Cross-sectional analysis. SETTING & PARTICIPANTS: Prospective cohort of 1,200 patients with active solid tumors recruited between April 2015 and September 2017. EXPOSURE: CKD-EPI equations without race combining B2M and/or BTP with creatinine with or without cystatin C (2-, 3-, or 4-marker panel eGFR). OUTCOME: Performance of equations compared with eGFRcr-cys and non-GFR determinants of serum B2M and BTP (SB2M, and SBTP, respectively). Measured GFR (mGFR) was determined using the plasma clearance of chromium-51 labeled ethylenediamine tetraacetic acid (51Cr-EDTA). ANALYTICAL APPROACH: Bias was defined as the median of the differences between mGFR and eGFR, and 1-P30 was defined as the percentage of estimates that differed by more than 30% from the mGFR (1-P30). Linear regression was used to assess association of clinical and laboratory variables with SB2M, and SBTP after adjustment for mGFR. RESULTS: Mean age and mGFR were 58.8±13.2 SD years and 78.4±21.7 SD mL/min/1.73m2, respectively. Performance of the 3-marker and 4-marker panel equations was better than eGFRcr-cys (lesser bias and 1-P30). Performance of 2-marker panel equations was as good as eGFRcr-cys (lesser bias and similar 1-P30). SB2M and SBTP were not strongly influenced by cancer site. LIMITATIONS: Participants may have had better clinical performance status than the general population of patients with solid tumors. CONCLUSIONS: B2M and BTP can improve the accuracy of eGFR and may be useful as confirmatory tests in patients with solid tumors, either by inclusion in a multimarker panel equation with creatinine and cystatin C, or by substituting for cystatin C in combination with creatinine. PLAIN-LANGUAGE SUMMARY: The most accurate method to assess estimate kidney function is estimated glomerular filtration rate (eGFR) using creatinine and cystatin C (eGFRcr-cys). We studied whether using ß2-microglobulin (B2M) and/or ß-trace protein (BTP) with creatinine with or without cystatin C (2-, 3-, or 4-marker panel eGFR) might be useful in patients with active solid tumors. The performance of the 3-marker and 4-marker panel equations was better than eGFRcr-cys. Performance of 2-marker panel equations was as good as eGFRcr-cys. We conclude that B2M and BTP can improve the accuracy of eGFR and may be useful as a confirmatory test in patients with solid tumors either by inclusion in multimarker panel equation with creatinine and cystatin C or by substituting for cystatin C in combination with creatinine.

Comparing Bayesian hierarchical meta-regression methods and evaluating the influence of priors for evaluations of surrogate endpoints on heterogeneous collections of clinical trials.

BACKGROUND: Surrogate endpoints, such as those of interest in chronic kidney disease (CKD), are often evaluated using Bayesian meta-regression. Trials used for the analysis can evaluate a variety of interventions for different sub-classifications of disease, which can introduce two additional goals in the analysis. The first is to infer the quality of the surrogate within specific trial subgroups defined by disease or intervention classes. The second is to generate more targeted subgroup-specific predictions of treatment effects on the clinical endpoint. METHODS: Using real data from a collection of CKD trials and a simulation study, we contrasted surrogate endpoint evaluations under different hierarchical Bayesian approaches. Each approach we considered induces different assumptions regarding the relatedness (exchangeability) of trials within and between subgroups. These include partial-pooling approaches, which allow subgroup-specific meta-regressions and, yet, facilitate data adaptive information sharing across subgroups to potentially improve inferential precision. Because partial-pooling models come with additional parameters relative to a standard approach assuming one meta-regression for the entire set of studies, we performed analyses to understand the impact of the parameterization and priors with the overall goals of comparing precision in estimates of subgroup-specific meta-regression parameters and predictive performance. RESULTS: In the analyses considered, partial-pooling approaches to surrogate endpoint evaluation improved accuracy of estimation of subgroup-specific meta-regression parameters relative to fitting separate models within subgroups. A random rather than fixed effects approach led to reduced bias in estimation of meta-regression parameters and in prediction in subgroups where the surrogate was strong. Finally, we found that subgroup-specific meta-regression posteriors were robust to use of constrained priors under the partial-pooling approach, and that use of constrained priors could facilitate more precise prediction for clinical effects in trials of a subgroup not available for the initial surrogacy evaluation. CONCLUSION: Partial-pooling modeling strategies should be considered for surrogate endpoint evaluation on collections of heterogeneous studies. Fitting these models comes with additional complexity related to choosing priors. Constrained priors should be considered when using partial-pooling models when the goal is to predict the treatment effect on the clinical endpoint.

Glucagon-like peptide-1 receptor agonists and the risk of atrial fibrillation in adults with diabetes: a real-world study.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular benefits in type 2 diabetes, but none of the cardiovascular trials studied atrial fibrillation/atrial flutter (AF) as a primary endpoint. Data from post-marketing surveillance studies remains sparse. OBJECTIVE: To examine the real-world risk of AF comparing GLP-1RA with other non-insulin glucose-lowering agents. DESIGN: Cohort study using de-identified electronic health record data from the Optum Labs Data Warehouse. PARTICIPANTS: Adult patients with diabetes who were newly prescribed add-on non-insulin glucose-lowering agents and were on metformin between 2005-2020. EXPOSURES: New users of GLP-1RA were separately compared with new users of dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), using 1:1 propensity score matching to adjust for differences in patient characteristics. MAIN MEASURES: The primary outcome was incident AF, defined and captured by diagnosis code for AF. Incidence rate difference (IRD) and hazard ratio (HR) were estimated in the matched cohorts. KEY RESULTS: In the matched cohort of 14,566 pairs of GLP-1RA and DPP4i followed for a median of 3.8 years, GLP-1RA use was associated with a lower risk of AF (IRD, -1.0; 95% CI, -1.8 to -0.2 per 1000 person-years; HR, 0.82; 95% CI, 0.70 to 0.96). In the matched cohort of 9,424 pairs of patients on GLP-1RA and SGLT2i with a median follow-up of 2.9 years, there was no difference in the risk for AF (IRD, 0.4; 95% CI -0.7 to 1.5 per 1000 person-years; HR, 1.12; 95% CI, 0.89 to 1.42). CONCLUSIONS: In this real-word study, GLP-1RA was associated with a lower risk of AF compared with DPP4i, but no difference compared with SGLT2i, suggesting that cardiovascular benefits of GLP-1RA use may extend to prevention for AF in patients with diabetes. Our findings call for future randomized controlled trials to focus on the effects of GLP-1RA on AF prevention.

VALOR-CKD: A Multicenter, Randomized, Double-Blind Placebo-Controlled Trial Evaluating Veverimer in Slowing Progression of CKD in Patients with Metabolic Acidosis.

SIGNIFICANCE STATEMENT: Metabolic acidosis is a common complication of CKD and is associated with more rapid decline of kidney function, but well-powered controlled randomized trials testing the effect of treating metabolic acidosis on slowing CKD progression have not been conducted. The VALOR-CKD study randomized 1480 individuals with CKD and metabolic acidosis, across 320 sites to placebo or veverimer (a novel hydrochloric acid binder). The findings did not demonstrate the efficacy of veverimer in slowing CKD progression, but the difference in serum bicarbonate between placebo and drug arms was only approximately 1 mEq/L. Veverimer was safe and well tolerated. BACKGROUND: Metabolic acidosis is common in CKD, but whether its treatment slows CKD progression is unknown. Veverimer, a novel hydrochloric acid binder that removes acid from the gastrointestinal tract, leads to an increase in serum bicarbonate. METHODS: In a phase 3, double-blind, placebo-controlled trial, patients with CKD (eGFR of 20-40 ml/min per 1.73 m 2 ) and metabolic acidosis (serum bicarbonate of 12-20 mEq/L) from 35 countries were randomized to veverimer or placebo. The primary outcome was the composite end point of CKD progression, defined as the development of ESKD (kidney transplantation or maintenance dialysis), a sustained decline in eGFR of ≥40% from baseline, or death due to kidney failure. RESULTS: The mean (±SD) baseline eGFR was 29.2±6.3 ml/min per 1.73 m 2 , and serum bicarbonate was 17.5±1.4 mEq/L; this increased to 23.4±2.0 mEq/L after the active treatment run-in. After randomized withdrawal, the mean serum bicarbonate was 22.0±3.0 mEq/L and 20.9±3.3 mEq/L in the veverimer and placebo groups at month 3, and this approximately 1 mEq/L difference remained stable for the first 24 months. A primary end point event occurred in 149/741 and 148/739 patients in the veverimer and placebo groups, respectively (hazard ratio, 0.99; 95% confidence interval, 0.8 to 1.2; P = 0.90). Serious and overall adverse event incidence did not differ between the groups. CONCLUSIONS: Among patients with CKD and metabolic acidosis, treatment with veverimer did not slow CKD progression. The lower than expected bicarbonate separation may have hindered the ability to test the hypothesis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: VALOR-CKD, NCT03710291 .

Association of Low Glomerular Filtration Rate With Adverse Outcomes at Older Age in a Large Population With Routinely Measured Cystatin C.

BACKGROUND: The commonly accepted threshold of glomerular filtration rate (GFR) to define chronic kidney disease (CKD) is less than 60 mL/min/1.73 m2. This threshold is based partly on associations between estimated GFR (eGFR) and the frequency of adverse outcomes. The association is weaker in older adults, which has created disagreement about the appropriateness of the threshold for these persons. In addition, the studies measuring these associations included relatively few outcomes and estimated GFR on the basis of creatinine level (eGFRcr), which may be less accurate in older adults. OBJECTIVE: To evaluate associations in older adults between eGFRcr versus eGFR based on creatinine and cystatin C levels (eGFRcr-cys) and 8 outcomes. DESIGN: Population-based cohort study. SETTING: Stockholm, Sweden, 2010 to 2019. PARTICIPANTS: 82 154 participants aged 65 years or older with outpatient creatinine and cystatin C testing. MEASUREMENTS: Hazard ratios for all-cause mortality, cardiovascular mortality, and kidney failure with replacement therapy (KFRT); incidence rate ratios for recurrent hospitalizations, infection, myocardial infarction or stroke, heart failure, and acute kidney injury. RESULTS: The associations between eGFRcr-cys and outcomes were monotonic, but most associations for eGFRcr were U-shaped. In addition, eGFRcr-cys was more strongly associated with outcomes than eGFRcr. For example, the adjusted hazard ratios for 60 versus 80 mL/min/1.73 m2 for all-cause mortality were 1.2 (95% CI, 1.1 to 1.3) for eGFRcr-cys and 1.0 (CI, 0.9 to 1.0) for eGFRcr, and for KFRT they were 2.6 (CI, 1.2 to 5.8) and 1.4 (CI, 0.7 to 2.8), respectively. Similar findings were observed in subgroups, including those with a urinary albumin-creatinine ratio below 30 mg/g. LIMITATION: No GFR measurements. CONCLUSION: Compared with low eGFRcr in older patients, low eGFRcr-cys was more strongly associated with adverse outcomes and the associations were more uniform. PRIMARY FUNDING SOURCE: Swedish Research Council, National Institutes of Health, and Dutch Kidney Foundation.