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).

Association between Acute Declines in Estimated Glomerular Filtration Rate during Renin-Angiotensin System Inhibition and Risk of Adverse Outcomes.

BACKGROUND: Declines in glomerular filtration rate (GFR) occur commonly when renin-angiotensin system (RAS) inhibitors are started. Our objective was to determine the relation between declines in estimated GFR during trials of RAS inhibition and kidney outcomes. METHODS: We included participants with CKD (estimated GFR<60 mL/min/1.73m2) from 16 trials of RAS inhibition. The exposure was subacute declines in estimated GFR expressed as % change between randomization and month 3, and in the subset of trials with data available, we also examined % change in eGFR between randomization and month 1. The primary outcome was kidney failure with replacement therapy. Cox proportional hazards models were used to examine the association between subacute declines in eGFR and risk of kidney failure. We used spline models to identify the threshold of change in eGFR below which RAS inhibition was favorable (conservatively comparing a given decline in eGFR with RAS inhibition to no decline in the comparator). RESULTS: 11,800 individuals with mean eGFR 43 (SD 11) mL/min/1.73m2 and median urine albumin/creatinine ratio of 362 mg/g (IQR 50, 1367) were included, and 1,162 (10%) developed kidney failure. The threshold of decline in eGFR that favored use of RAS inhibitors for kidney failure was estimated to be up to 13% (95%CI 8%, 17%) over a 3-month interval and up to 21% (95%CI 15%, 27%) over a 1-month interval after starting RAS inhibitors. CONCLUSIONS: In people treated with RAS inhibitors, ≤ 13% decline in eGFR over a 3-month period or ≤21% decline over a 1-month period was associated with lower risk of kidney failure compared with no decline with the use of placebo or other agents.

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.

Heterogeneity by age and gender in the association of kidney function with mortality among patients with diabetes - analysis of diabetes registry in Singapore.

BACKGROUND: We aimed to explore the three-way interaction among age, gender, and kidney function on the risk of all-cause mortality and cardiovascular mortality among patients with type 2 diabetes (T2D). METHODS: In a retrospective cohort study, patients aged > 40 years with T2D with serum creatinine and urine albumin measured from 2013 to 2019 were included from a multi-institutional diabetes registry. The exposure was estimated glomerular filtration rate (eGFR), outcomes were all-cause mortality (primary outcome) and cardiovascular disease (CVD) mortality (secondary outcome). We applied multivariable cox proportional hazards regression analysis to compute the association between eGFR and mortality. RESULTS: A total of 36,556 patients were followed for up to 6 years during which 2492 (6.82%) died from all causes, and 690 (1.9%) died from CVD. We observed a significant three-way interaction (p = 0.021) among age (younger, < 65; older, ≥65 years), gender and eGFR for the risk of all-cause mortality. Using age- and gender-specific eGFR of 90 ml/min/1.73m2 as the reference point, the adjusted hazard rate (HR) (95% CI) for all-cause mortality at eGFR of 40 ml/min/1.73m2 was 3.70 (2.29 to 5.99) in younger women and 1.86 (1.08 to 3.19) in younger men. The corresponding adjusted HRs in older women and older men were 2.38 (2.02 to 2.82) and 2.18 (1.85 to 2.57), respectively. Similar results were observed for CVD deaths, although the three-way interaction was not statistically significant. Sensitivity analysis yielded similar results. CONCLUSIONS: In this T2D population, younger women with reduced kidney function might be more susceptible to higher risks of all-cause mortality and CVD mortality than younger men.

Change in Albuminuria and GFR Slope as Joint Surrogate End Points for Kidney Failure: Implications for Phase 2 Clinical Trials in CKD.

SIGNIFICANCE STATEMENT: Changes in albuminuria and GFR slope are individually used as surrogate end points in clinical trials of CKD progression, and studies have demonstrated that each is associated with treatment effects on clinical end points. In this study, the authors sought to develop a conceptual framework that combines both surrogate end points to better predict treatment effects on clinical end points in Phase 2 trials. The results demonstrate that information from the combined treatment effects on albuminuria and GFR slope improves the prediction of treatment effects on the clinical end point for Phase 2 trials with sample sizes between 100 and 200 patients and duration of follow-up ranging from 1 to 2 years. These findings may help inform design of clinical trials for interventions aimed at slowing CKD progression. BACKGROUND: Changes in log urinary albumin-to-creatinine ratio (UACR) and GFR slope are individually used as surrogate end points in clinical trials of CKD progression. Whether combining these surrogate end points might strengthen inferences about clinical benefit is unknown. METHODS: Using Bayesian meta-regressions across 41 randomized trials of CKD progression, we characterized the combined relationship between the treatment effects on the clinical end point (sustained doubling of serum creatinine, GFR <15 ml/min per 1.73 m 2 , or kidney failure) and treatment effects on UACR change and chronic GFR slope after 3 months. We applied the results to the design of Phase 2 trials on the basis of UACR change and chronic GFR slope in combination. RESULTS: Treatment effects on the clinical end point were strongly associated with the combination of treatment effects on UACR change and chronic slope. The posterior median meta-regression coefficients for treatment effects were -0.41 (95% Bayesian Credible Interval, -0.64 to -0.17) per 1 ml/min per 1.73 m 2 per year for the treatment effect on GFR slope and -0.06 (95% Bayesian Credible Interval, -0.90 to 0.77) for the treatment effect on UACR change. The predicted probability of clinical benefit when considering both surrogates was determined primarily by estimated treatment effects on UACR when sample size was small (approximately 60 patients per treatment arm) and follow-up brief (approximately 1 year), with the importance of GFR slope increasing for larger sample sizes and longer follow-up. CONCLUSIONS: In Phase 2 trials of CKD with sample sizes of 100-200 patients per arm and follow-up between 1 and 2 years, combining information from treatment effects on UACR change and GFR slope improved the prediction of treatment effects on clinical end points.

Defining measures of kidney function in observational studies using routine health care data: methodological and reporting considerations.

The availability of electronic health records and access to a large number of routine measurements of serum creatinine and urinary albumin enhance the possibilities for epidemiologic research in kidney disease. However, the frequency of health care use and laboratory testing is determined by health status and indication, imposing certain challenges when identifying patients with kidney injury or disease, when using markers of kidney function as covariates, or when evaluating kidney outcomes. Depending on the specific research question, this may influence the interpretation, generalizability, and/or validity of study results. This review illustrates the heterogeneity of working definitions of kidney disease in the scientific literature and discusses advantages and limitations of the most commonly used approaches using 3 examples. We summarize ways to identify and overcome possible biases and conclude by proposing a framework for reporting definitions of exposures and outcomes in studies of kidney disease using routinely collected health care data.

A Community-Based Intervention for Managing Hypertension in Rural South Asia.

BACKGROUND: The burden of hypertension is escalating, and control rates are poor in low- and middle-income countries. Cardiovascular mortality is high in rural areas. METHODS: We conducted a cluster-randomized, controlled trial in rural districts in Bangladesh, Pakistan, and Sri Lanka. A total of 30 communities were randomly assigned to either a multicomponent intervention (intervention group) or usual care (control group). The intervention involved home visits by trained government community health workers for blood-pressure monitoring and counseling, training of physicians, and care coordination in the public sector. A total of 2645 adults with hypertension were enrolled. The primary outcome was reduction in systolic blood pressure at 24 months. Follow-up at 24 months was completed for more than 90% of the participants. RESULTS: At baseline, the mean systolic blood pressure was 146.7 mm Hg in the intervention group and 144.7 mm Hg in the control group. At 24 months, the mean systolic blood pressure fell by 9.0 mm Hg in the intervention group and by 3.9 mm Hg in the control group; the mean reduction was 5.2 mm Hg greater with the intervention (95% confidence interval [CI], 3.2 to 7.1; P<0.001). The mean reduction in diastolic blood pressure was 2.8 mm Hg greater in the intervention group than in the control group (95% CI, 1.7 to 3.9). Blood-pressure control (<140/90 mm Hg) was achieved in 53.2% of the participants in the intervention group, as compared with 43.7% of those in the control group (relative risk, 1.22; 95% CI, 1.10 to 1.35). All-cause mortality was 2.9% in the intervention group and 4.3% in the control group. CONCLUSIONS: In rural communities in Bangladesh, Pakistan, and Sri Lanka, a multicomponent intervention that was centered on proactive home visits by trained government community health workers who were linked with existing public health care infrastructure led to a greater reduction in blood pressure than usual care among adults with hypertension. (Funded by the Joint Global Health Trials scheme; COBRA-BPS ClinicalTrials.gov number, NCT02657746.).

Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression.

BACKGROUND: Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects. METHODS: To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. RESULTS: The mean acute effect across all studies was -0.21 ml/min per 1.73 m2 (95% confidence interval, -0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 ml/min per 1.73 m2). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. CONCLUSION: The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.

Chronic kidney disease.

Chronic kidney disease is a progressive disease with no cure and high morbidity and mortality that occurs commonly in the general adult population, especially in people with diabetes and hypertension. Preservation of kidney function can improve outcomes and can be achieved through non-pharmacological strategies (eg, dietary and lifestyle adjustments) and chronic kidney disease-targeted and kidney disease-specific pharmacological interventions. A plant-dominant, low-protein, and low-salt diet might help to mitigate glomerular hyperfiltration and preserve renal function for longer, possibly while also leading to favourable alterations in acid-base homoeostasis and in the gut microbiome. Pharmacotherapies that alter intrarenal haemodynamics (eg, renin-angiotensin-aldosterone pathway modulators and SGLT2 [SLC5A2] inhibitors) can preserve kidney function by reducing intraglomerular pressure independently of blood pressure and glucose control, whereas other novel agents (eg, non-steroidal mineralocorticoid receptor antagonists) might protect the kidney through anti-inflammatory or antifibrotic mechanisms. Some glomerular and cystic kidney diseases might benefit from disease-specific therapies. Managing chronic kidney disease-associated cardiovascular risk, minimising the risk of infection, and preventing acute kidney injury are crucial interventions for these patients, given the high burden of complications, associated morbidity and mortality, and the role of non-conventional risk factors in chronic kidney disease. When renal replacement therapy becomes inevitable, an incremental transition to dialysis can be considered and has been proposed to possibly preserve residual kidney function longer. There are similarities and distinctions between kidney-preserving care and supportive care. Additional studies of dietary and pharmacological interventions and development of innovative strategies are necessary to ensure optimal kidney-preserving care and to achieve greater longevity and better health-related quality of life for these patients.

Healthcare professionals' perspectives on facilitators of and barriers to CKD management in primary care: a qualitative study in Singapore clinics.

INTRODUCTION: The burden of chronic kidney disease (CKD) is rising globally including in Singapore. Primary care is the first point of contact for most patients with early stages of CKD. However, several barriers to optimal CKD management exist. Knowing healthcare professionals' (HCPs) perspectives is important to understand how best to strengthen CKD services in the primary care setting. Integrating a theory-based framework, we explored HCPs' perspectives on the facilitators of and barriers to CKD management in primary care clinics in Singapore. METHODS: In-depth interviews were conducted on a purposive sample of 20 HCPs including 13 physicians, 2 nurses and 1 pharmacist from three public primary care polyclinics, and 4 nephrologists from one referral hospital. Interviews were audio recorded, transcribed verbatim and thematically analyzed underpinned by the Theoretical Domains Framework (TDF) version 2. RESULTS: Numerous facilitators of and barriers to CKD management identified. HCPs perceived insufficient attention is given to CKD in primary care and highlighted several barriers including knowledge and practice gaps, ineffective CKD diagnosis disclosure, limitations in decision-making for nephrology referrals, consultation time, suboptimal care coordination, and lack of CKD awareness and self-management skills among patients. Nevertheless, intensive CKD training of primary care physicians, structured CKD-care pathways, multidisciplinary team-based care, and prioritizing nephrology referrals with risk-based assessment were key facilitators. Participants underscored the importance of improving awareness and self-management skills among patients. Primary care providers expressed willingness to manage early-stage CKD as a collaborative care model with nephrologists. Our findings provide valuable insights to design targeted interventions to enhance CKD management in primary care in Singapore that may be relevant to other countries. CONCLUSIONS: The are several roadblocks to improving CKD management in primary care settings warranting urgent attention. Foremost, CKD deserves greater priority from HCPs and health planners. Multipronged approaches should urgently address gaps in care coordination, patient-physician communication, and knowledge. Strategies could focus on intensive CKD-oriented training for primary care physicians and building novel team-based care models integrating structured CKD management, risk-based nephrology referrals coupled with education and motivational counseling for patients. Such concerted efforts are likely to improve outcomes of patients with CKD and reduce the ESKD burden.

Dietary Intakes of Trace Elements and the Risk of Kidney Cancer: The Singapore Chinese Health Study.

Background: Epidemiological studies have demonstrated separately that patients with kidney stone may have higher dietary intake of zinc and higher risk of developing kidney cancer. We prospectively assessed the associations of dietary zinc and other trace elements with kidney cancer risk for the first time.Methods: We used data from the prospective Singapore Chinese Health Study that recruited 63,257 adult Chinese residing in Singapore between 1993 and 1998. A validated food frequency questionnaire and the Singapore Food Composition Database was used to compute the values of intake for zinc, copper and manganese. We identified incident cancer cases via linkage with nationwide cancer registry, and used Cox proportional hazard models to compute hazard ratio (HR) and 95% confidence interval (CI) for the association with kidney cancer risk.Results: There were 229 incident kidney cancer cases after median follow-up of 20.1 years. Dietary zinc intake was positively associated with higher kidney cancer risk; the HR comparing the extreme quartiles of zinc intake was 1.74 (95% CI: 1.02-2.97; P-trend = 0.033). Conversely, intakes of copper and manganese were not associated with kidney cancer risk.Conclusions: The positive association between dietary zinc and risk of kidney cancer suggests that zinc may be implicated in renal carcinogenesis.

Freestanding Dialysis Facility Quality Incentive Program Scores and Mortality Among Incident Dialysis Patients in the United States.

RATIONALE & OBJECTIVE: The Centers for Medicare & Medicaid Services introduced the Quality Incentive Program (QIP) along with the bundled payment reform to improve the quality of dialysis care in the United States. The QIP has been criticized for using easily obtained laboratory indicators without patient-centered measures and for a lack of evidence for an association between QIP indicators and patient outcomes. This study examined the association between dialysis facility QIP performance scores and survival among patients after initiation of dialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Study participants included 84,493 patients represented in the US Renal Disease System's patient-level data who had initiated dialysis between January 1, 2013, and December 1, 2013, and who did not, during the first 90 days after dialysis initiation, die, receive a transplant, or become lost to follow-up. Patients were followed up for the study outcome through March 31, 2014. PREDICTOR: Dialysis facility QIP scores. OUTCOME: Mortality. ANALYTICAL APPROACH: Using a unique facility identifier, we linked Medicare freestanding dialysis facility data from 2015 with US Renal Disease System patient-level data. Kaplan-Meier product limit estimator was used to describe the survival of study participants. Cox proportional hazards regression was used to assess the multivariable association between facility performance scores and patient survival. RESULTS: Excluding patients who died during the first 90 days of dialysis, 11.8% of patients died during an average follow-up of 5 months. Facilities with QIP scores<45 (HR, 1.39; 95% CI, 1.15-1.68) and 45 to<60 (HR, 1.21; 95% CI, 1.10-1.33) had higher patient mortality rates than facilities with scores≥90. LIMITATIONS: Because the Centers for Medicare & Medicaid Services have revised QIP criteria each year, the findings may not relate to years other than those studied. CONCLUSIONS: Dialysis facilities characterized by lower QIP scores were associated with higher rates of patient mortality. These findings need to be replicated to assess their consistency over time.

Establishing Core Cardiovascular Outcome Measures for Trials in Hemodialysis: Report of an International Consensus Workshop.

Cardiovascular disease (CVD) affects more than two-thirds of patients receiving hemodialysis and is the leading cause of death in this population, yet CVD outcomes are infrequently and inconsistently reported in trials in patients receiving hemodialysis. As part of the Standardised Outcomes in Nephrology-Haemodialysis (SONG-HD) initiative, we convened a consensus workshop to discuss the potential use of myocardial infarction and sudden cardiac death as core outcome measures for CVD for use in all trials in people receiving hemodialysis. Eight patients or caregivers and 46 health professionals from 15 countries discussed selection and implementation of the proposed core outcome measures. Five main themes were identified: capturing specific relevance to the hemodialysis population (acknowledging prevalence, risk, severity, unique symptomology, and pathophysiology), the dilemmas in using composite outcomes, addressing challenges in outcome definitions (establishing a common definition and addressing uncertainty in the utility of biomarkers in hemodialysis), selecting a meaningful metric for decision making (to facilitate comparison across trials), and enabling and incentivizing implementation (by ensuring that cardiologists are involved in the development and integration of the outcome measure into registries, trial design, and reporting guidelines). Based on these themes, participants supported the use of myocardial infarction and sudden cardiac death as core outcome measures of CVD to be reported in all hemodialysis trials.

Identifying critically important cardiovascular outcomes for trials in hemodialysis: an international survey with patients, caregivers and health professionals.

BACKGROUND: Cardiovascular disease (CVD) is a major contributor to morbidity and mortality in people on hemodialysis (HD). Cardiovascular outcomes are reported infrequently and inconsistently across trials in HD. This study aimed to identify the priorities of patients/caregivers and health professionals (HPs) for CVD outcomes to be incorporated into a core outcome set reported in all HD trials. METHODS: In an international online survey, participants rated the absolute importance of 10 cardiovascular outcomes (derived from a systematic review) on a 9-point Likert scale, with 7-9 being critically important. The relative importance was determined using a best-worst scale. Likert means, medians and proportions and best-worst preference scores were calculated for each outcome. Comments were thematically analyzed. RESULTS: Participants included 127 (19%) patients/caregivers and 549 (81%) HPs from 53 countries, of whom 530 (78%) completed the survey in English and 146 (22%) in Chinese. All but one cardiovascular outcome ('valve replacement') was rated as critically important (Likert 7-9) by all participants; 'sudden cardiac death', 'heart attack', 'stroke' and 'heart failure' were all rated at the top by patients/caregivers (median Likert score 9). Patients/caregivers ranked the same four outcomes as the most important outcomes with mean preference scores of 6.2 (95% confidence interval 4.8-7.5), 5.9 (4.6-7.2), 5.3 (4.0-6.6) and 4.9 (3.6-6.3), respectively. The same four outcomes were ranked most highly by HPs. We identified five themes underpinning the prioritization of outcomes: 'clinical equipoise and potential for intervention', 'specific or attributable to HD', 'severity or impact on the quality of life', 'strengthen knowledge and education', and 'inextricably linked burden and risk'. CONCLUSIONS: Patients and HPs believe that all cardiovascular outcomes are of critical importance but consistently identify sudden cardiac death, myocardial infarction, stroke and heart failure as the most important outcomes to be measured in all HD trials.

Performance of GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Statistical Simulation.

BACKGROUND: Randomized trials of CKD treatments traditionally use clinical events late in CKD progression as end points. This requires costly studies with large sample sizes and long follow-up. Surrogate end points like GFR slope may speed up the evaluation of new therapies by enabling smaller studies with shorter follow-up. METHODS: We used statistical simulations to identify trial situations where GFR slope provides increased statistical power compared with the clinical end point of doubling of serum creatinine or kidney failure. We simulated GFR trajectories based on data from 47 randomized treatment comparisons. We evaluated the sample size required for adequate statistical power based on GFR slopes calculated from baseline and from 3 months follow-up. RESULTS: In most scenarios where the treatment has no acute effect, analyses of GFR slope provided similar or improved statistical power compared with the clinical end point, often allowing investigators to shorten follow-up by at least half while simultaneously reducing sample size. When patients' GFRs are higher, the power advantages of GFR slope increase. However, acute treatment effects within several months of randomization can increase the risk of false conclusions about therapies based on GFR slope. Care is needed in study design and analysis to avoid such false conclusions. CONCLUSIONS: Use of GFR slope can substantially increase statistical power compared with the clinical end point, particularly when baseline GFR is high and there is no acute effect. The optimum GFR-based end point depends on multiple factors including the rate of GFR decline, type of treatment effect and study design.

Regional variation in chronic kidney disease and associated factors in hypertensive individuals in rural South Asia: findings from control of blood pressure and risk attenuation-Bangladesh, Pakistan and Sri Lanka.

BACKGROUND: We aimed to determine the prevalence of chronic kidney disease (CKD) and its cross-country variation among hypertensive individuals in rural Bangladesh, Pakistan and Sri Lanka. We also explored the factors associated with CKD in these populations. METHOD: We studied baseline data from the Control of Blood Pressure and Risk Attenuation-Bangladesh, Pakistan and Sri Lanka (COBRA-BPS) trial, an ongoing cluster randomized controlled trial on 2643 hypertensive adults ≥40 years of age from 30 randomly selected rural clusters, 10 in each of the three countries. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or a urine albumin:creatinine ratio (UACR) ≥30 mg/g. Determinants for CKD were assessed using logistic regression analysis. RESULTS: The overall prevalence of CKD was 38.1% (95% confidence interval 36.2-40.1%): 21.5% with eGFR <60 mL/min/1.73 m2 and 24.4% with UACR ≥30 mg/g. CKD prevalence varied across the three countries (58.3% in Sri Lanka, 36.4% Bangladesh and 16.9% Pakistan; P <0.001). The factors independently associated with higher odds of CKD were older age, being unmarried, higher 24-h urinary sodium excretion, presence of diabetes, elevated systolic blood pressure, diuretic use and living in Bangladesh or Sri Lanka (versus Pakistan). CONCLUSIONS: The prevalence of CKD is alarmingly high in community-dwelling hypertensive adults, with significant cross-country variation in South Asia. Our findings underscore the urgency for further research into the etiology of CKD and address associated factors in targeted public health strategies with hypertension care outreach services in rural South Asia. CLINICALTRIALS.GOV: NCT02657746.

Family dynamics in a multi-ethnic Asian society: comparison of elderly CKD patients and their family caregivers experience with medical decision making for managing end stage kidney disease.

BACKGROUND: Elderly end stage kidney patients face a decision concerning whether or not to initiate dialysis. In Asia, this decision is highly influenced by family caregivers. The objective of this paper was to understand patients' experience with and preferences for family involvement in treatment decisions, and via a series of hypothetical vignettes, to identify whether there was discordance in treatment preferences between patients and their caregivers, and how any potential conflicts were reconciled. METHODS: We conducted a survey with 151 elderly (aged ≥65) chronic kidney disease patients and their caregivers at outpatient renal clinics. The survey asked, when making treatment decisions, whom they wish makes the final decisions (i.e., preference) and who usually makes the final decisions (i.e., experience). The survey also presented a series of choice vignettes for managing patient's condition and asked respondents to choose between two hypothetical treatment profiles in each vignette. Patients and caregivers were first interviewed separately in tandem, and then were brought together to choose a treatment jointly for vignettes where the initial treatment choice differed within the dyad. We used multivariate regressions to investigate the predictors of discordance and reconciliation. RESULTS: We found that most (51%) patients preferred and experienced (64%) significant involvement from caregivers. However, 38% of patients preferred to make final decisions alone but only 27% of patients did. In the hypothetical vignettes, caregivers chose the more intensive option (i.e., dialysis) more than patients did (26% vs 19%; p < 0.01). Overall, 44% of the dyads had discordance in at least 3 vignettes, and the odds of discordance within patient-caregiver dyads was higher when caregivers chose dialysis or treatment with the higher cost (p < 0.01). In half the cases, discordance resolved in the patients' favor, and this was more likely to be the case if the patient was employed and wanted to be in charge of final decisions (p < 0.01). CONCLUSIONS: Our results highlight the important role of caregivers in decision-making but also the potential for them to overstep. Clinicians should be aware of this challenge and identify strategies that minimize the chances that patients may receive treatments not consistent with their preferences.

Validation of the kidney failure risk equation for end-stage kidney disease in Southeast Asia.

BACKGROUND: Patients with chronic kidney disease (CKD) are at high risk of end-stage kidney disease (ESKD). The Kidney Failure Risk Equation (KFRE), which predicts ESKD risk among patients with CKD, has not been validated in primary care clinics in Southeast Asia (SEA). Therefore, we aimed to (1) evaluate the performance of existing KFRE equations, (2) recalibrate KFRE for better predictive precision, and (3) identify optimally feasible KFRE thresholds for nephrologist referral and dialysis planning in SEA. METHODS: All patients with CKD visiting nine primary care clinics from 2010 to 2013 in Singapore were included and applied 4-variable KFRE equations incorporating age, sex, estimated glomerular filtration rate (eGFR), and albumin-to-creatinine ratio (ACR). ESKD onset within two and five years were acquired via linkage to the Singapore Renal Registry. A weighted Brier score (the squared difference between observed vs predicted ESKD risks), bias (the median difference between observed vs predicted ESKD risks) and precision (the interquartile range of the bias) were used to select the best-calibrated KFRE equation. RESULTS: The recalibrated KFRE (named Recalibrated Pooled KFRE SEA) performed better than existing and other recalibrated KFRE equations in terms of having a smaller Brier score (square root: 2.8% vs. 4.0-9.3% at 5 years; 2.0% vs. 6.1-9.1% at 2 years), less bias (2.5% vs. 3.3-5.2% at 5 years; 1.8% vs. 3.2-3.6% at 2 years), and improved precision (0.5% vs. 1.7-5.2% at 5 years; 0.5% vs. 3.8-4.2% at 2 years). Area under ROC curve for the Recalibrated Pooled KFRE SEA equations were 0.94 (95% confidence interval [CI]: 0.93 to 0.95) at 5 years and 0.96 (95% CI: 0.95 to 0.97) at 2 years. The optimally feasible KFRE thresholds were > 10-16% for 5-year nephrologist referral and > 45% for 2-year dialysis planning. Using the Recalibrated Pooled KFRE SEA, an estimated 82 and 89% ESKD events were included among 10% of subjects at highest estimated risk of ESKD at 5-year and 2-year, respectively. CONCLUSIONS: The Recalibrated Pooled KFRE SEA performs better than existing KFREs and warrants implementation in primary care settings in SEA.

Development of Risk Prediction Equations for Incident Chronic Kidney Disease.

Importance: Early identification of individuals at elevated risk of developing chronic kidney disease (CKD) could improve clinical care through enhanced surveillance and better management of underlying health conditions. Objective: To develop assessment tools to identify individuals at increased risk of CKD, defined by reduced estimated glomerular filtration rate (eGFR). Design, Setting, and Participants: Individual-level data analysis of 34 multinational cohorts from the CKD Prognosis Consortium including 5 222 711 individuals from 28 countries. Data were collected from April 1970 through January 2017. A 2-stage analysis was performed, with each study first analyzed individually and summarized overall using a weighted average. Because clinical variables were often differentially available by diabetes status, models were developed separately for participants with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external cohorts (n = 2 253 540). Exposures: Demographic and clinical factors. Main Outcomes and Measures: Incident eGFR of less than 60 mL/min/1.73 m2. Results: Among 4 441 084 participants without diabetes (mean age, 54 years, 38% women), 660 856 incident cases (14.9%) of reduced eGFR occurred during a mean follow-up of 4.2 years. Of 781 627 participants with diabetes (mean age, 62 years, 13% women), 313 646 incident cases (40%) occurred during a mean follow-up of 3.9 years. Equations for the 5-year risk of reduced eGFR included age, sex, race/ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, body mass index, and albuminuria concentration. For participants with diabetes, the models also included diabetes medications, hemoglobin A1c, and the interaction between the 2. The risk equations had a median C statistic for the 5-year predicted probability of 0.845 (interquartile range [IQR], 0.789-0.890) in the cohorts without diabetes and 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes. Calibration analysis showed that 9 of 13 study populations (69%) had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 of 18 (89%) had a slope of observed to predicted risk between 0.80 and 1.25. Conclusions and Relevance: Equations for predicting risk of incident chronic kidney disease developed from more than 5 million individuals from 34 multinational cohorts demonstrated high discrimination and variable calibration in diverse populations. Further study is needed to determine whether use of these equations to identify individuals at risk of developing chronic kidney disease will improve clinical care and patient outcomes.