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Evidence supports the use of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) in patients with hypertension and stage 3 or milder chronic kidney disease (CKD). This systematic review and individual-level meta-analysis summarizes the evidence supporting the use of the medications in patients with hypertension and more advanced CKD. 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 m 2. 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 m 2), 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 m 2 , 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) [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background New equations to estimate glomerular filtration rate based on creatinine (eGFRcr), cystatin C (eGFRcys) or both (eGFRcr-cys) have been developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the European Kidney Function Consortium (EKFC). There is a need to evaluate the performance of these equations in diverse European settings to inform implementation decisions, especially among people with key comorbid conditions. Methods We performed a cross-sectional study including 6174 adults referred for single-point plasma clearance of iohexol in Stockholm, Sweden, with 9579 concurrent measurements of creatinine and cystatin C. We assessed the performance of the CKD-EPI 2009/2012/2021, EKFC 2021/2023, revised Lund-Malmö (RLM) 2011 and Caucasian, Asian, Pediatric and Adult (CAPA) 2014 equations against measured GFR (mGFR). Results Mean age was 56 years, median mGFR was 62 mL/min/1.73 m2 and 40% were female. Comorbid conditions were common: cardiovascular disease (30%), liver disease (28%), diabetes (26%) and cancer (26%). All eGFRcr-cys equations had small bias and P30 (the percentage of estimated values within 30% of mGFR) close to 90%, and performed better than eGFRcr or eGFRcys equations. Among eGFRcr equations, CKD-EPI 2009 and CKD-EPI 2021 showed larger bias and lower P30 than EKFC 2021 and RLM. There were no meaningful differences in performance across eGFRcys equations. Findings were consistent across comorbid conditions, and eGFRcr-cys equations showed good performance in patients with liver disease, cancer and heart failure. Conclusions In conclusion, eGFRcr-cys equations performed best, with minimal variation among equations in this Swedish cohort. The lower performance of CKD-EPI eGFRcr equations compared with EKFC and RLM may reflect differences in population characteristics and mGFR methods. Implementing eGFRcr equations will require a trade-off between accuracy and uniformity across regions. [ABSTRACT FROM AUTHOR]

The commonly accepted glomerular filtration rate (GFR) threshold used to define chronic kidney disease is based on associations between estimated GFR (eGFR) and the frequency of adverse outcomes. However, the appropriateness of the threshold in older adults is uncertain, partly because the studies measuring these associations included relatively few outcomes and estimated GFR on the basis of creatinine level (eGFR cr), which may be less accurate in older adults. This study evaluated associations between eGFR cr versus eGFR based on creatinine and cystatin C levels and 8 outcomes in older adults. Visual Abstract. Association of Low Glomerular Filtration Rate With Adverse Outcomes at Older Age in a Large Population With Routinely Measured Cystatin C: The commonly accepted glomerular filtration rate (GFR) threshold used to define chronic kidney disease is based on associations between estimated GFR (eGFR) and the frequency of adverse outcomes. However, the appropriateness of the threshold in older adults is uncertain, partly because the studies measuring these associations included relatively few outcomes and estimated GFR on the basis of creatinine level (eGFR cr), which may be less accurate in older adults. This study evaluated associations between eGFR cr versus eGFR based on creatinine and cystatin C levels and 8 outcomes in older adults. Background: The commonly accepted threshold of glomerular filtration rate (GFR) to define chronic kidney disease (CKD) is less than 60 mL/min/1.73 m 2. 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 (eGFR cr), which may be less accurate in older adults. Objective: To evaluate associations in older adults between eGFR cr versus eGFR based on creatinine and cystatin C levels (eGFR cr-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 eGFR cr-cys and outcomes were monotonic, but most associations for eGFR cr were U-shaped. In addition, eGFR cr-cys was more strongly associated with outcomes than eGFR cr. For example, the adjusted hazard ratios for 60 versus 80 mL/min/1.73 m 2 for all-cause mortality were 1.2 (95% CI, 1.1 to 1.3) for eGFR cr-cys and 1.0 (CI, 0.9 to 1.0) for eGFR cr , 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 eGFR cr in older patients, low eGFR cr-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Whether treating metabolic acidosis slows progression of chronic kidney disease (CKD) has not been established. Veverimer is a novel hydrochloric acid binder that removes acid from the gastrointestinal tract leading to an increase in serum bicarbonate; it is being developed to treat metabolic acidosis with the goal of slowing progression of CKD. Methods The VALOR-CKD trial is an international, randomized, multicenter, double-blind, placebo-controlled study designed to evaluate the effect of once-daily veverimer on kidney disease progression in patients with metabolic acidosis and CKD. Eligibility criteria include a serum bicarbonate in the range of 12–20 mmol/L and an estimated glomerular filtration rate (eGFR) of 20–40 mL/min/1.73 m2. The primary outcome is kidney disease progression defined as the development of end-stage kidney disease, a sustained decline in eGFR of >40% from baseline or death due to kidney failure. Key secondary endpoints include effects on physical function. Results Between December 2018 and December 2021, 1480 participants were randomized. The mean age at baseline was 65.1 years and 42% of the patients were female. The mean baseline eGFR was 29.1 mL/min/1.73 m2 and mean serum bicarbonate was 17.5 mmol/L. The median urine albumin-to-creatinine ratio at screening was 201 mg/g and the median 5-year predicted risk of kidney failure was 32%. Diabetes and hypertension were present in 56% and 98% of participants, respectively. Conclusions VALOR-CKD has recruited a large population of people with metabolic acidosis at high risk for CKD progression to determine the effects of veverimer on the risk of progressive loss of kidney function. [ABSTRACT FROM AUTHOR]

Background While American nephrology societies recommend using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) equation without a Black race coefficient, it is unknown how this would impact disease distribution, prognosis and kidney failure risk prediction in predominantly White non-US populations. Methods We studied 1.6 million Stockholm adults with serum/plasma creatinine measurements between 2007 and 2019. We calculated changes in eGFR and reclassification across KDIGO GFR categories when changing from the 2009 to 2021 CKD-EPI equation; estimated associations between eGFR and the clinical outcomes kidney failure with replacement therapy (KFRT), (cardiovascular) mortality and major adverse cardiovascular events using Cox regression; and investigated prognostic accuracy (discrimination and calibration) of both equations within the Kidney Failure Risk Equation. Results Compared with the 2009 equation, the 2021 equation yielded a higher eGFR by a median [interquartile range (IQR)] of 3.9 (2.9–4.8) mL/min/1.73 m2, which was larger at older age and for men. Consequently, 9.9% of the total population and 36.2% of the population with CKD G3a–G5 was reclassified to a higher eGFR category. Reclassified individuals exhibited a lower risk of KFRT, but higher risks of all-cause/cardiovascular death and major adverse cardiovascular events, compared with non-reclassified participants of similar eGFR. eGFR by both equations strongly predicted study outcomes, with equal discrimination and calibration for the Kidney Failure Risk Equation. Conclusions Implementing the 2021 CKD-EPI equation in predominantly White European populations would raise eGFR by a modest amount (larger at older age and in men) and shift a major proportion of CKD patients to a higher eGFR category. eGFR by both equations strongly predicted outcomes. [ABSTRACT FROM AUTHOR]

Objective: To predict adverse kidney outcomes for use in optimizing medical management and clinical trial design.Research Design and Methods: In this meta-analysis of individual participant data, 43 cohorts (N = 1,621,817) from research studies, electronic medical records, and clinical trials with global representation were separated into development and validation cohorts. Models were developed and validated within strata of diabetes mellitus (presence or absence) and estimated glomerular filtration rate (eGFR; ≥60 or <60 mL/min/1.73 m2) to predict a composite of ≥40% decline in eGFR or kidney failure (i.e., receipt of kidney replacement therapy) over 2-3 years.Results: There were 17,399 and 24,591 events in development and validation cohorts, respectively. Models predicting ≥40% eGFR decline or kidney failure incorporated age, sex, eGFR, albuminuria, systolic blood pressure, antihypertensive medication use, history of heart failure, coronary heart disease, atrial fibrillation, smoking status, and BMI, and, in those with diabetes, hemoglobin A1c, insulin use, and oral diabetes medication use. The median C-statistic was 0.774 (interquartile range [IQR] = 0.753, 0.782) in the diabetes and higher-eGFR validation cohorts; 0.769 (IQR = 0.758, 0.808) in the diabetes and lower-eGFR validation cohorts; 0.740 (IQR = 0.717, 0.763) in the no diabetes and higher-eGFR validation cohorts; and 0.750 (IQR = 0.731, 0.785) in the no diabetes and lower-eGFR validation cohorts. Incorporating the previous 2-year eGFR slope minimally improved model performance, and then only in the higher-eGFR cohorts.Conclusions: Novel prediction equations for a decline of ≥40% in eGFR can be applied successfully for use in the general population in persons with and without diabetes with higher or lower eGFR. [ABSTRACT FROM AUTHOR]

Background Verinurad is a human uric acid (UA) transporter (URAT1) inhibitor known to decrease serum UA (sUA) levels and that may reduce albuminuria. In a Phase 2a study (NCT03118739), treatment with verinurad + febuxostat lowered urine albumin-to-creatinine ratio (UACR) at 12 weeks by 39% (90% confidence interval 4–62%) among patients with Type 2 diabetes mellitus, hyperuricaemia and albuminuria. The Phase 2b, randomized, placebo-controlled Study of verinurAd and alloPurinol in Patients with cHronic kIdney disease and hyperuRicaEmia (SAPPHIRE; NCT03990363) will examine the effect of verinurad + allopurinol on albuminuria and estimated glomerular filtration rate (eGFR) slope among patients with chronic kidney disease (CKD) and hyperuricaemia. Methods Adults (≥18 years of age) with CKD, eGFR ≥25 mL/min/1.73 m2, UACR 30–5000 mg/g and sUA ≥6.0 mg/dL will be enrolled. Approximately 725 patients will be randomized 1:1:1:1:1 to 12, 7.5 or 3 mg verinurad + allopurinol, allopurinol or placebo. An 8-week dose-titration period will precede a 12-month treatment period; verinurad dose will be increased to 24 mg at Month 9 in a subset of patients in the 3 mg verinurad + allopurinol arm. The primary efficacy endpoint the is change from baseline in UACR at 6 months. Secondary efficacy endpoints include changes in UACR, eGFR and sUA from baseline at 6 and 12 months. Conclusions This study will assess the combined clinical effect of verinurad + allopurinol on kidney function in patients with CKD, hyperuricaemia and albuminuria, and whether this combination confers renoprotection beyond standard-of-care. [ABSTRACT FROM AUTHOR]

Importance: At a given estimated glomerular filtration rate (eGFR), individuals who are Black have higher rates of mortality and kidney failure with replacement therapy (KFRT) compared with those who are non-Black. Whether the recently adopted eGFR equations without race preserve racial differences in risk of mortality and KFRT at a given eGFR is unknown.Objective: To assess whether eGFR equations with and without race and cystatin C document racial differences in risk of KFRT and mortality in populations including Black and non-Black participants.Design, Setting, and Participants: Retrospective individual-level data analysis of 62 011 participants from 5 general population and 3 chronic kidney disease (CKD) US-based cohorts with serum creatinine, cystatin C, and follow-up for KFRT and mortality from 1988 to 2018.Exposures: Chronic Kidney Disease Epidemiology Collaboration equation with serum creatinine (eGFRcr with and without race), cystatin C (eGFRcys without race), or both markers (eGFRcr-cys without race).Main Outcomes and Measures: The prevalence of decreased eGFR at baseline and hazard ratios of KFRT and mortality in Black vs non-Black participants were calculated, adjusted for age and sex. Analyses were performed within each cohort and with random-effect meta-analyses of the models.Results: Among 62 011 participants (20 773 Black and 41 238 non-Black; mean age, 63 years; 53% women), the prevalence ratio (95% CI; percent prevalences) of eGFR less than 60 mL/min/1.73 m2 comparing Black with non-Black participants was 0.98 (95% CI, 0.93-1.03; 11% vs 12%) for eGFRcr with race, 0.95 (95% CI, 0.91-0.98; 17% vs 18%) for eGFRcys, and 1.2 (95% CI, 1.2-1.3; 13% vs 11%) for eGFRcr-cys but was 1.8 (95% CI, 1.7-1.8; 15% vs 9%) for eGFRcr without race. During a mean follow-up of 13 years, 8% and 4% of Black and non-Black participants experienced KFRT and 34% and 39% died, respectively. Decreased eGFR was associated with significantly greater risk of both outcomes for all equations. At an eGFR of 60 mL/min/1.73 m2, the hazard ratios for KFRT comparing Black with non-Black participants were 2.8 (95% CI, 1.6-4.9) for eGFRcr with race, 3.0 (95% CI, 1.5-5.8) for eGFRcys, and 2.8 (95% CI, 1.4-5.4) for eGFRcr-cys vs 1.3 (95% CI, 0.8-2.1) for eGFRcr without race. The 5-year absolute risk differences for KFRT comparing Black with non-Black participants were 1.4% (95% CI, 0.2%-2.6%) for eGFRcr with race, 1.1% (95% CI, 0.2%-1.9%) for eGFRcys, and 1.3% (95% CI, 0%-2.6%) for eGFRcr-cys vs 0.37% (95% CI, -0.32% to 1.05%) for eGFRcr without race. Similar patterns were observed for mortality.Conclusions and Relevance: In this retrospective analysis of 8 US cohorts including Black and non-Black individuals, the eGFR equation without race that included creatinine and cystatin C, but not the eGFR equation without race that included creatinine without cystatin C, demonstrated racial differences in the risk of KFRT and mortality throughout the range of eGFR. The eGFRcr-cys equation may be preferable to the eGFRcr equation without race for assessing racial differences in the risk of KFRT and mortality associated with low eGFR. [ABSTRACT FROM AUTHOR]

Background To characterize the use of nephrotoxic medications in patients with chronic kidney disease (CKD) Stages G3–5 in routine care. Methods We studied cohorts of adults with confirmed CKD G3–5 undergoing routine care from 1 January 2016 through 31 December 2018 in two health systems [Stockholm CREAtinine Measurements (SCREAM), Stockholm, Sweden (N  = 57 880) and Geisinger, PA, USA (N  = 16 255)]. We evaluated the proportion of patients receiving nephrotoxic medications within 1 year overall and by baseline kidney function, ranked main contributors and examined the association between receipt of nephrotoxic medication and age, sex, CKD G-stages comorbidities and provider awareness of the patient's CKD using multivariable logistic regression. Results During a 1-year period, 20% (SCREAM) and 17% (Geisinger) of patients with CKD received at least one nephrotoxic medication. Among the top nephrotoxic medications identified in both cohorts were non-steroidal anti-inflammatory drugs (given to 11% and 9% of patients in SCREAM and Geisinger, respectively), antivirals (2.5% and 2.0%) and immunosuppressants (2.7% and 1.5%). Bisphosphonate use was common in SCREAM (3.3%) and fenofibrates in Geisinger (3.6%). Patients <65 years of age, women and those with CKD G3 were at higher risk of receiving nephrotoxic medications in both cohorts. Notably, provider awareness of a patient's CKD was associated with lower odds of nephrotoxic medication use {odds ratios [OR] 0.85[95% confidence interval (CI) 0.80–0.90] in SCREAM and OR 0.80 [95% CI 0.72–0.89] in Geisinger}. Conclusions One in five patients with CKD received nephrotoxic medications in two distinct health systems. Strategies to increase physician's awareness of patients' CKD and knowledge of drug nephrotoxicity may reduce prescribing nephrotoxic medications and prevent iatrogenic kidney injury. [ABSTRACT FROM AUTHOR]

Introduction: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome.Methods: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12-70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30-90 mL/min/1.73 m2, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR.Results: A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy.Discussion/conclusion: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry. [ABSTRACT FROM AUTHOR]

Background A simple equation for glomerular filtration rate (GFR) measurement based on only plasma samples during the slow compartment after injection of iohexol was previously developed among children with chronic kidney disease and adult men with or at risk of HIV infection [Chronic Kidney Disease in Children (CKiD)-Multicenter AIDS Cohort Study (MACS) equation], but has not been externally validated. We aimed to evaluate the performance of the CKiD-MACS equation among elderly participants in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort who underwent directly measured iohexol GFR. Methods Using data from 287 participants of the MESA-Kidney study who underwent a five-sample measured iohexol GFR (two and three samples in the fast and slow compartments, respectively), we assessed the performance of the CKiD-MACS equation using only plasma samples in the slow compartment by sex, race and age. Agreement was assessed by bias, correlation, proportion within 5 and 10%, and the root mean square error (RMSE). Results The average age and GFR of the participants were 71 years and 70.8 mL/min/1.73 m2, respectively, and 46% were black. The equation yielded excellent agreement within stratified groups with high correlation (>0.96), low bias (≤1.2 mL/min/1.73 m2) and low RMSE (<4.2 mL/min/1.73 m2). Conclusions The CKiD-MACS equation demonstrated valid GFR measurement using only samples in the slow compartment in this racially diverse, elderly population. While the equation yielded practically the same results as the original Brochner-Mortensen equation, the CKiD-MACS equation conforms to theoretical principles embedded in the two-compartment model of direct GFR measurement. [ABSTRACT FROM AUTHOR]

Introduction: Chronic kidney disease (CKD) is a major public health challenge given its high global prevalence and associated risks of cardiovascular disease and progression to end stage renal disease. Although it is known that numerous metabolic changes occur in CKD patients, identifying novel metabolite associations with kidney function may enhance our understanding of the physiologic pathways relating to CKD. Objectives: The objective of this study was to elucidate novel metabolite associations with kidney function among participants of two community-based cohorts with carefully ascertained metabolomics, kidney function, and covariate data. Methods: Untargeted ultrahigh-performance liquid chromatography–tandem mass spectrometry was used to detect and quantify blood metabolites. We used multivariate adjusted linear regression to examine associations between single metabolites and creatinine-based estimated glomerular filtration rate (eGFRcr) among 1243 Bogalusa Heart Study (BHS) participants (median eGFRcr: 94.4, 5th–95th percentile: 66.0–119.6 mL/min/1.73 m2). Replication, determined by statistical significance and consistent effect direction, was tested using gold standard measured glomerular filtration rate (mGFR) among 260 Multi-Ethnic Study of Atherosclerosis (MESA) participants (median mGFR: 72.0, 5th–95th percentile: 43.5–105.0 mL/min/1.73 m2). All analyses used Bonferroni-corrected alpha thresholds. Results: Fifty-one novel metabolite associations with kidney function were identified, including 12 from previously unrelated sub-pathways: N6-carboxymethyllysine, gulonate, quinolinate, gamma-CEHC-glucuronide, retinol, methylmalonate, 3-hydroxy-3-methylglutarate, 3-aminoisobutyrate, N-methylpipecolate, hydroquinone sulfate, and glycine conjugates of C10H12O2 and C10H14O2(1). Significant metabolites were generally inversely associated with kidney function and smaller in mass-to-charge ratio than non-significant metabolites. Conclusion: The 51 novel metabolites identified may serve as early, clinically relevant, kidney function biomarkers. [ABSTRACT FROM AUTHOR]

In March of 2018, the National Kidney Foundation, in collaboration with the US Food and Drug Administration and the European Medicines Agency, sponsored a workshop in which surrogate endpoints other than currently established event-time endpoints for clinical trials in chronic kidney disease (CKD) were presented and discussed. One such endpoint is a slope-based parameter describing the rate of decline in the estimated glomerular filtration rate (eGFR) over time. There are a number of challenges that can complicate such slope-based analyses in CKD trials. These include the possibility of an early but short-term acute treatment effect on the slope, both within-subject and between-subject heteroscedasticity, and informative censoring resulting from patient dropout due to death or onset of end-stage kidney disease. To address these issues, we first consider a class of mixed-effects models for eGFR that are linear in the parameters describing the mean eGFR trajectory but which are intrinsically nonlinear when a power-of-mean variance structure is used to model within-subject heteroscedasticity. We then combine the model for eGFR with a model for time to dropout to form a class of shared parameter models which, under the right specification of shared random effects, can minimize bias due to informative censoring. The models and methods of analysis are described and illustrated using data from two CKD studies one of which was one of 56 studies made available to the workshop analytical team. Lastly, methodology and accompanying software for prospectively determining sample size/power estimates are presented. [ABSTRACT FROM AUTHOR]

Background: Dietary acid load is a clinically important aspect of the diet that reflects the balance between acid-producing foods, for example, meat and cheese, and base-producing foods, for example, fruits and vegetables.Methods: We used metabolomics to identify blood biomarkers of dietary acid load in 2 independent studies of chronic kidney disease patients: the African American Study of Kidney Disease and Hypertension (AASK, n = 689) and the Modification of Diet in Renal Disease (MDRD, n = 356) study. Multivariable linear regression was used to assess the cross-sectional association between serum metabolites whose identity was known (outcome) and dietary acid load (exposure), estimated with net endogenous acid production (NEAP) based on 24-h urine urea nitrogen and potassium, and adjusted for age, sex, race, randomization group, measured glomerular filtration rate, log-transformed urine protein-to-creatinine ratio, history of cardiovascular disease, BMI, and smoking status.Results: Out of the 757 known, nondrug metabolites identified in AASK, 26 were significantly associated with NEAP at the Bonferroni threshold for significance (P < 6.6 × 10-5). Twenty-three of the 26 metabolites were also identified in the MDRD study, and 13 of the 23 (57%) were significantly associated with NEAP (P < 2.2 × 10-3), including 5 amino acids (S-methylmethionine, indolepropionylglycine, indolepropionate, N-methylproline, N-δ-acetylornithine), 2 cofactors and vitamins (threonate, oxalate), 1 lipid (chiro-inositol), and 5 xenobiotics (methyl glucopyranoside, stachydrine, catechol sulfate, hippurate, and tartronate). Higher levels of all 13 replicated metabolites were associated with lower NEAP in both AASK and the MDRD study.Conclusion: Metabolomic profiling of serum specimens from kidney disease patients in 2 study populations identified 13 replicated metabolites associated with dietary acid load. Additional studies are needed to validate these compounds in healthy populations. These 13 compounds may potentially be used as objective markers of dietary acid load in future nutrition research studies. [ABSTRACT FROM AUTHOR]

Background. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations are recommended for glomerular filtration rate (GFR) estimation in the general population. They have not been evaluated in community-based populations, including Blacks at higher levels of GFR, but are commonly applied in such populations. Methods. In an ancillary study of Multi-Ethnic Study of Atherosclerosis conducted at one site, we evaluated the performance of the CKD-EPI equations for creatinine (eGFRcr), cystatin C (eGFRcys) or the combination (eGFRcr-cys) compared with GFR measured as plasma clearance of iohexol. Results. Among 294 participants, the mean age was 71 (SD 9) years, 47% were Black, 48% were women and themean measured GFR (mGFR) was 72.6 (SD 18.8) mL/min/1.73 m2. The CKDEPI equations overestimated mGFR with a larger median bias for eGFRcr and eGFRcr-cys than eGFRcys [-8.3 (95% confidence interval -9.7, -6.5), -7.8 (-9.2, -6.2) and -3.7 (-5.0, -1.8) mL/min/1.73 m2, respectively], with smaller bias for those with lower compared with higher eGFR and by race compared with sex. Conclusion. The small differential bias of the CKD-EPI equation between races suggests that they can be used in Blacks as well as Whites in older community-based adults. The large differential bias in women versus men in all equations is in contrast to other studies and is unexplained. Further studies are required in multiracial and multiethnic community-based cohorts, taking into account differences in GFR measurement methods. [ABSTRACT FROM AUTHOR]

Background: Increases in measured inulin clearance, measured creatinine clearance, and estimated glomerular filtration rate (eGFR) have been observed with bardoxolone methyl in 7 studies enrolling approximately 2,600 patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). The largest of these studies was Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), a multinational, randomized, double-blind, placebo-controlled phase 3 trial which enrolled patients with T2D and CKD stage 4. The BEACON trial was terminated after preliminary analyses showed that patients randomized to bardoxolone methyl experienced significantly higher rates of heart failure events. We performed post-hoc analyses to characterize changes in kidney function induced by bardoxolone methyl.Methods: Patients in -BEACON (n = 2,185) were randomized 1: 1 to receive once-daily bardoxolone methyl (20 mg) or placebo. We compared the effects of bardoxolone methyl and placebo on a post-hoc composite renal endpoint consisting of ≥30% decline from baseline in eGFR, eGFR <15 mL/min/1.73 m2, and end-stage renal disease (ESRD) events (provision of dialysis or kidney transplantation).Results: Consistent with prior studies, patients randomized to bardoxolone methyl experienced mean increases in eGFR that were sustained through study week 48. Moreover, increases in eGFR from baseline were sustained 4 weeks after cessation of treatment. Patients randomized to bardoxolone methyl were significantly less likely to experience the composite renal endpoint (hazards ratio 0.48 [95% CI 0.36-0.64]; p < 0.0001).Conclusions: Bardoxolone methyl preserves kidney function and may delay the onset of ESRD in patients with T2D and stage 4 CKD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recommendations for apixaban dosing on the basis of kidney function are inconsistent between the US Food and Drug Administration and European Medicines Agency for patients with atrial fibrillation. Optimal apixaban dosing in chronic kidney disease remains unknown. METHODS: With the use of deidentified electronic health record data from the Optum Labs Data Warehouse, patients with atrial fibrillation and chronic kidney disease stage 4/5 initiating apixaban between 2013 and 2021 were identified. Risks of bleeding and stroke/systemic embolism were compared by apixaban dose (5 versus 2.5 mg), adjusted for baseline characteristics by the inverse probability of treatment weighting. The Fine-Gray subdistribution hazard model was used to account for the competing risk of death. Cox regression was used to examine risk of death by apixaban dose. RESULTS: Among 4313 apixaban new users, 1705 (40%) received 5 mg and 2608 (60%) received 2.5 mg. Patients treated with 5 mg apixaban were younger (mean age, 72 versus 80 years), with greater weight (95 versus 80 kg) and higher serum creatinine (2.7 versus 2.5 mg/dL). Mean estimated glomerular filtration rate was not different between the groups (24 versus 24 mL⋅min-1⋅1.73 m-2). In inverse probability of treatment weighting analysis, apixaban 5 mg was associated with a higher risk of bleeding (incidence rate 4.9 versus 2.9 events per 100 person-years; incidence rate difference, 2.0 [95% CI, 0.6-3.4] events per 100 person-years; subdistribution hazard ratio, 1.63 [95% CI, 1.04-2.54]). There was no difference between apixaban 5 mg and 2.5 mg groups in the risk of stroke/systemic embolism (3.3 versus 3.0 events per 100 person-years; incidence rate difference, 0.2 [95% CI, -1.0 to 1.4] events per 100 person-years; subdistribution hazard ratio, 1.01 [95% CI, 0.59-1.73]), or death (9.9 versus 9.4 events per 100 person-years; incidence rate difference, 0.5 [95% CI, -1.6 to 2.6] events per 100 person-years; hazard ratio, 1.03 [95% CI, 0.77-1.38]). CONCLUSIONS: Compared with 2.5 mg, use of 5 mg apixaban was associated with a higher risk of bleeding in patients with atrial fibrillation and severe chronic kidney disease, with no difference in the risk of stroke/systemic embolism or death, supporting the apixaban dosing recommendations on the basis of kidney function by the European Medicines Agency, which differ from those issued by the US Food and Drug Administration. [ABSTRACT FROM AUTHOR]

IMPORTANCE The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of-57% or greater) is a late event. OBJECTIVE To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated. DATA SOURCES AND STUDY SELECTION Individual meta-analysis of 1.7 million participants with 12 344 ESRD events and 223 944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data. DATA EXTRACTION AND SYNTHESIS Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012. MAIN OUTCOMES AND MEASURES End-Stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR. RESULTS The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m², the adjusted HRs for ESRD were 32.1 (95% Cl, 22.3-46.3) for changes of -57% in estimated GFR and 5.4 (95% Cl, 4.5-6.4) for changes of -30%. However, changes of -30% or greater (6.9% [95% Cl, 6.4%-7.4%] of the entire consortium) were more common than changes of -57% (0.79% [95% Cl, 0.52%-1.06%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m²) was 99% (95% Cl, 95%-100%) for estimated GFR change of -57%, was 83% (95% Cl, 71%-93%) for estimated GFR change of -40%, and was 64% (95% Cl, 52%-77%) for estimated GFR change of -30% vs 18% (95% Cl, 15%-22%) for estimated GFR change of 0%. Corresponding mortality risks were 77% (95% Cl, 71%-82%), 60% (95% Cl, 56%-63%), and 50% (95% Cl, 47%-52%) vs 32% (95% Cl, 31%-33%), showing a similar but weaker pattern. CONCLUSIONS AND RELEVANCE Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression. [ABSTRACT FROM AUTHOR]

Background Glomerular filtration rate (GFR) estimating equations using the combination of creatinine and cystatin C (eGFRcr-cys) are more accurate than equations using either alone (eGFRcr or eGFRcys). New guidelines suggest measuring cystatin C as a confirmatory test when eGFRcr may be inaccurate, but do not specify demographic or clinical conditions in which eGFRcys or eGFRcr-cys are more accurate than eGFRcr nor which estimate to use in such circumstances. Methods We compared the performance of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in 1119 subjects in the CKD-EPI cystatin C external validation dataset. Subgroups were defined by eGFRcr, age, sex, diabetes status and body mass index (BMI). The reference test was GFR measured using urinary or plasma clearance of exogenous filtration markers. Cystatin C and creatinine assays were traceable to primary reference materials. Accuracy was defined as the absolute difference in eGFR compared with mGFR. Results The mean mGFR was 70 ± 41 (SD) mL/min/1.73 m2. eGFRcys was more accurate than eGFRcr at lower BMI and less accurate at higher BMI, especially at higher levels of eGFRcr. There were small differences in accuracy in people according to the diabetes status. eGFRcr-cys was as accurate or more accurate than eGFRcr or eGFRcys in these and all other subgroups. Conclusions eGFRcr-cys, but not eGFRcys, is more accurate than eGFRcr in most subgroups we studied, suggesting preferential use of eGFRcr-cys when serum cystatin C is measured as a confirmatory test to obtain more accurate eGFR. Further studies are necessary to evaluate diagnostic strategies for using eGFRcys and eGFRcr-cys. [ABSTRACT FROM PUBLISHER]

OBJECTIVE--Patients with diabetes have a high risk of end-stage renal disease (ESRD). We examined whether prediction of this outcome, according to chronic kidney disease (CKD) staging by creatinine-based estimates of the glomerular filtration rate (eGFRcreat), is improved by further staging with serum cystatin C-based estimates (eGFRcyst). RESEARCH DESIGN AND METHODS--Patients with diabetes in CKD stages 1-3 were selected from three cohorts: two from Joslin Diabetes Center, one with type 1 diabetes (N = 364) and one with type 2 diabetes (N = 402), and the third from the Finnish Diabetic Nephropathy (FinnDiane) Study of type 1 (N = 399). Baseline serum concentrations of creatinine and cystatin C were measured in all patients. Follow-up averaged 8-10 years and onsets of ESRD (n = 246) and death unrelated to ESRD (n = 159) were ascertained. RESULTS--Although CKD staging by eGFRcyst was concordant with that by eGFRcreat for 62% of Joslin patients and 73% of FinnDiane patients, those given a higher stage by eGFRcyst than eGFRcreat had a significantly higher risk of ESRD than those with concordant staging in all three cohorts (hazard ratio 2.3 [95% CI 1.8-3.1]). Similarly, patients at a lower stage by eGFRcyst than by eGFRcreat had a lower risk than those with concordant staging (0.30 [0.13-0.68]). Deaths unrelated to ESRD followed the same pattern, but differences were not as large. CONCLUSIONS--In patients with diabetes, CKD staging based on eGFRcyst significantly improves ESRD risk stratification based on eGFRcreat. This conclusion can be generalized to patients with type 1 and type 2 diabetes and to diabetic patients in the U.S. and Finland. [ABSTRACT FROM AUTHOR]

Context.--: Use of cystatin C for glomerular filtration rate estimation (eGFR) has garnered heightened interest as a means to avoid race-based medicine, since eGFRcys equations do not require specification of race. Before considering more widespread use of cystatin C, it is important to confirm that assays provide accurate measurements of cystatin C concentration, to ensure accurate GFR estimates. Objective.--: To determine if the accuracy of cystatin C measurements in laboratories participating in the College of American Pathologists (CAP) Cystatin C (CYS) survey has improved since 2014. Design.--: Two fresh frozen serum pools, the first from healthy donors without chronic kidney disease (CKD), and the second from patients with CKD, along with a synthetically prepared elevated cystatin C pool, were sent to laboratories participating in the 2019 CYS-A survey. Target values were established by using 2 immunoassays and a bracketed 2-point calibration with diluted ERM-DA471/IFCC reference material. Results.--: For the healthy donor fresh frozen pool (ERM-DA471/IFCC-traceable target of 0.725 mg/L), the all-method mean (standard deviation, coefficient of variation) was 0.731 mg/L (0.071, 9.7%). For the CKD pool (ERM-DA471/IFCC-traceable target of 2.136 mg/L), the all-method mean was 2.155 mg/L (0.182, 8.4%). For the synthetically spiked pool (ERM-DA471/IFCC-traceable target of 1.843 mg/L), the all-method mean was 1.886 mg/L (0.152, 8.1%). This represents marked improvement in accuracy and between-method agreement compared to the 2014 CAP survey. Conclusions.--: Manufacturers have markedly improved accuracy and between-method agreement of cystatin C measurement procedures since 2014, which allows for greater confidence in estimated GFR relying on cystatin C. [ABSTRACT FROM AUTHOR]

The article reviews the uses of glomerular filtration rate (GFR) and albuminuria level in testing for acute and chronic kidney disease (CKD). Topics discussed are clinical approach to detection, evaluation and management of acute kidney disease (AKD) and CKD, advances in clinical evaluation of GFR and albuminuria, risk factors for cardiovascular disease (CVD), eligibility criteria and end points for clinical trials of kidney disease progressions and risk prediction instruments for CKD outcomes.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure (HF) hospitalizations, recurrent cardiovascular events, and chronic kidney disease (CKD) progression, and thus constitute a Class 1a recommendation in people with diabetes and atherosclerotic cardiovascular disease, HF, or CKD and in people with severe albuminuria or HF, regardless of diabetes status. The purpose of this study was to comprehensibly characterize the rate of SGLT2 inhibitor prescriptions among people with a Class 1a recommendation for SGLT2 inhibitor use. Among 3,189,827 adults from 28 U.S. health systems within Optum Labs Data Warehouse between April 1, 2022, and March 31, 2023, we assessed SGLT2 inhibitor prescription rates, stratified by presence of diabetes and Class 1a recommendation. Among 716,387 adults with diabetes, 63.4% had a Class 1a recommendation for SGLT2 inhibitor therapy. There was little difference by Class 1a recommendation status (present: 11.9%; 95% CI: 11.9%-12.0% vs absent: 11.4%; 95% CI: 11.3%-11.6%; standardized mean difference: 1.3%). Among 2,473,440 adults without diabetes, 6.2% had a Class 1a recommendation for SGLT2 inhibitor therapy, and 3.1% (3.0%-3.2%) of those received a prescription. Internists/family practitioners initiated SGLT2 inhibitor prescriptions most commonly among people with diabetes, whereas specialists initiated SGLT2 inhibitor prescriptions most commonly among people without diabetes. No health system had >25% SGLT2 inhibitor prescription rate among people with a Class 1a recommendation. Health systems with higher proportions of patients with commercial insurance and lower proportions with Medicare had higher SGLT2 inhibitor prescription rates. In this analysis of U.S. data from 2022 to 2023, SGLT2 inhibitor prescription among people with a Class 1a recommendation is low. Interventions are needed to increase uptake of guideline-recommended SGLT2 inhibitor use. [ABSTRACT FROM AUTHOR]

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. Patients with chronic kidney disease often require complex polypharmacy, require dose adjustments or discontinuation with changes in kidney function, and can be susceptible to the adverse effects of medications. This Review discusses the principles of drug stewardship — that is, the effective, safe and sustainable use of medications — for people with chronic kidney disease. Key points: Medication reconciliation and review is an essential first step in patient-centred drug stewardship. Doses should be adjusted according to a patient's glomerular filtration rate (GFR). Most pharmacokinetic information available is derived from creatinine-based equations, and for many medications, different creatinine-based equations to estimate GFR are interchangeable; however, use of equations that utilize both creatinine and cystatin C, or direct measurement of GFR, is advocated when the therapeutic range is narrow and precision is needed. Drug choice should consider relative and absolute contraindications by GFR, and the increased nephrotoxicity of nephrotoxic medications to people with chronic kidney disease. Acute illness and fluctuations in GFR should prompt frequent reassessment of GFR and medications; however, the implementation of routine sick-day rules has a substantial cost or opportunity cost, is not supported by evidence and may cause more harm than good. For people with chronic kidney disease who might become pregnant, education around potential teratogens is important, but people should not be denied medication on the basis that they might become pregnant. Culturally appropriate, multi-faceted educational and empowerment activities may include written instructional materials and digital technologies. Health care workers and patients should collaborate to promote more equitable access to evidence-based medications within their countries and globally. [ABSTRACT FROM AUTHOR]

The article presents the authors' opinions rejecting calls for U.S. medical guidelines to be amended to require age calibration for diagnosis and classification of chronic kidney disease (CKD). Topics addressed include assertions that treatments should be tailored for age differences but the disease should not be redefined, commentary on the broad consensus and acceptance of the current guidelines, and assertions that just because CKD is common in older people it is not necessarily normative.

The article presents reply of the author on their article on managing Chronic Kidney Disease (CKD) in older people is presented.

Abstract: Background: Often, patients with chronic kidney disease are reported to be unaware of it. We prospectively evaluated the association between awareness of kidney disease to end-stage renal disease and mortality. Methods: We utilized 2000-2009 data from the National Kidney Foundation''s Kidney Early Evaluation Program. Mortality was determined by cross reference to the Social Security Administration Death Master File and development of end stage by cross reference with the United States Renal Data System. Results: Of 109,285 participants, 28,244 (26%) had chronic kidney disease defined by albuminuria or estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Only 9% (n=2660) reported being aware of kidney disease. Compared with those who were not aware, participants aware of chronic kidney disease had lower eGFR (49 vs 62 mL/min/1.73 m2) and a higher prevalence of albuminuria (52% vs. 46%), diabetes (47% vs 42%), cardiovascular disease (43% vs 28%), and cancer (23% vs 14%). Over 8.5 years of follow-up, aware participants compared with those unaware had a lower rate of survival for end stage (83% and 96%) and mortality (78% vs 81%), P <.001. After adjustment for demographics, socioeconomic factors, comorbidity, and severity of kidney disease, aware participants continued to demonstrate an increased risk for end-stage renal disease (hazard ratio 1.37; 95% confidence interval, 1.07-1.75; P <.0123) and mortality (hazard ratio 1.27; 95% confidence interval, 1.07-1.52; P <.0077) relative to unaware participants with chronic kidney disease. Conclusions: Among patients identified as having chronic kidney disease at a health screening, only a small proportion had been made aware of their diagnosis previously by clinicians. This subgroup was at a disproportionately high risk for mortality and end-stage renal disease. [Copyright &y& Elsevier]

Evaluation of glomerular filtration rate (GFR) is central to the assessment of kidney function in medical practice, research and public health. Measured GFR (mGFR) remains the reference standard, but the past 20 years have seen major advances in estimated GFR (eGFR). Both eGFR and mGFR are associated with error compared with true GFR. eGFR is now recommended by clinical practice guidelines, regulatory agencies and public health agencies for the initial evaluation of GFR, with measured GFR (mGFR) typically considered an important confirmatory test, depending on how accurate the assessment of GFR needs to be for application to the clinical, research or public health setting. Our approach is to use initial and confirmatory tests as needed to develop a final assessment of true GFR. We suggest that GFR evaluation might be improved by more complete implementation of current recommendations and by further research to improve the accuracy of mGFR and eGFR. [ABSTRACT FROM AUTHOR]

Context.--Cystatin C is becoming an increasingly popular biomarker for estimating glomerular filtration rate, and accurate measurements of cystatin C concentrations are necessary for accurate estimates of glomerular filtration rate. Objective.--To assess the accuracy of cystatin C concentration measurements in laboratories participating in the College of American Pathologists CYS Survey. Design.--Two fresh frozen serum pools, the first from apparently healthy donors and the second from patients with chronic kidney disease, were prepared and distributed to laboratories participating in the CYS Survey along with the 2 usual processed human plasma samples. Target values were established for each pool by using 2 immunoassays and ERM DA471/IFCC international reference material. Results.--For the normal fresh frozen pool (ERM-DA471/IFCC-traceable target of 0.960 mg/L), the all-method mean (SD, % coefficient of variation [CV]) reported by all of the 123 reporting laboratories was 0.894 mg/L (0.128 mg/L, 14.3%). For the chronic kidney disease pool (ERM-DA471/IFCC-traceable target of 2.37 mg/L), the all-method mean (SD, %CV) was 2.258 mg/L (0.288 mg/L, 12.8%). There were substantial method-specific biases (mean milligram per liter reported for the normal pool was 0.780 for Siemens, 0.870 for Gentian, 0.967 for Roche, 1.061 for Diazyme, and 0.970 for other/ not specified reagents; and mean milligram per liter reported for the chronic kidney disease pool was 2.052 for Siemens, 2.312 for Gentian, 2.247 for Roche, 2.909 for Diazyme, and 2.413 for other/not specified reagents). Conclusions.--Manufacturers need to improve the accuracy of cystatin C measurement procedures if cystatin C is to achieve its full potential as a biomarker for estimating glomerular filtration rate. [ABSTRACT FROM AUTHOR]