Clinical Trial Considerations in Developing Treatments for Early Stages of Common, Chronic Kidney Diseases: A Scientific Workshop Cosponsored by the National Kidney Foundation and the US Food and Drug Administration.

In the past decade, advances in the validation of surrogate end points for chronic kidney disease (CKD) progression have heightened interest in evaluating therapies in early CKD. In December 2020, the National Kidney Foundation sponsored a scientific workshop in collaboration with the US Food and Drug Administration (FDA) to explore patient, provider, and payor perceptions of the value of treating early CKD. The workshop reviewed challenges for trials in early CKD, including trial designs, identification of high-risk populations, and cost-benefit and safety considerations. Over 90 people representing a range of stakeholders including experts in clinical trials, nephrology, cardiology and endocrinology, patient advocacy organizations, patients, payors, health economists, regulators and policy makers attended a virtual meeting. There was consensus among the attendees that there is value to preventing the development and treating the progression of early CKD in people who are at high risk for progression, and that surrogate end points should be used to establish efficacy. Attendees also concluded that cost analyses should be holistic and include aspects beyond direct savings for treatment of kidney failure; and that safety data should be collected outside/beyond the duration of a clinical trial. Successful drug development and implementation of effective therapies will require collaboration across sponsors, patients, patient advocacy organizations, medical community, regulators, and payors.

Association of Rosuvastatin Use with Risk of Hematuria and Proteinuria.

BACKGROUND: Despite reports of hematuria and proteinuria with rosuvastatin use at the time of its approval by the US Food and Drug Association (FDA), little postmarketing surveillance exists to assess real-world risk. Current labeling suggests dose reduction (maximum daily dose of 10 mg) for patients with severe CKD. METHODS: Using deidentified electronic health record data, we analyzed 152,101 and 795,799 new users of rosuvastatin and atorvastatin, respectively, from 2011 to 2019. We estimated inverse probability of treatment-weighted hazard ratios (HRs) of hematuria, proteinuria, and kidney failure with replacement therapy (KFRT) associated with rosuvastatin. We reported the initial rosuvastatin dose across eGFR categories and evaluated for a dose effect on hematuria and proteinuria. RESULTS: Overall, we identified 2.9% of patients with hematuria and 1.0% with proteinuria during a median follow-up of 3.1 years. Compared with atorvastatin, rosuvastatin was associated with increased risk of hematuria (HR, 1.08; 95% confidence interval [95% CI], 1.04 to 1.11), proteinuria (HR, 1.17; 95% CI, 1.10 to 1.25), and KFRT (HR, 1.15; 95% CI, 1.02 to 1.30). A substantial share (44%) of patients with eGFR <30 ml/min per 1.73 m2 was prescribed high-dose rosuvastatin (20 or 40 mg daily). Risk was higher with higher rosuvastatin dose. CONCLUSIONS: Compared with atorvastatin, rosuvastatin was associated with increased risk of hematuria, proteinuria, and KFRT. Among patients with eGFR <30 ml/min per 1.73 m2, 44% were prescribed a rosuvastatin daily dose exceeding the FDA's recommended 10 mg daily dose. Our findings suggest the need for greater care in prescribing and monitoring rosuvastatin, particularly in patients who receive high doses or who have severe CKD.

Rationale, design, demographics and baseline characteristics of the randomized, controlled, Phase 2b SAPPHIRE study of verinurad plus allopurinol in patients with chronic kidney disease and hyperuricaemia.

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.

A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease.

BACKGROUND: In response to a national call for re-evaluation of the use of race in clinical algorithms, the National Kidney Foundation (NKF) and the American Society of Nephrology (ASN) established a Task Force to reassess inclusion of race in the estimation of glomerular filtration rate (GFR) in the United States and its implications for diagnosis and management of patients with, or at risk for, kidney diseases. PROCESS & DELIBERATIONS: The Task Force organized its activities over 10 months in phases to (1) clarify the problem and evidence regarding GFR estimating equations in the United States (described previously in an interim report), and, in this final report, (2) evaluate approaches to address use of race in GFR estimation, and (3) provide recommendations. We identified 26 approaches for the estimation of GFR that did or did not consider race and narrowed our focus, by consensus, to 5 of those approaches. We holistically evaluated each approach considering 6 attributes: assay availability and standardization; implementation; population diversity in equation development; performance compared with measured GFR; consequences to clinical care, population tracking, and research; and patient centeredness. To arrive at a unifying approach to estimate GFR, we integrated information and evidence from many sources in assessing strengths and weaknesses in attributes for each approach, recognizing the number of Black and non-Black adults affected. RECOMMENDATIONS: (1) For US adults (>85% of whom have normal kidney function), we recommend immediate implementation of the CKD-EPI creatinine equation refit without the race variable in all laboratories in the United States because it does not include race in the calculation and reporting, included diversity in its development, is immediately available to all laboratories in the United States, and has acceptable performance characteristics and potential consequences that do not disproportionately affect any one group of individuals. (2) We recommend national efforts to facilitate increased, routine, and timely use of cystatin C, especially to confirm estimated GFR in adults who are at risk for or have chronic kidney disease, because combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone. If ongoing evidence supports acceptable performance, the CKD-EPI eGFR-cystatin C (eGFRcys) and eGFR creatinine-cystatin C (eGFRcr-cys_R) refit without the race variables should be adopted to provide another first-line test, in addition to confirmatory testing. (3) Research on GFR estimation with new endogenous filtration markers and on interventions to eliminate race and ethnic disparities should be encouraged and funded. An investment in science is needed for newer approaches that generate accurate, unbiased, and precise GFR measurement and estimation without the inclusion of race, and that promote health equity and do not generate disparate care. IMPLEMENTATION: This unified approach, without specification of race, should be adopted across the United States. High-priority and multistakeholder efforts should implement this solution.

A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease.

BACKGROUND: In response to a national call for re-evaluation of the use of race in clinical algorithms, the National Kidney Foundation (NKF) and the American Society of Nephrology (ASN) established a Task Force to reassess inclusion of race in the estimation of GFR in the United States and its implications for diagnosis and management of patients with, or at risk for, kidney diseases. PROCESS DELIBERATIONS: The Task Force organized its activities over 10 months in phases to ( 1 ) clarify the problem and evidence regarding eGFR equations in the United States (described previously in an interim report), and, in this final report, ( 2 ) evaluate approaches to address use of race in GFR estimation, and ( 3 ) provide recommendations. We identified 26 approaches for the estimation of GFR that did or did not consider race and narrowed our focus, by consensus, to five of those approaches. We holistically evaluated each approach considering six attributes: assay availability and standardization; implementation; population diversity in equation development; performance compared with measured GFR; consequences to clinical care, population tracking, and research; and patient centeredness. To arrive at a unifying approach to estimate GFR, we integrated information and evidence from many sources in assessing strengths and weaknesses in attributes for each approach, recognizing the number of Black and non-Black adults affected. RECOMMENDATIONS: ( 1 ) For US adults (>85% of whom have normal kidney function), we recommend immediate implementation of the CKD-EPI creatinine equation refit without the race variable in all laboratories in the United States because it does not include race in the calculation and reporting, included diversity in its development, is immediately available to all laboratories in the United States, and has acceptable performance characteristics and potential consequences that do not disproportionately affect any one group of individuals. ( 2 ) We recommend national efforts to facilitate increased, routine, and timely use of cystatin C, especially to confirm eGFR in adults who are at risk for or have CKD, because combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone. If ongoing evidence supports acceptable performance, the CKD-EPI eGFR-cystatin C (eGFRcys) and eGFR creatinine-cystatin C (eGFRcr-cys_R) refit without the race variables should be adopted to provide another first-line test, in addition to confirmatory testing. ( 3 ) Research on GFR estimation with new endogenous filtration markers and on interventions to eliminate race and ethnic disparities should be encouraged and funded. An investment in science is needed for newer approaches that generate accurate, unbiased, and precise GFR measurement and estimation without the inclusion of race, and that promote health equity and do not generate disparate care. IMPLEMENTATION: This unified approach, without specification of race, should be adopted across the United States. High-priority and multistakeholder efforts should implement this solution.

Association Between Renin-Angiotensin System Blockade Discontinuation and All-Cause Mortality Among Persons With Low Estimated Glomerular Filtration Rate.

Importance: It is uncertain whether and when angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) treatment should be discontinued in individuals with low estimated glomerular filtration rate (eGFR). Objective: To investigate the association of ACE-I or ARB therapy discontinuation after eGFR decreases to below 30 mL/min/1.73 m2 with the risk of mortality, major adverse cardiovascular events (MACE), and end-stage kidney disease (ESKD). Design, Setting, and Participants: This retrospective, propensity score-matched cohort study included 3909 patients from an integrated health care system that served rural areas of central and northeastern Pennsylvania. Patients who initiated ACE-I or ARB therapy from January 1, 2004, to December 31, 2018, and had an eGFR decrease to below 30 mL/min/1.73 m2 during therapy were enrolled, with follow-up until January 25, 2019. Exposures: Individuals were classified based on whether they discontinued ACE-I or ARB therapy within 6 months after an eGFR decrease to below 30 mL/min/1.73 m2. Main Outcomes and Measures: The association between ACE-I or ARB therapy discontinuation and mortality during the subsequent 5 years was assessed using multivariable Cox proportional hazards regression models, adjusting for patient characteristics at the time of the eGFR decrease in a propensity score-matched sample. Secondary outcomes included MACE and ESKD. Results: Of the 3909 individuals receiving ACE-I or ARB treatment who experienced an eGFR decrease to below 30 mL/min/1.73 m2 (2406 [61.6%] female; mean [SD] age, 73.7 [12.6] years), 1235 discontinued ACE-I or ARB therapy within 6 months after the eGFR decrease and 2674 did not discontinue therapy. A total of 434 patients (35.1%) who discontinued ACE-I or ARB therapy and 786 (29.4%) who did not discontinue therapy died during a median follow-up of 2.9 years (interquartile range, 1.3-5.0 years). In the propensity score-matched sample of 2410 individuals, ACE-I or ARB therapy discontinuation was associated with a higher risk of mortality (hazard ratio [HR], 1.39; 95% CI, 1.20-1.60]) and MACE (HR, 1.37; 95% CI, 1.20-1.56), but no statistically significant difference in the risk of ESKD was found (HR, 1.19; 95% CI, 0.86-1.65). Conclusions and Relevance: The findings suggest that continuing ACE-I or ARB therapy in patients with declining kidney function may be associated with cardiovascular benefit without excessive harm of ESKD.

Assessment of Glomerular Filtration Rate and End-Stage Kidney Disease Risk in Living Kidney Donor Candidates: A Paradigm for Evaluation, Selection, and Counseling.

Living donor kidney transplantation is the preferred treatment option for ESRD. However, recent data suggest a small increase in the long-term risk of kidney failure in living kidney donors when compared to healthy nondonors. These data have led to a need for reconsideration of how donor candidates are evaluated and selected for donation. A Kidney Disease: Improving Global Outcomes (KDIGO) work group completed a comprehensive clinical practice guideline for evaluation of living kidney donor candidates in 2017, based on systematic evidence review, de novo evidence generation, and expert opinion. Central to the evaluation framework is assessment of glomerular filtration rate (GFR), which is used to screen for kidney disease and aid the prediction of long-term kidney failure risk after donation. Accurate estimation of the level of GFR and risk of kidney failure, and communication of estimated risks, can support evidence-based donor selection and shared decision-making. In this review, we discuss approaches to optimal GFR estimation in the donor evaluation process, long-term risk projection, and risk communication to donor candidates, integrating recommendations from the new KDIGO guideline, other recent literature, and experience from our own research and practice. We conclude by highlighting topics for further research in this important area of transplant medicine.

A Metabolome-Wide Association Study of Kidney Function and Disease in the General Population.

Small molecules are extensively metabolized and cleared by the kidney. Changes in serum metabolite concentrations may result from impaired kidney function and can be used to estimate filtration (e.g., the established marker creatinine) or may precede and potentially contribute to CKD development. Here, we applied a nontargeted metabolomics approach using gas and liquid chromatography coupled to mass spectrometry to quantify 493 small molecules in human serum. The associations of these molecules with GFR estimated on the basis of creatinine (eGFRcr) and cystatin C levels were assessed in ≤1735 participants in the KORA F4 study, followed by replication in 1164 individuals in the TwinsUK registry. After correction for multiple testing, 54 replicated metabolites significantly associated with eGFRcr, and six of these showed pairwise correlation (r≥0.50) with established kidney function measures: C-mannosyltryptophan, pseudouridine, N-acetylalanine, erythronate, myo-inositol, and N-acetylcarnosine. Higher C-mannosyltryptophan, pseudouridine, and O-sulfo-L-tyrosine concentrations associated with incident CKD (eGFRcr <60 ml/min per 1.73 m(2)) in the KORA F4 study. In contrast with serum creatinine, C-mannosyltryptophan and pseudouridine concentrations showed little dependence on sex. Furthermore, correlation with measured GFR in 200 participants in the AASK study was 0.78 for both C-mannosyltryptophan and pseudouridine concentration, and highly significant associations of both metabolites with incident ESRD disappeared upon adjustment for measured GFR. Thus, these molecules may be alternative or complementary markers of kidney function. In conclusion, our study provides a comprehensive list of kidney function-associated metabolites and highlights potential novel filtration markers that may help to improve the estimation of GFR.