Lesley A Inker

• Tufts Medical Center

Background Slope of the glomerular filtration rate (GFR) is considered a validated surrogate endpoint for chronic kidney disease (CKD) trials. However, differing short and long-term treatment effects on GFR slope can create ambiguities concerning the appropriate time period for evaluating slope, in part because current methods cannot separate the d...

Assessing glomerular filtration rate (GFR) is critical for diagnosis, staging, and management of kidney disease. However, accuracy of estimated GFR (eGFR) is limited by large errors (>30% error present in >10–50% of patients), adversely impacting patient care. Errors often result from variation across populations of non-GFR determinants affecting t...

Background Patients with atrial fibrillation and severe chronic kidney disease have higher risks of bleeding, thromboembolism, and mortality. However, optimal anticoagulant choice in these high‐risk patients remains unclear. Methods and Results Using deidentified electronic health records from the Optum Labs Data Warehouse, adults with atrial fibr...

Rationale & Objective In 2021, the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) updated the creatinine-based estimated glomerular filtration rate (eGFR) equation and removed the coefficient for race. The development and validation of this equation involved binarizing race into African American and non-African American, involving...

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...

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/1.73m ² ) from 16 tr...

e24143 Background: Accurate assessment of glomerular filtration rate (GFR) is crucial to guiding drug eligibility, dose-adjusting systemic therapy, and minimizing the risks of both undertreatment and toxicity in patients with cancer. To date, there has been a lack of guidance to standardize approaches to GFR estimation in the cancer population base...

Background and Aims Focal segmental glomerulosclerosis (FSGS) is a major cause of glomerular disease that affects both adults and children. FSGS can rapidly progress to end-stage kidney disease. Lack of safe and effective treatment represents a significant unmet need for patients with FSGS. Development of treatments has been hampered by complexitie...

Background and Aims Evidence on the risks of adverse outcomes associated with glomerular filtration rate (GFR) has been limited to estimated GFR (eGFR), due to limited availability of large-scale data with measured GFR (mGFR). These studies either used creatinine (eGFRcr), cystatin C (eGFRcys), or both (eGFRcr-cys), which can be influenced by the n...

Background and Aims The pathogenesis of IgA nephropathy (IgAN) includes the deposition of immune complexes in the kidney and activation of the complement system. Complement components, including C5a (anaphylatoxin) and C5b-9 (membrane attack complex), are generated leading to mesangial inflammation and glomerular injury [1]. Ravulizumab, a humanize...

Key Points c The SAPPHIRE trial was designed to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with allopurinol in patients with CKD. c Verinurad 3, 7.5, and 12 mg in combination with allopurinol 300 mg did not reduce albuminuria during 34 weeks treatment compared with allopurinol alone or placebo. c Ver...

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)...

Early trials of dihydropyridine calcium channel blockers (DCCBs) suggest a detrimental effect on intraglomerular pressure and an association with albuminuria. We sought to evaluate the associations of DCCB initiation with albuminuria and kidney failure with replacement therapy (KFRT) and to determine whether renin-angiotensin system (RAS) blockade...

Introduction: Multiple clinical practice guidelines strongly recommend sodium-glucose cotransporter-2 inhibitors (SGLT2i) for people with diabetes and atherosclerotic cardiovascular disease or chronic kidney disease as well as for people with urine albumin-to-creatinine ≥200 mg/g or heart failure (HF), regardless of diabetes status. We characterize...

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 s...

Background Hyperuricemia is associated with elevated risks of cardiovascular and chronic kidney disease (CKD). Since inhibition of urate transporter 1 has been suggested to be potentially nephroprotective, we performed a phase 2b study to assess albuminuria lowering effects of the urate transporter 1 inhibitor verinurad combined with the xanthine o...

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...

Background: The commonly accepted threshold of glomerular filtration rate (GFR) to define chronic kidney disease (CKD) is less than 60 mL/min/1.73 m2. This threshold is based partly on associations between estimated GFR (eGFR) and the frequency of adverse outcomes. The association is weaker in older adults, which has created disagreement about the...

Background Metabolic acidosis is common in chronic kidney disease (CKD), but whether its treatment slows CKD progression is unknown. Veverimer, a novel hydrochloric acid binder that removes acid from the gastrointestinal tract, leads to an increase in serum bicarbonate. Methods In a Phase 3, double-blind, placebo-controlled trial, patients with CK...

Glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular benefits in type 2 diabetes, but none of the cardiovascular trials studied atrial fibrillation/atrial flutter (AF) as a primary endpoint. Data from post-marketing surveillance studies remains sparse. To examine the real-world risk of AF comparing GLP-1RA with other non-insulin...

Background The growth of oral muscle relaxant prescriptions among older adults in the United States is concerning due to the drugs' adverse sedative effects. Baclofen is a gamma‐aminobutyric acid agonist muscle relaxant that is associated with encephalopathy. We characterized the risk of fall and fracture associated with oral baclofen against other...

Background New CKD-EPI and EKFC estimated GFR (eGFR) equations using creatinine (eGFRcr), cystatin C (eGFRcys) and both (eGFRcr-cys) have sufficient accuracy for use in clinical practice. A better understanding of the equations, including their performance in race, sex and age subgroups, is important for selection of eGFR equations for global imple...

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 fr...

Rigorous evaluation of surrogate endpoints is performed in a trial‐level analysis in which the strength of the association between treatment effects on the clinical and surrogate endpoints is quantified across a collection of previously conducted trials. To reduce bias in measures of the performance of the surrogate, the statistical model must acco...

Rationale & Objective Creatinine-based GFR estimating (eGFRcr) equations may be inaccurate in populations with acute or chronic illness. The accuracy of GFR equations that use cystatin C (eGFRcys) or creatinine-cystatin C (eGFRcr-cys) is not well studied in these populations. Study Design A systematic review of original articles identified from Pu...

Rationale & Objective Use of cystatin C in addition to creatinine to estimate glomerular filtration rate (estimated glomerular filtration rate based on cystatin C [eGFRcys] and estimated glomerular filtration rate based on creatinine [eGFRcr], respectively) is increasing. When eGFRcr and eGFRcys are discordant, it is not known which is more accurat...

In 2021, the National Kidney Foundation (NKF) and American Society of Nephrology (ASN) Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease called for the discontinuation of race-based glomerular filtration rate (GFR) estimation in the United States, and issued recommendations for immediate implementation of the 2021 race-fr...

Glomerular filtration rate (GFR) decline is causally associated with kidney failure and is a candidate surrogate endpoint for clinical trials of chronic kidney disease (CKD) progression. Analyses across a diverse spectrum of interventions and populations is required for acceptance of GFR decline as an endpoint. In an analysis of individual particip...

Background and Aims Focal segmental glomerulosclerosis (FSGS) is a disease of podocytes. Complications include nephrotic syndrome and progressive kidney failure. FSGS is a condition with high unmet need and there is no approved treatment. The angiotensin II receptor type 1 (AT1R) and chemokine receptor 2 (CCR2) are G protein coupled receptors that...

Background and Aims New equations to estimate GFR (eGFR) based on creatinine, cystatin C or both have been developed in the last two years. A comprehensive comparison of their accuracy is currently lacking, particularly in cohorts not involved in their development or validation and among people with comorbid conditions. Method We included 6174 adu...

Background and Aims Cystatin C is recommended for use along with creatinine in estimating glomerular filtration rate (eGFR) when precise estimates are needed for clinical decision-making. Although eGFR based on both creatinine and cystatin (eGFRcr-cys) is the most accurate in research studies, it is uncertain as to whether this remains true in real...

Rationale and objective: Acute declines in glomerular filtration rate (GFR) occur commonly during intensive BP lowering. Our objective was to determine the relationship between acute declines in estimated GFR and patient outcomes. Study design: Retrospective observational study. Setting, and participants: Participants from four randomized cont...

Rationale & objective: Cystatin C is recommended for estimating glomerular filtration rate (eGFR) when estimates based on creatinine (eGFRcr) are not thought to be accurate enough for clinical decision making. While global adoption is slow, routine cystatin C testing in Sweden has been available for over a decade, providing real-world evidence abo...

Objective: To quantify the risk of encephalopathy associated with oral baclofen compared with other muscle relaxants-tizanidine or cyclobenzaprine. Patients and methods: We conducted a new-user, active-comparator study of 2 pairwise cohorts using tertiary health system data from Geisinger Health in Pennsylvania (January 1, 2005, through December...

Doubling of serum creatinine (equivalent to a 57% decline in the estimated glomerular filtration rate (eGFR)) is an accepted component of a composite kidney endpoint in clinical trials. Smaller declines in eGFR (40%, 50%) have been applied in several recently conducted clinical trials. Here, we assessed the effects of newer kidney protective agents...

Background: Cystatin C is recommended as a confirmatory test to estimate glomerular filtration rate (eGFR) when more precise estimates are needed for clinical decision-making. Although eGFR based on both creatinine and cystatin (eGFRcr-cys) is the most accurate estimate in research studies, it is uncertain whether this is true in real-world settin...

Background: Change in log urinary albumin to creatinine ratio (UACR) and GFR slope are individually used as surrogate endpoints in clinical trials of CKD progression. Whether combining these surrogate endpoints might strengthen inferences about clinical benefit is unknown. Methods: Using Bayesian meta-regressions across 41 randomized trials of C...

Introduction: Renal dose adjustment is imperative to appropriate direct oral anticoagulant (DOAC) prescribing among patients with atrial fibrillation (AF). Serum creatinine is routinely used to estimate GFR (eGFRcr) in clinical practice, but eGFRcr may be less accurate in certain settings. It is unknown whether other kidney function biomarkers, lik...

Background: Landmark trials of direct oral anticoagulants (DOACs) versus warfarin for non-valvular atrial fibrillation (NVAF) excluded patients with severe chronic kidney disease (CKD). Real-world data on safety and effectiveness of DOACs in severe CKD is limited. Methods: New users of DOACs (apixaban, rivaroxaban, and dabigatran) or warfarin with...

Background: The cause for differences in serum creatinine between Black and non-Black individuals incorporated into prior GFR estimating equations is not understood. We explored whether social determinates of health can account for this difference. Methods: We conducted a secondary analysis of baseline data of the Modification of Diet in Renal D...

Background: The US Food and Drug Administration (FDA) has prioritized efforts to expand availability of therapies, including anticancer agents, for patients with chronic kidney disease (CKD). FDA Guidance recommends inclusion of study participants with CKD in clinical trials, improving pharmacokinetic characterization in people with decreased glom...

Background: The GFR slope has been evaluated as a surrogate end point for kidney failure in meta-analyses on a broad collection of randomized controlled trials (RCTs) in CKD. These analyses evaluate how accurately a treatment effect on GFR slope predicts a treatment effect on kidney failure. We sought to determine whether severity of CKD in the pa...

Background: Low muscle mass is related to frailty and increased mortality in older adults. However, muscle mass is not easily assessed in routine clinical practice. Methods: This study describes a novel creatinine muscle index (CMI) on the basis of serum creatinine and cystatin C in a community-based sample of older adults from the Atheroscleros...

Background The kidney failure risk equation (KFRE) uses age, sex, GFR, and urine albumin-to-creatinine ratio (ACR) to predict kidney failure risk in people with GFR <60 ml/min per 1.73 m ² . Methods Using 59 cohorts with 312,424 patients with CKD, we tested several modifications to the KFRE for their potential to improve the KFRE: using the CKD-EP...

Background: The effect of intensive BP lowering (to systolic BP of <120 mm Hg) on the risk of kidney failure requiring KRT remains unclear in patients with advanced CKD. Such patients were not well-represented in trials evaluating intensive BP control. Methods: To examine the effect of intensive BP lowering on KRT risk-or when not possible, tria...

Background and objectives Alport syndrome is an inherited disease characterized by progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in patients with Alport syndrome. Design, setting, participants, & measurements We randomly assigned patients with Alport syndrome, ages 12–70 years and eGFR 30–9...

Background The National Kidney Foundation and American Society of Nephrology Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease recently recommended a new race-free creatinine-based equation for eGFR. The effect on recommended clinical care across race and ethnicity groups is unknown. Methods We analyzed nationally repres...