Importance Lower estimated glomerular filtration rate (eGFR) is associated with increased rates of death and kidney and cardiovascular events. Associations of measured GFR (mGFR) with outcomes remain unclear. Objective To quantify associations between mGFR and adverse clinical outcomes and to compare these with eGFR-based associations. Design, Setting, and Participants Retrospective observational cohort study of 6174 adults from Stockholm, Sweden, between January 1, 2011, and December 31, 2021. Exposure Measured GFR was obtained based on plasma clearance of intravenously administered iohexol (primary independent variable of interest). Estimated GFR was calculated with plasma creatinine (eGFRcr), cystatin C (eGFRcys), or both (eGFRcr-cys), using the Chronic Kidney Disease Epidemiology Collaboration 2021 and 2012 equations. Main Outcomes and Measures Primary outcomes were all-cause mortality and kidney failure with replacement therapy. Associations of each GFR measure with outcomes were evaluated using hazard ratios adjusted for age, sex, body mass index (calculated as weight in kilograms divided by height in meters squared), medical history, medications, and urine albumin to creatinine ratio. Results Of 6174 participants (median age, 59 years [IQR, 43-69]; 3686 [60%] were male and 2488 [40%] were female), 1977 (32%) died and 426 (6.9%) developed kidney failure with replacement therapy during a median follow-up of 5.9 years (IQR, 3.0-8.8 years). Compared with a baseline mGFR of 90 mL/min/1.73 m 2 , an mGFR of 60 mL/min/1.73 m 2 was associated with higher rates of all-cause mortality (27.6 vs 22.4 per 1000 person-years; hazard ratio [HR], 1.21; 95% CI, 1.14-1.28) and kidney failure with replacement therapy (1.2 vs 0.4 per 1000 person-years; HR, 2.85; 95% CI, 2.06-3.94). For all-cause mortality, associations for eGFRcr-cys did not significantly differ from those for mGFR (ratio of HRs [RHRs] at 60 mL/min/1.73 m 2 , 1.03; 95% CI, 0.96-1.10), whereas eGFRcr underestimated the mGFR-based association (RHR, 0.87; 95% CI, 0.79-0.95) and eGFRcys overestimated it (RHR, 1.17; 95% CI, 1.08-1.27). Conclusions and Relevance Among adults in Sweden, mGFR values of 60 mL/min/1.73 m 2 were associated with higher rates of all-cause mortality and kidney failure compared with mGFR values of 90 mL/min/1.73 m 2 , supporting the current GFR threshold of 60 mL/min/1.73 m 2 to define chronic kidney disease. Associations of mGFR with mortality were most closely represented by the association of eGFRcr-cys with mortality, whereas eGFRcr underestimated and eGFRcys overestimated mortality risk.

The use of surrogate endpoints can improve feasibility of clinical trials. The results of trial-level analyses are a key factor affecting regulatory policy regarding the uptake of a surrogate endpoint. Trial-level analyses aim to quantify the strength of association between treatment effects on an established clinical endpoint and treatment effects on the surrogate. Unfortunately, there is a well-documented lack of standardization in the meta-regression models used for these analyses. Common models differ in how they account for estimation errors, leading to variation in surrogacy estimands across approaches. This has caused confusion regarding surrogate quality. Moreover, the most used modeling approaches can lead to pessimistic inferences of surrogate quality. We overview common meta-regression models and their corresponding estimands for evaluating trial-level surrogacy, focusing on how each modeling approach accounts for sampling errors. Two broad classes of models can be differentiated. The models in the first class quantify the association between observed, estimated treatment effects, based on unweighted (least squares) or weighted linear regression (weighted least squares with weights proportional to trial sample size). The second class consists of hierarchical meta-regression models, which quantify the association between latent, true treatment effects. We target the trial-level coefficient of determination (R2) in our inferences. We use patient-level meta-analysis of 66 previously conducted chronic kidney disease clinical trials and a small statistical simulation to characterize differences in results between modeling approaches. Across our analyses, use of simple and weighted linear regression produced R2 estimates which were lower than those produced by the hierarchical models. In simulation analyses, use of simple and weighted linear regression resulted in downward bias in R2 when the estimand is defined as the R2 representing the trial-level association of true treatment effects on the clinical and surrogate endpoints. Commonly used methods for evaluating surrogate endpoints can produce unduly pessimistic conclusions of surrogate quality depending on the target of inference. This is because these methods partially or completely ignore estimation error in the analysis. Hierarchical models can be used to overcome such limitations.

KEY POINTS:Use of glucocorticoids, opioids, and loop diuretics raised cystatin C independent of GFR. Except for glucocorticoids, cystatin C increases were small and likely clinically nonmeaningful. Consequently, the underestimation of eGFR cys was larger in medication users; combined eGFR cr-cys was most accurate. BACKGROUND:Serum cystatin C is influenced by factors beyond GFR, and several medications have been hypothesized to alter its generation. Whether reported associations reflect effects on cystatin C independent of measured GFR (mGFR) or confounding by illness remains unclear. METHODS:We studied 5595 adults who underwent outpatient cystatin C (and creatinine) testing with mGFR determination using iohexol clearance in Stockholm health care. Associations between eight candidate medication classes and cystatin C were assessed using both interindividual and intraindividual analyses, sequentially adjusting for mGFR, clinical variables, and ongoing medications. We further evaluated the effect of these medications on cystatin C-based eGFR (eGFR cys ) bias compared with serum creatinine-based (eGFR cr ) and combined (eGFR cr-cys ) equations. RESULTS:After adjustment for mGFR and confounders, the use of systemic glucocorticoids, opioids, and loop diuretics was associated with higher cystatin C. The magnitude of increase was potentially clinically meaningful for glucocorticoid use, particularly for greater estimated daily dose categories, whereas the smaller increases observed with opioid and loop diuretic use likely reflect clinically nonmeaningful effects. No associations were observed for use of allopurinol, immunosuppressants, thyroid hormone analogues, or antipsychotics or for paracetamol after adjustment for concomitant medications. eGFR cys underestimated mGFR more in users than in nonusers, while eGFR cr overestimated mGFR similarly in users and nonusers. eGFR cr-cys provided the least biased GFR estimates. CONCLUSIONS:This study suggests that systemic glucocorticoids, opioids, and loop diuretics may increase cystatin C independent of mGFR. The use of eGFR cr-cys was consistently more accurate than either eGFR cr or eGFR cys alone in patients using these treatments.

Background:Serum cystatin C is influenced by factors beyond glomerular filtration rate (GFR), andseveral medications have been hypothesized to alter its generation. Whether reportedassociations reflect effects on cystatin C independent of measured GFR (mGFR) orconfounding by illness remains unclear. Methods:We studied 5595 adults who underwent outpatient cystatin C (and creatinine) testingwith mGFR determination using iohexol clearance in Stockholm healthcare.Associations between eight candidate medication classes and cystatin C were essed using both inter- and intra-individual analyses, sequentially adjusting formGFR, clinical variables, and ongoing medications. We further evaluated the effect ofthese medications on cystatin C-based eGFR (eGFRcys) bias compared with serumcreatinine-based (eGFRcr) and combined (eGFRcr-cys) equations. Results:After adjustment for mGFR and confounders, use of systemic glucocorticoids, opioidsand loop diuretics was associated with higher cystatin C. The magnitude of increasewas potentially clinically meaningful for glucocorticoid use, particularly for greaterestimated daily dose categories, whereas the smaller increases observed with opioidand loop diuretic use likely reflect clinically non-meaningful effects. No associationswere observed for use of allopurinol, immunosuppressants, thyroid hormoneanalogues, or antipsychotics, or for paracetamol after adjustment for concomitantmedications. eGFRcys underestimated mGFR more in users than in non-users, whileeGFRcr overestimated mGFR similarly in users and non-users. eGFRcr-cys providedthe least biased GFR estimates. Conclusions:This study suggests that systemic glucocorticoids, opioids and loop diuretics mayincrease cystatin C independent of mGFR. Use of eGFRcr-cys was consistently moreaccurate than either eGFRcr or eGFRcys alone in patients using these treatments.

BACKGROUND:The European Kidney Function Consortium (EKFC) 2021 equation to estimate GFR performs as well or better than the CKD-EPI 2009 equation in predominantly White adult European populations, with less bias and greater accuracy against measured GFR. This study explores how changing from the CKD-EPI to the EKFC equation in a large European health system may affect disease distribution, prognosis, and clinical decisions. METHODS:We studied >1.7 million adults in Stockholm undergoing routine care during 2006-2021. We compared eGFR values and reclassification across KDIGO GFR categories when changing from the CKD-EPI to EKFC equation and examined associations of eGFR and reclassification with risk for kidney failure with replacement therapy (KFRT), mortality, and major adverse cardiovascular events (MACE) using Cox models. We also modeled the impact of eGFR equation change on clinical decisions such as nephrology referral or medication eligibility/contraindication. RESULTS:EKFC yielded modestly lower eGFR values than CKD-EPI by a median (IQR) of -4.9 (-8.3 to -2.2) ml/min/1.73 m². As a result, CKD G3-G5 prevalence rose from 4.5% to 6.2%. Both equations strongly predicted KFRT, mortality, and MACE. Participants reclassified to lower eGFR categories were older; after adjustment for age, participants had similar risks of mortality and MACE to those not reclassified and a lower risk of KFRT. Changing to the EKFC equation would impact clinical decisions at low eGFR thresholds, such as nephrology referrals (22% higher), eligibility for SGLT2 is (39% higher), or contraindication for spironolactone in heart failure (26% higher). CONCLUSIONS:Adopting the EKFC equation in this Northern European health system would modestly lower eGFR estimates, increasing the prevalence of moderate/severe CKD and affecting clinical classification and decisions. eGFR by both equations strongly predicted outcomes, but individuals reclassified to a lower eGFR category by EKFC did not have consistent associations across outcomes.

Robust and reproducible assays capable of specific and quantitative monitoring of multiple biologically important proteins, among the thousands of human plasma proteins, can be used to represent the overall health of an individual and distinguish health versus disease. In this study, we established an LC-MS assay to monitor a Health Surveillance Panel (HSP), comprising 60 circulating plasma proteins selected based on their biological functions and/or disease associations. Plasma samples were prepared for proteomic analysis in an automated process and analyzed using an optimized, scheduled LC-MRM assay composed of 60 endogenous proteins monitored by 364 transitions from 117 proteotypic peptides, along with their stable isotopically labeled standard peptides. For each proteotypic peptide, a quantifier ion and at least two qualifier ions were selected based on consistent peak area ratios, a linear response for the quantifier ion, and a low limit of quantification. As proof of concept, we evaluated the performance of our HSP assay in a case-control study of progressive chronic kidney disease (CKD). Reduced plasma concentrations of alpha-2-antiplasmin, antithrombin-III, and immunoglobulin heavy constant alpha 1 correlated with CKD, with p-values <0.05. These results demonstrate that CKD-associated differences can be detected with a multiplexed HSP assay panel.

In randomized trials, the primary analysis often estimates the average treatment effect on a clinical endpoint. Some treatments also lead to early changes in a biomarker that is prognostic for the clinical endpoint, prompting investigators to explore how these acute biomarker changes might inform the treatment's effect on long-term clinical outcomes. A naive analysis that directly examines treatment-by-biomarker-change interactions may lead to biased estimates because it fails to account for the fact that biomarker changes are influenced by the treatment and post-randomization factors. A key statistical challenge is that we do not know whether the observed biomarker change in an individual patient truly reflects a treatment-induced effect or whether the change would have occurred under placebo as well. This uncertainty makes it difficult to disentangle the causal effect of the treatment from natural biomarker variability. We apply principal stratification with a normal copula governed by the correlation [Formula: see text] between the potential acute biomarker changes under treatment and placebo. A flexible model for the conditional distribution of the clinical endpoint given the biomarker change enables estimation of the conditional average treatment effect on the clinical endpoint, given the acute biomarker change under treatment, as a function of [Formula: see text]. We illustrate the method by determining how knowledge of acute change in estimated glomerular filtration rate modifies the expected effect of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on clinical endpoints in patients with chronic kidney disease.

Glomerular filtration markers are exogenous or endogenous solutes that are eliminated from the circulation primarily by glomerular filtration. Their rate of elimination is directly related to the GFR, and their plasma concentration is inversely related to the GFR. GFR cannot be measured directly in humans, but it can be assessed by using filtration markers—either as measured GFR (mGFR) from clearance measurements using exogenous filtration markers (such as iothalamate and iohexol) or as eGFR from estimating equations using plasma concentrations of endogenous filtration markers (metabolites, such as creatinine, and low molecular weight proteins, such as cystatin C). Thus, both mGFR and eGFR may differ from true GFR, and understanding the physiologic processes affecting filtration markers is required for clinical evaluation of GFR. Processes other than GFR that affect the plasma concentration of filtration markers are collectively defined as non-GFR determinants. By design, exogenous filtration markers are minimally affected by non-GFR determinants, but both urinary and plasma clearance measurements are associated with error in mGFR. By contrast, by definition, all endogenous filtration markers are affected by non-GFR determinants, but not by error in clearance measurements. The major limitations of mGFR procedures are complexity and inconvenience of clearance measurements, which constrain their utility in clinical practice. The major limitation of eGFR is error because of variation in the non-GFR determinants of the filtration markers, which can be minimized by use of a panel of markers (panel eGFR). There is ongoing interest in the discovery of new exogenous filtration markers that would enable widespread implementation of mGFR procedures and novel metabolite and low molecular weight endogenous filtration markers that would enable a panel eGFR. In this review, we discuss current and emerging insights into existing and novel filtration markers.

RATIONALE & OBJECTIVE:Creatinine-based estimated glomerular filtration rate (eGFRcr) and cystatin C-based eGFR (eGFRcys) may be inaccurate for patients with rheumatoid arthritis (RA) due to sarcopenia and inflammation. This study characterized changes in eGFRcys and eGFRcr after 2 RA treatment regimens and their association with RA disease activity biomarkers. STUDY DESIGN:Secondary observational analysis of randomized controlled trial of tumor necrosis factor (TNF) inhibitor plus methotrexate (MTX) versus triple therapy (MTX, sulfasalazine, and hydroxychloroquine). SETTING & PARTICIPANTS:Patients with active RA enrolled at multiple US institutions into an immunomodulatory treatment trial. EXPOSURE:RA disease activity biomarkers. OUTCOME:eGFRcys and eGFRcr at baseline and weeks 6, 18, and 24. ANALYTICAL APPROACH:Describing eGFRcys and eGFRcr at baseline and during the follow-up period in the overall cohort and by treatment arm. Adjusted mixed-effects linear models to estimate the associations of RA activity biomarkers with eGFR. RESULTS:The study included 157 eligible trial participants (median age, 58 years; 75% female). At baseline, the mean eGFRcys was lower than the eGFRcr (63.3 vs 84.2; difference, -20.9 mL/min/1.73 m2 [95% CI, -24.7 to -17.0]). Over 24 weeks, neither eGFRcys nor eGFRcr changed overall (1.74 mL/min/1.73 m2 [95% CI, -0.77 to 4.24] and -0.28 mL/min/1.73 m2 [95% CI, -3.71 to 3.15], respectively). Multiple disease activity biomarkers, including vascular cell adhesion protein 1, interleukin 6, tumor necrosis factor receptor 1 (TNFR1), leptin, and resistin, were inversely associated with eGFRcys and/or eGFRcr at baseline in adjusted models. During the follow-up period, only TNF-RI change was inversely associated with eGFRcys change (-2.91 mL/min/1.73 m2 [95% CI, -4.48 to -1.33]) in adjusted models whereas no biomarker change was significantly related to eGFRcr change. LIMITATIONS:No measured GFR, a relatively short follow-up period, and potential false discovery because of the large number of associations examined. CONCLUSIONS:Among patients with actively treated RA, eGFRcys is consistently lower than eGFRcr. Overall, neither eGFRcys nor eGFRcr demonstrated a significant change following RA treatments, despite reductions in disease activity biomarkers. Further studies incorporating directly measured GFR are warranted. PLAIN-LANGUAGE SUMMARY:Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that can also affect the kidneys. Doctors often check kidney function using blood tests for creatinine or cystatin C, but inflammation and RA medications may influence these tests differently. We studied patients with RA who began either a conventional drug combination (triple therapy) or a tumor necrosis factor (TNF) inhibitor. We measured kidney function and inflammation markers over a 6-month period after the treatment. We found that both cystatin C-based and creatinine-based estimates of kidney function were unchanged overall. An analysis of trial participants who received triple therapy showed an increase in cystatin C-based kidney function, along with a decrease in 1 inflammatory biomarker, TNF receptor 1 (TNFR1); however, the creatinine-based estimates remained unchanged. Understanding how RA treatment and inflammation affect kidney function tests may help develop better ways to monitor kidney function in people with inflammatory diseases.

Glomerular filtration markers are exogenous or endogenous solutes that are eliminated from the circulation primarily by glomerular filtration. Their rate of elimination is directly related to the GFR, and their plasma concentration is inversely related to the GFR. GFR cannot be measured directly in humans, but it can be assessed by using filtration markers-either as measured GFR (mGFR) from clearance measurements using exogenous filtration markers (such as iothalamate and iohexol) or as eGFR from estimating equations using plasma concentrations of endogenous filtration markers (metabolites, such as creatinine, and low molecular weight proteins, such as cystatin C). Thus, both mGFR and eGFR may differ from true GFR, and understanding the physiologic processes affecting filtration markers is required for clinical evaluation of GFR. Processes other than GFR that affect the plasma concentration of filtration markers are collectively defined as non-GFR determinants. By design, exogenous filtration markers are minimally affected by non-GFR determinants, but both urinary and plasma clearance measurements are associated with error in mGFR. By contrast, by definition, all endogenous filtration markers are affected by non-GFR determinants, but not by error in clearance measurements. The major limitations of mGFR procedures are complexity and inconvenience of clearance measurements, which constrain their utility in clinical practice. The major limitation of eGFR is error because of variation in the non-GFR determinants of the filtration markers, which can be minimized by use of a panel of markers (panel eGFR). There is ongoing interest in the discovery of new exogenous filtration markers that would enable widespread implementation of mGFR procedures and novel metabolite and low molecular weight endogenous filtration markers that would enable a panel eGFR. In this review, we discuss current and emerging insights into existing and novel filtration markers.

OBJECTIVE:The objective of this study is to examine real-world dose titration patterns of semaglutide for weight management (Wegovy, Novo Nordisk A/S) in US adults and identify characteristics associated with early discontinuation. METHODS:We identified 15,811 commercially insured adults who started semaglutide for weight management (administrated through single-dose prefilled pens) between June 2021 and December 2023. We depicted dose-titration patterns over 5 months and identified factors associated with discontinuation using multivariable Cox regression. Sensitivity analyses examined patterns after supply shortage resolution (after October 2023). RESULTS:Most semaglutide users deviated from the recommended monthly dose-escalation schedule within the first 5 months. By the fifth month, nearly one-half (46%) had discontinued the treatment, with similar rates (48%) among those initiating after supply stabilization. Discontinuation was strongly associated with copayment amount, with rates increased from 41% in the lowest quintile ($1-$54 per month) to 51% in the highest quintile ($161-$1460 per month). Higher discontinuation rates were also associated with lower household income and education level. CONCLUSIONS:The deviations from the recommended dose-escalation schedule and high discontinuation rate among real-world semaglutide users indicate important challenges in the delivery of evidence-based care. Policy interventions that reduce financial barriers to the persistence of semaglutide are needed.

INTRODUCTION:Developing effective treatments in chronic, progressive diseases like chronic kidney disease (CKD) is challenging because patients may only experience relevant outcomes such as kidney failure after long periods of disease progression. Surrogate endpoints provide a valuable alternative to definitive final patient-relevant outcomes, which may accelerate clinical development processes. However, optimal utilization of surrogate endpoints for reimbursement decisions requires alignment across multiple stakeholders, including health technology assessment (HTA) bodies and reimbursement agencies, who are generally more cautious than regulatory bodies in their acceptance of surrogate endpoint evidence. The aim of this paper is to propose a strategic roadmap to facilitate cross-stakeholder collaboration and support the consideration of surrogate endpoints in regulatory and reimbursement decisions. METHODS:An international group of experts in surrogate endpoints, reimbursement decisions, and kidney disease formed The REnal Surrogacy accEpTance in Chronic Kidney Disease (RESET CKD) Collaboration. This scientific steering committee held several meetings to develop a roadmap of activities with the aim of enabling the appropriate consideration of surrogate endpoints through structured multi-stakeholder engagement involving regulators, clinicians, HTA bodies, payers, industry, and patients. RESULTS:The strategic roadmap focuses on four areas: identifying the need for evidence; engaging stakeholders; collaborating in regulatory and reimbursement processes; and disseminating evidence. The RESET CKD collaboration is currently implementing the roadmap in the field of CKD through collating relevant evidence for a CKD-relevant surrogate endpoint in a scientific playbook, conducting economic evaluations, developing a position paper, and engaging patient groups. CONCLUSIONS:Disparities between regulatory and reimbursement processes and decisions underscore the need for a structured approach to enhancing transparency, consistency, and timeliness in the use of surrogate endpoint evidence in healthcare decision-making. The roadmap developed through the RESET CKD Collaboration addresses this need and is already demonstrating practical value in its implementation. Although initially focused on CKD, the framework is designed to be transferable to other therapeutic areas. Key challenges remain, including the integration of surrogate endpoints into adaptive pricing models and performance-based agreements.

Key PointsAcute effects impact the clinical endpoint independently of treatment effects on the chronic slope.Our findings support the 3-year total slope as the primary slope-based outcome in randomized trials.BackgroundSlope of the GFR is considered a validated surrogate endpoint for CKD trials. However, differing short-term and long-term treatment effects on GFR slope can create ambiguities concerning the appropriate period for evaluating slope, in part because current methods cannot separate the distinct contributions of the acute (before 3 months) and chronic (after 3 months) slopes for treatment effects on clinical endpoints (CEs).MethodsWe estimated treatment effects on the acute and chronic GFR slopes and on the established CE of kidney failure or serum creatinine doubling for 66 randomized treatment comparisons from previous CKD clinical trials. We used a novel Bayesian meta-regression framework to relate treatment effects on the established CE to both the acute and chronic slopes in a single multivariable model to determine the independent contributions of the acute and chronic slopes.ResultsTreatment effects on both the acute and chronic slopes independently predicted the treatment effect on the established CE with a high median R2 (95% credible interval) of 0.95 (0.79 to 1.00). For a fixed treatment effect on the chronic slope, each 1 ml/min per 1.73 m2 greater acute GFR decline for the treatment versus control increased the hazard ratio for the established CE by 11.4% (7.9%-15.0%), against the treatment. The optimal weights for the acute and chronic slopes were consistent with the 3-year total slope defined as the average slope extending from baseline to 3 years.ConclusionsTreatment effects on both the acute and chronic GFR slopes are independent determinants of the effects on the established CE, with variation in acute effects accounting for much of the observed variation in treatment effects on the CE across previous trials. Our results establish that acute effects affect the CE independently of treatment effects on the chronic slope and support the 3-year total slope as the primary slope-based outcome in randomized trials.

Glomerular filtration rate (GFR) estimation is a key issue in determining cancer treatment eligibility and dosing of treatments with narrow therapeutic index. Yet, little is known about the accuracy of GFR estimation among people with cancer in routine care. In a cross-sectional study including 1611 adults with cancer referred for 1837 determinations of measured GFR (mGFR), we assessed the accuracy of estimated GFR based on creatinine (eGFRcr), cystatin C (eGFRcys) and their combination (eGFRcr-cys). Accuracy was reported as percentage of patients with estimated values within 30% of mGFR; bias and precision as the median and interquartile range of eGFR-mGFR, respectively. Dosing accuracy was assessed by calculating expected dose of carboplatin for area under the curve of 5 mg/mL/min using the Calvert formula. Median age was 68 (IQI 61 to 74) years, 38.5% were female with mean mGFR 75 (SD 30) mL/min; 17% had metastatic disease. Accuracy, bias and precision were best for eGFRcr-cys. Using eGFRcr would recommend an “overdose” of carboplatin in 10–20% of participants: this was 3–4 times less common using eGFRcr-cys. eGFRcr-cys equations provide the most accurate estimates of mGFR in patients with cancer, with potential to improve dosing accuracy substantially compared to eGFRcr.

Importance:Estimated glomerular filtration rates (eGFRs) can differ according to whether creatinine or cystatin C is used for the eGFR calculation, but the prevalence and importance of these differences remain unclear. Objectives:To evaluate the prevalence of a discordance between cystatin C-based eGFR (eGFRcys) and creatinine-based eGFR (eGFRcr), identify characteristics associated with greater discordance, and evaluate associations of discordance with adverse outcomes. Data Sources:Participants in the Chronic Kidney Disease Prognosis Consortium (CKD-PC). Study Selection:Participants with concurrent cystatin C and creatinine measurements and clinical outcome measurement. Data Extraction and Synthesis:Between April 2024 and August 2025, data were synthesized using individual-level meta-analysis. Main Outcomes and Measures:The primary independent measurement was a large negative eGFR difference (eGFRdiff), defined as an eGFRcys that was at least 30% lower than eGFRcr. Secondary (dependent) outcomes included all-cause and cardiovascular mortality, atherosclerotic cardiovascular disease, heart failure, and kidney failure with replacement therapy. Results:A total of 821 327 individuals from 23 outpatient cohorts (mean [SD] age, 59 [12] years; 48% female; 13.5% with diabetes; 40% with hypertension) and 39 639 individuals from 2 inpatient cohorts (mean [SD] age, 67 [16] years; 31% female; 30% with diabetes; 72% with hypertension) were included. Among outpatient participants, 11% had a large negative eGFRdiff (range, 3%-50%). Among inpatients, 35% had a large negative eGFRdiff. Among outpatient participants, at a mean (SD) follow-up of 11 (4) years, a large negative eGFRdiff, compared with an eGFRdiff between -30% and 30%, was associated with higher rates of all-cause mortality (28.4 vs 16.8 per 1000 person-years [PY]; hazard ratio [HR], 1.69 [95% CI, 1.57-1.82]), cardiovascular mortality (6.1 vs 3.8 per 1000 PY; HR, 1.61 [95% CI, 1.48-1.76]), atherosclerotic cardiovascular disease (13.3 vs 9.8 per 1000 PY; HR, 1.35 [95% CI, 1.27-1.44]), heart failure (13.2 vs 8.6 per 1000 PY; HR, 1.54 [95% CI, 1.40-1.68]), and kidney failure with replacement therapy (2.7 vs 2.1 per 1000 PY; HR, 1.29 [95% CI, 1.13-1.47]). Conclusions and Relevance:In the CKD-PC, 11% of outpatient participants and 35% of hospitalized patients had an eGFRcys that was at least 30% lower than their eGFRcr. In the outpatient setting, presence of eGFRcys at least 30% lower than eGFRcr was associated with significantly higher rates of all-cause mortality, cardiovascular events, and kidney failure.

Background: Patients with sarcopenia and elevated body mass index (BMI) are at high risk of platinum-associated adverse events (AEs). This study examines the association between sarcopenia, BMI, and AEs in patients with non–small cell lung cancer (NSCLC). Methods: This retrospective cohort study included adult patients with NSCLC who started cisplatin or carboplatin between 2015 and 2022. Sarcopenia was defined on CT using sex-specific cutoffs for skeletal muscle index. We evaluated the association between CT-defined sarcopenia and grade ≥2 AEs (including anemia, thrombocytopenia, neutropenia, and increased creatinine), chemotherapy discontinuation, and 90-day mortality in patients with normal (<25 kg/m 2 ) and elevated (≥25 kg/m 2 ) BMI using a Fine-Gray subdistribution hazard model. The association between receiving an excess carboplatin dose and AEs was evaluated. Results: Of 604 included patients, the mean [SD] age was 66 [10] years, 307 (51%) were female, and 167 (28%) had sarcopenia. Sarcopenia and elevated BMI (n=67) was associated with an increased risk of grade ≥2 anemia (subdistribution hazard ratio [sHR], 1.64; 95% CI, 1.17–2.29; P =.004), thrombocytopenia (sHR, 2.25; 95% CI, 1.16–4.36; P =.016), and increased creatinine (sHR, 2.72; 95% CI, 1.45–5.13; P =.002). Sensitivity analyses demonstrated that patients whose Cockcroft-Gault–based glomerular filtration rate (GFR) dictated a carboplatin dose ≥25 mg higher than CKD-EPI GFR were at significantly higher risk of grade ≥2 AEs and chemotherapy discontinuation. Conclusions: Combined CT-defined sarcopenia with elevated BMI is associated with an increased risk of platinum-associated AEs in patients with NSCLC; this may be due to GFR misestimation in patients with low muscle mass and elevated BMI.

Chronic kidney disease (CKD) and cardiovascular disease are tightly interconnected, with common mechanisms that underlie the development and progression of both diseases, recently articulated into the framework of the cardiovascular-kidney-metabolic syndrome. CKD and heart failure commonly coexist in the same individual, with increasing evidence for common therapies in both disease states. It is valuable for patients, clinicians, and regulatory agencies to understand how to best assess CKD progression in patients with heart failure for evaluation of individual patients and as part of an endpoint for outcome trials. Given the relatively short duration of most heart failure outcome trials, early measures of CKD progression prior to the occurrence of clinical events of kidney replacement therapy would be desirable. Such surrogate measures include slowing of the decline in glomerular filtration rate (GFR) decline either computed as annualized mean change in GFR (GFR slope) or time to substantial declines in GFR by specified threshold percentages (40% or 50% GFR decline). Regulatory agencies accept these endpoints for full drug approval which has enabled progress in design and conduct of trials for CKD progression. Application of these endpoints in heart failure outcome trials has the potential for similar progress. However, an immediate reduction in GFR is common following initiation of several of the guideline directed therapy for heart failure. Understanding how to best interpret an immediate GFR reduction vs long term kidney benefit is critical to optimal assessment of endpoint in an outcome trial and in the use of these medications for management of patients with heart failure. Here, the intersection of heart failure and CKD is described, how GFR and its change over time are assessed in both individual patients and in interventional trials, the evidence supporting use of GFR changes as endpoints in CKD progression trials, and the challenges and possible solutions for the use of GFR as endpoint in heart failure outcome trials and for care of individual patients, guided by case studies to inform the discussion.

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 distinct contributions of the acute (before three months) and chronic (after three months) slopes for treatment effects on clinical endpoints. Methods: We estimated treatment effects on the acute and chronic GFR slopes and on the established clinical endpoint (CE) of kidney failure or serum creatinine doubling for 66 randomized treatment comparisons from previous CKD clinical trials. We used a novel Bayesian meta-regression framework to relate treatment effects on the established CE to both the acute and chronic slopes in a single multivariable model to determine the independent contributions of the acute and chronic slopes. Results: Treatment effects on both the acute and chronic slopes independently predicted the treatment effect on the established CE with a high median R 2 (95% credible interval) of 0.95 (0.79,1.00). For a fixed treatment effect on the chronic slope, each 1 mL/min/1.73m 2 greater acute GFR decline for the treatment vs. control increased the HR for the established CE by 11.4% (7.9%, 15.0%), against the treatment. The optimal weights for the acute and chronic slopes were consistent with the three-year total slope defined as the average slope extending from baseline to three years. Conclusion: Treatment effects on both the acute and chronic GFR slopes are independent determinants of the effects on the established CE, with variation in acute effects accounting for much of the observed variation in treatment effects on the CE across previous trials. Our results establish that acute effects impact the CE independently of treatment effects on the chronic slope, and support the three-year total slope as the primary slope-based outcome in randomized trials.