#2588 Renal trajectories in the french RaDiCo Alport syndrome cohort

Rapid Decline in Kidney Function in Sickle Cell Disease

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Frailty is a process theorized to be, at least in part, attributable to chronic inflammation marked by hormonal changes, anorexia, decreased muscle strength, and depression. The phenotypic definition operationalized by Fried et al. ([1][1]) includes any three or more of the following: weight loss,

Association of Estimated GFR Slope and Heart Failure Progression in Older Adults.

The Important Role of Egfr Change in Patients with Multiple Myeloma

Defining and Predicting Rapid Egfr Decline in Sickle Cell Disease

Background and Aims Severe COVID-19 infection, which usually presents as a viral pneumonia, has been observed to frequently be accompanied by acute kidney injury (AKI). However, possible effects of COVID-19 on long-term kidney function decline are not well quantified. We investigated whether kidney function decline is accelerated after COVID-19 infection, and whether the progression of decline differs from other respiratory tract infections. Method We undertook an observational study using the SCREAM project, including adults from Stockholm who survived COVID-19 infection (February 2020-December 2021), and adults who survived pneumonia caused by other pathogens (February 2018-December 2019, historical comparison cohort). We used generalized estimating equations to examine the age- and sex-adjusted slopes of estimated glomerular filtration rate (eGFR) decline in the 2 years before versus after each infection (i.e., intra-individual changes). We also compared to post-infection eGFR slopes of COVID-19 versus pneumonia (i.e., inter-individual changes) adjusting for a broad range of demographic, socioeconomic and clinical covariates (including pre-infection eGFR slope). We stratified analyses by whether the infection required hospitalization, hypothesizing more severe infection may lead to more rapid eGFR decline. Results We identified 59 267 COVID-19 survivors and 20 138 pneumonia survivors with repeated outpatient eGFR measurements. The pneumonia group was older, with lower income, and more comorbidities and healthcare utilization than the COVID-19 group. Both infections resulted in an accelerated decline of the observed eGFR slope, but with a greater magnitude of intraindividual slope changes after COVID-19 (Fig. 1): eGFR decline was 6.14 (95% confidence interval [95% CI] 5.88-6.41) ml/min/1.73 m2/year faster after COVID-19, and 2.52 (95% CI 2.17-2.88) ml/min/1.73 m2/year faster after pneumonia. When adjusting for pre-infection slope and other identified confounders (Fig. 2), COVID-19 survivors had an eGFR decline that was 0.47 (95% CI 0.29-0.66) ml/min/1.73 m2/year faster than that of pneumonia survivors. Observed intra- and inter-individual differences were larger in magnitude among participants whose infection required hospitalization. Conclusion COVID-19 infection is associated with a subsequent acceleration in eGFR decline, of a larger magnitude than other respiratory tract infections, and particularly among more severe cases that required hospitalization. We propose that survivors of severe COVID-19 receive monitoring of kidney function, and that policymakers consider implications for future healthcare planning and renal service provision.

Background and Aims C3 glomerulopathy (C3G), is an ultra-rare primary glomerulonephritis caused by overactivation of the alternative complement pathway (AP). Iptacopan (LNP023) is an oral, proximal complement inhibitor that targets Factor B to selectively inhibit the AP of the complement cascade. The estimated glomerular filtration rate (eGFR) slope (i.e. the rate of decline over time) is accepted as a surrogate endpoint in glomerular diseases. We have previously reported stabilization of eGFR parameters with iptacopan treatment across Phase 2 and 3 studies. This pooled analysis aims to demonstrate the long-term stabilization of eGFR observed with iptacopan treatment in patients with native C3G. Method In this pooled exploratory analysis, data spanning up to 57 months were combined for all patients with native C3G from Study X2202 (Phase 2), APPEAR-C3G (Phase 3), and Study B12001B (Phase 3b, roll-over extension; Table 1). Improvement in kidney function through long-term stabilization of eGFR was evaluated by comparing the change in eGFR slope from prior to treatment with iptacopan to post-iptacopan treatment initiation (200 mg b.i.d.) in the overall study population and subgroups of participants with baseline eGFR <90 mL/min/1.73 m2 versus ≥90 mL/min/1.73 m2 (normal range). Historical serum creatinine data (collected up to 2 years before randomization) were used to calculate eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Pooling the data allowed for more precise eGFR slope reporting. Before iptacopan treatment, a common eGFR slope was assumed for all treatment arms. Results A total of 90 patients with native C3G were included in the pooled analysis (baseline eGFR ≥90 mL/min/1.73 m2, n = 47; <90 mL/min/1.73 m2, n = 43). In the overall study population, an improvement in post-iptacopan treatment initiation eGFR slope was observed (change in slope: 7.62 mL/min/1.73 m2/year, P < 0.0001; Table 2). Subgroup analyses demonstrated an improvement in post-iptacopan treatment initiation eGFR slope in participants with baseline eGFR <90 mL/min/1.73 m2 (eGFR slope change: 12.98 mL/min/1.73 m2/year, P < 0.0001) but not in participants with baseline eGFR ≥90 mL/min/1.73 m2 (eGFR slope change: 0.57 mL/min/1.73 m2/year, P = NS; Table 2). In the subgroup with eGFR ≥90 mL/min/1.73 m2, the eGFR slope was only minimally negative in the prior to treatment with iptacopan period and remained unchanged post-iptacopan treatment initiation. These pooled data are consistent with eGFR slopes from the individual studies. Conclusion The findings from this pooled analysis indicate that in patients with native C3G, treatment with iptacopan 200 mg b.i.d. resulted in the stabilization of eGFR trajectory, with significant change observed in patients with at least mild renal impairment from C3G disease at baseline (<90 mL/min/1.73 m2) and maintenance of stable eGFR in those with normal baseline eGFR (≥90 mL/min/1.73 m2). eGFR slope analysis has demonstrated valuable utility in monitoring kidney function over time, and these data suggest iptacopan treatment results in a long-term, clinically relevant positive impact on kidney function.

Pitfalls in Using Estimated Glomerular Filtration Rate Slope as a Surrogate for the Effect of Drugs on the Risk of Serious Adverse Renal Outcomes in Clinical Trials of Patients With Heart Failure.

Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial

BackgroundAn analysis of European and American individuals revealed that a reduction in estimated glomerular filtration rate (eGFR) slope by 0.5 to 1.0 mL/min/1.73 m2 per year is a surrogate endpoint for end-stage kidney disease (ESKD) in patients with early chronic kidney disease. However, it remains unclear whether this can be extrapolated to Japanese patients.MethodsUsing data from the Japan diabetes comprehensive database project based on an advanced electronic medical record system (J-DREAMS) cohort of 51,483 Japanese patients with diabetes and a baseline eGFR ≥ 30 mL/min/1.73 m2, we examined whether the eGFR slope could be a surrogate indicator for ESKD. The eGFR slope was calculated at 1, 2, and 3 years, and the relationship between each eGFR slope and ESKD risk was estimated using a Cox proportional hazards model to obtain adjusted hazard ratios (aHRs).ResultsSlower eGFR decline by 0.75 mL/min/1.73 m2/year reduction in 1-, 2-, and 3-year slopes was associated with lower risk of ESKD (aHR 0.93 (95% confidence interval (CI) 0.92–0.95), 0.84 (95% CI 0.82–0.86), and 0.77 (95% CI 0.73–0.82), respectively); this relationship became more apparent as the slope calculation period increased. Similar results were obtained in subgroup analyses divided by baseline eGFR or baseline urine albumin-creatinine ratio (UACR), with a stronger correlation with ESKD in the baseline eGFR < 60 mL/min/1.73 m2 group and in the baseline UACR < 30 mg/gCre group.ConclusionWe found that changes in the eGFR slope were associated with ESKD risk in this population.

Background and Aims Determining prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD) heavily relies on the height-adjusted total kidney volume (HtTKV) Mayo classification. This classification predicts kidney outcomes on a group level but lacks precision in individual patients. Recently, several urine and blood biomarkers have demonstrated prognostic value in ADPKD, independent of HtTKV and baseline eGFR. This study compares the prognostic value of various biomarkers to aid selection when developing novel risk stratification tools. Method Included were participants of the DIPAK studies with a follow-up duration of &amp;gt;1 year and ≥3 eGFR measurements. We excluded patients with diabetes mellitus and patients using tolvaptan or somatostatin analogues. At baseline, urine samples were analyzed for albumin, urea, creatinine, β2-microglobulin (β2-MG), monocyte chemotactic protein-1 (MCP-1), TmP/GFR (tubular maximum reabsorption rate of phosphate to GFR), and blood was drawn to measure creatinine, urea (for assessment of urinary-to-plasma urea ratio; UP urea), glucagon, fibroblast growth factor 23 (FGF-23) and copeptin. Albumin, β2-MG and MCP-1 were divided by urinary creatinine concentration to account for concentration effects. The cross-sectional and longitudinal association with baseline eGFR and eGFR decline over time was analyzed using multivariate linear regression and repeated measures linear mixed model regression. Furthermore, logistic regression models were tested to identify patients with rapidly-progressive disease (eGFR slope ≤ −3.0 ml/min/1.73 m2/year). Lastly, multivariate Cox regression analysis was conducted to evaluate the time to the combined endpoint of 30% decline in eGFR, reaching an eGFR ≤ 15 ml/min/1.73 m2, initiation of dialysis or receiving a kidney transplant. Results 565 patients were included with a mean age of 47 ± 11 years, eGFR of 64 ± 27 ml/min/1.73 m2 and HtTKV of 858 [IQR: 540, 1305] ml/m. During a mean follow-up of 5.2 ± 2.2 years, the mean eGFR decline was −3.38 ± 2.37 mL/min/1.73 m2/year. Of these patients, 283 (50.1%) had rapidly progressive disease and 267 (47.3%) reached the combined kidney endpoint. All biomarkers except glucagon were associated with baseline eGFR and eGFR decline over time after adjustment for established clinical risk factors for disease progression (sex, PKD mutation and baseline age and eGFR). After adjustment for the same covariates, albumin/creatinine, MCP-1/creatinine, FGF-23, UP-urea and copeptin were predictive of rapid disease progression. The area under the curve (AUC) value for predicting rapidly progressive disease for the Mayo HtTKV classification alone was 0.694, which could be improved to 0.766 (P &amp;lt; .001) by a risk prediction model that also included the aforementioned predictive clinical risk factors. The introduction of several biomarkers further improved this clinical model, including albumin/creatinine (AUC 0.794, p = 0.03), MCP-1/creatinine (AUC 0.804, p = 0.04) and copeptin (AUC 0.789, p = 0.05). Similar results were seen in multivariate Cox regression models after adjustment for covariates, with independent predictors of the combined endpoint being again albumin/creatinine (P &amp;lt; .001), MCP-1 creatinine (P &amp;lt; .001), copeptin (p = 0.012), but now also UP-urea (p = 0.008) and FGF-23 (P &amp;lt; .001). These findings appeared robust in subgroup analyses of 200 patients with Mayo HtTKV class 1C and 122 patients with early disease (age ≤ 40 years and eGFR ≥ 60 ml/min/1.73 m2 at baseline), in whom predicting prognosis is most challenging. Conclusion In patients with ADPKD, albumin/creatinine, MCP-1/creatinine, FGF-23 and copeptin are consistent predictors of kidney outcomes after adjustment for established clinical risk factors. Our data suggest that these biomarkers should be prioritized when developing novel multimarker models to enhance precision of risk prediction in ADPKD.

Steroidal mineralocorticoid receptor antagonists (MRAs) form a cornerstone of the management of heart failure (HF), but little is known about the long-term effects of MRA therapy on kidney function. We evaluated acute and chronic estimated glomerular function (eGFR) slopes in the two largest completed trials testing steroidal MRAs in chronic HF. We conducted parallel post hoc eGFR slope analyses in two multinational, double-blind randomized, placebo-controlled trials of steroidal MRAs in chronic HF with reduced ejection fraction (EMPHASIS-HF) and preserved ejection fraction (TOPCAT Americas region). GFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. Annual slopes of eGFR were assessed by generalized random coefficient models. Least square mean differences in eGFR slopes between steroidal MRA and placebo arms were assessed. Median follow-up was 1.8 years (EMPHASIS-HF) and 3.3 years (TOPCAT Americas). From baseline to month 4-6 ('acute eGFR slope'), compared to placebo, MRA treatment led to an acute decline in eGFR of -2.4ml/min/1.73 m2 (95% confidence interval [CI] -3.4 to -1.4; p < 0.001) and -2.0ml/min/1.73 m2 (95% CI -3.0 to -1.8; p < 0.001) in EMPHASIS-HF and TOPCAT Americas, respectively. From month 4-6 to end of study, there was no difference in 'chronic eGFR slope' between MRA and placebo arms (-0.3ml/min/1.73 m2 /year [95% CI -1.3 to 0.7; p=0.53] and 0.1ml/min/1.73 m2 /year [95% CI -1.4 to 1.7; p=0.86]) in EMPHASIS-HF and TOPCAT Americas, respectively. Steroidal MRAs result in acute declines in eGFR but do not modify long-term kidney disease trajectories in chronic HF with reduced or preserved ejection fraction. EMPHASIS-HF (ClinicalTrials.gov NCT00232180) and TOPCAT (ClinicalTrials.gov NCT00094302).

Background and Aims Treatment with vascular endothelial growth factor signalling pathway inhibitors (VSPI) and immune checkpoint inhibitors (ICI) has transformed outcomes in advanced kidney cancer. VSPI and ICI can both independently cause side effects that are risk factors for development or progression of chronic kidney disease (CKD). We analysed estimated glomerular filtration rate (eGFR) decline in people with kidney cancer following treatment with VSPI or ICI. Methods We linked routine healthcare databases in the West of Scotland, UK (spanning 2010–2020, population 1.4 million) to identify adults with advanced kidney cancer who received a VSPI and/or ICI. In the two years following therapy initiation, eGFR slope (defined as annualised rate of change in eGFR) was modelled using linear mixed-effects models for the whole group and subgroups of people who had nephrectomy, metastatic cancer and a baseline eGFR &amp;lt;60 mL/min/1.73 m² prior to systemic therapy. Additional outcomes were studied using competing risk regression considering the competing risk of death: 40% decline in eGFR, de-novo proteinuria (urine albumin creatinine ratio &amp;gt;3 mg/mmol), and progression to eGFR &amp;lt;15 mL/min/1.73 m2. The risk of all-cause mortality was estimated with Cox regression models. Results We studied 357 adults (62.5% male; median age 63.0 years, IQI 55.0-71.0) with kidney cancer who were treated with either VSPI and/or ICI. The median baseline eGFR before systemic therapy was 74.6 mL/min/1.73 m² (58.3-91.9) and most received VSPI monotherapy (86.0%). On average, eGFR remained relatively stable over time (average annual increase +1.03 mL/min/1.73 m²/year: 95% CI −1.64 to +3.70, p = 0.2). People who had nephrectomy prior to systemic therapy demonstrated the largest average increase in eGFR (+2.30 mL/min/1.73 m²/year: 95% CI −1.66 to + 6.26). People with baseline eGFR &amp;lt;60 mL/min/1.73 m² prior to systemic therapy had a small decline (−1.02 mL/min/1.73 m²/year: 95% CI −6.55 to +4.50) in eGFR (Fig. 1). A ≥40% decline in eGFR occurred in 82 people (23.0%) within one year of starting systemic therapy. People with diabetes were more likely to experience a ≥40% decline in eGFR (subdistribution HR 1.89: 95% CI 1.05-3.41, p = 0.04). A decline in eGFR to &amp;lt;15 mL/min/1.73 m² or kidney failure with replacement therapy was found in 4 (1.1%) people. Among the 75 people assessed for proteinuria, 30.2% developed de-novo microalbuminuria. Median overall survival was 1.36 years (IQI 1.11-1.75 years), but this was longer in people who had nephrectomy prior to systemic therapy: 2.13 years (IQI 1.82–2.57 years). A 40% acute or chronic decline in eGFR was not associated with increased hazards of death on univariable or multivariable analysis (adjusted HR: 1.11: 95% CI 0.85-1.46, p = 0.4). Conclusion Despite case series and prescribing guidelines highlighting adverse impact of VSPI/ICI therapy on kidney function, our results demonstrate that there is no significant impact on the average change in eGFR but highlights that people with diabetes are at higher risk of clinically significant renal events. With appropriate monitoring, more widespread use of these agents in patients with renal impairment may be warranted.

OBJECTIVES/SPECIFIC AIMS: The objective of this research is to determine under what conditions endpoints based on estimated glomerular filtration rate (eGFR) slope or on relatively small declines in eGFR provide valid and useful surrogate endpoints for pivotal clinical trials in chronic kidney disease (CKD) patients. METHODS/STUDY POPULATION: We consider 2 classes of surrogate endpoints. The first class includes endpoints defined by the average rate of change in eGFR during defined portions of the follow-up period of the trial, following initiation of the randomized treatment interventions. The second class includes composite endpoints defined by the time from randomization until the occurrence of a designated decline in eGFR or kidney failure. The true clinical endpoint is considered to be the time from randomization until kidney failure, irrespective of the trajectory in eGFR measurements prior to kidney failure. We apply statistical simulation to determine conditions under which alternative endpoints within the 2 classes are (1) valid surrogate endpoints, in the sense of preserving a low probability of rejecting the null hypothesis of no treatment effect on the surrogate endpoint when there is no treatment effect on the clinical endpoints and are also (2) useful surrogate endpoints, in the sense of providing increased statistical power that allows significant reductions in sample size and/or duration of follow-up. Input parameters for the simulations include (a) characteristics of the joint distribution of the longitudinal eGFR measurements and the time to occurrence of renal failure, (b) characteristics of the short-term and long-term effects of the treatment, and (c) design parameters, including the duration of accrual and follow-up and the spacing of eGFR measurements during the follow-up period. We use joint analyses of 19 treatment comparisons across 13 previous clinical trials of CKD patients to guide the selection of input parameters for the simulations. We apply longitudinal mixed effects models for analysis of endpoints based on eGFR slope, and Cox regression for analyses of the composite time-to-event endpoints. RESULTS/ANTICIPATED RESULTS: We have previously shown that surrogate endpoints defined by eGFR declines of 30% or 40% can provide valid and useful alternative endpoints in CKD clinical trials for interventions that do not produce short-term effects on eGFR which differ from the longer-term effects of the interventions. Other factors influencing the validity and utility of these endpoints include the average baseline eGFR, the mean rate of change in eGFR, and the extent to which the size of the treatment effect depends on the patient’s underling rate of eGFR decline. We will extend these results by presenting preliminary results describing conditions under which outcomes based on eGFR slope provide valid and useful alternatives to the clinical endpoint of time until occurrence of kidney failure. DISCUSSION/SIGNIFICANCE OF IMPACT: The statistical simulation strategy described in this research can be used during the design of clinical trials of chronic kidney disease to assist in the selection of endpoints that maximize savings in sample size and duration of follow-up while retaining a low risk of producing a false positive conclusion in the absence of a true effect of the treatment on the time until kidney failure.