INTRODUCTION:Prognostic models for mortality in patients receiving dialysis primarily use clinical predictors like age, comorbidities and laboratory markers. Studies in other fields suggest that patient-reported outcomes (PROs), like pain and fatigue, can be predictors of survival. Therefore, we aimed to assess the added value of PROs to predict mortality in incident dialysis patients. METHODS:Data from NECOSAD (1956 individuals) were used, and analyses were replicated in the EQUAL (415 individuals) and NECOSAD 65+ (862 individuals) studies. A base model for two-year mortality containing clinical predictors was extended using PROs (mental component score, physical component score, general health perception, depressive symptoms, number of symptoms, symptom burden, fatigue and pain). Logistic regression was used, and the added predictive performance of the PROs was evaluated using the area under the curve (AUC), measures of calibration, Brier score, likelihood ratio tests, reclassification tables, net reclassification indices, integrated discrimination improvements, and decision curve analyses. We also examined different combinations of predictors, and each PRO individually. RESULTS:Within two years, mortality rates were 22.9%, 24.3%, and 37.1% in NECOSAD, EQUAL, and NECOSAD 65+, respectively. The base model yielded optimism-corrected AUCs of 0.806, 0.781 and 0.699, which improved to 0.826, 0.878 and 0.746 after adding the PROs. Improvement of the calibration, Brier scores, and comparative measures confirmed their predictive value. The mental and physical component score, and symptom burden had the most consistent strong performance across all cohorts. CONCLUSIONS:PROs improved prognostic models for mortality of patients receiving incident dialysis, even when added to an already well-performing model of clinical predictors.

AIMS:In FIDELITY, finerenone improved kidney and cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines categorise CKD progression risk based on estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). This FIDELITY post hoc subanalysis investigated KDIGO risk category changes associated with finerenone. METHODS:Improvement or worsening in KDIGO risk category was defined by variation from baseline, with specified eGFR and UACR changes. Association of these category changes with a CV composite outcome was assessed. RESULTS:Finerenone therapy led to a higher likelihood of KDIGO risk category improvement (odds ratio [OR], month 36: 1.47; 95% confidence interval [CI], 1.31-1.65; p < 0.0001) and lower likelihood of worsening (OR, month 36: 0.83; 95% CI, 0.77-0.90; p < 0.0001) vs. placebo. Risk category improvement reduced the CV composite outcome risk (hazard ratio [HR]: 0.82; 95% CI, 0.68-0.99; p = 0.043) while worsening increased this risk (HR: 1.29; 95% CI, 1.06-1.56; p = 0.01). CONCLUSIONS:Finerenone therapy is associated with greater improvement and less worsening in KDIGO risk vs. placebo. The category changes are associated with lower risk of CV events in patients with CKD and T2D. TRIAL REGISTRATION NUMBER:FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049) are registered with ClinicalTrials.gov (funded by Bayer AG).

Fabry disease (FD) is a multisystemic disease affecting the heart and the kidneys of affected patients. In addition to FD-specific treatment, patients require concomitant medication for cardio- and nephroprotection. Sodium-dependent glucose transporter 2 inhibitors (SGLT2i) are recommended for patients with heart failure and/or kidney disease, but efficacy data for FD are scarce. In this multicenter study (n = 8), the effects of SGLT2i therapy after 12 months of treatment in 48 patients (12 females) on FD-specific therapy were examined. Patients were retrospectively analyzed at three time points (before SGLT2i: T-1; SGLT2i start: T0; and end of observation: T+1). Patients showed advanced cardiac manifestations with a high frequency of left ventricular hypertrophy (LVH) (females: 81.8

Importance:Glomerular diseases are a leading cause of chronic kidney disease (CKD) and kidney failure. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduces the risk of kidney function loss in CKD, but its effects in individuals with CKD due to glomerular diseases are uncertain. Objectives:To evaluate the efficacy and safety of finerenone in patients with glomerular diseases. Design, Setting, and Participants:Prespecified exploratory subgroup analysis of a phase 3, randomized, double-blind, placebo-controlled trial conducted across 24 countries and regions, focusing on participants with an investigator-reported glomerular disease diagnosis. The overall trial enrolled adults with nondiabetic CKD and an estimated glomerular filtration rate (eGFR) of either (1) at least 25 to less than 60 mL/min/1.73 m2 and urinary albumin to creatinine ratio of at least 200 mg/g to less than 500 mg/g or (2) an eGFR of at least 25 to less than 90 mL/min/1.73 m2 and urinary albumin to creatinine ratio of at least 500 mg/g to less than 3500 mg/g. Intervention:Finerenone 10 mg or 20 mg taken orally once daily (n = 446) vs matching placebo (n = 457). Main Outcomes and Measures:Annualized rate of eGFR decline (total eGFR slope) from baseline to month 32 (primary outcome of the main trial); percent change in albuminuria to 12 months; and a composite outcome of kidney failure or sustained 40% or more decline in eGFR (prespecified exploratory outcomes). Results:Of 1584 participants, 903 (57.0%) had investigator-reported glomerular disease, including 416 (46.1%) with immunoglobulin A nephropathy, 215 (23.8%) with focal segmental glomerulosclerosis, and 90 (10.0%) with membranous nephropathy. Participants with glomerular disease (mean [SD] age, 51.1 [13.6] years; 362 female [40.1%]; 558 Asian [61.9%]) had a mean eGFR of 48.8 mL/min/1.73 m2 and median urinary albumin to creatinine ratio of 839.6 mg/g. The total eGFR slope up to 32 months was -3.50 mL/min/1.73 m2 per year with finerenone and -4.23 mL/min/1.73 m2 per year with placebo (0.73 mL/min/1.73 m2 per year difference; 95% CI, 0.22-1.24). Finerenone reduced albuminuria at month 12 by 42% (95% CI, 35%-48%) and lowered the risk of kidney failure or 40% or more eGFR decline (7.42 vs 9.60 events per 100 patient-years; hazard ratio, 0.74; 95% CI, 0.57-0.97). Conclusions and Relevance:In this exploratory analysis, treatment with finerenone slowed kidney function decline, reduced albuminuria, and lowered the risk of kidney failure or substantial loss of kidney function in patients with glomerular diseases. These findings suggest an important role for finerenone in preserving kidney function in this population. Trial Registration:ClinicalTrials.gov Identifier: NCT05047263.

Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by cellular accumulation of globotriaosylceramide (Gb3). We investigated dermal Gb3 load as a potential surrogate marker for systemic FD manifestations by applying an automated image analysis pipeline to skin punch biopsies from the lower leg of 149 individuals carrying variants in GLA, the gene encoding alpha-galactosidase A. Variants were stratified by pathogenicity: Group 1 (pathogenic), Group 2 (non-pathogenic), and Group 3 (variants of unknown significance). Gb3 was visualized via Shiga toxin subunit B and quantified using CellProfiler (v4.1.3). Results were compared to healthy controls and patients with idiopathic small fiber neuropathy. Dermal Gb3 load was elevated in both men and women with pathogenic GLA variants (Group 1, p < 0.001), excluding those with the N215S variant. Increased Gb3 deposition was associated with pain in men (p < 0.05), but not with overall disease severity, treatment status, or cerebral white matter lesions. Diagnostic sensitivity and specificity to correctly determine FD were 67

Patients with chronic kidney disease (CKD) face a markedly elevated risk of death from cardiovascular disease (CVD); in particular, those requiring hemodialysis have a 10- to 30-fold higher risk than the general population. This extremely increased risk of CVD death reflects the coexistence of multiple traditional and nontraditional risk factors. The present narrative review considers two distinct steps: first, the occurrence of a CVD event, and second, death resulting from an inability to recover from the CVD event. Patients undergoing hemodialysis are at an increased risk for both of these steps, accounting for the dramatically higher risk of CVD death in this population. High risk for the second step-death following a CVD event-may be driven by conditions called decreased physical resilience and increased frailty. Studies of patients on hemodialysis show that predictors for death at this stage include key components of malnutrition-inflammation-atherosclerosis syndrome-also called the malnutrition-inflammation-complex-syndrome or protein-energy wasting-such as lower body mass index, lower serum albumin, and higher C-reactive protein. Other important contributors include higher age, longer dialysis duration, diabetic kidney disease, phosphate, calcium, serum calcification propensity (T50), and insulin-like growth factor 1 levels. Notably, some of these factors also predict death following infection, suggesting that the risk predictors for the second step are shared between CVD and infection. Recognizing these steps may facilitate prevention and greater preparedness for CVD, infection, and other stressful events among patients with CKD.

BACKGROUND:Urine tubular biomarkers have previously been associated with chronic kidney disease (CKD) progression independently of estimated glomerular filtration rate (eGFR) and albuminuria. We evaluated whether nine urine tubular biomarkers could improve prediction of kidney failure beyond serum creatinine and urine albumin-to-creatinine ratio among adults with CKD. METHODS:Among 5100 participants in EMPA-KIDNEY, a randomized trial which assessed the effects of empagliflozin 10 mg versus matching placebo among patients with CKD at risk of progression, nine urine creatinine-indexed tubular biomarkers were measured including alpha-1 microglobulin, dickkopf-3, epidermal growth factor [EGF], interleukin-18, kidney injury molecule-1 [KIM-1], monocyte chemoattractant protein-1 [MCP-1], neutrophil gelatinase-associated lipocalin, uromodulin, and human cartilage glycoprotein-40. Outcomes were kidney disease progression ('treated kidney failure', renal death, or sustained ≥40% eGFR decline) and treated kidney failure (maintenance dialysis or kidney transplant). Relative to models based on the linear predictor of the kidney failure risk equation (KFRE), improvements in discrimination were estimated with further addition of the nine tubular biomarkers using absolute difference in Uno's C-index. RESULTS:Over median 3.5 years of follow-up, 1191 participants experienced kidney disease progression and 461 experienced treated kidney failure. KFRE demonstrated excellent discrimination for treated kidney failure [C-index 0.858 (0.840,0.874)] and moderate discrimination for kidney disease progression [0.724 (0.705,0.743)]. Addition of three biomarkers (MCP-1, KIM-1, and EGF) most strongly associated with CKD outcomes yielded some further improvement in predicting kidney failure [absolute difference 0.014 (0.009,0.024)] and kidney disease progression [0.038 (0.026,0.053)]. Prediction of kidney outcomes were only slightly improved when further expanding from three to all ning tubular biomarkers. CONCLUSION:In a wide range of causes of CKD, adding three urine tubular biomarkers (MCP-1, KIM-1, EGF) to KFRE improves estimates of risk of CKD progression.

In Fabry disease (FD, OMIM #301500), a rare lysosomal storage disorder, the glucosylceramide synthase inhibitor lucerastat acts as substrate reduction therapy. The Phase 3, prospective, double-blind, placebo-controlled, 6-month, randomized clinical trial, MODIFY (NCT03425539), aimed to evaluate the efficacy, safety, and tolerability of lucerastat in adults with FD with moderate-to-severe neuropathic pain. The single-arm, open-label extension (OLE) (NCT03737214) evaluated the longer-term safety and tolerability of lucerastat over 72 months. Lucerastat 1000 mg twice daily (n = 80), compared with placebo (n = 37), failed to affect neuropathic pain at Month-6, with no significant difference between treatment groups (LSM difference –0.42 [95

Aims:Anderson-Fabry disease (FD) is a rare lysosomal storage disorder with multi-organ involvement. Cardiac manifestations are the major determinant of prognosis, yet reliable predictors of disease progression are lacking. Small fiber neuropathy can emerge in various aetiologies of hypertrophic cardiomyopathy, but its correlation remains unclear. Intraepidermal nerve fiber density (IENFD) from skin punch biopsy provides an established tool of measuring small fiber dysfunction. Clinically, we observed that FD patients with severe cardiac phenotypes often show markedly reduced IENFD without presentation of typical neurological symptoms matching small fiber neuropathy. Methods and results:FD patients with available skin biopsy samples evaluated between 2006 and 2022 were included. Patients were divided by median IENFD for clinical evaluation. Subsequent subgroup analysis for two predefined cardiac endpoints (development of late gadolinium enhancement (LGE) on cardiac MRI and cardiac device implantation) were done. Multivariable Cox regression analysis assessed the prognostic value of IENFD. A total of 170 patients (47% men) were analysed. Median IENFD was 3.8 fibers/mm. Patients with reduced IENFD showed more frequent cardiac (85% vs. 41%), renal (54% vs. 21%), and cerebrovascular (27% vs. 7%) involvement (all P < 0.001). FD cardiomyopathy was more advanced in those with low IENFD (IVSd: 12.5 ± 3.3 vs. 9.6 ± 2.3 mm, P < 0.001). In the conducted subgroup analysis IENFD < 4.2 fibers/mm independently predicted LGE (HR: 5.26, 95% CI: 1.53-18.06, P = 0.008, n = 55 patients included), while IENFD < 1 fiber/mm predicted device implantation (HR: 3.72, 95% CI: 1.00-13.78, P = 0.05, n = 124 patients included). Conclusion:IENFD was identified as independent risk factor for developing two major cardiac endpoints (LGE in MRI/device implantation) associated with poor cardiac outcome in FD. ClinicalTrialsgov Identifier:NCT03362164.

KEY POINTS:Treatment with semaglutide compared with placebo for 24 weeks reduced lean body mass and fat mass in adults with CKD and overweight or obesity. Changes in lean body mass or fat mass during semaglutide treatment did not correlate with changes in creatinine or cystatin C‑eGFR or measured GFR. Semaglutide significantly reduced extracellular water and BP, and changes in BP correlated with extracellular water. BACKGROUND:The glucagon-like peptide-1 receptor agonist semaglutide reduces hemoglobin A1c, body weight, BP, and GFR decline. Semaglutide may influence serum creatinine and cystatin C levels by nonkidney-related mechanisms and thereby affect eGFR. We studied the relationship between changes in body composition, eGFR and measured GFR (mGFR), and BP during semaglutide treatment. METHODS:We performed a prespecified analysis of a randomized placebo-controlled double-blind clinical trial in 101 adults with CKD with overweight status or obesity and without type 2 diabetes. Participants were randomized to 24 weeks of semaglutide 2.4 mg/wk subcutaneously or matched placebo treatment. We measured GFR with iohexol clearance, estimated GFR with creatinine and cystatin C, and used bioimpedance spectroscopy to determine lean body mass, fat mass, and extracellular water. RESULTS:After 24 weeks of treatment, semaglutide compared with placebo changed total body weight, lean body mass, and fat mass by -9.1 (95% confidence interval [CI], -11.0 to -7.2), -2.5 (95% CI, -6.6 to 1.6), and -3.9 (95% CI, -7.8 to 0.0) kg, respectively. No correlations were present between changes in total body weight, lean body mass, and fat mass with changes in eGFR (creatinine or cystatin C) or mGFR during semaglutide treatment (all Spearman correlation coefficients <0.23). Similar results were observed in multivariable adjusted analyses. Semaglutide compared with placebo changed extracellular water and systolic BP by -0.9 (95% CI, -1.6 to -0.1) L and -6.3 (95% CI, -10.9 to -1.7) mm Hg, respectively. Systolic BP changes during semaglutide treatment correlated with extracellular water changes (Spearman correlation 0.40; P = 0.005). CONCLUSIONS:Semaglutide reduced lean body mass and fat mass in patients with CKD with overweight status or obesity. These changes did not correlate with changes in creatinine or cystatin C eGFR or mGFR, suggesting that body weight reductions of 10% with semaglutide do not influence GFR estimates. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:ClinicalTrials.gov, NCT04889183 .

QuestionWhat is the effect of finerenone in patients with chronic kidney disease due to glomerular diseases?FindingsIn this prespecified exploratory analysis of a randomized clinical trial that enrolled 903 participants with glomerular diseases, finerenone, compared with placebo, slowed kidney function decline (difference in eGFR slope decline, 073 mL/min/1.73 m2 per year), reduced albuminuria, and lowered the risk of kidney failure or sustained loss of kidney function, with consistent effects across glomerular disease subtypes.MeaningFinerenone may have an important role in preserving kidney function in patients with glomerular diseases. ImportanceGlomerular diseases are a leading cause of chronic kidney disease (CKD) and kidney failure. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduces the risk of kidney function loss in CKD, but its effects in individuals with CKD due to glomerular diseases are uncertain.ObjectivesTo evaluate the efficacy and safety of finerenone in patients with glomerular diseases.Design, Setting, and ParticipantsPrespecified exploratory subgroup analysis of a phase 3, randomized, double-blind, placebo-controlled trial conducted across 24 countries and regions, focusing on participants with an investigator-reported glomerular disease diagnosis. The overall trial enrolled adults with nondiabetic CKD and an estimated glomerular filtration rate (eGFR) of either (1) at least 25 to less than 60 mL/min/1.73 m2 and urinary albumin to creatinine ratio of at least 200 mg/g to less than 500 mg/g or (2) an eGFR of at least 25 to less than 90 mL/min/1.73 m2 and urinary albumin to creatinine ratio of at least 500 mg/g to less than 3500 mg/g.InterventionFinerenone 10 mg or 20 mg taken orally once daily (n = 446) vs matching placebo (n = 457).Main Outcomes and MeasuresAnnualized rate of eGFR decline (total eGFR slope) from baseline to month 32 (primary outcome of the main trial); percent change in albuminuria to 12 months; and a composite outcome of kidney failure or sustained 40% or more decline in eGFR (prespecified exploratory outcomes).ResultsOf 1584 participants, 903 (57.0%) had investigator-reported glomerular disease, including 416 (46.1%) with immunoglobulin A nephropathy, 215 (23.8%) with focal segmental glomerulosclerosis, and 90 (10.0%) with membranous nephropathy. Participants with glomerular disease (mean [SD] age, 51.1 [13.6] years; 362 female [40.1%]; 558 Asian [61.9%]) had a mean eGFR of 48.8 mL/min/1.73 m2 and median urinary albumin to creatinine ratio of 839.6 mg/g. The total eGFR slope up to 32 months was -3.50 mL/min/1.73 m2 per year with finerenone and -4.23 mL/min/1.73 m2 per year with placebo (0.73 mL/min/1.73 m2 per year difference; 95% CI, 0.22-1.24). Finerenone reduced albuminuria at month 12 by 42% (95% CI, 35%-48%) and lowered the risk of kidney failure or 40% or more eGFR decline (7.42 vs 9.60 events per 100 patient-years; hazard ratio, 0.74; 95% CI, 0.57-0.97).Conclusions and RelevanceIn this exploratory analysis, treatment with finerenone slowed kidney function decline, reduced albuminuria, and lowered the risk of kidney failure or substantial loss of kidney function in patients with glomerular diseases. These findings suggest an important role for finerenone in preserving kidney function in this population.Trial RegistrationClinicalTrials.gov Identifier: NCT05047263 This exploratory analysis of a randomized clinical trial evaluates the efficacy and safety of finerenone in reducing chronic kidney disease of participants with glomerular diseases, including disease subtype.

Globally, the prevalence of chronic kidney disease is estimated to be approximately 850 million cases, with approximately 4 million individuals needing kidney replacement therapy for kidney failure. By 2050, chronic kidney disease is projected to become the fifth leading underlying cause of death worldwide. Despite its numerous causes, chronic kidney disease can be screened for, diagnosed, and staged with simple laboratory tests. Individuals with chronic kidney disease are at increased risk of kidney failure and many other health implications. Risk of premature cardiovascular disease is particularly noteworthy, as most patients with chronic kidney disease develop a disability or die from cardiovascular disease before ever progressing to kidney failure. Since 2019, large randomised trials have identified several effective treatments that both slow progressive kidney function decline and reduce cardiovascular risk, greatly expanding available treatments for chronic kidney disease. The wide range of complications associated with chronic kidney disease means that patients encounter many different specialties. Active engagement in chronic kidney disease identification and timely initiation of cost-effective interventions by all clinicians could now substantially reduce the global burden of complications of chronic kidney disease and kidney failure.

BACKGROUND:With decreasing estimated glomerular filtration rate (eGFR) and increasing albuminuria, the risk of cardiovascular events and overall mortality increases in chronic kidney disease (CKD). Established clinical renal endpoints often correspond to the late stage of CKD. Early stages are often initially asymptomatic. OBJECTIVE:This article classifies the eGFR progression and changes in albuminuria as early markers and possible surrogate endpoints in CKD studies and describes key aspects for their clinical and methodological use in studies and benefit assessment. RESULTS:The eGFR and the urine albumin-creatinine ratio (UACR) are complementary for risk stratification and progress monitoring, including in the cardiorenal context. Variability and influencing factors such as volume status, infections and blood pressure necessitate repeated measurements and contextual interpretation, especially in heart failure and after initiation of treatment with acute effects. For the eGFR Slope, a distinction is made between total Slope over several years and chronic Slope after the early acute phase. A meta-analysis of randomized studies reported a strong association between the total Slope averaged over 3 years and renal endpoints with a median R2 of 0.97, while the predictive accuracy of the chronic eGFR Slope was lower. Concerning albuminuria, it has been shown that higher UACR values are independently associated with cardiovascular mortality and that a reduction in UACR is associated with a more favorable renal prognosis. CONCLUSION:The progression of the eGFR and albuminuria can improve the practicality of studies in early stages of CKD, lead to faster results and facilitate interdisciplinary classification if validation, time window, acute phase, standard treatment and competing risks are reported in a comprehensible manner.

Key Points Treatment with semaglutide compared with placebo for 24 weeks reduced lean body mass and fat mass in adults with CKD and overweight or obesity. Changes in lean body mass or fat mass during semaglutide treatment did not correlate with changes in creatinine or cystatin C‑eGFR or measured GFR. Semaglutide significantly reduced extracellular water and BP, and changes in BP correlated with extracellular water. Background The glucagon-like peptide-1 receptor agonist semaglutide reduces hemoglobin A1c, body weight, BP, and GFR decline. Semaglutide may influence serum creatinine and cystatin C levels by nonkidney-related mechanisms and thereby affect eGFR. We studied the relationship between changes in body composition, eGFR and measured GFR (mGFR), and BP during semaglutide treatment. Methods We performed a prespecified analysis of a randomized placebo-controlled double-blind clinical trial in 101 adults with CKD with overweight status or obesity and without type 2 diabetes. Participants were randomized to 24 weeks of semaglutide 2.4 mg/wk subcutaneously or matched placebo treatment. We measured GFR with iohexol clearance, estimated GFR with creatinine and cystatin C, and used bioimpedance spectroscopy to determine lean body mass, fat mass, and extracellular water. Results After 24 weeks of treatment, semaglutide compared with placebo changed total body weight, lean body mass, and fat mass by −9.1 (95% confidence interval [CI], −11.0 to −7.2), −2.5 (95% CI, −6.6 to 1.6), and −3.9 (95% CI, −7.8 to 0.0) kg, respectively. No correlations were present between changes in total body weight, lean body mass, and fat mass with changes in eGFR (creatinine or cystatin C) or mGFR during semaglutide treatment (all Spearman correlation coefficients <0.23). Similar results were observed in multivariable adjusted analyses. Semaglutide compared with placebo changed extracellular water and systolic BP by −0.9 (95% CI, −1.6 to −0.1) L and −6.3 (95% CI, −10.9 to −1.7) mm Hg, respectively. Systolic BP changes during semaglutide treatment correlated with extracellular water changes (Spearman correlation 0.40; P = 0.005). Conclusions Semaglutide reduced lean body mass and fat mass in patients with CKD with overweight status or obesity. These changes did not correlate with changes in creatinine or cystatin C eGFR or mGFR, suggesting that body weight reductions of 10% with semaglutide do not influence GFR estimates. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT04889183.