Glomerular Filtration Rate Slope Research Articles

Estimated Glomerular Filtration Rate Slope as an Endpoint in Cardiovascular Trials.

End stage kidney disease can be a slow process and it may be challenging to achieve required follow-up for sufficient events. Therefore, a surrogate kidney endpoint, such as estimated glomerular filtration rate (eGFR) slope maybe attractive to assess the kidney in cardiovascular trials, especially heart failure (HF). eGFR slope can generate informative results in a shorter follow-up period, has decreased risk of type-2 error, and is less sensitive to eGFR shifts compared with other surrogate kidney endpoints (eGFR decline≥40% or doubling creatinine). However, eGFR slope has its limitations with acute effects, heterogeneity in slope calculation/reporting, and deviations from linearity. eGFR slope is a kidney endpoint which may be well-suited for HF trials. Cross-collaborated guideline recommendations are needed to optimize the use of eGFR slope as a kidney endpoint in patients with HF.

#1179 Early change of eGFR predicts long-term renal event in patients with hypertensive chronic kidney disease using a RAS blocker

Abstract Background and Aims The renin-angiotensin-aldosterone inhibitor (RASI) is one of the important medications for chronic kidney disease (CKD) with potential decrease of glomerular filtration rate (GFR) after initiation. There are few studies about the effect of GFR change by the RASI on variations of GFR and albuminuria. Method This observational cohort study was the extension of an open-label, case-controlled randomized clinical trial (NCT01552954) including adult hypertensive CKD patients with estimated GFR ≥30 ml/min/1.73 m2 and random urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine. In the trial phase, the angiotensin receptor blocker (ARB: Olmesartan 40 mg/day) was prescribed to participants after cessation of RASIs for 8 weeks of screening phase. (0-week). Participants had the second visit at 8 weeks after initiation of ARB (8-week) with randomization into the intensive education for low salt diet and the conventional education. Third visit was conducted at 16 weeks after 0-week (16-week). After 27 (19∼38) months later, we recruited participants for the cohort observation and finished at 38 (29∼48) months after 0-week visit. We grouped patients by tertiles of percent change of initial GFR during the first 8 weeks (from 0-week to 8-week) (pcGFRi) and compared the change of UACR from 24-hour urine and estimated GFR during trial and observational period. Results We analyzed data from 174 people finished 38-month observation among 235 participants enrolled for the trial phase. Initial GFR and 24-h urine UACR were 67 ± 24 ml/min/1.73 m2 and 829 ± 829 mg/g cr, respectively. There were −16.0 (−41.5∼−8.1) %, −2.8 (−7.3∼1.6) %, and 8.3 (1.8∼28.4) % pcGFRi in the first tertile group (group 1), the second tertile group (group 2), and the third tertile group (group 3), respectively. There were no differences in age, gender, GFR, 24-hour UACR, and 24-hour sodium excretion among the tertile groups at 0-week visit. The pcGFRi and the tertile group showed positive correlation with GFR change during 16 weeks of the trial, however, were not related to the percent change of 24-hour UACR during the trial phase. They were also positively correlated to the percent change of GFR during whole study period of 38 months (factor B = 8.180 and p-value< 0.001 for the group and factor B = 0.801 and p-value< 0.001 for pcGFRi), although, they did not show relationships with the percent change of 24-hour UACR during whole study period and UACR at last visit. The GFR slopes per year during 38 (29∼48) months were −2.9 (−4.0∼ −1.8), −1.3 (−2.4∼-0.3), and 0.1 (−1.0∼1.2) ml/min/1.73 m2/year in group 1, group 2, and group 3, respectively (p = 0.001 by the ANCOVA test). The relative risks to estimate GFR decrease ≥ 30% during whole study period were 0.237 (0.07∼0.798) (p = 0.020) and 0.035 (0.004∼0.302) (p = 0.035) in group 2 and group 3 compared to group 1, respectively. The AUC to estimate GFR decline ≥ 30% by the pcGFRi was 0.787 (0.685∼0.889, p< 0.001). The cut-off value 7.25% of pcGFRi estimates GFR decline ≥ 30% with 71.4% sensitivity and 70.9% specificity. Conclusion The decline of GFR by initiation of RASI predicts long-term renal event of GFR decline ≥ 30% in users of RASI, strongly. We need to compare the renal outcomes between RASI users with initial decrease of GFR and non-users to make guideline adjusting RASI usage according to initial change of GFR with RASI prescription.

#2456 Real world outcomes of Fabry disease in Italian excellence centers: the ground study

Abstract Background and Aims Fabry disease (FD) is an X-linked lysosomal storage disorder with an estimated prevalence from 1:1368 to 1:8882, caused by galactosidase alpha gene (GLA) mutations, resulting in renal, cardiac and central nervous system involvement with significant morbidity and mortality in both sexes. Treatment includes enzyme replacement therapies (ERTs) and chaperone therapy. A better understanding of this disorder from its diagnostic journey, along with the impact of patient characteristics and available treatments on disease prognosis are relevant topics for physicians dealing with FD. The Global buRden and treatment trajectOries in Italian patients with Fabry disease: a retrospective longitUdinal and cross-sectioNal study–GROUND describes a cohort of FD Italian patients, addressing the unmet needs arising from this condition while providing a real-world picture from which further research insights can be derived. Methods This was a retrospective, longitudinal and cross-sectional study. Data about adult patients of either sex living or deceased with a documented FD diagnosis and at least 3 years of follow-up or early occurrence of severe/fatal outcomes were collected. Occurrence of severe/fatal events (renal, cardiac, cerebral events, death) from birth to last follow-up visit was the composite primary outcome. Other outcomes assessed were disease progression measured by FAbry STabilization indEX (FASTEX), occurrence of clinically significant events/FD related symptoms (i.e., renal function decline, detection/worsening of left ventricular hypertrophy (LVH), lysoGb3 increase, new FD symptoms), time from first manifestation to diagnosis, treatment trajectories. Results From June 2021 to June 2022, 199 patients, 73 males and 126 females, including 169 classic and 30 late-onset phenotypes, were enrolled at 8 Italian centers. Median time from onset of FD symptoms to diagnosis was 60.3 months [95% confidence interval (IC) 38.8-89.7], with a median of 0.64 years (range 0-19.29) from diagnosis to beginning of treatment. Chronic pain and angiokeratomas were the most common initial symptoms (18.1% and 13.1% of patients respectively); acroparesthesia and abdominal pain were reported in 12.5% of patients and LVH in 8.5%. Among the 143 missense/nonsense mutations identified, 14 were Variants of Uncertain Significance (VUS). Overall, 82% of patients were treated with 1 FD specific therapy, of whom 24% switched at least one treatment, while 5% definitively stopped. The composite primary outcome was experienced by 31.7% of patients for a total of 85 severe/fatal events. Specifically, 7.5% (n = 15, all treated) patients experienced a renal event; 20.6% of patients had a cardiac event (n = 41, 38/41 treated); 11.1% (n = 22, all but 1 treated) of subjects experienced a cerebral event; fatal events occurred in 7 patients of whom 1 was untreated. In addition, 88.9% of patients reported at least one clinically significant event, among which detection/worsening of LVH was the most common (41.2%). Estimated Glomerular Filtration rate (eGFR) slopes in the last 1-3 years of follow up were −2.07 [Standard Error (SE): 1.38] and −0.76 (SE: 1.75) in classic males and females, respectively. Long-term (i.e., from diagnosis to last available measure) FASTEX identified 31.1% of patients as being unstable. Conclusions In this real-world Italian FD cohort, patients were promptly treated after diagnosis according to existing guidelines, following expert evaluation. Nevertheless, severe clinical events occurred in about 30% of the cohort, mainly among classic treated males, revealing persistent unmet needs such as a better assessment of determinants of disease progression and outcomes, as well as response to treatment and further insights on the potential benefit of new therapeutic options.

#2424 Higher 24-hour urine sodium-to-potassium ratio is associated with worse renal outome

Abstract Background and Aims Low sodium and high potassium intake are advised to control blood pressure and may improve long term cardiorenal outcomes. The optimal potassium intake for patients with chronic kidney disease remains to be defined. We investigated whether the 24-hour urine sodium-to-potassium ratio (Na/K-ratio), which incorporates estimates of both sodium and potassium intake, could predict long-term renal outcome. Method We selected adult outpatients of a Dutch tertiary hospital who collected at least one 24-hour urine collection with available sodium and potassium measurements between 1998-2023. Patients with a history of dialysis or kidney transplantation were excluded. We examined the need for persistent renal replacement therapy (RRT), defined as dialysis or kidney transplantation, using Cox regression. The association between the 24-hour urine Na/K-ratio and the estimated glomerular filtration rate (eGFR) slope was assessed using linear regression in patients who had ≥3 eGFR measurements available in ≥3 years. The linear regression analysis was adjusted for age, sex, baseline eGFR, diabetes mellitus and hypertension. In the Cox regression analysis, we additionally adjusted for the interaction between the 24-hour urine Na/K-ratio and baseline eGFR. Hypertension was defined as a clinical diagnosis or an office blood pressure ≥140/90 mmHg. Results We included 720 patients aged 50 ± 15 years, of whom 52% were male, 58% had hypertension and 31% diabetes mellitus. The baseline eGFR was 64 ± 34 ml/min/1.73 m2. The 24-hour urine Na/K ratio was 2.5 ± 1.2 in a median number of 1 (IQR = 1-2) urine collection. During a median follow-up of 11.2 (14.0) years, 29% of patients needed RRT. In 575 patients with sufficient eGFR measurements (mean 12 ± 8 measurements per subject) the median annual eGFR decline was 1.51 (IQR = 0.49-3.98) ml/min/1.73 m2. Every unit increase in the 24-hour urine Na/K-ratio was associated with a 19% higher risk for persistent RRT need (HR 1.19, 95% CI 1.03-1.39; p = 0.02) and an additional 0.44 ml/min/1.73 m2 (95% CI −0.83, −0.04; p = 0.03) decline in eGFR. Conclusion This study suggests that higher 24-hour urine Na/K-ratio is associated with faster kidney function decline and the need for RRT, independent of hypertension, in a selected group of outpatients.

Visceral Adiposity and Progression of ADPKD: A Cohort Study of Patients From the TEMPO 3:4 Trial

Rationale & ObjectiveBody-mass index (BMI) is an independent predictor of kidney disease progression in individuals with autosomal dominant polycystic kidney disease (ADPKD). Adipocytes do not simply act as a fat reservoir but are active endocrine organs. We hypothesized that greater visceral abdominal adiposity would associate with more rapid kidney growth in ADPKD and influence the efficacy of tolvaptan. Study DesignA retrospective cohort study. Setting & Participants1053 patients enrolled in the TEMPO 3:4 tolvaptan trial with ADPKD and high risk of rapid disease progression. PredictorEstimates of visceral adiposity extracted from coronal plane MRIs using deep learning. OutcomeAnnual change in total kidney volume (TKV) and effect of tolvaptan on kidney growth. Analytical ApproachMultinomial logistic regression and linear mixed models. ResultsIn fully adjusted models, the highest tertile of visceral adiposity was associated with greater odds of annual change in TKV of ≥7% vs. <5% (OR: 4.78 [3.03, 7.47]). The association was stronger in females than males (interaction p<0.01). In linear mixed models with an outcome of % change in TKV per year, tolvaptan efficacy (% change in TKV) was reduced with higher visceral adiposity (three-way interaction of treatment*time*visceral adiposity p=0.002). Visceral adiposity significantly improved classification performance of predicting rapid annual % change in TKV for individuals with a normal BMI (De-Long’s test Z-score: -2.03; p=0.04). Greater visceral adiposity was not associated with estimated glomerular filtration rate (eGFR) slope in the overall cohort; however, visceral adiposity was associated with more rapid decline in eGFR slope (below the median) in females (fully adjusted OR 1.06 [1.01, 1.11] per 10 unit increase in visceral adiposity) but not males (0.98 [0.95, 1.02]). LimitationsRetrospective; rapid progressors; computational demand of deep learning. ConclusionsVisceral adiposity that can be quantified by MRI in the coronal plane using a deep learning segmentation model, independently associates with more rapid kidney growth, and improves classification of rapid progression in individuals with a normal BMI. Tolvaptan efficacy decreases with increasing visceral adiposity.

Updated Evaluation of Agalsidase Alfa Enzyme Replacement Therapy for Patients with Fabry Disease: Insights from Real-World Data.

The clinical use of agalsidase alfa as enzyme replacement therapy (ERT) for Fabry disease (FD) has spread since 2001, and a large body of evidence of its effectiveness has been collected. This review presents the clinical and laboratory results achieved with agalsidase alfa, which has been published in the literature. Agalsidase alfa infusion slows down or stops the progression of renal damage, expressed by reduction or stabilization of the annual decline of the glomerular filtration rate; yearly decrease of glomerular filtration rate (slope) sometimes is reduced until its stabilization. ERT prevents or reduces the occurrence of hypertrophic cardiomyopathy or slows the increase over time if it is already present. Moreover, regarding neurological manifestations, ERT improves neuropathic pain and quality of life, and recent data indicated that it may also prevent the burden of cerebrovascular disease. In addition to ERT's clinical benefits, crucial topics like the most appropriate time to start therapy and the role of anti-drug antibodies (ADA) are analyzed. Treatment with agalsidase alfa in patients with FD substantially improves their outcomes and enhances their quality of life in patients with FD.

Body mass index and cardiorenal outcomes in the EMPEROR-Preserved trial: Principal findings and meta-analysis with the DELIVER trial.

Both low and high body mass index (BMI) are associated with poor heart failure outcomes. Whether BMI modifies benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in heart failure with preserved ejection fraction (HFpEF) requires further investigation. Using EMPEROR-Preserved data, the effects of empagliflozin versus placebo on the risks for the primary outcome (hospitalization for heart failure [HHF] or cardiovascular [CV] death), change in estimated glomerular filtration rate (eGFR) slopes, change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), and secondary outcomes across baseline BMI categories (<25 kg/m2, 25 to <30 kg/m2, 30 to <35 kg/m2, 35 to <40 kg/m2 and ≥40 kg/m2) were examined, and a meta-analysis conducted with DELIVER. Forty-five percent had a BMI of ≥30 kg/m2. For the primary outcome, there was a consistent treatment effect of empagliflozin versus placebo across the BMI categories with no formal interaction (p trend = 0.19) by BMI categories. There was also no difference in the effects on secondary outcomes including total HHF (p trend = 0.19), CV death (p trend = 0.20), or eGFR slope with slower declines with empagliflozin regardless of BMI (range 1.12-1.71 ml/min/1.73 m2 relative to placebo, p trend = 0.85 for interaction), though there was no overall impact on the composite renal endpoint. The difference in weight change between empagliflozin and placebo was -0.59, -1.48, -1.54, -0.87, and - 2.67 kg in the lowest to highest BMI categories (p trend = 0.016 for interaction). A meta-analysis of data from EMPEROR-Preserved and DELIVER showed a consistent effect of SGLT2i versus placebo across BMI categories for the outcome of HHF or CV death. There was a trend toward greater absolute KCCQ-CSS benefit at 32 weeks with empagliflozin at higher BMIs (p = 0.08). Empagliflozin treatment resulted in broadly consistent cardiac effects across the range of BMI in patients with HFpEF. SGLT2i treatment yields benefit in patients with HFpEF regardless of baseline BMI.

The 10-Year Effects of Intensive Lifestyle Intervention on Kidney Outcomes

Limited data exist on longitudinal kidney outcomes after nonsurgical obesity treatments. We investigated the effects of intensive lifestyle intervention on kidney function over 10 years. Post hoc analysis of Action for Health in Diabetes (Look AHEAD) randomized controlled trial. We studied 4,901 individuals with type 2 diabetes and body mass index of≥25kg/m2 enrolled in Look AHEAD (2001-2015). The original Look AHEAD trial excluded individuals with 4+urine dipstick protein, serum creatinine level of>1.4mg/dL (women), 1.5mg/dL (men), or dialysis dependence. Intensive lifestyle intervention versus diabetes support and education (ie, usual care). Primary outcome was estimated glomerular filtration rate (eGFR, mL/min/1.73m2) slope. Secondary outcomes were mean eGFR, slope, and mean urine albumin to creatinine ratio (UACR, mg/mg). Linear mixed-effects models with random slopes and intercepts to evaluate the association between randomization arms and within-individual repeated measures of eGFR and UACR. We tested for effect modification by baseline eGFR. At baseline, mean eGFR was 89, and 83% had a normal UACR. Over 10 years, there was no difference in eGFR slope (+0.064 per year; 95% CI: -0.036 to 0.16; P=0.21) between arms. Slope or mean UACR did not differ between arms. Baseline eGFR, categorized as eGFR of<80, 80-100, or>100, did not modify the intervention's effect on eGFR slope or mean. Loss of muscle may confound creatinine-based eGFR. In patients with type 2 diabetes and preserved kidney function, intensive lifestyle intervention did not change eGFR slope over 10 years. Among participants with baseline eGFR<80, lifestyle intervention had a slightly higher longitudinal mean eGFR than usual care. Further studies evaluating the effects of intensive lifestyle intervention in people with kidney disease are needed.

Renal Hemodynamic and Functional Changes in ADPKD Patients.

Although the mechanisms underlying cyst enlargement in autosomal dominant polycystic kidney disease (ADPKD) are becoming clearer, those of renal dysfunction are not fully understood. In particular, total kidney volume (TKV) and renal function do not always correspond. To elucidate this discrepancy, we studied in detail glomerular hemodynamic changes during ADPKD progression. Sixty-one ADPKD patients with baseline height-adjusted TKV (Ht-TKV) of 933±537 ml/m and serum creatinine of 1.16±0.62 mg/dl were followed for 2 years. Glomerular filtration rate (GFR) and renal plasma flow (RPF) slopes were calculated from inulin clearance (Cin) and para-aminohippuric acid (PAH) clearance (CPAH), respectively, while glomerular hydrostatic pressure (Pglo), afferent resistance (RA), and efferent resistance (RE) were estimated using the Gomez formulae. Each parameter was compared with baseline Ht-TKV. Patients were also subclassified into 1A-1B and 1C-1E groups according to the baseline Mayo imaging classification (MIC), and then compared with respect to GFR, RPF, FF and glomerular hemodynamics. After 2 years, Ht-TKV increased (933±537 to 1000±648 ml/m, P<0.01), GFR decreased (66.7±30 to 57.3±30.1 ml/min/1.73m2, P<0.001), and RPF decreased (390±215 to 339±190 ml/min/1.73m2, P<0.05). Further, Pglo was decreased and RA was increased. Baseline Ht-TKV was inversely correlated with GFR (r=-0.29, P<0.05), but there was no association between baseline Ht-TKV and RPF, Pglo, RA, or RE annual changes. However, despite an increase in RE in 1A-1B group, RE was decreased in 1C-1E group. As a result, RE slope was significantly lower in 1C-1E group than 1A-1B group over time (-83(-309 to 102) to 164(-34 to 343) dyne・s・cm-5, P<0.01). This is the first report examining yearly changes of GFR (Inulin), RPF (PAH), and renal microcirculation parameters in ADPKD patients. Our results demonstrate that GFR reduction was caused by RA increase, which was faster due to RE decrease in subjects with faster Ht-TKV increase.

Changes in estimated glomerular filtration rate in patients administered proton pump inhibitors: a single-center cohort study.

Proton pump inhibitor (PPI) use may be associated with renal dysfunction. Renal dysfunction in PPI users requires evaluation of development and progression risks simultaneously, using estimated glomerular filtration rate (eGFR) slope, which indicates changes in eGFR per year. To the best of our knowledge, no studies have evaluated eGFR slope in PPI users. This study investigated the association between PPI use and renal dysfunction using eGFR slope.A single-center cohort study was conducted using the health records data at Hamamatsu University Hospital in Japan. Participants were defined as first users of acid-suppressing drugs (PPIs or Histamine H2 receptor antagonists (H2RAs)) from 2010 to 2021 and continuously prescribed for ≥ 90days. The H2RA group was used for the propensity-score matching (PSM) to the PPI group to minimize the effects of confounders. The eGFR slope was estimated using a linear mixed effects model. Participants were stratified by baseline eGFR and age, respectively, as subgroup analyses.A total of 4,649 acid-suppressing drug users met the inclusion criteria, including 950 taking H2RAs and 3,699 PPIs. After PSM, 911 patients were assigned to each group. The eGFR slopes of the PPI and H2RA users were -4.75 (95% CI: -6.29, -3.20) and -3.40 (-4.38, -2.42), respectively. The difference between the groups was not significant. Significant declines in eGFR were observed with PPIs with baseline eGFR ≥ 90 and age < 65.PPI use for ≥ 90days may hasten eGFR decline compared to H2RA use, especially in patients with eGFR ≥ 90 or age < 65.

CA-125 concentrations are associated with renal function decline but not congestion or prognosis in patients with chronic heart failure: results from EMPEROR-POOLED

Abstract Background Carbohydrate antigen 125 (CA-125, also described as cancer antigen 125), has emerged as a candidate biomarker of congestion in heart failure (HF). Effects of sodium/glucose cotransporter-2 inhibitor therapy on CA-125 and its role as a prognostic measure in HF remains uncertain. Purpose In study participants from the EMPEROR-Preserved and EMPEROR-Reduced trials, across a wide spectrum of ejection fraction (EF) and renal function, we sought to investigate associations between CA-125 and congestion, the effect of empagliflozin on CA-125 concentrations, and the ability of the biomarker to predict cardio-renal outcomes. Methods 1111 patients with HF and available biomarker data were included into this analysis. Serum CA-125 was measured at baseline, 12 and 52 weeks using an Electroluminescence assay. The measurements were performed within a biomarker research agreement of Boehringer Ingelheim, the sponsor of these trials and Roche Diagnostics International Ltd. Congestion signs or symptoms were evaluated across CA-125 tertiles. A mixed model for repeated measurements was used to compare the treatment effects on CA-125. Multivariable analyses adjusted for the prespecified EMPEROR baseline variables plus N-terminal pro-B type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) were used to examine the association of CA-125 with HF hospitalization or cardiovascular (CV) death and estimated glomerular filtration rate (eGFR) slope. Results Across CA-125 tertiles at baseline, no significant association was present with HF symptom severity, jugular vein distention, pulmonary rales, S3 gallop or peripheral oedema (all p-values &amp;gt;0.10). Treatment with empagliflozin was associated with 7% greater reduction of CA-125 level versus placebo to week 12 (adjusted geometric mean ratio: 0.93; 95% confidence interval [CI], 0.87-0.99, p = 0.03) but not to week 52 (adjusted geometric mean ratio: 0.97, 95% CI 0.90-1.06; p = 0.50). No significant association was found for tertiles of CA-125 at baseline with the risk of CV death/HF hospitalization; with a hazard ratio (HR) for higher vs lower CA-125 tertiles of 1.34 (95% CI 0.91–1.96). In the same model NT-proBNP and hs-cTnT were strongly prognostic (both p-values &amp;lt;0.0001). Compared to lower tertiles, study participants in the third CA-125 tertile had higher rate of kidney function decline with a more negative eGFR slope (p for trend = 0.03). Conclusion In chronic HF, across a wide range of EF and of renal function, CA-125 levels were not strongly associated with clinical signs or symptoms of congestion. Empagliflozin lowered CA-125 levels more than placebo at week 12 but not at week 52. Among individuals with HF, CA-125 concentrations did not provide additional prognostic information for CV death/HF hospitalization beyond conventional cardiac biomarkers but may predict subsequent kidney function decline.

Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study

BackgroundPegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular...

Abstract 14614: Effect of SGLT2 Inhibitors on Renal Outcomes Across Various Patient Populations

Background: The effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on renal outcomes in patients with varying combinations of heart failure (HF), chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) remains unclear. Methods: Online databases were queried up to May 2023 for primary and secondary analysis of trials of SGLT2i in patients with HF, CKD, or T2DM. Outcomes of interest were composite renal endpoint (defined as an eGFR &lt;15 mL/min/1.73 m2, doubling of serum creatinine, some percent change in eGFR, and/or need for kidney replacement therapy) and change in estimated glomerular filtration rate (eGFR) slope. Hazard ratios (HR) and mean difference with their 95% confidence intervals were pooled using the generic inverse variance method and a random-effects model. Results: 10 trials (n=70,117 patients) were included. Compared with placebo, SGLT2i reduced the risk of composite renal endpoint by 35% in HF (HR: 0.65; 95% CI: 0.50-0.84), 38% in CKD (HR: 0.62; 95% CI: 0.54-0.71), and 37% in DM (HR:0.63; 95% CI: 0.54, 0.73). A similar pattern of benefit was observed in different combinations of these diseases ( Figure 1 ), as well as patients without baseline HF (HR:0.57; 95% CI: 0.51, 0.63), CKD (HR:0.64; 95% CI: 0.42, 0.98) and T2DM (HR:0.62; 95% CI: 0.45, 0.86). Findings were similar for change in eGFR slope. Conclusions: SGLT2i improve renal outcomes in cohorts of HF, CKD and T2DM and these effects appear consistent across patients with different combinations of these conditions.

Abstract 11936: Cardiorenal Prognostic Significance of IGFBP-7 Concentrations in Chronic Heart Failure: Findings From EMPEROR-Pooled

Introduction: Insulin-like growth factor binding protein-7 (IGFBP-7) is a biomarker of tissue senescence with a role in heart failure (HF) pathophysiology. We examined the association of IGFBP-7 with risk of HF hospitalization or cardiovascular (CV) death and progression of renal disease in the EMPEROR-Reduced and EMPEROR-Preserved Trials. Methods: IGFBP-7 was measured in serum samples in the placebo and empaglifozin arms at baseline (N= 561, 564), 12 weeks (N=558, 557) and 52 weeks (N=355, 358). IGFBP-7 was measured using Roche Cobas Elecsys assay within the Biomarker Research Agreement of Boehringer Ingelheim, the sponsor of the EMPEROR trials and Roche Diagnostics International Ltd. Association between IGFBP-7 and risk of HF hospitalization or CV death, estimated glomerular filtration rate (eGFR) slope, and renal composite outcome of sustained eGFR reduction ≥40% or end-stage renal disease were evaluated using multivariable modeling. Results: Study participants with IGFBP-7 levels in the third tertile had a higher risk clinical profile compared to those with lower values. Empagliflozin was not meaningfully associated with change in IGFBP7 at 12 or 52 weeks. In Cox proportional hazards models adjusted for clinical variables, N-terminal pro-B type natriuretic peptide and high-sensitivity cardiac troponin T, baseline IGFBP-7 values above the second tertile predicted a higher risk of HF hospitalization or CV death (HR: 2.00 95% CI 1.28-3.10, p=0.002), higher rate of eGFR decline (β estimate: -2.45, 95% CI: -3.40 - -1.50, p for trend =0.005) and higher risk of renal composite endpoint (HR: 4.66, 95% CI: 1.61-13.53, p=0.005). Empagliflozin reduced risk for CV death/HF hospitalization irrespective of baseline IGFBP-7 (p-trend across IGFBP-7 tertiles=0.26). Concentrations of IGFBP-7 were moderately correlated with other prognostic HF biomarkers of tissue remodeling including fatty acid binding protein-3, growth differentiation factor-15, and angiopoietin-2. Conclusions: IGBP-7 was correlated with worse clinical presentation and associated with adverse cardiovascular outcomes even in models adjusted for conventional biomarkers. Empagliflozin did not significantly affect IGFBP-7 levels over time.

Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis

BackgroundAn unmet need exists for focal segmental glomerulosclerosis (FSGS) treatment. In an 8-week, phase 2 trial, sparsentan, a dual endothelin–angiotensin receptor antagonist, reduced proteinuria in patients with FSGS. The efficacy and safety of longer-term treatment with sparsentan for FSGS are unknown.MethodsIn this phase 3 trial, we enrolled patients with FSGS (without known secondary causes) who were 8 to 75 years of age; patients were randomly assigned to receive sparsentan or irbesartan (active control) for 108 weeks. The surrogate efficacy end point assessed at the prespecified interim analysis at 36 weeks was the FSGS partial remission of proteinuria end point (defined as a urinary protein-to-creatinine ratio of ≤1.5 [with protein and creatinine both measured in grams] and a >40% reduction in the ratio from baseline). The primary efficacy end point was the estimated glomerular filtration rate (eGFR) slope at the time of the final analysis. The change in eGFR from baseline to 4 weeks after the end of treatment (week 112) was a secondary end point. Safety was also evaluated.ResultsA total of 371 patients underwent randomization: 184 were assigned to receive sparsentan and 187 to receive irbesartan. At 36 weeks, the percentage of patients with partial remission of proteinuria was 42.0% in the sparsentan group and 26.0% in the irbesartan group (P=0.009), a response that was sustained through 108 weeks. At the time of the final analysis at week 108, there were no significant between-group differences in the eGFR slope; the between-group difference in total slope (day 1 to week 108) was 0.3 ml per minute per 1.73 m2 of body-surface area per year (95% confidence interval [CI], −1.7 to 2.4), and the between-group difference in the slope from week 6 to week 108 (i.e., chronic slope) was 0.9 ml per minute per 1.73 m2 per year (95% CI, −1.3 to 3.0). The mean change in eGFR from baseline to week 112 was −10.4 ml per minute per 1.73 m2 with sparsentan and −12.1 ml per minute per 1.73 m2 with irbesartan (difference, 1.8 ml per minute per 1.73 m2; 95% CI, −1.4 to 4.9). Sparsentan and irbesartan had similar safety profiles, and the frequency of adverse events was similar in the two groups.ConclusionsAmong patients with FSGS, there were no significant between-group differences in eGFR slope at 108 weeks, despite a greater reduction in proteinuria with sparsentan than with irbesartan. (Funded by Travere Therapeutics; DUPLEX ClinicalTrials.gov number, NCT03493685.)

Baseline Urine Albumin-to-Creatinine Ratio is Associated With Decline of Estimated Glomerular Filtration Rate in Patients Newly Diagnosed With Type 2 Diabetes Mellitus: An Observational 5-year Cohort Study

ObjectiveThis study aimed to investigate the association between baseline albuminuria and the progression of diabetic kidney disease (DKD) in patients newly diagnosed with type 2 diabetes mellitus (DM). MethodsA retrospective cohort study was conducted among 604 patients aged ≥18 years who were newly diagnosed with type 2 DM between January 2014 and 31 December 2017 at an outpatient clinic in a tertiary hospital in China. The incidence of albuminuria was determined and the associations between albuminuria at baseline and the progression of DKD estimated by estimated glomerular filtration rate slope were evaluated using binary logistic regression analysis. ResultsAt diagnosis of type 2 DM, 18.8% of patients had albuminuria, with 17.4% having microalbuminuria and the other 1.4% having macroalbuminuria. During the 5-year follow-up period, patients with albuminuria at the baseline experienced a more rapid decline of estimated glomerular filtration rate over time than patients with normoalbuminuria at baseline (−2.6 vs −1.5 mL/min/1.73 m2 per year, P =.01). Albuminuria at baseline is independently associated with the progression of DKD. ConclusionsThe prevalence of albuminuria is 18.8% in patients newly diagnosed with type 2 diabetes and the occurrence of albuminuria can predict steeper annual decline in kidney function.

EGFR slope as a surrogate endpoint for end-stage kidney disease in patients with diabetes and eGFR > 30 mL/min/1.73 m2 in the J-DREAMS cohort

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.

Association between estimated glomerular filtration rate slope and cardiovascular disease among individuals with and without diabetes: a prospective cohort study

BackgroundPrevious studies have reported an association between a significant decline in estimated glomerular filtration rate (eGFR) over time and an increased risk of cardiovascular disease (CVD). This study aimed to investigate the association between the eGFR slope and CVD among individuals with and without diabetes.MethodsThis prospective cohort study was conducted within the Tehran Lipid and Glucose Study (TLGS) framework. We studied 6919 adults aged 20–70 years, including 985 with diabetes and 5934 without diabetes. The eGFR slope was determined based on repeated measurements of eGFR through linear mixed-effects models. A multivariable Cox proportional hazard model was employed to evaluate the association between eGFR slope, both in continuous and categorical form, and the risk of CVD.ResultsThe slopes of eGFR exhibited a bell-shaped distribution, with a mean (standard deviation (SD)) of -0.63 (0.13) and − 0.70 (0.14) ml/min per 1.73 m2 per year in individuals with and without diabetes, respectively. During a median follow-up of 8.22 years, following the 9-year eGFR slope ascertainment period, a total of 551 CVD events (195 in patients with diabetes) were observed. Among individuals with diabetes, a steeper decline in eGFR slope was significantly associated with a higher risk of CVD events, even after adjusting for baseline eGFR, demographic factors, and traditional risk factors for CVD; slopes of (-1.05 to -0.74) and (-0.60 to -0.52) were associated with 2.12 and %64 higher risks for CVD, respectively, compared with a slope of (-0.51 to 0.16). Among individuals without diabetes, the annual eGFR slope did not show a significant association with the risk of CVD.ConclusionMonitoring the eGFR slope may serve as a potential predictor of CVD risk in individuals with diabetes.

Association of eGFR slope with all-cause mortality, macrovascular and microvascular outcomes in people with type 2 diabetes and early-stage chronic kidney disease

AimsThe association of estimated glomerular filtration rate (eGFR) slope with progression of complications in people with type 2 diabetes (T2D) and early-stage chronic kidney disease (CKD) is less clear. MethodsWe identified 115,139 T2D participants without decreased eGFR (>60 mL/min/1.73 m2) between 2008 and 2015 from the electronic database of the Hong Kong Hospital Authority. eGFR slope calculated by linear-mixed effects model using 3-year eGFR measurements was categorized into quintiles. With Quintile 3 of eGFR slope as the reference group, we used Cox proportional or cause-specific models to investigate the association between eGFR slope and all-cause mortality, macrovascular and microvascular complications, as appropriate. ResultsOver a median follow-up of 7.8 years, fastest eGFR declines (Quintile 1 with median eGFR slope: −4.32 mL/min/1.73 m2/year) were associated with increased risk of all adverse outcomes (adjusted hazard ratio [aHR] 1.36 to 2.97, all P < 0.0001), compared with less steep eGFR declines (Quintile 3: −1.08 mL/min/1.73 m2/year). Substantial eGFR increases (Quintile 5: 1.34 mL/min/1.73 m2/year) were associated with decreased risk of CKD and ≥ 40 % decline in eGFR (aHR [95 % CI] 0.65 [0.63, 0.67] and 0.85 [0.82, 0.89], respectively) and higher risk of death, CVD, DR and DN (aHR [95 % CI] 1.48 [1.40, 1.56], 1.19 [1.14, 1.25], 1.07 [1.004, 1.15] and 1.62 [1.37, 1.91], respectively). ConclusionsIn a cohort of T2D people without decreased eGFR, accelerated declines and increases in eGFR were associated with all-cause mortality, macrovascular and microvascular complications, supporting the potential prognostic utility of eGFR slope in T2D people with early-stage CKD.

The effects of canagliflozin in type 2 diabetes in subgroups defined by population-specific body mass index: Insights from the CANVAS Program and CREDENCE trial.

To assess the effects of canagliflozin on clinical outcomes and intermediate markers across population-specific body mass index (BMI) categories in the CANVAS Program and CREDENCE trial. Individual participant data were pooled and analysed in subgroups according to population-specific BMI. The main outcomes of interest were: major adverse cardiovascular events (MACE, a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death); composite renal outcome; and changes in systolic blood pressure (SBP), body weight, albuminuria and estimated glomerular filtration rate (eGFR) slope. Cox proportional hazards models and mixed-effect models were used. A total of 14 520 participants were included, of whom 9378 (65%) had obesity. Overall, canagliflozin reduced the risk of MACE (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.75 to 0.93) with no heterogeneity of treatment effect across BMI subgroups (Pheterogeneity = 0.76). Similarly, canagliflozin reduced composite renal outcomes (HR 0.75, 95% CI 0.66 to 0.84) with no heterogeneity across subgroups observed (Pheterogeneity = 0.72). The effects of canagliflozin on body weight and SBP differed across BMI subgroups (Pheterogeneity <0.01 and 0.04, respectively) but were consistent for albuminuria (Pheterogeneity = 0.60). Chronic eGFR slope with canagliflozin treatment was consistent across subgroups (Pheterogeneity >0.95). The cardiovascular and renal benefits of canagliflozin and its safety profile were consistent across population-specific BMI subgroups for adults in the CANVAS Program and CREDENCE trial.