Glomerular Filtration Rate Slope Research Articles

Dapagliflozin for rheumatic musculoskeletal disease in patients with chronic kidney disease.

To elucidate the effectiveness of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, on renal function in patients with rheumatic musculoskeletal diseases complicated by chronic kidney disease (CKD) and identify factors associated with the response to dapagliflozin. We conducted a retrospective analysis of patients with rheumatic musculoskeletal disease and CKD who were treated with dapagliflozin for more than a year. The good response was defined as an improvement in the estimated glomerular filtration rate (eGFR) slope per year after dapagliflozin treatment compared to that before treatment. Additionally, we investigated the response rate and its predictive factors. In this analysis, 43 patients were included. The average eGFR slope demonstrated a significant improvement after dapagliflozin treatment compared to that before the treatment (0.04 vs -0.55 mL/min/1.73m²/year, p=0.001). A good response rate was 69.8% and was associated with low average levels of C-reactive protein, a high frequency of angiotensin II receptor blocker (ARB) use, and a low frequency of tacrolimus use compared to non-response (0.08 ± 0.18 vs 0.25 ± 0.29 mg/dL, p=0.03; 80.0% vs 38.4%, p=0.01; 10.0% vs 76.9%, p<0.01). Dapagliflozin is effective for rheumatic musculoskeletal diseases patients with CKD for preventing deterioration of renal function. Antihypertensive treatment with ARBs and inflammation control without tacrolimus was associated with a high likelihood of favorable response to dapagliflozin.

Associations between Kidney Disease Progression and Metabolomic Profiling in Stable Kidney Transplant Recipients-A 3 Year Follow-Up Prospective Study.

Background: kidney transplant recipients are exposed to multiple pathogenic pathways that may alter short and long-term allograft survival. Metabolomic profiling is useful for detecting potential biomarkers of kidney disease with a predictive capacity. This field is still under development in kidney transplantation and metabolome analysis is faced with analytical challenges. We performed a cross-sectional study including stable kidney transplant patients and aimed to search for relevant associations between baseline plasmatic and urinary metabolites and relevant outcomes over a follow-up period of 3 years. Methods: we performed a cross-sectional study including 72 stable kidney transplant patients with stored plasmatic and urinary samples at the baseline evaluation which were there analyzed by nuclear magnetic resonance in order to quantify and describe metabolites. We performed a 3-year follow-up and searched for relevant associations between renal failure outcomes and baseline metabolites. Between-group comparisons were made after classification by observed estimated glomerular filtration rate slope during the follow-up: positive slope and negative slope. Results: The mean estimated GFR (glomerular filtration rate) was higher at baseline in the patients who exhibited a negative slope during the follow-up (63.4 mL/min/1.73 m2 vs. 55.8 mL/min/1.73 m2, p = 0,019). After log transformation and division by urinary creatinine, urinary dimethylamine (3.63 vs. 3.16, p = 0.027), hippuric acid (7.33 vs. 6.29, p = 0.041), and acetone (1.88 vs. 1, p = 0.023) exhibited higher concentrations in patients with a negative GFR slope when compared to patients with a positive GFR slope. By computing a linear regression, a significant low-strength regression equation between the log 2 transformed plasmatic level of glycine and the estimated glomerular filtration rate was found (F (1,70) = 5.15, p = 0.026), with an R2 of 0.069. Several metabolites were correlated positively with hand grip strength (plasmatic tyrosine with r = 0.336 and p = 0.005 and plasmatic leucine with r = 0.371 and p = 0.002). Other urinary metabolites were found to be correlated negatively with hand grip strength (dimethylamine with r = -0.250 and p = 0.04, citric acid with r = -0.296 and p = 0.014, formic acid with r = -0.349 and p = 0.004, and glycine with r = -0.306 and p = 0.01). Conclusions: some metabolites had different concentrations compared to kidney transplant patients with negative and positive slopes, and significant correlations were found between hand grip strength and urinary and plasmatic metabolites.

The association between the eGFR slope and cardiorenal prognosis in patients with renoprotective treatments: A systematic review and meta-analysis.

The associations between the estimated glomerular filtration rate (eGFR) slope and the cardiorenal prognosis in patients with renoprotective drugs have not been well characterized yet. PubMed, Medline, Embase, The Cochrane Library, CNKI, WanFang, Weipu databases and Clinicaltrial.gov were searched from inception to April 2023. Event-driven randomized controlled trials (RCTs) investigating renoprotective drugs and reporting eGFR slopes in patients with atherosclerotic cardiovascular disease, heart failure, type 2 diabetes, or chronic kidney disease were included. In all, 25 RCTs with 179,893 participants were included. The preservation of eGFR was observed in patients with renoprotective drugs, with a comparator-adjusted total eGFR slope of 0.51mL/min per 1.73 m2/year (95% CI, 0.31 to 0.70). It was indicated that the eGFR preservation reflected by the positive comparator-adjusted total eGFR slope was associated with a reduced risk of composite renal outcome (β=-0.097,95% CI, -0.178 to -0.016, p=0.022), but was not associated with the risks of major adverse cardiovascular events (MACE) or all-cause mortality. In patients with SGLT2i, MRA, or RAASi treatments, the placebo-adjusted acute eGFR slope was -0.59mL/min per 1.73 m2 per week (95% CI, -0.74 to -0.43), which was marginally associated with a reduced risk of composite renal outcome (β=0.290,95% CI, 0.000 to 0.581, p=0.050), but was not associated with the risks of MACE or all-cause mortality. The eGFR preservation reflected by the positive comparator-adjusted total eGFR slope was associated with a reduced risk of composite renal outcome in patients receiving renoprotective agents. Greater acute decline in eGFR during the initiation of the treatment might confer a trend of fewer renal events in patients receiving SGLT2i, MRA, or RAASi.

O80 A HIGH 24-HOUR URINE SODIUM-TO-POTASSIUM RATIO IS ASSOCIATED WITH WORSE RENAL OUTCOME

Background and Objective: 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 and. 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. Methods: We selected adult outpatients of a Dutch tertiary hospital who collected at least one 24-hour urine collection 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, 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/1.73m2. 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. The median annual eGFR decline was 1.51 (IQR=0.49-3.98) ml/min/1.73m2. Every unit increase in 24-hour urine Na/K-ratio was associated with a 19% higher risk for RRT (HR 1.19, 95% CI 1.03-1.39; p=0.02) and an additional 0.44 ml/min/1.73m2 (95% CI -0.83, -0.04; p=0.03) annual eGFR decline. Conclusions: 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 with available 24-hour urine measurements.

Safety and Efficacy of a Preemptive Mycophenolate Mofetil Dose Reduction Strategy in Kidney Transplant Recipients.

There are no high-quality data to guide long-term mycophenolate mofetil (MMF) dosing in kidney transplant recipients (KTRs) to balance the long-term risks of allograft rejection with that of infections and malignancy. At our center, KTRs are managed with either a "preemptive" dose reduction strategy, where the MMF dose is reduced after the first year before the development of adverse events, or with a "reactive" dosing strategy, where they are maintained on the same MMF dose and only reduced if they develop an adverse event. We hypothesized that a preemptive MMF dosing strategy after the first year of transplantation is associated with decreased infections without increasing alloimmune complications. We conducted a retrospective cohort study of all KTRs receiving MMF from January 1, 2015, to December 31, 2020. The primary outcome was the incidence of infections requiring hospitalization. One hundred forty-two KTRs met the inclusion criteria, of whom 44 (31%) were in the preemptive group and 98 (69%) were in the reactive group. The median follow-up was 4 y (interquartile range, 3.8-4.0). Multivariable analysis showed that a preemptive MMF dose reduction strategy was associated with a lower risk of infections requiring hospitalization (adjusted hazard ratio = 0.39; 95% confidence interval, 0.16-0.92). There was no difference in graft loss, rejection, or estimated glomerular filtration rate slope. Preemptive MMF dose reduction in KTRs may be an effective strategy to prevent infections without increasing the risk of allograft rejection. Randomized clinical trials are needed to confirm these findings.

A randomized, open-label, clinical trial examined the effects of canagliflozin on albuminuria and eGFR decline using an individual pre-intervention eGFR slope

Demonstrating drug efficacy in slowing kidney disease progression requires large clinical trials when targeting participants with an early stage of chronic kidney disease (CKD). In this randomized, parallel-group, open-labeled trial (CANPIONE study), we assessed the effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin using the individual’s change in estimated glomerular filtration rate (eGFR) slope before (pre-intervention slope) and during treatment (chronic slope).We randomly assigned (1:1) participants with type 2 diabetes, urinary albumin-to-creatinine ratio (UACR) of 50 to under 300 mg/g, and an eGFR of at least 45 ml/min/1.73m2 to receive canagliflozin or guideline-recommended treatment except for SGLT2inhibitors (control). The first and second primary outcomes were the geometric mean percentage change from baseline in UACR and the change in eGFR slope, respectively. Of 98 randomized participants, 96 received at least one study treatment. The least-squares mean change from baseline in log-transformed geometric mean UACR was significantly greater in the canagliflozin group than the control group (between group-difference, −30.8% (95% confidence interval −42.6 to −16.8). The between-group difference (canagliflozin group – control group) of change in eGFR slope (chronic – pre-intervention) was 4.4 (1.6 to 7.3) ml/min/1.73 m2 per year, which was more pronounced in participants with faster eGFR decline. In summary, canagliflozin reduced albuminuria and the participant-specific natural course of eGFR decline in participants with type 2 diabetes and microalbuminuria. Thus, the CANPIONE study suggest that the within-individual change in eGFR slope may be a novel approach to determine the kidney protective potential of new therapies in early stages of CKD.

The impact of VEGF signalling pathway inhibitors and/or immune checkpoint inhibitors on kidney function over time: a single centre retrospective analysis

BackgroundDrugs targeting angiogenesis and immunotherapy have transformed outcomes in renal cancer but may contribute to progressive kidney disease.MethodsWe linked healthcare databases in the West of Scotland (spanning 2010–2020) to identify adults with renal cancer who received one or both classes of drugs. Over two years following initiation, estimated glomerular filtration rate (eGFR) slope was modelled using linear mixed-effects models. Additional renal outcomes used competing risk regression considering the competing risk of death.ResultsAmongst 357 adults (62.5% male; median age 63.0 years, IQI 55.0–71.0), there was no significant change in eGFR (annual eGFR change +1.03 mL/min/1.73 m²/year, 95%CI −1.64 to +3.70), nor in subgroups of patients who had nephrectomy, metastatic cancer or an eGFR < 60 mL/min/1.73 m² prior to systemic therapy. A ≥ 40% decline in eGFR occurred in 82 people (23.0%) within one year of starting systemic therapy and was associated with pre-existing diabetes (subhazard ratio 1.89, 95%CI 1.05–3.41).DiscussionAnti-angiogenic and immune therapy had no substantial impact on the average change in eGFR but 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.

Estimated glomerular filtration rate slope and risk of primary and secondary major adverse cardiovascular events and heart failure hospitalization in people with type 2 diabetes: An analysis of the EXSCEL trial.

The decline in estimated glomerular filtration rate (eGFR), a significant predictor of cardiovascular disease (CVD), occurs heterogeneously in people with diabetes because of various risk factors. We investigated the role of eGFR decline in predicting CVD events in people with type 2 diabetes in both primary and secondary CVD prevention settings. Bayesian joint modelling of repeated measures of eGFR and time to CVD event was applied to the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial to examine the association between the eGFR slope and the incidence of major adverse CV event/hospitalization for heart failure (MACE/hHF) (non-fatal myocardial infarction, non-fatal stroke, CV death, or hospitalization for heart failure). The analysis was adjusted for age, sex, smoking, systolic blood pressure, baseline eGFR, antihypertensive and lipid-lowering medication, diabetes duration, atrial fibrillation, high-density cholesterol, total cholesterol, HbA1c and treatment allocation (once-weekly exenatide or placebo). Data from 11 101 trial participants with (n = 7942) and without (n = 3159) previous history of CVD were analysed. The mean ± SD eGFR slope per year in participants without and with previous CVD was -0.68 ± 1.67 and -1.03 ± 2.13 mL/min/1.73 m2, respectively. The 5-year MACE/hHF incidences were 7.5% (95% CI 6.2, 8.8) and 20% (95% CI 19, 22), respectively. The 1-SD decrease in the eGFR slope was associated with increased MACE/hHF risks of 48% (HR 1.48, 95% CI 1.12, 1.98, p = 0.007) and 33% (HR 1.33, 95% CI 1.18,1.51, p < 0.001) in participants without and with previous CVD, respectively. eGFR trajectories over time significantly predict incident MACE/hHF events in people with type 2 diabetes with and without existing CVD, with a higher hazard ratio for MACE/hHF in the latter group.

Multiomic profiling of new-onset kidney function decline: insights from the STANISLAS study cohort with a 20-year follow-up.

Identifying the biomarkers associated with new-onset glomerular filtration rate (GFR) decrease in an initially healthy population could offer a better understanding of kidney function decline and help improving patient management. Here we described the proteomic and transcriptomic footprints associated with new-onset kidney function decline in an initially healthy and well-characterized population with a 20-year follow-up. This study was based on 1087 individuals from the familial longitudinal Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux (STANISLAS) cohort who attended both visit 1 (from 1993 to 1995) and visit 4 (from 2011 to 2016). New-onset kidney function decline was approached both in quantitative (GFR slope for each individual) and qualitative (defined as a decrease in GFR of >15ml/min/1.7m2) ways. We analysed associations of 445 proteins measured both at visit 1 and visit 4 using Olink Proseek® panels and 119 765 genes expressions measured at visit 4 with GFR decline. Associations were assessed using multivariable models. The Bonferroni correction was applied. We found several proteins (including PLC, placental growth factor (PGF), members of the tumour necrosis factor receptor superfamily), genes (including CCL18, SESN3), and a newly discovered miRNA-mRNA pair (MIR1205-DNAJC6) to be independently associated with new-onset kidney function decline. Complex network analysis highlighted both extracellular matrix and cardiovascular remodelling (since visit 1) as well as inflammation (at visit 4) as key features of early GFR decrease. These findings lay the foundation to further assess whether the proteins and genes herein identified may represent potential biomarkers or therapeutic targets to prevent renal function impairment.

Guidelines for clinical evaluation of chronic kidney disease in early stages

BackgroundFor the development of pharmaceutical products in kidney field, appropriate surrogate endpoints which can predict long-term prognosis are needed as an alternative to hard endpoints, such as end-stage kidney disease. Though international workshop has proposed estimated glomerular filtration rate (GFR) slope reduction of 0.5–1.0 mL/min/1.73 m /year and 30% decrease in albuminuria/proteinuria as surrogate endpoints in early and advanced chronic kidney disease (CKD), it was not clear whether these are applicable to Japanese patients.MethodsWe analyzed J-CKD-DB and CKD-JAC, Japanese databases/cohorts of CKD patients, and J-DREAMS, a Japanese database of patients with diabetes mellitus to investigate the applicability of eGFR slope and albuminuria/proteinuria to the Japanese population. Systematic review on those endpoints was also conducted including the results of clinical trials published after the above proposal.ResultsOur analysis showed an association between eGFR slope and the risk of end-stage kidney disease. A 30% decrease in albuminuria/proteinuria over 2 years corresponded to a 20% decrease in the risk of end-stage kidney disease patients with baseline UACR ≥ 30 mg/gCre or UPCR ≥ 0.15 g/gCre in the analysis of CKD-JAC, though this analysis was not performed on the other database/cohort. Those results suggested similar trends to those of the systematic review.ConclusionThe results suggested that eGFR slope and decreased albuminuria/proteinuria may be used as a surrogate endpoint in clinical trials for early CKD (including diabetic kidney disease) in Japanese population, though its validity and cutoff values must be carefully considered based on the latest evidence and other factors.

Clinical trial designs to assess treatment effects on glomerular filtration rate decline

Glomerular filtration rate (GFR) decline is used as surrogate endpoint for kidney failure. Interventions that reduce chronic kidney disease (CKD) progression often exert acute GFR reductions which differ from their long-term benefits and complicate the estimation of long-term benefit. Here, we assessed the utility of two alternative trial designs (wash-out design and active run-in randomized withdrawal design) that attempt to exclude the impact of acute effects. Post-hoc analyses of two clinical trials that characterized the effect of an intervention with acute reductions in GFR were conducted. The two trials included a wash-out period (EMPAREG-Outcome testing empagliflozin vs placebo) or an active run-in period with a randomized withdrawal (SONAR testing atrasentan vs placebo). We compared the drug effect on GFR decline calculated from the first on-treatment visit to the end-of-treatment (chronic effect in a standard randomized trial design) with GFR change calculated from randomization to end-of-wash-out, or GFR change from treatment specific baseline GFR values (GFR at start-of-run-in for placebo and end-of-run-in for atrasentan) until end-of-treatment. The effect of empagliflozin versus placebo on chronic GFR slope was 1.72 (95% confidence interval 1.49-1.94) mL/min/1.73m2 /year, similar to total GFR decline from baseline to the end of wash-out period using a linear mixed model 1.64 (1.44-1.85) mL/min/1.73m2 /year). The effect of atrasentan versus placebo on chronic GFR slope was 0.72 (0.32-1.11) mL/min/1.73m2 /year, similar to total slope from a single slope model when estimated from treatment specific baseline GFR values 0.77 (0.39-1.14) mL/min/1.73m2 /year). Statistical power of the two designs outperformed the standard randomized design. Thus, wash-out and active-run-in randomized-withdrawal trial designs are appropriate models to compute treatment effects on GFR decline.

Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial

People with type 2 diabetes and chronic kidney disease have a high risk for kidney failure and cardiovascular (CV) complications. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors (SGLT2i) independently reduce CV and kidney events. The effect of combining both is unclear. FLOW trial participants with type 2 diabetes and chronic kidney disease were stratified by baseline SGLT2i use (N = 550) or no use (N = 2,983) and randomized to semaglutide/placebo. The primary outcome was a composite of kidney failure, ≥50% estimated glomerular filtration rate reduction, kidney death or CV death. The risk of the primary outcome was 24% lower in all participants treated with semaglutide versus placebo (95% confidence interval: 34%, 12%). The primary outcome occurred in 41/277 (semaglutide) versus 38/273 (placebo) participants on SGLT2i at baseline (hazard ratio 1.07; 95% confidence interval: 0.69, 1.67; P = 0.755) and in 290/1,490 versus 372/1,493 participants not taking SGLT2i at baseline (hazard ratio 0.73; 0.63, 0.85; P < 0.001; P interaction 0.109). Three confirmatory secondary outcomes were predefined. Treatment differences favoring semaglutide for total estimated glomerular filtration rate slope (ml min−1/1.73 m2/year) were 0.75 (−0.01, 1.5) in the SGLT2i subgroup and 1.25 (0.91, 1.58) in the non-SGLT2i subgroup, P interaction 0.237. Semaglutide benefits on major CV events and all-cause death were similar regardless of SGLT2i use (P interaction 0.741 and 0.901, respectively). The benefits of semaglutide in reducing kidney outcomes were consistent in participants with/without baseline SGLT2i use; power was limited to detect smaller but clinically relevant effects. ClinicalTrials.gov identifier: NCT03819153.

A meta-analysis of randomized controlled clinical trials for implications of acute treatment effects on glomerular filtration rate for long-term kidney protection

Pharmacologic interventions to slow chronic kidney disease progression, such as ACE-inhibitors, angiotensin receptor blockers, or sodium glucose co-transporter 2 inhibitors, often produce acute treatment effects on glomerular filtration rate (GFR) that differ from their long-term chronic treatment effects. Observational studies assessing the implications of acute effects cannot distinguish acute effects from GFR changes unrelated to the treatment. Here, we performed meta-regression analysis of multiple trials to isolate acute effects to determine their long-term implications. In 64 randomized controlled trials (RCTs), enrolling 154,045 participants, we estimated acute effects as the mean between-group difference in GFR slope from baseline to three months, effects on chronic GFR slope (starting at three months after randomization), and effects on three composite kidney endpoints defined by kidney failure (GFR 15 ml/min/1.73m2 or less, chronic dialysis, or kidney transplantation) or sustained GFR declines of 30%, 40% or 57% decline, respectively. We used Bayesian meta-regression to relate acute effects with treatment effects on chronic slope and the composite kidney endpoints. Overall, acute effects were not associated with treatment effects on chronic slope. Acute effects were associated with the treatment effects on composite kidney outcomes such that larger negative acute effects were associated with lesser beneficial effects on the composite kidney endpoints. Associations were stronger when the kidney composite endpoints were defined by smaller thresholds of GFR decline (30% or 40%). Results were similar in a subgroup of interventions with supposedly hemodynamic effects that acutely reduce GFR. For studies with GFR 60 mL/min/1.73m2 or under, negative acute effects were associated with larger beneficial effects on chronic GFR slope. Thus, our data from a large and diverse set of RCTs suggests that acute effects of interventions may influence the treatment effect on clinical kidney outcomes.

Dapagliflozin treatment in patients with chronic kidney disease associated with autosomal dominant polycystic kidney disease.

The DAPA-CKD study showed a protective effect of dapagliflozin on kidney function in chronic kidney disease (CKD) patients with and without diabetes mellitus. Although dapagliflozin is expected to be effective also in CKD patients with autosomal dominant polycystic kidney disease (ADPKD), its efficacy and safety in this population remain unknown because ADPKD was an exclusion criterion in the DAPA-CKD study. Therefore, we evaluated the effects of dapagliflozin in CKD patients with ADPKD. We performed a retrospective observational study of seven patients with ADPKD treated with dapagliflozin at Toranomon Hospital, Tokyo, Japan. We analyzed changes in estimated glomerular filtration rate (eGFR) slope and annual height-corrected total kidney volume before and after starting dapagliflozin treatment. The median observation period after starting dapagliflozin was 20 months. Four patients received concomitant tolvaptan. The eGFR slope before and after initiation of dapagliflozin could be calculated in six patients and improved in all of them except the one who did not receive a renin-angiotensin system (RAS) inhibitor. Annual height-corrected total kidney volume increased in all patients. Concurrent tolvaptan treatment had no effect. In CKD patients with ADPKD, dapagliflozin may increase kidney volume but may have a protective effect on kidney function when used concomitantly with RAS inhibitors.

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&amp;lt; 0.001 for the group and factor B = 0.801 and p-value&amp;lt; 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&amp;lt; 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.

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.