eGFR Decline Research Articles

#3029 Vitamin D-binding protein: a candidate biomarker for CKD progression

Abstract Background and Aims The toxic effects of filtered proteins on the tubules cause a more rapid progression of disease in individuals with higher levels of proteinuria, suggesting the presence of “high-risk candidate” proteins that could contribute to CKD progression. In our previous cross-sectional proteomic study, vitamin D-binding protein (VTDB) showed a significant association with kidney function. However, its persistent expression as a urinary protein in CKD patients remains unknown. Therefore, our aim was to investigate the persistent expression of VTDB in CKD patients and healthy controls during the follow-up period. Method The urinary proteomics was investigated using liquid chromatography-mass spectrometry in 18 follow-up CKD patients with stages 1-3 and 15 follow-up healthy individuals. Data analysis was performed by Mascot-SwissProt and STATA software. Parametric and nonparametric statistics were used to analyze results and the relationship between baseline characteristics and proteomic profile. Exponentially Modified Protein Abundance Index (emPAI) was used to estimate peptide count of proteins. Results The participant's baseline characteristics are presented in Table 1. The median (IQR) follow-up time for all participants was 368 (250-472) days. A statistically significant difference was found in the initial emPAI of VTDB between the HC and CKD groups. However, there was no statistically significant difference in the follow-up emPAI of VTDB between the two groups. Notably, emPAI values of VTDP decreased over the follow-up period compared to the initial values. Correlation analysis (Table 2) showed that the elevated levels of urinary VTDB emPAI are associated with decreased levels of initial and follow-up eGFR. A higher negative percentage change (a decline in eGFR over time) was also associated with elevated levels of VTDB protein over the follow-up period. Also, urinary VTDP protein has demonstrated a significant positive correlation with 24 h proteinuria. Conclusion In this proteomics study cohort, we observed persistent expression of urinary VTDB protein during the follow-up period in CKD patients compared to healthy controls. Additionally, a statistically significant negative correlation between VTDB protein and eGFR was observed. These findings need further validation using different measurement tools for urinary VTDB assessments and in a larger cohort of CKD patients. Declaration We have no conflict of interest to disclose.

Hypertension and Kidney Function After Living Kidney Donation

Recent guidelines call for better evidence on health outcomes after living kidney donation. To determine the risk of hypertension in normotensive adults who donated a kidney compared with nondonors of similar baseline health. Their rates of estimated glomerular filtration rate (eGFR) decline and risk of albuminuria were also compared. Prospective cohort study of 924 standard-criteria living kidney donors enrolled before surgery and a concurrent sample of 396 nondonors. Recruitment occurred from 2004 to 2014 from 17 transplant centers (12 in Canada and 5 in Australia); follow-up occurred until November 2021. Donors and nondonors had the same annual schedule of follow-up assessments. Inverse probability of treatment weighting on a propensity score was used to balance donors and nondonors on baseline characteristics. Living kidney donation. Hypertension (systolic blood pressure [SBP] ≥140 mm Hg, diastolic blood pressure [DBP] ≥90 mm Hg, or antihypertensive medication), annualized change in eGFR (starting 12 months after donation/simulated donation date in nondonors), and albuminuria (albumin to creatinine ratio ≥3 mg/mmol [≥30 mg/g]). Among the 924 donors, 66% were female; they had a mean age of 47 years and a mean eGFR of 100 mL/min/1.73 m2. Donors were more likely than nondonors to have a family history of kidney failure (464/922 [50%] vs 89/394 [23%], respectively). After statistical weighting, the sample of nondonors increased to 928 and baseline characteristics were similar between the 2 groups. During a median follow-up of 7.3 years (IQR, 6.0-9.0), in weighted analysis, hypertension occurred in 161 of 924 donors (17%) and 158 of 928 nondonors (17%) (weighted hazard ratio, 1.11 [95% CI, 0.75-1.66]). The longitudinal change in mean blood pressure was similar in donors and nondonors. After the initial drop in donors' eGFR after nephrectomy (mean, 32 mL/min/1.73 m2), donors had a 1.4-mL/min/1.73 m2 (95% CI, 1.2-1.5) per year lesser decline in eGFR than nondonors. However, more donors than nondonors had an eGFR between 30 and 60 mL/min/1.73 m2 at least once in follow-up (438/924 [47%] vs 49/928 [5%]). Albuminuria occurred in 132 of 905 donors (15%) and 95 of 904 nondonors (11%) (weighted hazard ratio, 1.46 [95% CI, 0.97-2.21]); the weighted between-group difference in the albumin to creatinine ratio was 1.02 (95% CI, 0.88-1.19). In this cohort study of living kidney donors and nondonors with the same follow-up schedule, the risks of hypertension and albuminuria were not significantly different. After the initial drop in eGFR from nephrectomy, donors had a slower mean rate of eGFR decline than nondonors but were more likely to have an eGFR between 30 and 60 mL/min/1.73 m2 at least once in follow-up. ClinicalTrials.gov Identifier: NCT00936078.

#1392 MEST-C score correlation with proteinuria reduction after SGLT2i treatment in patients with IgA nephropathy

Abstract Background and Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with better cardiovascular outcomes and with nephroprotection independent of diabetes status. Recent data suggest that SGLT2i significantly reduce proteinuria in patients with IgA nephropathy (IgAN). Data available for the use of the MEST-C score to determine if treatment would benefit IgAN patients is scarce. The aim of our study was to assess the degree of proteinuria reduction after SGLT2i treatment in IgAN and its possible association with the MEST-C score. Method 63 adult patients with biopsy-proven IgA nephropathy, eGFR ≥ 30 mL/min/1.73 m2 (CKD-epi), and total urine protein of >0.5 grams/day at screening were included. Patients with secondary IgAN and crescents were excluded. All receiving maximally tolerated RASi for at least 12 weeks. All patients started dapagliflozin 10 mg once per day after baseline data were registered. The total follow-up was 12 months. The main outcome was the decline in eGFR and the reduction in 24-hour proteinuria from SGLT2i initiation to 1,3, 6, 9, 12 months, end-stage renal disease, or kidney or cardiovascular death. Three repeated measurements of proteinuria (mg/24H) were performed, 90 days before SGLT2i treatment initiation, and only patients with stable proteinuria were enrolled in the study. Results 49 patients (35/14 M/F), with mean age of 41,9 ± 19,6 years, completed follow up. 8 patients discontinued treatment due to adverse events attributed to dapagliflozin. At baseline eGFR was 68.21±18,1 ml/min/1.73 m2 and Upr: 2196±1091 mg/24H. The MEST-C scores were correlated with the serum creatinine level, proteinuria, and hematuria. The mean serum creatinine level was higher in M1, E1, S1, and T1 compared with score “0”. It was statistically significant (p = 0.03) only in the T-score. The mean proteinuria level was again higher in M1, S1, and T1 but reached statistical significance (p = 0.037) in only the T1-score. E1 has higher hematuria. The Upr/24H difference for dapagliflozin was −24.7% (95% CI −27.5, −23.2; p < 0.001) at the end of follow-up (month 12). Proteinuria reduction was similar across all eGFRs, age, and baseline proteinuria. Among MEST-C score parameters, T1 had a negative impact on the antiproteinuric effect of dapagliflozin (p = 0.01) No hypoglycemic events were reported and no deaths occurred. Conclusion In the present study, the use of SGLT2i was associated with a significant reduction of proteinuria in patients with IgA nephropathy and maximally tolerated RASi. We analyzed renal outcomes in association with pathologic features. We established that the presence of the T1 score has a negative impact on proteinuria reduction after SGLT2i treatment. Further studies are needed to investigate the impact of the use of the Oxford Classification score for developing individual treatment therapies.

#755 Endotrophin as an early marker of kidney outcomes in persons with type 2 diabetes: findings from the PROVALID study

Abstract Background and Aims Diabetic kidney disease (DKD) is driven by a set of pathophysiological processes, including fibrosis. Endotrophin (ETP), a pro-fibrotic fragment generated during collagen type VI formation, has previously been shown to be a biomarker of DKD progression. The aim of this study was to investigate, for the first time, circulating ETP as a risk marker for kidney outcomes in persons with type 2 diabetes (T2D) being taken care of at the primary level of healthcare. Method Levels of ETP were measured using the nordicPRO-C6TM ELISA in plasma at baseline from 3226 persons with T2D enrolled in the Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers (PROVALID). Outcomes included a composite kidney endpoint defined as a sustained 40% decline in estimated glomerular filtration rate (eGFR) < an eGFR of 60 ml/min/173 m2, sustained 30% increase in albuminuria including a transition in albuminuria stage, or kidney failure with replacement therapy or kidney death. A decline in eGFR and an increase in albuminuria were considered sustained if they persisted over at least two consecutive measurements. Crude and adjusted Cox proportional hazards regression models were applied to investigate the potential of ETP as a risk marker of the kidney endpoint. Levels of ETP were log-transformed before analysis. The Kaplan–Meier estimator was used to compare the risks of experiencing the kidney endpoint according to ETP levels split by the median in persons with baseline eGFR > 90 ml/min/1.73 m2 (n = 976). Results The cohort consisted of 57% males; median age was 64 (58-70) years, and mean eGFR was 79 ± 24 ml/min/1.73 m2. Median follow-up was 3.9 years. Higher levels of ETP were associated with a higher risk of developing the kidney endpoint, with a hazard ratio (HR) of 1.63 (p = 0.0012; n = 293/3226). After adjustment for the refined variables: age, diabetes duration, HbA1c, atherosclerotic cardiovascular disease, blood pressure, duration of hypertension, BMI, LDL-cholesterol, HDL-cholesterol, and eGFR, the HR was 1.55 (p = 0.012). In persons with an eGFR > 90 ml/min/1.73 m2, higher ETP was also associated with an increased risk of developing the kidney endpoint (p = 0.03; n = 69/976). Conclusion Plasma ETP was an independent risk marker for kidney outcomes in persons with T2D with early kidney disease. Higher levels of plasma ETP were associated with a significantly increased risk of developing the kidney endpoint in persons with eGFR > 90 ml/min/1.73 m2. These findings demonstrate that biomarkers of fibrosis, such as ETP, may serve as early markers for kidney disease progression or kidney failure in persons with T2D and apparently normal kidney function.

#2338 Potassium-competitive acid blocker use is associated with a lower risk of renal function deterioration compared to proton pump inhibitor use

Abstract Background and Aims Proton pump inhibitors (PPI) are commonly used drugs worldwide and have been linked to worsening renal function and incident chronic kidney disease. Recently, potassium-competitive acid blockers (P-CAB) have emerged as alternative gastric acid-reducing agents with a comparable effect as PPIs. However, little is known about the renal safety of P-CAB. We aimed to compare the renal outcomes of patients treated with P-CAB and those treated with PPI. Method We retrospectively identified all patients who were prescribed P-CAB (tegoprazan) or PPI (esomeprazole) for 30 days or more in outpatient clinics of a tertiary care center between 2019 and 2023. Longitudinal serum creatinine data and various demographic and clinical variables were collected. Renal outcomes were defined as creatinine doubling or decline in estimated glomerular filtration rate (eGFR) of 30%. Patients with baseline eGFR < 15 mL/min/1.73 m2 and those who do not have sufficient creatinine measures to assess renal outcomes were excluded. Cox proportional hazard analyses were performed for renal outcomes with adjustment of multiple clinical covariates. Results Among 8 436 patients with a mean followup of 21 months, 2 214 and 6 222 patients were treated with P-CAB and PPI, respectively, for esophageal and gastric diseases. P-CAB group showed lower rates of creatinine doubling (Log-rank P = 0.001) and decline of eGFR (Log-rank P = 0.001) compared to PPI group. P-CAB use was associated with a 0.50-fold (95% confidence interval [CI] 0.33–0.75) lower risk for creatinine doubling and 0.58-fold (95% CI 0.42–0.81) lower risk for eGFR decline in unadjusted analysis. After adjusting multiple covariates including baseline eGFR, prescription days, major comorbidities, and concomitant use of other medications, hazard ratios for creatinine doubling and eGFR decline were 0.64 (95% CI 0.42–0.98) and 0.73 (95% CI 0.53–1.02), respectively. Conclusion Use of P-CAB is associated with a lower risk for renal function deterioration compared to PPI. Given the renal safety concerns of PPIs, using P-CAB could be a relatively safer strategy for preserving kidney function in patients who need long-term gastric acid suppression. Further studies with a larger cohort incorporating other P-CABs are required to validate this finding.

#1486 Looking for a new role of known players: the additional value of plasmatic C3 and C4 in predicting IgA Nephropathy prognosis, an observational study

Abstract Background and Aims IgA Nephropathy (IgAN) is the most common glomerular disease worldwide [1]. Complement system activation through the alternative and lectin pathways is crucial in its pathogenesis and leads to worse outcome, eliciting the need for (new) biomarkers to assess risk of disease progression and potential response to new targeted treatments [2, 3]. Only few works have correlated serum C3 and C4 with disease activity and prognosis [4, 5]. Our work explores the potential advantages of incorporating serum C3 and C4 levels into a standardized prognostic model to assess kidney outcome in IgAN. Method This retrospective study, conducted at Sant'Orsola University Hospital in Bologna, investigated the prognostic value of serum complement C3 and C4 in patients with IgAN. The primary outcome was defined as a 40% decline in eGFR or the onset of kidney failure. The study aimed to evaluate whether the addition of serum C3 and C4 to an established predictive model, incorporating variables from the International IgA Prediction Tool (IntIgAPT), enhances the accuracy of outcome prediction. We computed the measures of goodness of fit for each model: Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC), Nagelkerke R2 test (NR2) that depicts the% explained variation of the outcome based on the set of variables included, and Likelihood Ratio Test (LRT); discrimination with the c-index. Furthermore, we aimed to evaluate the characteristics of patients stratified by baseline serum C3 levels (Low <90 mg/dl, Medium 90-140 mg/dl, High >140 mg/dl). Results 101 patients were included in the cohort. 90% were Caucasian and 65.3% were male with a mean age of 42.6 years. As reported in Table 1, mean eGFR and median proteinuria levels at baseline were 70.4 ml/min/1.73 m² and 1.04 g/24 h respectively. Mean serum C3 was 114.9 mg/dL. The Low group had lower values of eGFR at baseline (47.0 vs 75.67 and 68.64 ml/min/1.73 m², p = 0.015), while the Medium group had lower values of uProt (0.75 vs 1.81 and 1.46 g/24 h, p = 0.004). During a median 54.28 months follow-up, the Low group exhibited significantly higher primary outcome incidence (16.3 events vs 2.9 and 1.7 events x 100 pts/year, p = 0.003). We computed a first model (M1) based upon IntIgAPT variables and then a second model (M2) as the same of M1 plus serum C3 and C4 at baseline (Table 2). C3 showed a negative association with outcome (OR 0.88, CI 0.78 to 0.99, p = 0.05) whereas C4 had a positive one (OR 1.21, CI 1.02 to 1.48, p = 0.05). M2 had an improved prediction accuracy than M1, as evidenced by lower AIC (49.1 vs 53.8), higher c-index (0.74 vs 0.65), and NR2 (0.76 vs 0.65). Likelihood ratio test was significant between the two (p = 0.008). Conclusion The inclusion of serum C3 and C4 in a validated prognostic model enhances prediction accuracy and improves the percentage of events explained, highlighting complement's inherent informativeness. In our population lower C3 and higher C4 levels were associated with poorer prognosis in IgAN, characterizing a more ‘Complement-Pathic’ subset of patients. This result expands the current evidence, for the first time to our knowledge, in a Caucasian-prevalent study population.

#1405 Salt sensitivity and hypertensive nephropathy: a link to be discovered

Abstract Background and Aims Sodium sensitivity (SS) is a change in blood pressure (BP) depending on Na+ intake, 30% of population has it. Either a salt load test or a sodium dietary protocol can be used to stratify the population into 3 groups based on BP variation: sodium sensitive (SS), sodium resistant (SR), inverse sodium sensitivity (ISS), based on an increase, a non-significant variation or a decrease in BP following the administration of Na+. SNPs located in genes related with Na+ metabolism, aldosterone synthesis and kidney tubular Na+ reabsorption are related to this phenotype. Method We analyzed data collected from the follow-up (FUP) of 127 subjects with a new diagnosis of hypertension, categorized by their profile through acute salt load test. We analyzed the kidney damage by annual decline of eGFR and development of microalbuminuria. Genetic polymorphism analysis has been executed. Results No differences in the decline of eGFR are observed among the groups (−1.3084 ml/min ± 0.16 p-Value 0.372). SR subjects seem to be more prone to develop earlier microalbuminuria (χ 2 10.682, p = 0.005) even with an adequate BP control (P-Anova SBP 0.766; P-Anova DBP 0.856). An inverse correlation exists between pressure-natriuresis ratio and decline in eGFR (R −0.194 p = 0.016). Polymorphism in CYP11B2 (0.72 OR p = 0.045) and NEDD4L (0.74 OR p = 0.027) are protective against eGFR decline. ADD3 polymorphism (3.73 OR p = 0.049) is a risk factor for development of microalbuminuria. KL (0.15 OR p = 0.034), PKD and TRPC6 (p-Value 0.037, p-Value 0.009) polymorphism are protective factor against microalbuminuria. Conclusion SR patients are more at risk of developing hypertensive nephropathy earlier than other groups; steeper pressure natriuresis ratio is involved in quicker decline in renal function possibly accelerating development of hypertensive nephropathy. Further studies with larger sample and standardization in salt sensitivity test are needed to translate this knowledges into clinical setting.

#1707 Antiphospholipid antibodies in lupus nephritis

Abstract Background and Aims Antiphospholipid antibodies (aPL) constitute a heterogeneous family of antibodies against anionic phospholipids or phospholipid-binding proteins. They may occur in association with autoimmune diseases, infections, and sometimes in the general population. Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE). The aim of this study was to investigate the association of aPL with clinical activity, renal damage, renal activity and outcomes in patients with LN. Method A total of 157 patients (11 male, 146 female, age between 17 and 58 years) with LN were included in this study. The International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of LN was used to classify the patients into LN subsets. Histopathological renal activity and damage were estimated using the Activity Index (AI) and Chronicity Index (CI), respectively. Levels of anticardiolipin (aCL) antibodies, anti-β2-glycoprotein I (anti-β2-GPI) antibodies and lupus anticoagulant (LAC) were measured, and other clinical and pathological data were also obtained. Long-term renal outcome was determined by the estimated glomerular filtration rate (eGFR) and the Chronic Kidney Disease stage, after a median follow-up of 20,5 ± 8, 7 years, counting from the occasion of the first renal biopsy. Renal and extra-renal symptoms were analyzed. Patients which have more than one class LN features, were excluded from the study. The treatment includes standard treatment for LN, inhibitors of the angiotensin system in patients with hypertension and proteinuria, steroids, anticoagulants, cyclophosphamide, mycophenolate mofetil, azathioprine. Results LN patients were classified according to the baseline renal biopsies as patients with: minimal mesangial LN (4), mesangial-proliferative LN (30), focal proliferative LN (31), diffuse proliferative LN (48), membranous LN (44). aPL antibodies were detected in 89 (56,69%) patients, aCL antibodies – in 72 (45,86%), anti-β2-GPI antibodies – in 58 (36,94%) and LAC were detected in 46 (29,30%) patients. None of these patients had a concomitant diagnosis of antiphospholipid syndrome nephropathy. Follow-up was similar between aPL-positive and aPL-negative patients. LN patients with positive aPL antibodies had significantly higher SLEDAI (p < 0,05), anti-dsDNA levels (p < 0,05), anti-ribosomal-P antibodies levels (p < 0,05), anti-C1q antibodies (p < 0,05), lower serum C3 (p < 0,005) and C4 (p < 0,05) levels, and higher intensity of complement C3 (p < 0,05) deposits in kidney tissue than the aCL antibody–negative LN patients. aPL-seropositivity was associated with more rapid decline in eGFR (–1,06 mL/min/year compared to –0,45 mL/min/year in aPL-seronegative patients) and showed inferior patient survival (89,8% and 67,9% at 10 and 15 years, respectively, compared to 97,3% and 76% in aPL-seronegative patients). No significant correlation was found between serum aPL antibodies levels and activity or chronicity index scores in renal biopsies at baseline, ANA levels, or age. Conclusion We concluded that aPL-seropositivity are correlated with clinical activity in patients with LN and are associated with inferior long-term patient survival.

#1720 Insights from sodium-glucose transport 2 (SGLT2) inhibitors treatment in patients with systemic lupus erythematosus

Abstract Background and Aims Kidney involvement is common among patients with systemic lupus erythematosus (SLE) and it is an important cause of morbidity and mortality among this population. Recently, the EULAR 2023 update of the recommendations for the management of SLE advised considering the use of sodium-glucose transport 2 inhibitors (SGLT2i) as kidney protective agents in patients with chronic kidney disease with reduced glomerular filtration rate (GFR). Aims: To assess clinical characteristics and outcomes of Israeli patients with SLE treated with SLGT2i. Method This retrospective study, conducted between 2014–2023, included adult patients with SLE diagnosed for at least 12 months. Patients receiving SGLT2i for a duration of three months or longer were compared with a control group consisting of patients who were not treated with these agents. Associated variables were assessed including disease-related characteristics, kidney-related factors, and comorbidities such as diabetes and heart failure. Clinical outcomes including severe infections, hospitalizations, and all-cause mortality were recorded. Repeated measures analysis model was applied to compare the estimated GFR (eGFR) at different time points (before diagnosis, at diagnosis, and at the last follow-up), among the SGLT2i-treated patients and controls. Protein to creatinine ratio was compared before starting treatment with SGLT2i and on treatment at the last follow-up. Results A total of 165 consecutive patients were included in this analysis, with a mean follow-up from SLE diagnosis of 15.6 ± 11.8 years. Of them, 7 were treated chronically with SGLT2i and had available data. While age at SLE diagnosis was comparable between the two groups (29.8 ± 12.2 years in the SGLT2i group and 32.6 ± 14.3 years in controls, p = 0.6), SGLT2i treated patients were significantly older at last follow-up (62.1 ± 13.5 years vs. 47.3 ± 16.3 years, p = 0.019), and as a consequence, the duration of follow-up since SLE diagnosis was longer among them (26.2 ± 11 years vs. 15.3 ± 11.7 years in the controls, p = 0.04). Diabetes was diagnosed in 16 out of 165 patients (9.7%), and 5 out of 7 patients treated with SGLTi were diabetic (71.4% vs. 7.0% in controls, p < 0.01). Heart failure was diagnosed in 7.3% of the cohort, and was more prevalent among the SGLTi group (28.6% vs 6.3% in controls, p = 0.03). Only 26.6% of patients with diabetes and 16.7% of patients with heart failure were treated with SGLTi. On repeated measures analysis, eGFR decreased significantly during the study period (p = 0.043, Fig. 1). The decline in eGFR throughout the study period was comparable between the groups. Protein to creatinine ratio decreased significantly in the SGLTi-treated patients after starting treatment (1516 ± 1685 mg/g before treatment vs. 611 ± 875 mg/g after treatment, p = 0.05). The prevalence of severe infections requiring hospitalization was comparable between groups (28.6% in SGLTi vs 29.9% in controls, p = 0.9). Hospitalizations for SLE exacerbations, as well as hospitalization for cardiovascular events, were similarly comparable between groups (28.6% vs, 28.5%, p = 0.9 and 14.3% vs. 15.3%, p = 0.9; respectively). During the study period, 10 patients developed end-stage kidney disease and 11 patients died, with no significant difference between groups. Conclusion While the SGLT2i-treated patients were older and had higher rates of comorbidities such as diabetes, chronic kidney disease, and heart failure, a similar rate of kidney function decline was observed in both SGLT2i-treated patients and controls. Additionally, a comparable rate of severe infections was found in both groups of patients. This relatively small cohort could support the use of these kidney and heart protective agents in patients with SLE and kidney involvement. A special consideration should be given to patients with comorbid diabetes and heart failure.

#1052 Associations of new-onset proteinuria during hospitalization with all-cause mortality and kidney outcome

Abstract Background and Aims Proteinuria has been routinely screened in hospitalized patients at admission, but the changes in urinary protein during hospitalization is usually neglected. The epidemiology and clinical implication of new-onset proteinuria during hospitalization remains unclear. We aim to examine the associations between new-onset proteinuria during hospitalization with all-cause mortality, cardiovascular mortality, and composite kidney outcomes after discharge. Method We conducted a multicenter cohort of hospitalized adults without proteinuria at admission and with at least one repeated urinary protein test before discharge from the China Renal Data System. New-onset proteinuria was defined as a change in the urine dipstick protein test from negative to 1+ or more during hospitalization. The primary outcome was all-cause mortality after discharge. Secondary outcomes included cardiovascular mortality and composite kidney outcomes of sustained new-onset eGFR<60 ml/min/1.73 m2, >40% decline in eGFR, maintain dialysis, kidney transplant, or end stage renal disease. The associations between new-onset proteinuria and study outcomes were assessed by Cox proportional hazard models. Results Among 219,669 inpatients with mean age of 54 years, new-onset proteinuria occurred in 7.3% of the study population during hospitalization. After a mean follow-up of 4.9 years, patients with new-onset proteinuria during hospitalization was significantly associated with increased risk of all-cause mortality (hazard ratio [HR] 1.16; 95% confidence interval [CI], 1.07-1.25), cardiovascular deaths (HR 1.25; 95% CI, 1.07-1.46), and adverse kidney outcomes (HR 1.51; 95% CI, 1.14-2.01), compared to those without proteinuria. These associations were independent of the occurrence of AKI and remained consistent across subgroups and multiple sensitivity analyses, regardless of the severity and recovery status of new-onset proteinuria. Conclusion The presence of new-onset proteinuria during hospitalization demonstrated significant prognostic value and should be carefully monitored to improve patient care.

#2766 Impact of CKD screening in high-risk populations and guideline-directed therapy on CV event occurrence and costs in Europe: an IMPACT CKD analysis

Abstract Background and Aims Chronic kidney disease (CKD) is a growing health problem in Europe exacerbated by aging and the rise of comorbidities such as diabetes mellitus (DM) and hypertension (HTN). Patients with CKD are often multi-morbid and commonly present with cardiovascular (CV) complications. While CV events including myocardial infarction (MI), stroke, and hospitalization for heart failure (HHF) occur more often in patients with advanced CKD, patients with early-stage CKD are also at increased risk. Patients with CKD also experience an increased risk of CV-related mortality, with many patients dying from CV events prior to kidney failure and renal replacement therapy. CV events also present a significant burden to clinicians and healthcare systems due to the high costs and resource use required to manage and treat them. Despite this multidimensional burden, CKD is currently underdiagnosed in Europe, and CKD screening and treatment are rarely included in public health strategies to improve mortality and health outcomes. This study aims to explore the impact of targeted CKD screening followed by guideline-directed therapy in high-risk populations on CV event occurrence and associated treatment costs across Europe. Method The IMPACT CKD microsimulation model simulates CKD progression, CV events, and comorbidities. CKD status is assigned based on estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio levels (UACR), and CKD progression is predicted by an annual eGFR decline rate. The model was used to compare two scenarios in four country populations (Germany, Netherlands, Spain, United Kingdom [UK]): 1) targeted screening for people with DM and/or HTN followed by optimal compliance to guideline-directed therapy and 2) current practice (no screening, underdiagnosis, low treatment rates). Annual targeted screening assumed both eGFR and UACR testing. Treatment initiation for people diagnosed with CKD was based on Kidney Disease Improving Global Outcomes guidelines with a 90% compliance assumed to approximate maximum clinical benefit. Therapies were assumed to have a multiplicative treatment effect on eGFR decline and CV events. Current practice assumed observed diagnosis rates without screening and observed treatment rates in each country. For both scenarios, the model projected incidence of CV events and associated management costs in year 10 (2032) and cumulatively over the 10 simulated years (2023-2032). Results Results compare the targeted screening followed by guideline-directed treatment scenario to continuation of current practices for Germany, Netherlands, Spain, and UK (Table 1). The timely diagnosis of patients with CKD and effective treatment was associated with a reduction of 46.7-53.3%, 38.9-41.6%, and 42.1-50.5% in the number of MI, stroke, and HHF events, respectively in 2032 across the four countries. These decreases in the number of CV events were accompanied by proportional reductions in costs to treat the events. Additionally, this policy approach resulted in declines in the cumulative 10-year CV event development and associated healthcare costs, with MI having the largest reductions (40.6-47.2%), followed by HHF (37.4-43.0%), and stroke (29.8-36.1%) across the four countries. Conclusion This study illustrated that early identification of high-risk patients with CKD coupled with guideline-directed treatment would yield substantial clinical and economic benefits from reducing CV events across all four European countries. Fewer MI, stroke, and HHF events were projected in patients with CKD in both 2032 and cumulatively from 2023 to 2032 due to delayed disease progression following effective interventions. Driven by the reduced clinical burden, lower healthcare costs for CV event management were also predicted. These findings support the need for the adoption of policies for early diagnosis and treatment of CKD to slow disease progression and mitigate the growing CV disease burden among patients with CKD and for health systems. Future studies should explore the costs associated with targeted CKD screening and the guideline-directed pharmacological therapies for CKD.

#150 Effect of dapagliflozin in patients with CKD depending on primary kidney disease

Abstract Background and Aims Multiple trials have reported that SGLT2 inhibitors reduce the risk of its primary composite outcome of kidney disease progression or cardiovascular death in a wide range of patients with CKD. Our aim was to compare effects on kidney outcomes among the different types of kidney diseases. Method Eligible patients with eGFRs ≥30-45, or ≥45-90 ml/min/1.73 m2 with a urinary albumin-to-creatinine ratio of ≥300 mg/g, and receiving renin angiotensin system inhibitor, where indicated and tolerated were randomized to dapagliflozin 10 mg once daily vs placebo. Kidney disease progression was defined as a sustained ≥30% eGFR decline from randomization or to <10 mL/min/1.73 m2, start of maintenance dialysis or receipt of a kidney transplant, or renal death, and the effects of dapagliflozin were analyzed using a pre-specified Cox model. Testing for heterogeneity of effect between pre-specified kidney disease subgroups was performed, including exploratory analyses by specific glomerular disease etiologies. Results 362 participants were followed for a median of 2.0 years. 90 (24.8%) had diabetic kidney disease, 126 (34.8%) had glomerular disease, 94 (26%) had hypertensive or renovascular disease, and 52 (14.4%) had other or unknown causes. Overall, dapagliflozin reduced the risk of kidney disease progression by 34% (dapagliflozin 29/178 vs placebo 48/184; hazard ratio 0.62, 95% CI 0.51-0.78). This relative risk reduction appeared broadly similar in subgroup analyses by primary cause of kidney disease and by different types of glomerular disease. Conclusion Our study with a few numbers of patients with diabetic and non-diabetic causes of CKD showed that dapagliflozin reduced risk of kidney disease progression with relative risk reductions that were broadly similar across the different CKD etiologies.

#2644 Clinical impact of proteinuria and hematuria remission criteria in IgA nephropathy patients defined by the Japanese Society of Nephrology

Abstract Background and Aims IgA nephropathy (IgAN) is one of the most common glomerulonephritis worldwide, especially in the Pacific Rim and Mediterranean countries. Hematuria is almost inevitable clinical findings and massive proteinuria is well established risk factor in IgAN. However, a few studies reported hematuria and proteinuria remission in IgAN, and their definition varies in clinical studies. The Japanese Society of Nephrology (JSN) defined new criteria for hematuria and proteinuria remission and relapse for IgAN patients. The objective of the present study was to analyze the utility of JSN criteria to predict renal prognosis among IgAN patients after immunosuppressive treatment. Method One hundred IgAN patients were recruited between 2003 and 2014 at Nagoya University Hospital and followed up until December 2017. According to JSN criteria, hematuria remission (HR) and proteinuria remission (PR) are defined as < 5 RBC/HPF, and < 0.3 g/g Cr, in three consecutive urine exams over six months of observation, respectively. Clinical remission (CR) is defined as both HR and PR in 3 consecutive urinalysis over six months. HR, PR and CR were analysed with 30% eGFR decline as a renal outcome. Results Baseline proteinuria, serum creatinine, and eGFR were 1.3g/day, 0.8 mg/dL, and 80 mL/min/1.73 m2. The mean age was 34.7 ± 12.5 years old, and 61% of the study population was female. Seventy-two percent of patients received intensive methylprednisolone pulse therapy (mPSL), and the incidence of HR, PR and CR were 76, 50 and 46%, 50%, respectively. Kaplan-Meier curves analyses showed a significant difference between HR and non-HR, PR and non-PR, and CR and non-CR groups (Fig.). In univariate analyses, hypertension, eGFR, HR, PR, CR, and T-score in the Oxford classification of IgAN were significantly associated with renal outcome. In multivariate Model-A, HR, and PR were significant factors for renal outcome after adjusting with sex, hypertension, eGFR and T-score. While in multivariate model-B, CR was also significantly associated with renal outcome after adjustment (Table). However, 36% and 46% of patients demonstrated hematuria and proteinuria relapses after remission. Conclusion JSN novel criteria for HR and PR predict renal outcomes in IgAN patients. Further studies are required to verify their clinical utility of JSN criteria in a larger sample size with different ethnicities.

#2565 Urine amino acid profiles enlighten new prediction models for renal Fanconi syndrome and its association with eGFR level

Abstract Background and Aims Renal Fanconi syndrome (FS) presented dysfunctions of renal proximal tubular (PT) transport with or without excessive urine amino acids (AAs) excretion, which might contribute to the progression of eGFR decline. This study aimed to explore the clinical benefit of 21 urinary AAs excretion patterns in renal FS and eGFR decline. Method Liquid chromatography-tandem Mass spectrometry (LC-MS-MS) is currently quantitative and detects over 21 types of amino acids in 157 patients with renal proximal tubular dysfunctions. To evaluate the diagnostic values of urine AAs in renal FS, we established a machine learning algorithm to perform binary classification using Random Forest Regressor in Python (version 3.8.8) with a training set and a testing set (8:2). We used Randomized search to find out the best model hyperparameters, calculated feature importance for contribution evaluation, and Receiver Operating Characteristic (ROC) curves to evaluate the performance of classification algorithms. Results A model based on a machine learning algorithm of all urine AAs to diagnose renal FS established with sensitivity = 0.71, specificity = 0.73, and AUC = 0.83 (95% CI 0.648-0.957) (Fig. 1), with similar performance in combined six urine AAs (citrulline, asparagine, threonine, phenylalanine, ornithine, and proline) models. The urine proline level independently correlated with eGFR < 60 ml/min/1.73 m2 (bias regression coefficient 0.84, P = 0.001, OR = 2.31, 95% CI 1.41-3.80) when adjusted by age, etiology, gender, and blood urea nitrogen level. For the primary diseased diagnosis, the most susceptible urine AAs were citrulline (56.7%), proline (56.0%,) threonine (52.2%), and ornithine (45.9%) and the less susceptible ones were histidine (24.8%), aspartate (16.6%), and arginine (13.4%). Accordingly, the most common affected AA transporters were SLC6A19 (B0AT1) and etiology-specific urine AA atlas major in the eight urine AAs (isoleucine, glutamine, methionine, proline, alanine, ornithine, lysine, and arginine). Different from primary Sjӧgren syndrome patients (n = 26) with less susceptible, the patients with plasmacyte diseases (n = 8) showed elevations of almost all the urine AAs except glycine and aspartate. The connection between urine AAs excretion and hypouricemia showed gender differences, with 20 urine AAs significantly negatively correlating with serum uric acid levels in males but only five in females. Conclusion We first established a model based on the urine AA atlas detected by (LC-MS-MS) which contributed to differentiating the etiologies of renal tubular dysfunctions and associated well with eGFR. It shed light on the clinical practice in precision evaluation of tubule injury.

#2041 Analysis of current real-world management of IgAN in five European countries

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. Due to the often progressive nature of IgAN, patients generally face a poor prognosis if the condition is not appropriately controlled. Current treatment recommendations focus on disease management through the use of optimised supportive care, including use of an angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin receptor blocker (ARB). A physician questionnaire and patient chart review was conducted to investigate the real-world management of IgAN in five European countries. Method Between 21 December 2022 and 6 February 2023, physicians from France, Germany, Italy, Spain and the UK completed a questionnaire on IgAN management, and patient charts from their centres were analysed. Physicians included had to spend >40% of their time in a clinical setting, and have been in practice between 2 and 40 years. Physicians had to have ≥50 CKD stage 1–4 patients under their management, including ≥4 non-dialysis IgAN patients. Patient charts included in the analysis were required to be from patients ≥12 years of age, diagnosed with IgAN and not on dialysis, with an estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m2. Results A total of 261 physicians answered the questionnaire on IgAN management and completed chart audits on 473 of their most recently seen patients. Charts included in the audit were predominantly from male (71%), Caucasian (78%) patients. The mean age of patients was 47 years and 76% were in CKD stage 3 or later. At referral, 66% of patients were receiving an ACEi and/or ARB, 21% were receiving another antihypertensive agent and 6% were taking a sodium-glucose cotransporter 2 inhibitor (SGLT2i). Most patients (88%) had undergone ≥1 kidney biopsy. At the time of initial biopsy, average eGFR was 51.0 mL/min/1.73 m2 and proteinuria was 2.7 g/day. Of patients who had a biopsy, 73% had a mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T) and crescents (C) (MEST-C) score available. Due to biopsy results, 29% of patients initiated systemic steroids and 10% started an SGLT2i. On average, IgAN patients are prescribed five medications, with the number of medications increasing with age. The large majority of patients (92%) were taking an ACEi and/or ARB at the time of the most current visit; prescriptions with an ACEi and/or ARB included combination with an SGLT2i only (36%), with a systemic steroid only (10%), and with both an SGLT2i and a systemic steroid (5%). Less than half (41%) of patients were prescribed an ACEi and/or ARB alone. An ACEi and/or ARB were considered first-line therapy by 81% of physicians. Systemic steroids and SGLT2is were largely thought of as later line treatment options. The majority of physicians (66%) believed that their patients were completely adherent to their treatment regimen. Notably, over one-third (35%) of patients were on second-line therapy or later, with drivers of treatment change including increased proteinuria (31%), decreased eGFR (26%) and side effect management (15%). Over half (54%) of physicians were not completely satisfied with their patients’ overall response to treatment. Physicians anticipated that 74% of their patients would eventually progress to dialysis. Conclusion Many treating physicians are not satisfied with current treatment options for IgAN, with increasing levels of proteinuria, eGFR decline and side effects driving treatment change. Overall, this study indicates that there is a need for more effective and safe treatments for IgAN to prevent disease progression and improve prognosis.

#2284 Clinical characteristics and renal survival of patients with monoclonal gammopathy of renal significance (MGRS)

Abstract Background and Aims Monoclonal gammopathy of renal significance (MGRS) comprises a diverse group of renal disorders related to a nephrotoxic monoclonal immunoglobulin. Due to the rarity of the disease and the recent definition of MGRS-associated kidney lesions, data about long-term clinical outcomes remain limited. Method A single-center, retrospective cohort study was conducted including data of all patients with biopsy-proven MGRS who were followed at our center between 2005 and 2023. We examined the clinicopathologic characteristics and renal survival of the patients. Disease progression was defined as an eGFR decline >30% or end-stage kidney disease (ESKD). Univariate Cox regression analysis was used to assess the relationship between clinical features and disease progression. Results A total of 23 adults (males 43.5%) with a median age of 65 years (IQR 55-70) were included in our study. At presentation, median eGFR was 51 ml/min/1.73 m2 (IQR 40-80) and proteinuria 3.94 g/24 h (IQR 2.00-6.26). Serum or urine monoclonal protein was not detected in 4 patients (18.2%). MGRS-associated renal lesions included Ig-related amyloidosis (n = 8), monoclonal immunoglobulin deposition disease (n = 7), cryoglobulinemic glomerulonephritis (n = 2), C3 glomerulopathy (n = 2), proliferative glomerulonephritis with monoclonal IgG deposits (n = 1), immunotactoid glomerulopathy (n = 1) and miscellaneous (n = 2). Most patients were treated with a plasma cell-directed regimen (77.3%) and the rest with B-cell-directed (13.6%) or conservative therapy (9.1%). Median follow-up for the cohort was 45 months (IQR 27-67). Thirteen patients responded to treatment (52.1%), achieving a reduction in proteinuria (0.44 vs 3.94 g/24 h, p:001) and maintenance of eGFR (60 vs 56 ml/min, p:0.363) at the last follow-up visit. All responders had received clone-directed therapy. Disease progression occurred in 8 patients (34.8%), three of whom reached ESKD (13.0%). Renal survival, defined as survival without ESKD, was 84.6% at 48 months (CI 73.3-101.7). Factors that were associated with disease progression were Ig-related amyloidosis (HR: 6.94, CI: 1.30-36.84, p:0.023) and eGFR < 45 ml/min at diagnosis (HR: 14.73, CI: 1.62-132.95, p:0.017). Conclusion MGRS is a heterogeneous clinical entity manifesting with varying degrees of proteinuria and kidney injury. Impaired kidney function at diagnosis and Ig-related amyloidosis correlated with worse renal prognosis in our cohort. Early identification and clone-directed treatment of MGRS may improve long-term renal survival.

#2638 SGLT2i in CKD with high albuminuria: an observational real-world study

Abstract Background and Aims Dapagliflozin, a sodium–glucose co-transporter-2 inhibitor (SGLT2i), is indicated to treat chronic kidney disease (CKD). Clinical trials have shown that dapagliflozin significantly reduces albuminuria in patients with urine albumin-creatinine ratio (UACR) 200–5000 mg/g and has beneficial effects on estimated glomerular filtration rate (eGFR) decline and combined kidney outcomes. In the DAPA-CKD trial, dapagliflozin led to substantial reductions in the composite of sustained eGFR decline of ≥50%, end-stage kidney disease, and renal or cardiovascular death (hazard ratio [HR], 0.61; 95% confidence interval [CI]: 0.51, 0.72; p < 0.001), with similar reductions observed across UACR subgroups. Furthermore, compared with placebo, dapagliflozin reduced geometric mean UACR by 29.3% (95% CI: –33.1, –25.2; p < 0.0001), with no difference in relative UACR reduction by baseline UACR above or below 1000 mg/g. In the ZENITH-CKD study, over 12 weeks the combination of zibotentan (a novel endothelin A receptor antagonist) and dapagliflozin showed a robust reduction in UACR of 47.7% vs 28.3% for dapagliflozin alone, with this effect maintained in patients with UACR >700 mg/g. It is well known that renal disease progresses more quickly in patients with higher degree of albuminuria than in those with lower levels. We aimed to further characterize renal risk in patients with different levels of residual albuminuria despite standard of care treatment with renin–angiotensin system inhibitors (RASi) and SGLT2i. Methods We used a large USA claims database (Optum's de-identified Clinformatics® Data Mart Database [CDM]) to identify patients aged ≥18 years with CKD, defined as either two eGFR measurements ≤60 mL/min/1.73 m2 taken ≥90 days apart or a first eGFR ≤60 mL/min/1.73 m2 and a CKD diagnosis. Patients were indexed at the date of dapagliflozin 10 mg initiation between 30 April 2021 (date of approval for dapagliflozin in CKD) and March 2023. Patients with prior use of SGLT2i, immunosuppressive drugs, hydroxychloroquine, CKD stage 5 (based on eGFR <15 mL/min/1.73 m2 or dialysis), polycystic kidney disease, or type 1 or gestational diabetes were excluded. Patients were indexed on 1st January 2022 and grouped into two UACR groups: ≥700UACR group (≥700 mg/g) and <700UACR group (200–699 mg/g). Outcomes were UACR changes, eGFR slopes and CKD-associated hospitalizations within 1 year after dapagliflozin initiation. Hazard ratios were estimated using adjusted Cox survival regression. UACR follow-up analyses were restricted to patients with at least one follow-up measurement. Results In the 5908 patients with CKD, median UACRs at index in the ≥700UACR and <700UACR groups were 1414 mg/g and 102 mg/g, respectively. Patients in the ≥700UACR group vs <700UACR group had lower eGFR (40 vs 48 mL/min/1.73 m2), were younger (71 vs 74 years), and both groups had a high burden of comorbidities (heart failure: 38% vs 42%; type 2 diabetes: 74% vs 75%). RASi use was 81% and 74%, respectively. During follow-up, 22% of patients in the ≥700UACR group experienced a CKD-related hospitalization (25.1 events per 100 patient years) as compared to 19.5 events per 100 patient years in the <700UACR group (HR 1.38 [95% CI: 1.16, 1.64, p < 0.001]; Fig. panel A). The eGFR slope (95% Cl) of patients in the ≥700UACR group was –2.44 mL/min/1.73 m2 per year (–3.49, –1.65), compared with a flat eGFR trajectory in patients in the <700UACR group (0.39 [–0.11, 0.96]). In the ≥700UACR group with at least one follow-up measurement (n = 431), UACR lowered from 2077 mg/g to 1674 mg/g (–36.3%) within 1 month of dapagliflozin initiation but remained above 1200 mg/g throughout the 12-month follow-up period (Fig. panel B). Conclusions While treatment with RASi and SGLT2i are associated with reduced risk of renal outcomes in patients with CKD, awareness and management of residual albuminuria remains an area of unmet clinical need. The novel combination of zibotentan/dapagliflozin currently under investigation in the ZENITH High Proteinuria phase III trial (NCT06087835) seeks to address this need.

#1185 Cardiovascular, renal and mortality risk by the KDIGO risk classification: the first observational study in Japan

Abstract Background and Aims The prevalence of chronic kidney disease (CKD) has been increasing, affecting 850 million people worldwide and 13 million individuals in Japan. CKD is a risk factor for cardiovascular complications including heart failure, and dialysis. KDIGO risk classification is widely used for the management of people with CKD in Japan; however, risk of clinical outcomes by the KDIGO classification in Japanese population is unclear. The aim of this study is to describe the risk of major adverse cardiovascular event (MACE) and renal outcomes according to the KDIGO classification in Japanese clinical practice. Method This study was a cohort study using data collated from the RWD database which includes electronic medical records and claims data from approximately 200 medical institutions across Japan since 2000. Subjects aged ≥18 years with two or more consecutive results of eGFR <90 mL/min/1.73 m2 at least 90 days apart within a 360-day period were included, and those received renal replacement therapy (RRT; dialysis or renal transplantation) before the index date was excluded. The index date was defined as the date of the second eGFR measurement <90 mL/min/1.73 m2 between January 2004 and December 2020. Patients were categorized into KDIGO classification G2-G5 based on their eGFR values and A1-A3 based on urine protein test (quantitative test and urine dipstick) results and into `no urine protein data` if no urine protein test was available. The primary endpoint was MACE that was defined as a composite of myocardial infarction, stroke, heart failure hospitalization, and in-hospital death. The secondary endpoint was renal outcomes defined as a composite of RRT, eGFR decline >50%, eGFR <15 mL/min/1.73 m2, diagnosis of CKD stage 5, and in-hospital death, and was analyzed in the group excluding patients with eGFR <15 mL/min/1.73 m2 or with diagnosis of stage 5 CKD on or before the index date. The risk of MACE and renal outcomes were evaluated using the cox proportional hazards model with G2A1 as a reference. Sensitivity analyses were performed for the population excluding those without urine protein data and for the population with quantitative urine protein test results. Results This study included 543,606 patients who met the criteria. Mean age was 61.6 ± 15.3 years, and 50.1% was male. Of those, 222,246 (40.9%) had no urine protein data. Tables 1 and 2 show hazard ratio (HR) for MACE and renal outcomes, respectively. HR (95% confidence interval) for MACE was 1.17 (1.12-1.21) in G2A2 and 1.16 (1.12-1.20) in G3aA1, showing significantly increased risk in early stages of CKD, and continued to increase as disease advances to 2.83 (2.54-3.15) in G5A3. HR for renal outcomes was similarly significantly increased in early stages of CKD, and further increased to 19.96 (18.62-21.40) in G4A3. Results of two sensitivity analyses, excluding subjects with no urine protein data (n = 321,360, 59.1% of overall population) shown in Table 3 and 4, and excluding patients with no quantitative data (n = 36,615, 6.7% of overall population) showed similar trends, supporting the robustness of primary findings. Conclusion This study is the first to demonstrate the applicability of the KDIGO risk classification in assessing the risk of cardiovascular events, including heart failure, and renal outcomes in Japan. Risk of events was increased from early stages of CKD (G3aA1 and G2A2), suggesting the importance of early diagnosis and therapeutic intervention through appropriate testing. These findings may contribute to better management of people with CKD.

#1166 ACTION3 pivotal Phase 3 & open-label extension study assessing DMX-200 in adult & paediatric patients with focal segmental glomerulosclerosis (FSGS)

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a major cause of glomerular disease that affects both adults and children. FSGS can rapidly progress to end-stage kidney disease. Lack of safe and effective treatment represents a significant unmet need for patients with FSGS. Development of treatments has been hampered by complexities including the rare nature of the disease, varying drivers of pathogenesis, and the evolving diagnostic and clinical trial designs, necessitating innovative research approaches. DMX-200 (repagermanium) is a C-C motif chemokine receptor 2 (CCR2) pathway inhibitor. Activation of the angiotensin II type 1 receptor (AT1R) and CCR2 have been independently implicated in the pathogenesis and progression of FSGS. These receptors form a functional complex so inhibition of both receptors may provide an efficient approach to FSGS treatment. In vivo data shows co-administration of DMX-200 and the angiotensin receptor blocker (ARB) irbesartan demonstrated a synergistic reduction in proteinuria, macrophage infiltration, and podocyte loss compared with vehicle or either antagonist alone. A subsequent Phase 2a cross-over study (NCT03649152) in N = 8 patients with biopsy-proven primary FSGS showed that the combination of DMX-200 and irbesartan (compared to placebo) was well tolerated with most patients experiencing a reduction in proteinuria. Based on these data, the global Phase 3 study (ACTION3) was initiated to confirm the proteinuria lowering effects of DMX-200 and assess effects on eGFR decline. ACTION3 is a randomised, placebo-controlled, double-blind, long-duration study of FSGS patients and on completion will provide a resource for the wider nephrology community and advocacy groups on the natural history of FSGS patients and the effects of a CCR2-inhibitor on the background of an ARB. Here we present the baseline data from the first 90 patients enrolled in ACTION3 at 12th January 2024. Method The ACTION3 (NCT05183646) study is a pivotal Phase 3, multicentre study of the efficacy and safety of DMX-200, 120 mg twice daily compared with placebo in adult patients with biopsy-proven FSGS receiving maximal tolerated ARB, with persistent proteinuria >1.5g/ day and eGFR >25 ml/min/1.73 m2. The study plans to enroll approximately 286 patients with primary FSGS, genetic FSGS and FSGS of undetermined cause with the primary objective of evaluating the efficacy of DMX-200 in percent change in 24-hour urine PCR and eGFR slope. The initial 104-week randomized period will be extended in a 2-year open label extension study. A futility analysis by an Independent Data Monitoring Committee following the first 72 patients completing 35 weeks of treatment confirm that continuation of the study is non-futile. Results The study is actively recruiting at 71 sites in 11 countries listed in Table 1. Demographic data of randomised patients is listed in Table 2. Patients are predominantly male (65%), with an average age of 46.6 yrs. and mean eGFR 56.3 ± 27.6 (ml/min/1.73 m2). The study is expanding recruitment into additional countries in the Asia Pacific, Europe, and Latin American regions. Further, the study protocol has sought and received regulatory approval to enroll adolescent patients aged 12-18 in Argentina, Mexico, UK and the US. Conclusion DMX-200 (repagermanium) has shown encouraging signs of safety and efficacy in combination with an ARB for the treatment of FSGS. The contributing countries and baseline characteristics of the patients enrolled in ACTION3 are similar to the populations studied in other recent FSGS trials. No clinically significant safety concerns have been observed in patients enrolled to date in the ACTION3 Phase 3 study.

#2406 Echocardiographic characteristics of autosomal dominant polycystic kidney disease

Abstract Background and Aims Cardiovascular complications in patients with autosomal dominant polycystic kidney disease (ADPKD) are one of the most frequently investigated extrarenal manifestations. The results are many times contradictory. This is caused by a limited size of studied populations and high inter- and intrafamilial heterogeneity of ADPKD. Expanding knowledge of populations of patients from different regions and cohorts is crucial for improving the understanding and treatment of cardiovascular morbidity and mortality. This study aims to explore the prevalence of cardiovascular abnormalities in echocardiography and to analyze their relationships with clinical characteristics across different stages of CKD progression in patients with ADPKD. Method Sixty-eight patients were included in the study. All patients underwent transthoracic echocardiography with the use of GE Vingmed Ultrasound (GE Norway Health Tech, Oslo, Norway). Information about demography, prior medical history and taking antihypertension drugs was recorded. The results of creatinine, lipids and haemoglobin were collected. To diagnose the rapid progression of CKD, creatinine was sampled twice, in a one-year interval. Results Using different indicators of left ventricular hypertrophy (LVH), we found it in above 40% of ADPKD patients. A single associate of left ventricular mass was eGFR decline after one year of observation. Other highly prevalent findings were asymptomatic left ventricular diastolic dysfunction (ALVDD) (39%), left atrium (LA) enlargement (39%) and mild valvular regurgitations (80%). Ejection fraction, aortic root dimension, tricuspid annular plane systolic excursion (TAPSE) and prevalence of mitral valve prolapse were not importantly increased. Apart from age, the strong determinant of ALVDD diagnosis was the treatment with beta-blockers. Cardiac indices were not different across the eGFR stages. Conclusion LVH, LA enlargement, ALVDD and valvular regurgitations are characteristics of cardiac phenotype in ADPKD. Cardiac indices were not different across different stages of CKD pointing towards the diagnosis of ADPKD being main drive of their occurrence.