Significant Reduction In Proteinuria Research Articles

Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy

We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells. This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors. The primary end point was reduction of proteinuria. Secondary end points included change from baseline in estimated glomerular filtration rate (eGFR) and kidney histology. Although we could not detect significant reduction in proteinuria with fostamatinib overall, in a predetermined subgroup analysis, there was a trend for dose-dependent reduction in median proteinuria (from baseline to 24 weeks by 14%, 27%, and 36% in the placebo, fostamatinib 100 mg, and 150 mg groups, respectively) in patients with baseline urinary protein-to-creatinine ratios (UPCR) more than 1000 mg/g. Kidney function (eGFR) remained stable in all groups. Fostamatinib was well-tolerated. Side effects included diarrhea, hypertension, and increased liver enzymes. Thirty-nine patients underwent repeat biopsy showing reductions in SYK staining associated with therapy at low dose (-1.5 vs. 1.7 SYK+ cells/glomerulus in the placebo group, P< 0.05). There was a trend toward reduction in proteinuria with fostamatinib in a predefined analysis of high risk patients with IgAN despite maximal care, as defined by baseline UPCR greater than 1000 mg/g. Further study may be warranted.

Effect of SGLT2 inhibitors on the proteinuria reduction in patients with IgA nephropathy.

Recent trials suggest sodium-glucose cotransporter 2 inhibitors (SGLT2i) significantly reduced proteinuria in patients with IgA nephropathy (IgAN). While little was known its efficacy in clinical practice especially in those already received full dose reninangiotensin-aldosterone system (RAAS) inhibitors. A cohort of 93 Chinese patients with biopsy-proven IgAN and persistent proteinuria underwent full supportive therapy, including optimal blood pressure control and full dose angiotensin-converting enzyme-inhibitor or angiotensin receptor blocker therapy. Proteinuria reduction at three and six months after initiating SGLT2i therapy was analyzed. A total of 93 patients were enrolled in this study and 62 of them completed the six-month follow-up. After SGLT2i administration, a significant reduction in proteinuria was observed, with a decrease of 22.9% (p < 0.001) at three months and 27.1% (p < 0.001) at six months. During the six-month follow-up period, a decline of 3.0 mL/min/1.73m2 in estimated glomerular filtration rate (eGFR) (p = 0.012) and an increase of 0.8 g/L in albumin (p = 0.017) were observed. The anti-hypertensive effect of SGLT2i was not significant (p > 0.05). Notably, a consistent antiproteinuric effect of SGLT2i was observed across various settings, including different age groups, baseline levels of proteinuria/eGFR, use of immunosuppressive agents, and the presence of comorbid diabetes and hypertension (all p values >0.05). The proteinuria was significantly reduced after SGLT2i administration in IgAN patients with full dose angiotensin-converting enzyme-inhibitor or angiotensin receptor blocker therapy. Importantly, the antiproteinuric effect of SGLT2i was observed independently of immunosuppressive agent therapy, age, baseline eGFR and proteinuria levels, as well as the history of hypertension and diabetes.

Proteinuria as a Surrogate Endpoint for Disease Progression in IgA Nephropathy: Predicting Long-Term Treatment Effects of Sparsentan

IgA nephropathy (IgAN) is a rare, life-limiting disease for which there is significant unmet need. Until recently, drug development for IgAN had been impeded by the requirement for large-scale, long-term clinical trials to measure clinical outcomes. However, the recent establishment of ‘reduction in proteinuria’ as a surrogate endpoint to predict clinical outcomes in IgAN, as a basis for accelerated drug approval, has transformed the field. At the 60th European Renal Association (ERA) Congress in June 2023, two oral poster presentations focused on the use of early reduction in proteinuria as an endpoint for clinical studies in IgAN. Alex Mercer, Consultant in Clinical Drug Development at JAMCO Pharma Consulting in Stockholm, Sweden, presented data estimating the long-term clinical outcome of reductions in proteinuria (clinically meaningful extensions in time to kidney failure or death), which could help predict the future protective effect of any new intervention on kidney function. Following this, Jonathan Barratt, Mayer Professor of Renal Medicine at the University of Leicester, and Honorary Consultant Nephrologist at Leicester General Hospital, UK, described findings from the prespecified interim analysis of the Phase III PROTECT study of sparsentan (a novel dual endothelin angiotensin receptor antagonist) in IgAN, which included reduction in proteinuria as a primary endpoint. In patients with IgAN at high risk of disease progression, sparsentan produced a rapid and significant reduction in proteinuria of a level that, according to the study data presented by Mercer, would correspond to a substantially lowered risk of kidney failure or death. Long-term data to confirm this predicted clinical outcome on disease progression are anticipated.

The Effects of Perilla frutescens Extracts on IgA Nephropathy: A Systematic Review and Meta-Analysis.

(1) Background: Chronic renal disorders (CRD) are associated with significant comorbidities and necessitate complex therapeutic management. As time passed, Perilla frutescens (PF) became a promising therapeutic option for CRD. The aim of this systematic review and meta-analysis was to outline the therapeutic effects of PF extracts on various models of immunoglobulin a (IgA) nephropathy; (2) Methods: Medline, Embase, and Cochrane databases were used to find relevant studies. All prospective interventional studies that evaluated the effect of PF extract versus placebo on rat models of chronic renal disorders were assessed according to the international guidelines; (3) Results: Our search yielded 23 unique records, out of which only five were included in the analysis. Our results showed that administration of PF extracts led to a statistically significant reduction in proteinuria and PCNA levels in rats that received high doses of the extract as well as in the PCNA level and DNA synthesis in rats that received low doses of the extract. The evaluated outcomes benefited from a low degree of heterogeneity; (4) Conclusions: Some of the evaluated outcomes were significantly reduced by both high and low doses of extracts from Perilla frutescens. Further studies are needed to determine the exact effect over IgA nephropathy in human subjects.

#6423 LONG-TERM PROGNOSIS OF HYPOPROTEIC DIET SUPPLEMENTED WITH KETOANALOGUES IN PATIENTS WITH ADVANCED DIABETIC KIDNEY DISEASE AND SEVERE PROTEINURIA

Abstract Background and Aims Studies support the role of low-protein regimens in managing chronic kidney disease (CKD). In addition, some data emphasize the role of low-protein diets (LPDs) in postponing kidney replacement therapy (KRT) in patients with CKD, even in diabetic patients with heavy proteinuria. Although most results seem to be in favor of a LPD in CKD, even in patients with advanced diabetic kidney disease (DKD), there is insufficient data on long-term kidney and patient outcomes. This is a follow-up study aimed to determine the outcomes in kidney survival and patient survival in patients with DKD and severe proteinuria. Method The follow-up study included all patients with advanced DKD and severe proteinuria who previously participated in a twelve-month uni-centric prospective study looking to assess variations in kidney function and proteinuria. At baseline, 97 patients with DKD, with stable stage 4+ CKD and proteinuria of nephrotic-range, who proved adherent to protein restriction were enrolled and received LPD (0.6 g mixed protein/kg-day) supplemented with ketoanalogues of essential amino acids (Ketosteril®, Bad Homburg, Germany, 1 tb/10 kg dry ideal body weight per day) for 12 months. Ninety-two patients completed the study (5 patients received kidney transplant). The efficacy outcomes were assessed by the decline of kidney function and proteinuria. Safety parameters were evaluated by anthropometric measurements (Body Mass Index), Subjective Global Assessment score and serum albumin. Compliance to the LPD was assessed by urinary urea from a 24-hour urine collection to estimate protein intake (ePI) and a 3-day food diary to estimate the energy intake. After the end of the study, the patients continued to remain compliant to the nutritional intervention. The primary composite endpoint was the need for KRT or patient death. The census moment was either the occurrence of the primary endpoint or the 31st of January, 2023. Results At baseline, patients had a median age of 61 years (95% CI 58 to 67), 66% were men, with poorly controlled diabetes assessed by the level of the glycated hemoglobin [8.1% (95% CI 8.0 to 8.3)]. All patients had a good nutritional status (SGA A). The median estimated glomerular filtration rate (eGF) was 12.6 mL/min (95% CI 11.7 to 13.1) and the median proteinuria was 5.2 g/g creatininuria (95% CI 5.0 to 5.2). After 12 months, a significant reduction in proteinuria was observed (67%), as well as a reduction in the kidney function decline by almost 80% compared to the period before the inclusion and a preserved good nutritional status (SGA A). The median follow-up was 105 months (95% CI 103 to 106). After almost 9 years of follow-up, 83.7% of patients remained alive, despite significant comorbidities. The median survival was 62 months (95% CI 47 to 85). Seventy-six percent of patients required KRT, with a predilection for hemodialysis. The median period of time until KRT was 26 months (95% CI 24 to 29). In a Kaplan-Meier survival analysis, the compliance to the sLPD was associated with better kidney survival (p = 0.03). Conclusion Low-protein diets supplemented with ketoanalogues of essential amino acids seem to be associated with a better kidney outcome on long-term in patients with advanced diabetic kidney disease and heavy proteinuria.

#2652 ANTIPROTEINURIC EFFECT OF SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS IN GLOMERULAR AND SYSTEMIC DISEASES: A REAL-WORLD CLINICAL STUDY

Abstract Background and Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently begun to be used in glomerular/systemic autoimmune diseases with glomerular involvement for the treatment of proteinuria, although the information on real-world clinical settings is very scarce. Method Retrospective, observational, international cohort study. Adult patients with biopsy-proven glomerular diseases were included. The main outcome was the percentage reduction in 24-hour proteinuria from SGLT2i initiation to 3, 6, 9, 12 months. Secondary outcomes included percentage proteinuria reduction by type of disease and a reduction of proteinuria ≥30% from SGLT2i initiation. Results The study group consisted of 493 patients with a median age of 55 years. All patients were on renin-angiotensin system blockade. Geometric mean percentage change of proteinuria from baseline was –35%, –41%, –45% and –48% at 3, 6, 9 and 12 months after SGLT2i initiation, respectively. Geometric mean percentage change of eGFR was –6%, –3%, –8%, –10.5% at 3, 6, 9 and 12 months, respectively. Results were similar irrespective of the underlying disease. However, a significant correlation was found between body mass index (BMI) and percentage proteinuria reduction at last follow-up (R = –0.11; p = 0.02). By mixed-effects binomial logistic regression model, serum albumin at the onset of SGLT2i emerged as the main predictor of a ≥30% proteinuria reduction (odds ratio for albumin &amp;lt;3.5 g/dl: 0.53; 95% CI 0.30–0.91; p = 0.02). Finally, a slower eGFR decline over time was observed in patients achieving a ≥30% proteinuria reduction: –3.7 versus –5.3 ml/min/1.73m2/year (p = 0.001). Conclusion The use of SGLT2i was associated with a significant reduction of proteinuria, irrespective of the underlying glomerular/systemic disease. This percentage change was higher in patients with higher BMI. Higher serum albumin at SGLT2i onset is associated with higher probability of achieving a ≥30% proteinuria reduction.

Effect of SGLT-2 inhibitor (remogliflozin) plus DPP4 inhibitor (vildagliptin) on diabetic nephropathy in patients with type 2 diabetes mellitus comparison with combination of metformin and sulphonylureas

Background: Diabetes is leading cause of renal failure in entire world. Approximately 20-40 percent of patients with diabetes develop diabetic nephropathy. Newer drugs like SGLT-2 inhibitors and DPP-4 inhibitors are valuable option for Diabetic Nephropathy. Remogliflozin etabonate (RE) is the latest addition to the SGLT2 inhibitor class of drugs that have been recently approved in India for the management of T2DM.This study was conducted to elaborate effect of SGLT2 inhibitor (remogliflozin) plus DPP4 inhibitor (vildagliptin) on diabetic nephropathy in patients of Type 2 DM. Methods: This hospital based, comparative, open label, randomized controlled trial has been carried out in our department during January 2020 to October 2022 on 60 patients. Group 1 was given metformin 500 mg BD and glimepiride 1 mg BD and group 2 was given FDC of remogliflozin 100 mg and vildagliptin 50 mg BD with 32 patients in group 1 and 28 patients in group 2. The study was approved by ethical committee of our institute. Results: Mean (SD) of urine ACR in metformin and glimepiride group at screening, 12 weeks, 24 weeks, and at 36 weeks were 93.64 (53.92), 95.56 (52.76), 89.96 (50.22) and 90.9 (53.56) respectively mean (SD) of urine ACR in remogliflozin and vildagliptin group at screening, 12 weeks, 24 weeks, and at 36 weeks were 108.28 (68.5), 100.73 (55.5), 99.35 (55.71) and 75.1 (38.7) respectively. Mean (SD) of eGFR in metformin and glimepiride group at screening, 12 weeks, 24 weeks, and at 36 weeks were 59.62 (18.57), 61.2 (11.1), 60.06 (14.37) and 60.8 (13.3) respectively. Mean (SD) of eGFR in remogliflozin and vildagliptin group at screening, 12 weeks, 24 weeks, and at 36 weeks were 68.03 (16.35), 65.8 (7.96), 66.28 (15.13) and 68.4 (11.6) respectively. Conclusions: Remogliflozin and vildagliptin combination has significant reduction of proteinuria and eGFR improvement when compared to metformin plus glimepiride.

Blood Pressure Reducing Potential and Renoprotective Action of Cilnidipine Among Hypertensive Patients Suffering From Chronic Kidney Disease: A Meta-Analysis.

Hypertension is a risk factor for cardiovascular diseases which also causes progressive kidney damage leading to chronic kidney disease (CKD), so the rate of progression of CKD can be controlled by reducing blood pressure (BP). Many anti-hypertensive drugs are available. Cilnidipine is a new-generation calcium channel blocker (CCB). This meta-analysis is aimed to generate pooled evidence about the effectiveness of cilnidipine as an anti-hypertensive and to explore its reno-protective actions. Pubmed, Scopus, Cochrane Library, and Google Scholar were searched from January 2000 to December 2022 to include the studies. The pooled mean difference, along with 95% CI, was computed using Revman 5.4.1 software (Revman International, Inc., New York City, New York). The Cochrane risk-of-bias assessment tool was used for bias assessment. This meta-analysis was registered in PROSPERO with Reg. no. CRD42023395224. This meta-analysisincluded seven studies with 289 participants in the intervention groupand 269 in the comparator group, and were selected from Japan, India, and Korea. Systolic blood pressure (SBP) was significantly reduced in cilnidipine treated group among hypertensives with CKD subjects weighted mean difference (WMD) was 4.33, and the 95% confidence interval (CI) was 1.26 to 7.31as compared to the other group. Cilnidipine also shows a significant reduction in proteinuria with WMD 0.61 and 95% CI 0.42 to 0.80. Both groups were similar in adverse drug reactions (ADR). Cilnidipine is a more effective anti-hypertensive as compared to Amlodipine or other CCBs, mainly in reducing SBP. Besides this, cilnidipine also shows better reno-protective action because it also significantly reduces proteinuria in such patients.

SGLT-2 Inhibitors and Renal Outcomes in Non-Diabetic Patients: A Systematic Review

Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown positive renal outcomes in diabetic patients. There is also emerging evidence in non-diabetic patients. This review was conducted to analyse the renal outcomes of SGLT2i in patients without diabetes mellitus (DM). Methods: A systematic review was performed in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) compliant manner. We included only randomized trials that examined the effect of SGLT2i on renal outcomes in non-diabetic patients. Results: A total of ten randomized trials were included with a combined cohort of 26 298 patients. There was a tendency for lesser risk of adverse renal outcomes in heart failure (HF) patients with reduced ejection fraction (EF) (hazard ratio (HR) 0.50-0.71). Lesser effect on adverse renal outcomes was seen in HF patients with preserved EF (HR 0.95). For both preserved and reduced EF HF, there was a statistically significant reduction in the rate of decline in estimated glomerular filtration rate (eGFR) (p&lt;0.001). On a short follow-up, there was a significant reversible reduction in GFR. In the long term, chronic kidney disease (CKD) proteinuric patients had a statistically significant lesser risk of adverse renal outcomes (p&lt;0.001) and a significant reduction in albuminuria (p=0.0016). CKD patients, including non-proteinuric, had a significant reduction in the rate of kidney disease progression (HR = 0.71). Conclusion: Treatment with SGLT2i significantly reduces the rate of kidney disease progression in CKD non-diabetic patients with eGFR ≥ 20 mL/min/1.73 m2. Benefit seems greater in proteinuric patients. Benefit for eGFR &lt; 20 mL/min/1.73 m2, dialysis and kidney transplant patients is yet to be defined.

Engineered Bone Marrow Stem Cell-Sheets Alleviate Renal Damage in a Rat Chronic Glomerulonephritis Model

Although mesenchymal stem cell (MSC)-based regenerative therapy is being developed for the treatment of kidney diseases, cell delivery and engraftment still need to be improved. Cell sheet technology has been developed as a new cell delivery method, to recover cells as a sheet form retaining intrinsic cell adhesion proteins, which promotes its transplantation efficiency to the target tissue. We thus hypothesized that MSC sheets would therapeutically reduce kidney disease with high transplantation efficiency. When the chronic glomerulonephritis was induced by two injections of the anti-Thy 1.1 antibody (OX-7) in rats, the therapeutic efficacy of rat bone marrow stem cell (rBMSC) sheet transplantation was evaluated. The rBMSC-sheets were prepared using the temperature-responsive cell-culture surfaces and transplanted as patches onto the surface of two kidneys of each rat at 24 h after the first injection of OX-7. At 4 weeks, retention of the transplanted MSC-sheets was confirmed, and the animals with MSC-sheets showed significant reductions in proteinuria, glomerular staining for extracellular matrix protein, and renal production of TGFß1, PAI-1, collagen I, and fibronectin. The treatment also ameliorated podocyte and renal tubular injury, as evidenced by a reversal in the reductions of WT-1, podocin, and nephrin and by renal overexpression of KIM-1 and NGAL. Furthermore, the treatment enhanced gene expression of regenerative factors, and IL-10, Bcl-2, and HO-1 mRNA levels, but reduced TSP-1 levels, NF-kB, and NAPDH oxidase production in the kidney. These results strongly support our hypothesis that MSC-sheets facilitated MSC transplantation and function, and effectively retarded progressive renal fibrosis via paracrine actions on anti-cellular inflammation, oxidative stress, and apoptosis and promoted regeneration.

PS-B03-7: MAGNESIUM SULPHATE TREATMENT DURING HYPERTENSIVE PREGNANCY IMPROVES MATERNAL BUT NOT FETAL OUTCOMES IN RATS

Objective: There has been a recent rise in the incidence of cardiovascular disease amongst women of child-bearing age and hypertensive disorders in pregnancy, in particular pre-eclampsia. Though it is frequently diagnosed, therapeutic interventions are lacking. Magnesium sulphate (MgSO4) is known to induce a vasodilatory effect via increased NO production and improved endothelial function and is currently used to prevent the progression to eclampsia and seizures from pre-eclampsia in the clinic. Magnesium homeostasis is also crucial during a healthy pregnancy and hypomagnesemia has been linked to cardiovascular disease. We hypothesised that MgSO4 may be used as a preventative therapeutic during hypertensive pregnancies in a rodent model of super-imposed pre-eclampsia. Design and Methods: Spontaneously hypertensive stroke prone (SHRSP) female rats were time mated. On gestational day (GD) 10.5 0.9% saline (SHAM, n = 10) or 750ng/kg/min of ANGII (n = 17) were administered via mini pump. A subset of ANGII and SHAM animals received daily 1% w/v MgSO4 drinking water from GD0.5 (n = 4/group; SHAM/ANGII+MgSO4). Blood pressure, cardiac function, and uteroplacental blood flow were measured by tail-cuff plethysmography and Doppler ultrasound pre-pregnancy (PP) and at GD6.5, 12.5, and 18.5. Urine samples were collected by metabolic cage at PP, GD6.5, and GD18.5 for measurement of proteinuria. Fetal and placental measurements were collected at sacrifice. Results: ANGII shows features consistent with SPE in humans via decreased stroke volume and elevated blood pressure alongside decreased fetal and placental weights vs SHAM (****p &lt; 0.0001, **p &lt; 0.01, *p &lt; 0.05). Additionally, ANGII resulted in significantly altered fluid homeostasis and proteinuria vs SHAM (****p &lt; 0.0001, ***p &lt; 0.001, **p &lt; 0.01). ANGII+MgSO4 showed a decrease in blood pressure vs ANGII (**p &lt; 0.01). Treatment with MgSO4 had no significant effect on cardiac function, though there was a trend towards improvement in delta cardiac output. Neither ANGII nor additional MgSO4 altered indices of uteroplacental flow vs ANGII or SHAM. ANGII+MgSO4 exhibited a significant reduction in proteinuria vs ANGII (*p &lt; 0.05) as well as improvements in fluid homeostasis. Both fetal and placental weights were significantly reduced in ANGII+MgSO4 vs SHAM (**p &lt; 0.001) indicating a detrimental effect. Conclusions: These results suggest 1% w/v MgSO4 may be beneficial as a preventative therapeutic in pregnancies affected by super-imposed pre-eclampsia for maternal but not fetal outcomes. Further work is needed to elucidate the effects of MgSO4 in the context of hypertensive pregnancy.

Association of Serum Zinc Level with severity of chronic kidney disease in diabetic patients: a cross-sectional study

BackgroundIn recent years, it has been reported that diabetic patients tend to have a lower zinc intake due to unbalanced diet accompanying changes in lifestyle habits. We investigated serum zinc concentration in diabetic patients according to the stage of nephropathy.MethodsWe enrolled 227 diabetic patients (119 men, 108 women, average age 65.7 ± 14.7 [mean ± standard deviation]) who were hospitalized for diabetes treatment due to poor blood glucose control. We investigated the relationship between fasting serum zinc concentration and estimated glomerular filtration rate (eGFR) and albuminuria (urinary albumin-to-creatinine ratio, UACR), as well as serum zinc concentration by stage of diabetic kidney disease and chronic kidney disease.ResultsThe mean HbA1c value was 10.5 ± 2.1%. Serum zinc concentration was 75.5 ± 16.0 μg/dL in males and 75.7 ± 12.2 μg/dL in females, showing no gender difference and no significant relationship with diabetes type. The serum zinc concentration was negatively correlated with age (r = − 0.309, P < 0.001) and positively correlated with eGFR (r = 0.144, P = 0.030). A tendency was observed of serum zinc concentration to decrease after overt nephropathy, with values of 76.4 ± 14.1 μg/dL in pre-nephropathy (stage 1, n = 131), 78.5 ± 13.2 μg/dL in incipient nephropathy (stage 2, n = 65), 66.4 ± 14.3 μg/dL in overt nephropathy (stage 3, n = 25), and 65.7 ± 11.9 μg/dL in kidney failure (stage 4, n = 6). Serum zinc showed a negative trend with estimated GFR (P = 0.004) and significant reduction in albuminuria, with stage A3 (n = 29, 65.7 ± 13.9 μg/dL) having lower levels than A1 (n = 131, 76.4 ± 14.1 μg/dL, P = 0.001) and A2 (n = 67, 78.4 ± 13.1 μg/dL, P < 0.001).ConclusionsIn diabetic patients, serum zinc concentration tended to decrease as age increased and also as renal function deteriorated. This study suggests that consideration of zinc deficiency is necessary in patients with overt albuminuria.

Continuous Positive Airway Pressure Effect on Albuminuria Progression in Patients with Obstructive Sleep Apnea and Diabetic Kidney Disease: A Randomized Clinical Trial.

Rationale: Obstructive sleep apnea (OSA) is associated with impaired glycemic control and a higher risk of vascular complications, such as diabetic kidney disease (DKD). However, the effect of apnea-hypopnea suppression on DKD progression is unclear. Objectives: To assess the effect of continuous positive airway pressure (CPAP) on the urinary albumin-to-creatinine ratio (UACR) in patients with DKD and OSA. Methods: In a 52-week, multicentric, open-label, parallel, and randomized clinical trial, 185 patients with OSA and DKD were randomized to CPAP and usual care (n = 93) or usual care alone (n = 92). Measurements and Main Results: UACR, estimated glomerular filtration rate, serum concentrations of creatinine and glycated hemoglobin, insulin resistance, lipid concentrations, sleepiness, and quality of life. A 52-week change in UACR from baseline did not differ significantly between the CPAP group and the usual-care group. However, in per-protocol analyses that included 125 participants who met prespecified criteria for adherence, CPAP treatment was associated with a great reduction in UACR (mean difference, -10.56% [95% confidence interval, -19.06 to -2.06]; P = 0.015). CPAP effect on UACR was higher in nonsleepy patients with more severe OSA, worse renal function, and a more recent diagnosis of DKD. CPAP treatment also improved glycemic control and insulin resistance, as well as sleepiness and health-related quality of life. Conclusions: In patients with OSA and DKD, the prescription of CPAP did not result in a statistically significant reduction in albuminuria. However, good adherence to CPAP treatment in addition to usual care may result in long-term albuminuria reduction compared with usual care alone. Clinical trial registered with www.clinicaltrials.gov (NCT02816762).

Chlorthalidone and Advanced Chronic Kidney Disease.

Chlorthalidone and Advanced Chronic Kidney Disease.

Effect of glucagon-like peptide 1 receptor agonists on albuminuria in adult patients with type 2 diabetes mellitus: A systematic review and meta-analysis.

AimsTo determine the effect of glucagon‐like peptide 1 receptor agonists (GLP‐1RAs) on albuminuria in adult patients with type 2 diabetes mellitus (T2DM).MethodsMedline Ovid, Scopus, Web of Science, EMCARE and CINAHL databases from database inception until 27 January 2022. Studies were eligible for inclusion if they were randomized controlled trials that involved treatment with a GLP‐1RA in adult patients with T2DM and assessed the effect on albuminuria in each treatment arm. Data extraction was conducted independently by three individual reviewers. The PRISMA guidelines were followed regarding data extraction and quality assessment. Data were pooled using a random effects inverse variance model and all analysis was carried out with RevMan 5.4 software. The Jadad scoring tool was employed to assess the quality of evidence and risk of bias in the randomized controlled trials.ResultsThe initial search revealed 2419 articles, of which 19 were included in this study. An additional three articles were identified from hand‐searching references of included reviews. Therefore, in total, 22 articles comprising 39 714 patients were included. Meta‐analysis suggested that use of GLP1‐RAs was associated with a reduction in albuminuria in patients with T2DM (weighted mean difference −16.14%, 95% CI −18.42 to −13.86%; p < .0001) compared with controls.ConclusionsThis meta‐analysis indicates that GLP‐1RAs are associated with a significant reduction in albuminuria in adult patients with T2DM when compared with placebo.

FC052: Atrasentan for the Treatment of IGA Nephropathy: Interim Results from the Affinity Study

Abstract BACKGROUND AND AIMS IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the developed world. Up to 40% of patients with IgAN are at risk of progressing to end-stage kidney disease (ESKD), with proteinuria being a strong predictor of disease progression. Treatments that reduce proteinuria in IgAN are accompanied by eGFR preservation and improved kidney outcomes.[1] Endothelin A (ETA) receptor activation is a key driver of proteinuria, inflammation and fibrosis in patients with glomerular diseases.[2] Therefore, ETA receptor blockade has potential to be of therapeutic benefit for patients with proteinuric glomerular diseases, including IgAN. Atrasentan, a potent and selective ETA receptor antagonist that has demonstrated clinically significant reductions in proteinuria and risk of ESKD in a study of over 5300 patients with diabetic kidney disease (DKD), represents a potential therapy to reduce proteinuria and preserve kidney function in patients with IgAN and other glomerular diseases.[3] AFFINITY is a global, phase 2, open-label basket study to evaluate the efficacy and safety of atrasentan in patients with proteinuric glomerular diseases due to IgAN, Alport syndrome, focal segmental glomerulosclerosis and DKD. Here we present interim results from the first 17 patients enrolled in the IgAN cohort of the AFFINITY study, through week 12 of treatment. METHOD Approximately 20 patients will be enrolled in the IgAN cohort. They must have biopsy proven IgAN, be receiving a maximally tolerated and stable dose of renin angiotensin system inhibitor and have a urine protein creatinine ratio [UPCR] between 0.5 and &amp;lt;1.0 g/g from a first morning void urine sample. Patients are treated orally with 0.75 mg atrasentan daily. The primary endpoint is the change in 24-h UPCR from baseline to Week 12. Key exploratory endpoints include changes in eGFR from baseline to Week 56. RESULTS A total of 17 patients have enrolled in the IgAN cohort as of 4 January 2022. A total of 12 and 8 patients have completed visits through Week 6 and Week 12, respectively. The median age is 47 years and 41% are women. The geometric mean (GM) baseline proteinuria is 1.2 g/day, and median eGFR is 41 mL/min/1.73 m2 (Table 1). The 8 patients on treatment through Week 12 had a GM % reduction from baseline in 24-h UPCR of 43.6% [95% confidence interval (95% CI) 29.0–55.2] (Figure 1). Pharmacokinetic data are currently available for nine patients and showed a mean trough plasma atrasentan concentration in the targeted therapeutic range. Adverse events (AE) were observed in nne patients (53%), all mild or moderate in severity, most of which have resolved. One patient experienced an unrelated serious adverse event of traffic accident without long-term injuries. All patients remain on treatment with study drug except for one patient who discontinued drug due to an unrelated AE at week 13. CONCLUSION Treatment of patients with IgAN with atrasentan in addition to standard of care provided a &amp;gt;43% GM reduction in proteinuria after 12 weeks and was well tolerated, strongly supporting a key role of the endothelin pathway in the pathogenesis of IgAN. The ongoing phase 3 ALIGN study for patients with IgAN and proteinuria ≥1g/day will provide further assessment of the proteinuria lowering effects of atrasentan in this high-risk patient population.

MO640: Treatment with Sodium–Glucose Cotransporter 2 Inhibitors Increases Klotho in Type 2 Diabetic Patients

Abstract BACKGROUND AND AIMS Klotho (KL) is a transmembrane protein mainly expressed by the tubular cells of the kidneys, with an additional soluble form that is present in blood and urine. Preserved KL has been related to physiological protection of the kidneys. Sodium–glucose cotransporter type-2 inhibitors (SGLT2i) are a new class of anti-diabetic drugs with important renal benefits. The aim of the present study was to analyze the effect of treatment with SGLT2i on soluble KL concentrations as well as on mRNA expression levels of the KL gene in renal tubular cells. METHOD Fifty-seven patients (30 males and 27 females; mean age 61 ± 5 years) with type 2 diabetes and chronic kidney disease stage G2-A2, all treated with metformin and blockers of the renin–angiotensin system, were included in the study. All patients were in need of intensified anti-diabetic therapy at the discretion of their physicians in accordance with the routine clinical practice. Forty-five received SGLT2i during 3 months (15 empagliflozin, 15 canagliflozin and 15 dapagliflozin), and the evolution was compared with a group of 12 patients matched by age, sex and stage of CKD who received DPP4 inhibitors (control group). Serum and urine levels of soluble KL and tumor necrosis factor-alpha (TNFa) were determined by ELISA. In addition, the effect on mRNA expression levels of KL was assessed in vitro in renal tubular cells cultures. RESULTS Baseline values of serum and urinary KL and TNFa were similar in both groups. Urinary KL was inversely correlated with albuminuria (r = −0.45, P &amp;lt; 0.001) and urine TNFa excretion (r = −0.40, P &amp;lt; 0.01). At the end of the study, there was a similar improvement in metabolic control in both groups; however, only patients treated with SGLT2i showed a significant reduction in albuminuria and urinary TNFa (P &amp;lt; 0.01). Serum and urinary KL increased by 5.2% and 38.9%, respectively, only in patients receiving SGLT2i (P &amp;lt; 0.001 versus baseline), without changes in controls (P &amp;lt; 0.01 between groups). There were no differences among the three drugs in the SGLT2i group. The reduction in albuminuria (β = −0.35, P &amp;lt; 0.01) and urinary TNFa (β = −0.57, P &amp;lt; 0.001) were independently associated with the increase in urine KL, while the change in albuminuria was related to the increase in serum KL (β = −0.39, P &amp;lt; 0.05). Cultured renal tubular cells under high glucose, inflammatory stimulus with TWEAK or serum bovine albumin decreased Klotho mRNA and protein expression within 24 h, an effect that was prevented by all the SGLT2i when added to the cultures. CONCLUSION In type 2 diabetic patients, treatment with SGLT2i induces a reduction in albuminuria and modulates inflammation (as reflected by a decrease in the urinary excretion of TNFa), which is associated with a significant increase in soluble KL concentrations. In addition, SGLT2i prevent the reduction in protein and mRNA expression levels of the KL gene in renal tubular cells. The preservation of KL by SGLT2i may be an important mechanism of renal protection.

Management of IgA Nephropathy in Pediatric Patients

The onset of IgA nephritis in childhood and adolescence often develops into chronic glomerulonephritis with declining renal function. Although these long-term consequences are known, there is still a lack of evidence-based treatment recommendations in this age group. We report data from 22 pediatric patients who were biopsied to confirm the diagnosis of IgAN at our clinical center. 14 of them were treated with corticosteroids according to the recommendations for IgA nephritis vasculitis of the German Society of Pediatric Nephrology (GPN). Improvement was achieved in the majority of all cases, with a significant reduction in proteinuria five months after initiation of therapy. Our data suggest that treatment regimens for acute IgA nephritis and IgA vasculitis nephritis may be unified and are discussed in the context of current studies.

Renal Pathophysiological Changes During Chronic Metabolic Acidosis Associated Increased Blood Pressure

Activation of renal angiotensin II works synergistically with renal superoxides to promote an increase in blood pressure during chronic acidotic conditions has been previously delineated. Uncontrolled high blood pressure instigates renal pathophysiological function and eventual end organ damage is evident. This study aims to investigate the renal consequences of increased blood pressure provoked during chronic metabolic acidosis (CMA). It was a challenging prospect, as both hypertension and chronic metabolic acidosis are two different pathological conditions and can exist independent of each other. Renal functions in rats grouped in 3 groups; i) Control (nonacidotic and normotensive), ii) CMA (acidotic and hypertensive), iii) CMA+captopril+tempol (acidotic and normotensive) were critically assessed by measuring Glomerular Filtration Rate (GFR), Fractional excretion of sodium (FENa), urine flow rate, weight of the kidneys and albuminuria. Picro‐sirius staining of the cortical sections was performed to examine the collagen content as an index of fibrosis. The results demonstrated significant attenuation of GFR in the CMA group compared to the control group. However, GFR in captopril+tempol treated acidotic rats is significantly increased compared to the CMA groups, which suggested that the reduced GFR in CMA group is because the rats are hypertensive. Conversely, the FENa was significantly increased in the CMA group compared to the control but the captopril+tempol treated group showed a significant decrease in FENa compared to the CMA group, this implied that hypertension but not acidosis is the cause of increased FENa which increases blood flow to the kidney potentially leading to the pressure natriuresis and could potentially lead to kidney damage. The urinary albumin excretion was also significantly elevated in acidotic rats as compared to control but the captopril+tempol treated group showed a significant reduction in albuminuria, which revealed the acidosis‐induced hypertension is contributing for impaired renal infiltration and augmenting the albuminuria. The morphological analysis of renal changes using Picro‐sirius staining revealed significant structural damage in the glomeruli of chronically acidotic rats. However, when these rats were treated with captopril and tempol combined, the glomeruli were intact and a reduction in fibrosis was observed. Overall, our results suggested the renal consequences of acidosis induced hypertension can lead to eventual end organ damage which is independent to the function of acidosis. Hence, intrarenal Ang II and superoxide release in the kidney could be a potential target to reduce the blood pressure, albuminuria, and protection of renal function and delayed the onset of end‐stage renal disease associated with acidosis evoked hypertension.

POS-544 Atrasentan in Patients with Proteinuric Glomerular Diseases (The AFFINITY Study)

Glomerular diseases are a leading cause of morbidity and mortality worldwide and are characterized by proteinuria, a strong predictor of disease progression and end-stage kidney disease. Currently, there are limited therapies and despite the recent approval of sodium glucose co-transporter 2 inhibitors (SGLT2i), residual risk remains. It is known that endothelin A (ETA) receptor activation drives glomerular injury, inflammation, and fibrosis through a common pathogenic pathway. Atrasentan, a potent and selective ETA receptor antagonist that has shown clinically significant reduction in proteinuria and risk of kidney failure in a study of over 5,300 patients with diabetic kidney disease (DKD), represents a promising therapy to reduce proteinuria and preserve kidney function in proteinuric glomerular diseases.