RATIONALE & OBJECTIVE: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist (DEARA) examined in the ongoing phase 2 DUET trial for focal segmental glomerulosclerosis (FSGS). In the DUET 8-week double-blind period, sparsentan resulted in greater proteinuria reduction versus irbesartan. We report the long-term efficacy and safety of sparsentan during the open-label extension over more than 4 years. STUDY DESIGN: Patients were examined from their first sparsentan dose (double-blind period or open-label extension) through 4.6 years. SETTING & PARTICIPANTS: Patients with FSGS, excluding secondary FSGS. INTERVENTION: Sparsentan (200, 400, and 800 mg/d). OUTCOMES: Urinary protein-creatinine ratio, FSGS partial remission endpoint (urinary protein-creatinine ratio ≤1.5 g/g and >40% reduction from baseline), estimated glomerular filtration rate, and blood pressure approximately every 12 weeks. Treatment-emergent adverse events by year and cases/100 patient-years. RESULTS: 109 patients were enrolled; 108 received ≥1 sparsentan dose; 103 entered the open-label extension (68 sparsentan, 35 irbesartan during the double-blind period). Sparsentan was ongoing in 45/108 patients (41.7%); median time to treatment discontinuation was 3.9 years (95% CI, 2.6-5.2). Mean percent proteinuria reduction from baseline was sustained through follow-up. Achieving partial remission within 9 months of first sparsentan dose (52.8% of patients) versus not achieving (47.2%) was associated with significantly slower rate of estimated glomerular filtration rate decline over the entire treatment period (-2.70 vs -6.56; P = 0.03) and in the first 2 years (-1.69 vs -6.46; P = 0.03). The most common treatment-emergent adverse events (>9 cases/100 patient-years) were headache, peripheral edema, upper respiratory infection, hyperkalemia, and hypotension. Peripheral edema and hypotension declined from year 1 (13.9% and 15.7% of patients, respectively) to ≤4% in years ≥2. There were no cases of heart failure and no patient deaths. LIMITATIONS: The open-label extension does not include a comparison group. CONCLUSIONS: Long-term sparsentan treatment showed sustained proteinuria reduction and a consistent safety profile.

There is substantial unmet clinical need for safe and effective treatments for focal segmental glomerulosclerosis (FSGS), a kidney lesion with varied causes. Sparsentan is being studied for treatment of FSGS and targets 2 important pathways (endothelin-1 and angiotensin II) that lead to the loss of kidney function. In the 8-week randomized, double-blind DUET study in patients with FSGS, sparsentan reduced the amount of protein in the urine better than irbesartan (a blood pressure medicine often used to treat FSGS). We examined long-term treatment with sparsentan over >4 years in the DUET open-label extension. We found sustained proteinuria reduction in patients who continued treatment with sparsentan and a consistent safety profile with no new or unexpected adverse effects.

• Klíčová slova
• FPRE, FSGS partial remission endpoint, eGFR slope, kidney function, open-label extension, proteinuria, randomized controlled clinical trial, sparsentan,
• Publikační typ
• časopisecké články MeSH

RATIONALE AND OBJECTIVE: Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy (renin-angiotensin-aldosterone system [RAAS] inhibitor) to control proteinuria in primary and genetic focal segmental glomerulosclerosis (FSGS) follows guidelines based on other proteinuria-related kidney diseases. There is no consensus on the efficacy and safety of RAAS inhibitor therapies in primary and genetic FSGS. This systematic review assessed the effects of RAAS inhibitor therapy on kidney outcomes in these patients. STUDY DESIGN: Systematic review of randomized controlled trials, interventional nonrandomized studies, observational studies, and retrospective studies. SETTING & STUDY POPULATIONS: Patients with primary and genetic FSGS. SELECTION CRITERIA FOR STUDIES: PubMed, Cochrane Library, and Embase. DATA EXTRACTION: 2 investigators independently screened studies and extracted data. ANALYTICAL APPROACH: Results were summarized as the ratio of means (ROM) between baseline and follow-up measurements or as the hazard ratio using random-effects models. RESULTS: 30 publications were selected; 5 were controlled trials (4 randomized controlled trials). 8 assessed RAAS inhibitor monotherapy, while the rest studied RAAS inhibitors in combination with other drugs, mainly immunosuppressants. On average, a 32% proteinuria reduction (ROM, 0.68; 95% CI, 0.47-0.98) and no change in creatinine clearance (ROM, 0.95; 95% CI, 0.77-1.16) from baseline to the last reported follow-up was observed in patients treated with RAAS inhibitor monotherapy. When a RAAS inhibitor was combined with other drugs, a 72% proteinuria reduction was observed from baseline to the last reported follow-up (ROM, 0.24; 95% CI, 0.08-0.75). The published data did not allow for the assessment of the effects of RAAS inhibitor monotherapy on estimated glomerular filtration rate and end-stage kidney disease risks. LIMITATIONS: Large study heterogeneity in design, patient populations, and treatment regimens. No access to individual patient-level data. CONCLUSIONS: This review supports the tendency to observe a proteinuria reduction with RAAS inhibitors in patients with primary FSGS. RAAS inhibitor monotherapy was associated with maintained kidney function, as shown by no change in creatinine clearance. Strong evidence to quantify the effects of RAAS inhibitor monotherapy on end-stage kidney disease and glomerular filtration rate was lacking. Larger, well-designed clinical trials are needed to better understand the effects of RAAS inhibitors on primary FSGS.

• Klíčová slova
• End-stage kidney disease, end-stage renal disease, focal segmental glomerulosclerosis, proteinuria, renin-angiotensin-aldosterone system inhibitor,
• Publikační typ
• časopisecké články MeSH

IgA nephropathy is the most common primary glomerulonephritis with potentially serious outcome leading to end stage renal disease in 30 to 50% of patients within 20 to 30 years. Renal biopsy, which might be associated with risks of complications (bleeding and others), still remains the only reliable diagnostic tool for IgA nephropathy. Therefore, the search for non-invasive diagnostic and prognostic markers for detection of subclinical types of IgA nephropathy, evaluation of disease activity, and assessment of treatment effectiveness, is of utmost importance. In this review, we summarize treatment options for patients with IgA nephropathy including the drugs currently under evaluation in randomized control trials. An early initiation of immunosupressive regimens in patients with IgA nephropathy at risk of progression should result in the slowing down of the progression of renal function to end stage renal disease.

• Klíčová slova
• ACEI, CKD, IgAN, corticosteroids, progression, proteinuria,
• MeSH
• biologické modely MeSH
• IgA nefropatie terapie   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• rizikové faktory MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

OBJECTIVE: Our previous study in heterozygous Ren-2 transgenic rats (TGR) demonstrated that long-term treatment with endothelin receptor A (ETA) blocker atrasentan added to the renin-angiotensin system (RAS) blockade had renoprotective effects in a model of chronic kidney disease (CKD) induced by partial nephrectomy. Since ETA blockade is known to cause edema, we were interested whether diuretic treatment added to this therapy would be beneficial. DESIGN AND METHODS: Partial nephrectomy (NX) was performed at the age of 3 months in TGR rats which were subjected to: (i) RAS blockade alone (angiotensin receptor blocker losartan and angiotensin converting enzyme inhibitor trandolapril), (ii) combined RAS (losartan and trandolapril) and ETA receptor blockade (atrasentan), or (iii) diuretic (hydrochlorothiazide) added to the combined RAS + ETA blockade for 50 weeks following NX. RESULTS: At the end of the study systolic blood pressure and cardiac hypertrophy were similarly decreased in all treated groups. Survival was significantly improved by ETA receptor blockade added to RAS blockade with no further effects of diuretic treatment. However, additional diuretic treatment combined with RAS + ETA blockade decreased body weight and had beneficial renoprotective effects - reductions of both kidney weight and kidney damage markers. Proteinuria gradually increased in rats treated with RAS blockade alone, while it was substantially lowered by additional ETA blockade. In rats treated with additional diuretic, proteinuria was progressively reduced throughout the experiment. CONCLUSION: A diuretic added to the combined RAS and ETA blockade has late renoprotective effects in CKD induced by partial nephrectomy in Ren-2 transgenic rats. The diuretic improved: renal function (evaluated as proteinuria and creatinine clearance), renal morphology (kidney mass, glomerular volume), and histological markers of kidney damage (glomerulosclerosis index, tubulointerstitial injury).

• Klíčová slova
• atrasentan, chronic kidney disease, hydrochlorothiazide, losartan, nephrectomy, renoprotection, trandolapril,
• Publikační typ
• časopisecké články MeSH