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Item Effects of Bardoxolone Methyl in Alport Syndrome(Wolters Kluwer, 2022-12) Warady, Bradley A.; Pergola, Pablo E.; Agarwal, Rajiv; Andreoli, Sharon; Appel, Gerald B.; Bangalore, Sripal; Block, Geoffrey A.; Chapman, Arlene B.; Chin, Melanie P.; Gibson , Keisha L.; Goldsberry, Angie; Iijima, Kazumoto; Inker, Lesley A.; Kashtan, Clifford E.; Knebelmann, Bertrand; Mariani, Laura H.; Meyer, Colin J.; Nozu, Kandai; O’Grady, Megan; Rheault, Michelle N.; Silva, Arnold L.; Stenvinkel, Peter; Torra, Roser; Chertow, Glenn M.; Medicine, School of MedicineBackground and objectives Alport syndrome is an inherited disease characterized by progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in patients with Alport syndrome. Design, setting, participants, & measurements We randomly assigned patients with Alport syndrome, ages 12–70 years and eGFR 30–90 ml/min per 1.73 m2, to bardoxolone methyl (n=77) or placebo (n=80). Primary efficacy end points were change from baseline in eGFR at weeks 48 and 100. Key secondary efficacy end points were change from baseline in eGFR at weeks 52 and 104, after an intended 4 weeks off treatment. Safety was assessed by monitoring for adverse events and change from baseline in vital signs, 12-lead electrocardiograms, laboratory measurements (including, but not limited to, aminotransferases, urinary albumin-creatinine ratio, magnesium, and B-type natriuretic peptide), and body weight. Results Patients randomized to bardoxolone methyl experienced preservation in eGFR relative to placebo at 48 and 100 weeks (between-group differences: 9.2 [97.5% confidence interval, 5.1 to 13.4; P<0.001] and 7.4 [95% confidence interval, 3.1 to 11.7; P=0.0008] ml/min per 1.73 m2, respectively). After a 4-week off-treatment period, corresponding mean differences in eGFR were 5.4 (97.5% confidence interval, 1.8 to 9.1; P<0.001) and 4.4 (95% confidence interval, 0.7 to 8.1; P=0.02) ml/min per 1.73 m2 at 52 and 104 weeks, respectively. In a post hoc analysis with no imputation of missing eGFR data, the difference at week 104 was not statistically significant (1.5 [95% confidence interval, −1.9 to 4.9] ml/min per 1.73 m2). Discontinuations from treatment were more frequent among patients randomized to bardoxolone methyl; most discontinuations were due to protocol-specified criteria being met for increases in serum transaminases. Serious adverse events were more frequent among patients randomized to placebo. Three patients in each group developed kidney failure. Conclusions In adolescent and adult patients with Alport syndrome receiving standard of care, treatment with bardoxolone methyl resulted in preservation in eGFR relative to placebo after a 2-year study period; off-treatment results using all available data were not significantly different. Clinical Trial registry name and registration number: A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome - CARDINAL (CARDINAL), NCT03019185Item An International Cohort Study of Autosomal Dominant Tubulointerstitial Kidney Disease due to REN Mutations Identifies Distinct Clinical Subtypes(Elsevier, 2020-12) Živná, Martina; Kidd, Kendrah; Zaidan, Mohamad; Vyleťal, Petr; Barešová, Veronika; Hodaňová, Kateřina; Sovová, Jana; Hartmannová, Hana; Votruba, Miroslav; Trešlová, Helena; Jedličková, Ivana; Sikora, Jakub; Hůlková, Helena; Robins, Victoria; Hnízda, Aleš; Živný, Jan; Papagregoriou, Gregory; Mesnard, Laurent; Beck, Bodo B.; Wenzel, Andrea; Tory, Kálmán; Häeffner, Karsten; Wolf, Matthias T.F.; Bleyer, Michael E.; Sayer, John A.; Ong, Albert C.M.; Balogh, Lídia; Jakubowska, Anna; Łaszkiewicz, Agnieszka; Clissold, Rhian; Shaw-Smith, Charles; Munshi, Raj; Haws, Robert M.; Izzi, Claudia; Capelli, Irene; Santostefano, Marisa; Graziano, Claudio; Scolari, Francesco; Sussman, Amy; Trachtman, Howard; Decramer, Stephane; Matignon, Marie; Grimbert, Philippe; Shoemaker, Lawrence R.; Stavrou, Christoforos; Abdelwahed, Mayssa; Belghith, Neila; Sinclair, Matthew; Claes, Kathleen; Kopel, Tal; Moe, Sharon; Deltas, Constantinos; Knebelmann, Bertrand; Rampoldi, Luca; Kmoch, Stanislav; Bleyer, Anthony J.; Medicine, School of MedicineThere have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.Item Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome(Karger, 2021) Chertow, Glenn M.; Appel, Gerald B.; Andreoli, Sharon; Bangalore, Sripal; Block, Geoffrey A.; Chapman, Arlene B.; Chin, Melanie P.; Gibson, Keisha L.; Goldsberry, Angie; Iijima, Kazumoto; Inker, Lesley A.; Knebelmann, Bertrand; Mariani, Laura H.; Meyer, Colin J.; Nozu, Kandai; O'Grady, Megan; Silva, Arnold L.; Stenvinkel, Peter; Torra, Roser; Warady, Bradley A.; Pergola, Pablo E.; Pediatrics, School of MedicineIntroduction: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome. Methods: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12-70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30-90 mL/min/1.73 m2, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. Results: A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. Discussion/conclusion: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.