Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Anti-PR3 antibodies cause kidney disease.

<p>(A–C) PAS stained images of glomeruli from chimera mice 6 days after injection with anti-PR3 (n = 18, A, 400×; C, 600×) or control IgG (n = 8, B, 600×). Note extra-capillary proliferation and peri-glomerular inflammation (arrowhead) (A), and mesangiolysis (C, arrow) in anti-PR3 treated mice. (D–F) H & E stained sections of kidney from chimera mice treated with anti-PR3 (D, 40×) or disease control (E, 40×) IgG. There are regions of tubulointerstitial injury, with red cell cast formation (arrow). (F) Demonstrates intense peri-glomerular inflammation in an animal treated with anti-PR3 IgG (arrowhead, 400×). By comparison mice treated with disease control IgG showed minimal glomerular or tubulointerstitial changes. (G) Fractions of glomeruli affected in anti-PR3 (n = 18) and control IgG (n = 8) treated animals (Error bars depict SEM; ***<i>p</i> = 0.001) (H). Degree of tubulointerstitial disease in mice treated with anti-PR3 antibodies and control antibodies (*<i>P</i><0.05, median ± IQ ± max/min values). (Bars = 50 µm).</p

Characterization of chimerism in NOD-<i>scid</i>-<i>IL2Rγ^−/−</i> mice.

<p>(A–D) Flow cytometric analysis of leukocytes from tail bleeds six weeks after administration of HSCs (n = 26 mice). (A) Plots showing mouse leukocytes labelled with anti-mouse CD45 antibodies. Compared with control wild-type mouse blood, chimeras have populations of mCD45 negative leukocytes that show SSC characteristics of granulocytes (High), monocytes (Int) and lymphocytes (low). (B) Chimera blood leukocytes express human CD45 and many of these express CD11b. hCD45+,CD11b+ leukocytes predominantly express hCD15 and hCD66b compared with hCD45+,CD11b− leukocytes shown in histograms. (C) A proportion of hCD45+ leukocytes express CD19. (D) Some hCD45 leukocytes are CD14^high and some are CD16+,CD14^low. (E) In chimera bone marrow there are CD11b+ leukocytes which do not express mCD45 and among hCD45+ leukocytes a proportion express CD14 and a proportion express CD66b. (F) In chimera spleen there are CD11b+ leukocytes which express hCD45 and among hCD45+ leukocytes many express both CD14 and CD16. (G) Bone marrow spreads from wild type or chimera mice, labelled with anti-hMPO or anti-hPR3 IgG antibodies (red) purified from patients with vasculitis. Note that chimera bone marrow demonstrates anti-hMPO or anti-hPR3 antibody positive leukocytes with characteristic human neutrophil nuclear morphology. Wild type mouse bone marrow shows no cells positive for these antigens indicating that the anti-human antibodies do not cross react with mouse neutrophils.</p

Characterization of the chimeric immune system.

<p>Blood, bone marrow and splenic digests were analysed by flow cytometry to define the leukocyte populations (n = 26 mice). Treatment groups were matched by degree of peripheral blood chimerism prior to IgG injection. hMono = human monocytes. There was no significant difference in degree of chimerism or human granulocyte reconstitution between the experimental groups.</p

Gene expression analysis for glycosaminoglycan modifying/degrading enzymes in DM and GAGs treated groups related to control.

<p>Gray columns, DM; dark gray, FCS and black, ENX. *<i>p<</i>0.05 vs. control. HPSE, heparanase-1; CS, chondroitin sulfate; NDST-1, N-deacetylase/N-sulfotransferase; HS-3-ST-1, heparan sulfate-3-O-sulfotransferase 1.</p