Clinical characteristics and disease outcomes in non-diabetic chronic kidney disease: retrospective analysis of a US healthcare claims database.

BACKGROUND: The observational, real-world evidence FLIEDER study aimed to describe patient clinical characteristics and investigate clinical outcomes in non-diabetic patients with chronic kidney disease (CKD) using data collected from routine clinical practice in the United States. METHODS: Between 1 January, 2008-31 December, 2018, individuals aged ≥ 18 years, with non-diabetic, stage 3-4 CKD were indexed in the Optum® Clinformatics® Data Mart US healthcare claims database using International Classification of Diseases-9/10 codes for CKD or by laboratory values (estimated glomerular filtration rate [eGFR] 15-59 mL/min/1.73 m2). The primary outcomes were hospitalization for heart failure, a composite kidney outcome of end-stage kidney disease/kidney failure/need for dialysis and worsening of CKD stage from baseline. The effects of the intercurrent events of a sustained post-baseline decline in eGFR ≥ 30%, ≥ 40%, and ≥ 57% on the subsequent risk of the primary outcomes were also assessed. RESULTS: In the main study cohort (N = 504,924), median age was 75.0 years, and 60.5% were female. Most patients (94.7%) had stage 3 CKD at index. Incidence rates for hospitalization for heart failure, the composite kidney outcome, and worsening of CKD stage from baseline were 4.0, 10.3, and 4.4 events/100 patient-years, respectively. The intercurrent event analysis demonstrated that a relative decline in kidney function from baseline significantly increased the risk of cardiorenal events. CONCLUSIONS: This real-world study highlights that patients with non-diabetic CKD are at high risk of serious adverse clinical outcomes, and that this risk is amplified in patients who experienced greater post-baseline eGFR decline.

Finerenone Dose-Exposure-Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria.

BACKGROUND: Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist (MRA) that demonstrated efficacy in delaying the progression of chronic kidney disease (CKD) and reducing cardiovascular events in patients with CKD and type 2 diabetes mellitus in FIDELIO-DKD, where 5734 patients were randomized 1:1 to receive either finerenone or placebo, with a median follow-up of 2.6 years. Doses of finerenone 10 or 20 mg once daily were titrated based on (serum) potassium and estimated glomerular filtration rate. The MRA mode of action increases potassium. METHODS: Nonlinear mixed-effects population pharmacokinetic/pharmacodynamic models were used to analyze the finerenone dose-exposure-response relationship for potassium in FIDELIO-DKD. Individual time-varying exposures from pharmacokinetic analyses were related to the potassium response via a maximal effect, indirect-response model informed by 148,384 serum potassium measurements. RESULTS: Although observed potassium levels decreased with increasing dose (i.e., inverse relation), model-based simulations for a fixed-dose setting (i.e., no dose titration) revealed the intrinsic finerenone dose-exposure-potassium response, with potassium levels increasing in a dose- and exposure-dependent manner, thus explaining the apparent conflict. The potassium limit for inclusion and uptitration from finerenone 10 to 20 mg in FIDELIO-DKD was ≤ 4.8 mmol/L. Modified limits of ≤ 5.0 mmol/L were simulated, resulting in higher hyperkalemia frequencies for both the finerenone and the placebo arms, whereas the relative hyperkalemia risk of a finerenone treatment compared with placebo did not increase. CONCLUSIONS: The analyses demonstrated the effectiveness of finerenone dose titration in managing serum potassium and provide a quantitative basis to guide safe clinical use.

Comparative screening of glial cell types reveals extracellular matrix that inhibits retinal axon growth in a chondroitinase ABC-resistant fashion.

Glial cells provide an optimal surface for attachment, migration, and growth of CNS neurons. This study was designed to investigate the ability of four glia cell types, retinal Müller Glia (MG), cortical astrocytes (CA), A7, and Oli-neu to support the outgrowth of embryonic day 18 rat retinal explants. Extracellular matrix (ECM) prepared by water lysis of monolayers of A7, CA, and MG cells significantly increased, whereas Oli-neu-derived ECM inhibited fiber growth. Analogous results were obtained with explants on live monolayers. The inhibitory effect of Oli-neu matrix, but not of live cells, could be neutralized with the Rho-kinase inhibitor Y27632. Studies on the message and protein level revealed the expression of a range of ECM glycoproteins and the major chondroitin sulfate proteoglycans (CSPGs). Oli-neu produced large amounts of tenascin-C (TN-C), DSD-1-PG/phosphacan, and NG2, correlating with its inhibitory properties. Upon treatment with chondroitinase ABC (ChABC), retinal axon growth was increased on CA, MG, and A7, in accordance with the degradation of inhibitory CSPGs. In contrast, inhibition exerted by Oli-neu or postnatal oligodendrocytes was not abolished. When the neurite growth promoting properties of TN-C were neutralized by the monoclonal antibody J1/tn2, retinal axon growth was clearly diminished on MG, indicating a dominance of the FNIII domain D of TN-C in this cell type. The results suggest that glial cells construct complex ECM structures with distinct properties ranging from promotion to inhibition of retinal axons, depending on their composition. Furthermore, inhibitory ECM may resist ChABC treatment in some situations.