Translating the efficacy of dapagliflozin in chronic kidney disease to lower healthcare resource utilization and costs: a medical care cost offset analysis

AIMS: Dapagliflozin was approved for use in patients with chronic kidney disease (CKD) based on results of the DAPA-CKD trial, demonstrating attenuation of CKD progression and reduced risk of cardio-renal outcomes and all-cause mortality (ACM) versus placebo, in addition to standard therapy. The study objective was to assess the potential medical care cost offsets associated with reduced rates of cardio-renal outcomes across 31 countries and regions. MATERIALS AND METHODS: A comparative cost-determination framework estimated outcome-related costs of dapagliflozin plus standard therapy versus standard therapy alone over a 3-year horizon based on the DAPA-CKD trial. Incidence rates of end-stage kidney disease (ESKD), hospitalizations for heart failure (HHF), acute kidney injury (AKI), and ACM were estimated for a treated population of 100,000 patients. Associated medical care costs for non-fatal events were calculated using sources from a review of publicly available data specific to each considered setting. RESULTS: Patients treated with dapagliflozin plus standard therapy experienced fewer incidents of ESKD (7,221 vs 10,767; number needed to treat, NNT: 28), HHF (2,370 vs 4,684; NNT: 43), AKI (4,110 vs. 5,819; NNT: 58), and ACM (6,383 vs 8,874; NNT: 40) per 100,000 treated patients versus those treated with standard therapy alone. Across 31 countries/regions, reductions in clinical events were associated with a 33% reduction in total costs, or a cumulative mean medical care cost offset of $264 million per 100,000 patients over 3 years. LIMITATIONS AND CONCLUSIONS: This analysis is limited by the quality of country/region-specific data available for medical care event costs. Based on the DAPA-CKD trial, we show that treatment with dapagliflozin may prevent cardio-renal event incidence at the population level, which could have positive effects upon healthcare service delivery worldwide. The analysis was restricted to outcome-associated costs and did not consider the cost of drug treatments and disease management

The structure of galactic disks: Studying late-type spiral galaxies using SDSS

Using imaging data from the SDSS survey, we present the g' and r' radial stellar light distribution of a complete sample of ~90 face-on to intermediate inclined, nearby, late-type (Sb-Sdm) spiral galaxies. The surface brightness profiles are reliable (1sigma uncertainty less than 0.2 mag) down to mu=~27magsqarcsec. Only ~10% of all galaxies have a normal/standard purely exponential disk down to our noise limit. The surface brightness distribution of the rest of the galaxies is better described as a broken exponential. About 60% of the galaxies have a break in the exponential profile between ~1.5-4.5 times the scalelength followed by a downbending, steeper outer region. Another ~30% shows also a clear break between ~4.0-6.0 times the scalelength but followed by an upbending, shallower outer region. A few galaxies have even a more complex surface brightness distribution. The shape of the profiles correlates with Hubble type. Downbending breaks are more frequent in later Hubble types while the fraction of upbending breaks rises towards earlier types. No clear relation is found between the environment, as characterised by the number of neighbours, and the shape of the profiles of the galaxies.Comment: LaTeX, 69 pages, 213 (very low resolution) figures, A&A accepted. Second version to match the accepted one including all referee's comments. Version with full resolution figures (highly recommended, but with 7.6MB) available at http://www.astro.rug.nl/~pohlen/pohlenSDSS.pd

Nineteen novel NPHS1 mutations in a worldwide cohort of patients with congenital nephrotic syndrome (CNS)

Background. Recessive mutations in the NPHS1 gene encoding nephrin account for ∼40% of infants with congenital nephrotic syndrome (CNS). CNS is defined as steroid-resistant nephrotic syndrome (SRNS) within the first 90 days of life. Currently, more than 119 different mutations of NPHS1 have been published affecting most exons. Methods. We here performed mutational analysis of NPHS1 in a worldwide cohort of 67 children from 62 different families with CNS. Results. We found bi-allelic mutations in 36 of the 62 families (58%) confirming in a worldwide cohort that about one-half of CNS is caused by NPHS1 mutations. In 26 families, mutations were homozygous, and in 10, they were compound heterozygous. In an additional nine patients from eight families, only one heterozygous mutation was detected. We detected 37 different mutations. Nineteen of the 37 were novel mutations (∼51.4%), including 11 missense mutations, 4 splice-site mutations, 3 nonsense mutations and 1 small deletion. In an additional patient with later manifestation, we discovered two further novel mutations, including the first one affecting a glycosylation site of nephrin. Conclusions. Our data hereby expand the spectrum of known mutations by 17.6%. Surprisingly, out of the two siblings with the homozygous novel mutation L587R in NPHS1, only one developed nephrotic syndrome before the age of 90 days, while the other one did not manifest until the age of 2 years. Both siblings also unexpectedly experienced an episode of partial remission upon steroid treatmen

A systematic approach to mapping recessive disease genes in individuals from outbred populations

The identification of recessive disease-causing genes by homozygosity mapping is often restricted by lack of suitable consanguineous families. To overcome these limitations, we apply homozygosity mapping to single affected individuals from outbred populations. In 72 individuals of 54 kindred ascertained worldwide with known homozygous mutations in 13 different recessive disease genes, we performed total genome homozygosity mapping using 250,000 SNP arrays. Likelihood ratio Z-scores (ZLR) were plotted across the genome to detect ZLR peaks that reflect segments of homozygosity by descent, which may harbor the mutated gene. In 93% of cases, the causative gene was positioned within a consistent ZLR peak of homozygosity. The number of peaks reflected the degree of inbreeding. We demonstrate that disease-causing homozygous mutations can be detected in single cases from outbred populations within a single ZLR peak of homozygosity as short as 2 Mb, containing an average of only 16 candidate genes. As many specialty clinics have access to cohorts of individuals from outbred populations, and as our approach will result in smaller genetic candidate regions, the new strategy of homozygosity mapping in single outbred individuals will strongly accelerate the discovery of novel recessive disease genes

ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.ope

Comparative 3D analyses and palaeoecology of giant early amphibians (Temnospondyli: Stereospondyli)

Macroevolutionary, palaeoecological and biomechanical analyses in deep time offer the possibility to decipher the structural constraints, ecomorphological patterns and evolutionary history of extinct groups. Here, 3D comparative biomechanical analyses of the extinct giant early amphibian group of stereospondyls together with living lissamphibians and crocodiles, shows that: i) stereospondyls had peculiar palaeoecological niches with proper bites and stress patterns very different than those of giant salamanders and crocodiles; ii) their extinction may be correlated with the appearance of neosuchians, which display morphofunctional innovations. Stereospondyls weathered the end-Permian mass extinction, re-radiated, acquired gigantic sizes and dominated (semi) aquatic ecosystems during the Triassic. Because these ecosystems are today occupied by crocodilians, and stereospondyls are extinct amphibians, their palaeobiology is a matter of an intensive debate: stereospondyls were a priori compared with putative living analogous such as giant salamanders and/or crocodilians and our new results try to close this debate.Peer ReviewedPostprint (published version

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

Plasmapheresis-induced Clinical Improvement in a Patient with Steroid-Resistant Nephrotic Syndrome Due to Podocin (NPHS2) Gene Station

Podocin mutations (NPHS2 gene) are mostly responsible for steroid-resistant nephrotic syndrome (SRNS) of childhood onset. Patients with NPHS2 gene mutations do not respond to corticoids and other immunosuppressive agents; partial remission can be rarely induced by cyclosporin A. We present a boy, where SRNS was diagnosed within first year of life. By the age of 15 years, proteinuria reached 9000 mg/24 h, cholesterolemia 15 mmol/L, albuminemia 19.6 g/L, in spite of combined therapy with cyclosporine A, methylprednisolone, enalapril and losartan. At that time a combined heterozygous form of two NPHS2 gene mutations (p.R138Q and p.V290M) was diagnosed, methylprednisolone was discontinued and patient underwent ten plasmapheresis procedures. This resulted in clinical improvement (proteinuria 3000 mg/24 h, S-cholesterol 6 mmol/L, albumin 30g/L) lasting for three years. In conclusion, plasmapheresis can result in clinical improvement and stabilization of SRNS caused by podocine mutation, before renal replacement therapy is initiated