Effects of the chymase inhibitor fulacimstat in diabetic kidney disease—results from the CADA DIA trial

Abstract Background The protease chymase generates multiple factors involved in tissue remodelling including angiotensin II (Ang II) and has been implicated in the pathophysiology of diabetic kidney disease (DKD). This study investigated the effects of the chymase inhibitor fulacimstat on albuminuria in patients with Type II diabetes mellitus and a clinical diagnosis of DKD. Methods In this double-blind, randomized, placebo-controlled trial, patients were on the maximum tolerated dose of either an Ang II receptor blocker or an Ang-converting enzyme inhibitor since at least 3 months before the screening visit. Eligible patients were randomized in a 2:1 ratio to treatment with either 25 mg fulacimstat (n = 99) or placebo (n = 48) twice daily on top of standard of care. Results The randomized patients had a mean urine albumin–creatinine ratio (UACR) of 131 mg/g (range: 29–2429 mg) and a mean (standard deviation) estimated glomerular filtration rate of 60.8 ± 16.9 mL/min/1.73 m2 before treatment start. Fulacimstat was safe and well tolerated, and achieved mean total trough concentrations that were ∼9-fold higher than those predicted to be required for minimal therapeutic activity. UACR increased by 27.4% [coefficient of variation (CV) 86%] and 3% (CV 88.9%) after 24 weeks of treatment with placebo or fulacimstat, respectively. Analysis of covariance revealed a least square mean UACR ratio (fulacimstat/placebo) of 0.804 (90% CI 0.627–1.030, P = 0.1477), indicating a statistically non-significant UACR reduction of 19.6% after fulacimstat treatment compared with placebo. Conclusions Fulacimstat was safe and well tolerated but did not reduce albuminuria in patients with DKD. These findings do not support a therapeutic role for chymase inhibition in DKD.

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Connectivity mapping of glomerular proteins identifies dimethylaminoparthenolide as a new inhibitor of diabetic kidney disease

Scientific Reports ◽

10.1038/s41598-020-71950-7 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Julie Klein ◽

Cécile Caubet ◽

Mylène Camus ◽

Manousos Makridakis ◽

Colette Denis ◽

...

Keyword(s):

Kidney Disease ◽

Large Scale ◽

Diabetic Kidney Disease ◽

Enzyme Inhibitor ◽

Oral Treatment ◽

Drug Repurposing ◽

Water Soluble ◽

Diabetic Patients ◽

Diabetic Kidney ◽

Connectivity Mapping

Abstract While blocking the renin angiotensin aldosterone system (RAAS) has been the main therapeutic strategy to control diabetic kidney disease (DKD) for many years, 25–30% of diabetic patients still develop the disease. In the present work we adopted a systems biology strategy to analyze glomerular protein signatures to identify drugs with potential therapeutic properties in DKD acting through a RAAS-independent mechanism. Glomeruli were isolated from wild type and type 1 diabetic (Ins2Akita) mice treated or not with the angiotensin-converting enzyme inhibitor (ACEi) ramipril. Ramipril efficiently reduced the urinary albumin/creatine ratio (ACR) of Ins2Akita mice without modifying DKD-associated renal-injuries. Large scale quantitative proteomics was used to identify the DKD-associated glomerular proteins (DKD-GPs) that were ramipril-insensitive (RI-DKD-GPs). The raw data are publicly available via ProteomeXchange with identifier PXD018728. We then applied an in silico drug repurposing approach using a pattern-matching algorithm (Connectivity Mapping) to compare the RI-DKD-GPs’s signature with a collection of thousands of transcriptional signatures of bioactive compounds. The sesquiterpene lactone parthenolide was identified as one of the top compounds predicted to reverse the RI-DKD-GPs’s signature. Oral treatment of 2 months old Ins2Akita mice with dimethylaminoparthenolide (DMAPT, a water-soluble analogue of parthenolide) for two months at 10 mg/kg/d by gavage significantly reduced urinary ACR. However, in contrast to ramipril, DMAPT also significantly reduced glomerulosclerosis and tubulointerstitial fibrosis. Using a system biology approach, we identified DMAPT, as a compound with a potential add-on value to standard-of-care ACEi-treatment in DKD.

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1073-P: Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Soluble Guanylate Cyclase Stimulator Praliciguat in Patients with Diabetic Kidney Disease

Diabetes ◽

10.2337/db20-1073-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 1073-P

Author(s):

JOHN P. HANRAHAN ◽

IAN DE BOER ◽

GEORGE BAKRIS ◽

PHEBE WILSON ◽

JAMES D. WAKEFIELD ◽

...

Keyword(s):

Kidney Disease ◽

Guanylate Cyclase ◽

Diabetic Kidney Disease ◽

Soluble Guanylate Cyclase ◽

Controlled Trial ◽

Phase 2 ◽

Double Blind ◽

Diabetic Kidney ◽

Double Blind Placebo ◽

Soluble Guanylate Cyclase Stimulator

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Prevention of contrast-induced nephropathy with single bolus erythropoietin in patients with diabetic kidney disease: A randomized controlled trial

Nephrology ◽

10.1111/nep.12609 ◽

2016 ◽

Vol 21 (4) ◽

pp. 295-300 ◽

Cited By ~ 3

Author(s):

Lilach Shema-Didi ◽

Batya Kristal ◽

Sarit Eizenberg ◽

Nabil Marzuq ◽

Majdy Sussan ◽

...

Keyword(s):

Randomized Controlled Trial ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

Controlled Trial ◽

Contrast Induced Nephropathy ◽

Diabetic Kidney ◽

Single Bolus ◽

Randomized Controlled

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A Phase IIb Randomized Controlled Trial Investigating the Effects of Tocotrienol-Rich Vitamin E on Diabetic Kidney Disease

Nutrients ◽

10.3390/nu13010258 ◽

2021 ◽

Vol 13 (1) ◽

pp. 258

Author(s):

Yan Yi Koay ◽

Gerald Chen Jie Tan ◽

Sonia Chew Wen Phang ◽

J-Ian Ho ◽

Pei Fen Chuar ◽

...

Keyword(s):

Vitamin E ◽

Kidney Disease ◽

Serum Creatinine ◽

Diabetic Kidney Disease ◽

Controlled Trial ◽

Intervention Group ◽

Serum Biomarkers ◽

Double Blind ◽

Diabetic Kidney ◽

Vitamin E Supplementation

Diabetic kidney disease (DKD) is a debilitating complication of diabetes, which develops in 40% of the diabetic population and is responsible for up to 50% of end-stage renal disease (ESRD). Tocotrienols have shown to be a potent antioxidant, anti-inflammatory, and antifibrotic agent in animal and clinical studies. This study evaluated the effects of 400 mg tocotrienol-rich vitamin E supplementation daily on 59 DKD patients over a 12-month period. Patients with stage 3 chronic kidney disease (CKD) or positive urine microalbuminuria (urine to albumin creatinine ratio; UACR > 20–200 mg/mmol) were recruited into a randomized, double-blind, placebo-controlled trial. Patients were randomized into either intervention group (n = 31) which received tocotrienol-rich vitamin E (Tocovid SupraBioTM; Hovid Berhad, Ipoh, Malaysia) 400 mg daily or a placebo group which received placebo capsules (n = 28) for 12 months. HbA1c, renal parameters (i.e., serum creatinine, eGFR, and UACR), and serum biomarkers were collected at intervals of two months. Tocovid supplementation significantly reduced serum creatinine levels (MD: −4.28 ± 14.92 vs. 9.18 ± 24.96), p = 0.029, and significantly improved eGFR (MD: 1.90 ± 5.76 vs. −3.29 ± 9.24), p = 0.011 after eight months. Subgroup analysis of 37 patients with stage 3 CKD demonstrated persistent renoprotective effects over 12 months; Tocovid improved eGFR (MD: 4.83 ± 6.78 vs. −1.45 ± 9.18), p = 0.022 and serum creatinine (MD: −7.85(20.75) vs. 0.84(26.03), p = 0.042) but not UACR. After six months post washout, there was no improvement in serum creatinine and eGFR. There were no significant changes in the serum biomarkers, TGF-β1 and VEGF-A. Our findings verified the results from the pilot phase study where tocotrienol-rich vitamin E supplementation at two and three months improved kidney function as assessed by serum creatinine and eGFR but not UACR.

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Pentoxifylline in diabetic kidney disease (VA PTXRx): protocol for a pragmatic randomised controlled trial

BMJ Open ◽

10.1136/bmjopen-2021-053019 ◽

2021 ◽

Vol 11 (8) ◽

pp. e053019

Author(s):

David J Leehey ◽

Kimberly Carlson ◽

Domenic J Reda ◽

Ian Craig ◽

Christina Clise ◽

...

Keyword(s):

Kidney Disease ◽

Usual Care ◽

Large Scale ◽

Diabetic Kidney Disease ◽

Controlled Trial ◽

Scientific Journal ◽

Phosphodiesterase Inhibitor ◽

Major Adverse Cardiovascular Events ◽

Diabetic Kidney ◽

Study Results

IntroductionDiabetic kidney disease (DKD) is the most frequent cause of end-stage renal disease (ESRD) in the USA and worldwide. Recent experimental and clinical data suggest that the non-specific phosphodiesterase inhibitor pentoxifylline (PTX) may decrease progression of chronic kidney disease. However, a large-scale randomised clinical trial is needed to determine whether PTX can reduce ESRD and death in DKD.Methods and analysisVeterans Affairs (VA) PTXRx is a pragmatic, randomised, placebo-controlled multicentre VA Cooperative Study to test the hypothesis that PTX, when added to usual care, leads to a reduction in the time to ESRD or death in patients with type 2 diabetes with DKD when compared with usual care plus placebo. The study aims to enrol 2510 patients over a 4-year period with an additional up to 5-year follow-up to generate a total of 646 primary events. The primary objective of this study is to compare the time until ESRD or death (all-cause mortality) between participants randomised to PTX or placebo. Secondary endpoints will be: (1) health-related quality of life, (2) time to doubling of serum creatinine, (3) incidence of hospitalisations for congestive heart failure, (4) incidence of a three-point major adverse cardiovascular events composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), (5) incidence of peripheral vascular disease, (6) change in urinary albumin-to-creatinine ratio from baseline to 6 months and (7) rate of annual change in estimated glomerular filtration rate (eGFR) during the study period.Ethics and disseminationThis study was approved by the VA Central Institutional Review Board (cIRB/18-36) and will be conducted in compliance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. The Hines Cooperative Studies Programme will finalise the study results, which will be published in accordance with the Consolidated Standards of Reporting Trials statement in a peer-reviewed scientific journal.Trial registration numberNCT03625648.

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Effect of Dipeptidyl Peptidase-4 (DPP-4) Inhibition on Biomarkers of Kidney Injury and Vascular Calcification in Diabetic Kidney Disease: A Randomized Controlled Trial

Journal of Diabetes Research ◽

10.1155/2021/7382620 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Thananda Trakarnvanich ◽

Bancha Satirapoj ◽

Swangjit Suraamornkul ◽

Thanit Chirananthavat ◽

Anoma Sanpatchayapong ◽

...

Keyword(s):

Kidney Disease ◽

Vascular Calcification ◽

Diabetic Kidney Disease ◽

Controlled Trial ◽

Kidney Injury ◽

Dipeptidyl Peptidase ◽

Control Group ◽

Fatty Acid Binding ◽

Diabetic Kidney ◽

Dipeptidyl Peptidase 4

Introduction. Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control and have pleiotropic effects on kidney injury, albuminuria, and vascular inflammation, especially in animal models. We evaluated the effects of a potent DPP4 inhibitor (gemigliptin) on these processes among patients with diabetic kidney disease (DKD). Methods. This study employed a multicenter, prospective, randomized, placebo-controlled design. A total of 201 participants were enrolled and randomly assigned to one of two groups, one received treatment with 50 mg gemigliptin daily along with standard care for diabetes mellitus for 6 months. The changes in the coronary calcium score (CAC score), cardio-ankle vascular index (CAVI), estimated glomerular filtration rate (eGFR), vascular calcification level, and tubular renal injury marker expression were evaluated at baseline and 6 months. Results. In total, 182 patients completed the study. Significant reductions in hemoglobin A1C levels were observed in both groups. The changes in the CAC score, CAVI, eGFR, and level of proteinuria over the 6 months of the study did not significantly differ between the gemigliptin and control groups. However, biomarkers of vascular calcification, including serum bone alkaline phosphatase and kidney injury, including urine neutrophil gelatinase-associated lipocalin (NGAL)/Cr and urine liver fatty acid-binding protein (L-FABP)/Cr, were improved significantly in the gemigliptin treatment group compared with the control group. No serious adverse events were observed during the study. Conclusion. Our study showed that gemigliptin significantly improved the expression of renal tubular injury biomarkers and vascular calcification levels among patients with DKD; however, gemigliptin did not affect renal function or coronary calcification compared with those observed in the control. A larger study with a longer follow-up is essential to verify these beneficial effects. Clinical Trials. This trial is registered with ClinicalTrials.Gov Identifier NCT04705506.

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