Diabetic kidney disease - Emerging treatments

Pentoxifylline

Several small studies have suggested that pentoxifylline may decrease proteinuria and possibly slow decline of renal function in DKD. One Cochrane review meta-analysis on pentoxifylline in DKD concluded that there was insufficient evidence to support the use of pentoxifylline, but the authors of the review did stress the need for large-scale, rigorously designed, multicenter randomized trials to further assess its use in DKD.[211] [ ] The PREDIAN study reported that treatment with pentoxifylline slowed the progression of DKD in patients with type 2 diabetes and stage 3 to 4 chronic kidney disease (CKD) who were receiving standard medical care, which included maximum renin-angiotensin system (RAS) blockade.[212] Pentoxifylline decreased proteinuria and urinary concentration of tumor necrosis factor-alpha, and slowed the decline in estimated glomerular filtration rate (eGFR) by 4.3 mL/minute/1.73 m² when compared with standard medical care (P=0.001). No serious adverse events were reported. Adverse events that were more common in the treatment arm compared with placebo were mainly digestive symptoms (e.g., abdominal discomfort, flatus, dyspepsia, nausea, and vomiting). The favorable safety profile of pentoxifylline is supported by its extensive clinical experience and use in treating peripheral vascular disease. A Veterans Affairs (VA) Cooperative trial (PTXRx) testing the effects of this agent in high-risk patients with DKD is ongoing (NCT03625648).[213] The VA PTXRx is a double-blind, placebo-controlled, multicenter randomized controlled trial designed to evaluate the utility of pentoxifylline, when added to usual care, in terms of the time to end-stage renal disease (ESRD) or death in patients with type 2 diabetes with DKD.[213] The enrollment of patients for this study began in 2019 and the primary completion date will be at the beginning of 2028.

Paricalcitol

An active vitamin D analog, paricalcitol has been reported to reduce albuminuria in patients with diabetes and could be renoprotective.[214][215] One study has shown that paricalcitol in conjunction with salt restriction reduces albuminuria.[216] However, further clinical trials using hard endpoints are needed before this therapy can be widely recommended.

Sevelamer

Increased inflammation and oxidative stress may be caused by proteins and lipids modified by cytotoxic advanced glycation end products (AGEs) in food. Sevelamer, a phosphate-binding agent used in CKD and end-stage kidney disease patients, sequesters cytotoxic AGEs in the gut, preventing their uptake and thereby reducing AGE-induced abnormalities. In a single-center, randomized, 2-month, open-label, intention-to-treat, crossover study that compared sevelamer with calcium carbonate treatment in stage 2 to 4 diabetic CKD, sevelamer significantly reduced HbA1c, fibroblast growth factor 23, lipids, and markers of inflammation and oxidative stress; it also markedly increased antioxidant markers, independently of phosphorus, in patients with diabetes and early kidney disease. Whether or not these changes affect progression of early diabetic CKD requires further study.[217]

Genomics/proteomics/metabonomics

With the development of mass spectroscopy, liquid chromatography, and microarray protocols, evaluation of DNA, RNA, or protein is increasingly being applied to all disease states. Genomics has, for example, been touted as a potential replacement for kidney biopsies in the diagnosis of acute cellular rejection in kidney transplant patients. Similarly, microRNAs in DKD will pave the way for development of future biomarkers and therapeutic options.[218]

Endothelin-1 receptor antagonists

Preclinical and clinical studies have described that endothelin-1 activity is increased in patients with diabetes, and that endothelin-1 receptor antagonists reduce albuminuria and protect renal function.[219] Endothelin-1 receptor antagonists may improve intraglomerular pressure to preserve renal function and reduce the risk of heart failure due to hypervolemia by inhibiting endothelin-A receptors.[219] Endothelin-1 receptor antagonists have been confirmed to protect glycocalyx function in hyperglycemic environments, which may be one of the mechanisms leading to the improvement in albuminuria in patients with diabetes.[219] Endothelin-1 receptor antagonists can preserve podocyte function and reduce the release of endothelin-1 in the kidney.[219] The investigational endothelin-1 receptor antagonists avosentan and atrasentan have been evaluated for their efficacy and safety in studies of diabetic nephropathy, and a meta-analysis of data in patients with DKD receiving combined treatment with endothelin-1 receptor antagonists and renin-angiotensin-aldosterone system inhibitors showed a reduction in albuminuria, improvement in eGFR, and blood pressure reduction.[219] Endothelin-1 receptor antagonists may be an effective intervention for controlling blood pressure and albuminuria in patients with DKD with decreased eGFR.[219] However, the presence of adverse effects, such as heart failure, anemia, and hypoglycemia, need to be addressed before endothelin-1 receptor antagonists can be put into clinical use.[219]

GMA131/GMA301

GMA131 is the first endothelin-A receptor specific monoclonal antibody to be approved for the clinical study of DKD. Clinical trials of small molecule endothelin receptor antagonists have shown that endothelin-A receptor selective antagonists can reduce proteinuria and improve renal function in patients with DKD. However, water/sodium retention due to nonspecific binding with the endothelin-B receptor and the adverse effects due to the specific structure of small molecules are the main obstacles for clinical application of small molecule endothelin receptor antagonists. In clinical trials, GMA301 (which is the same molecule as GMA131) has shown a superior safety profile in healthy volunteers and pulmonary arterial hypertension patients, without water/sodium retention and edema commonly associated with small molecule endothelin receptor antagonists.[220][221]