Abstract

Diabetic kidney disease (DKD) is the most common cause of ESKD in the United States and worldwide. Current treatment for DKD includes strict glycemic control and normalization of BP with renin-angiotensin-aldosterone system (RAAS) blockade. Although RAAS blockers slow progression of disease, they do not generally prevent ESKD and none of the studies with these agents in DKD included patients who were nonproteinuric, which make up an increasingly large percentage of patients with diabetes now seen in clinical practice. Recent studies with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown beneficial renal effects, and the benefits of SGLT2 inhibitors likely extend to patients who are nonproteinuric. However, there remains a need to develop new therapies for DKD, particularly in those patients with advanced disease. A role of chronic low-grade inflammation in microvascular complications in patients with diabetes has now been widely accepted. Large clinical trials are being carried out with experimental agents such as bardoxolone and selonsertib that target inflammation and oxidative stress. The Food and Drug Administration-approved, nonspecific phosphodiesterase inhibitor pentoxifylline (PTX) has been shown to have anti-inflammatory effects in both animal and human studies by inhibiting the production of proinflammatory cytokines. Small randomized clinical trials and meta-analyses indicate that PTX may have therapeutic benefits in DKD, raising the possibility that a clinically available drug may be able to be repurposed to treat this disease. A large, multicenter, randomized clinical trial to determine whether this agent can decrease time to ESKD or death is currently being conducted, but results will not be available for several years. At this time, the combination of RAAS blockade plus SGLT2 inhibition is considered standard of care for DKD, but it may be reasonable for clinicians to consider addition of PTX in patients whose disease continues to progress despite optimization of current standard-of-care therapies.

Highlights

  • Diabetic kidney disease (DKD) is the most common cause of ESKD in the United States [1]

  • Conclusions there is much evidence that inflammation is important in the progression of DKD, there are no large clinical trials showing benefit of anti-inflammatory therapies

  • The current literature suggests that PTX may have therapeutic benefits in addition to renin-angiotensin-aldosterone system (RAAS) blockade in DKD

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Summary

Introduction

Diabetic kidney disease (DKD) is the most common cause of ESKD in the United States [1]. In a recent meta-analysis, serum and urinary concentrations of TNF-a are elevated in patients with DKD and these concentrations increase concomitantly with the progression of CKD [31] This cytokine is cytotoxic to glomerular cells in vitro [32] and increases protein permeability in isolated glomeruli, independent of hemodynamic alterations or effects of recruited inflammatory cells [33]. PTX has been shown to decrease oxidative stress in diabetic animal models [58] Another possible anti-inflammatory effect of PTX may be stimulation of Klotho, a type I single-pass transmembrane protein predominantly expressed in the kidneys [61]. In a recent post hoc analysis of the PREDIAN trial by Navarro-González et al [67], administration of PTX to patients with type 2 DM with CKD stages 3 and 4 resulted in some reduction of serum and urinary TNF-a and increased serum and urinary Klotho concentrations. Meta-analyses of small trials are insufficient to guide therapy because they tend to overestimate treatment effects compared to large trials, partly due to publication bias

Conclusions
American Diabetes Association
Findings
49. US Food and Drug Administration

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