Targeting Inflammation in Diabetic Kidney Disease: Is There a Role for Pentoxifylline?

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.

Keywords: Anti-Inflammatory Agents; Diabetes and the Kidney; Diabetic Nephropathies; Inflammation; Pentoxifylline; Sodium-Glucose Transporter 2 Inhibitors; Standard of Care.

Figure 1.

Pentoxifylline inhibits phosphodiesterase activity, increasing cAMP levels that activate protein kinase A. Active protein kinase A (aPKA) would inhibit ubiquitination that drives inhibitor of κ B α (IκBα) to 26S proteasome degradation and p50/p65 activation of the expression of cytokines and other genes. Decreased levels of TNF-α (TNF) and TNF-related weak inducer of apoptosis (TWEAK) increases Klotho (KL) expression, whereas KL inhibits the production of proinflammatory cytokines and TNF-induced adhesion molecules. AC, adenylate cyclase; CRP, C-reactive protein; ICAM1, intercellular adhesion molecule 1; IFNG, IFN-γ; P, phosphorylation; p50, NF-κB p50 subunit (NF-κ-light-chain-enhancer of activated B cells 1); p65, NF-κB p65 subunit (RelA; v-rel avian reticuloendotheliosis viral oncogene homolog A); PTX, pentoxifylline; VCAM1, vascular cell adhesion molecule 1. Reprinted from reference 43 (Donate-Correa J, Tagua VG, Ferri C, Martín-Núñz E, Hernández- Carballo C, Ureña-Torres P, Ruiz-Ortega M, Ortiz A, Mora-Fernández C, Navarro-González JF: Pentoxifylline for renal protection in diabetic kidney disease. A model of old drugs for new horizons. J Clin Med 8: E287, 2019), which is available under the terms of the Creative Commons Attribution License.