Pentoxifylline for Renal Protection in Diabetic Kidney Disease. A Model of Old Drugs for New Horizons

Abstract

Diabetic kidney disease is one of the most relevant complications in diabetes mellitus patients, which constitutes the main cause of end-stage renal disease in the western world. Delaying the progression of this pathology requires new strategies that, in addition to the control of traditional risk factors (glycemia and blood pressure), specifically target the primary pathogenic mechanisms. Nowadays, inflammation is recognized as a critical novel pathogenic factor in the development and progression of renal injury in diabetes mellitus. Pentoxifylline is a nonspecific phosphodiesterase inhibitor with rheologic properties clinically used for more than 30 years in the treatment of peripheral vascular disease. In addition, this compound also exerts anti-inflammatory actions. In the context of diabetic kidney disease, pentoxifylline has shown significant antiproteinuric effects and a delay in the loss of estimated glomerular filtration rate, although at the present time there is no definitive evidence regarding renal outcomes. Moreover, recent studies have reported that this drug can be associated with a positive impact on new factors related to kidney health, such as Klotho. The use of pentoxifylline as renoprotective therapy for patients with diabetic kidney disease represents a new example of drug repositioning.

Hypothesis: Pentoxifylline is a potential cytokine modulator therapeutic in COVID‐19 patients

“…9 More recently pentoxifylline has been determined to have extensive anti-inflammatory properties. 10 Pentoxifylline inhibits 5′-nucleotidase and phosphodiesterase (PDE). PDE inhibition results in increased cAMP levels, increased protein kinase A (PKA) activity and altered transcriptional regulation of pro-inflammatory genes through modulation of the NFkB/IkB pathway.…”

“…PDE inhibition results in increased cAMP levels, increased protein kinase A (PKA) activity and altered transcriptional regulation of pro-inflammatory genes through modulation of the NFkB/IkB pathway. 10 Pentoxifylline also has beneficial therapeutic properties mediated by Adenosine A2A Receptor pathways in immune cells and in particular lung macrophages. Pentoxifylline downregulates transcription and expression levels of TNF alpha, IL1b, IL6, IFN gamma, ICAM1, and VCAM1.…”

Hypothesis: Pentoxifylline is a potential cytokine modulator therapeutic in COVID-19 patients

“…pentoxifylline has rheological actions increasing erythrocyte deformability and was originally licensed for the treatment of peripheral vascular disease on the basis of suggested improvement of microvascular and capillary blood flow [7]. More recently pentoxifylline has been determined to have extensive anti-inflammatory properties [8]. pentoxifylline inhibits 5'-nucleotidase and phosphodiesterases (PDE).…”

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

“…A role of chronic low-grade inflammation in the microvascular complications in diabetic patients has now been widely accepted [42,43]. Several approaches have been proposed to treat inflammation in DKD, including lifestyle modifications (diet and exercise) and medications.…”

“…PTX inhibits predominantly the PDE3 and PDE4 isoforms and thus primarily affects cAMP. The PTXinduced increase in cAMP will in turn increase protein kinase A (PKA) activation, leading to a reduction in synthesis of the inflammatory cytokines IL-1, IL-6, and TNF-α [43,50].…”