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Pentoxifylline: An old drug with new potential

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The American Diabetes Association (ADA) and KDIGO recently issued a consensus statement highlighting shared recommendations for the management of patients living with DKD:1,2

All patients should be treated with a comprehensive plan that optimises nutrition, and encourages exercising, smoking cessation, and weight management. The plan should also include pharmacotherapies aimed at preserving organ function, as well as achieving targets for glycaemia, blood pressure (BP), and lipids.1

An angiotensin-converting-enzyme inhibitor or angiotensin II receptor blocker is recommended for patients who have hypertension and albuminuria, titrated to the maximum antihypertensive or highest tolerated dose.1

A statin is recommended for all patients. A moderate-intensity statin is recommended for primary prevention of atherosclerotic CVD (ASCVD). A high-intensity statin is recommended for patients with known or multiple ASCVD risk factors.1

Metformin is recommended for patients with T2DM, DKD, and an eGFR rate of ≥30ml/min/1.73m2. The dose should be reduced to 1000mg daily in patients with eGFR 30 ml/min/1.73m2-44mL/min/1.73 m2 and in some patients with eGFR 45ml/min/1.73 m2-59mL/min/1.73 m2 who are at high risk of lactic acidosis.1

A sodium-glucose cotransporter 2 inhibitor (SGLT2i) with proven kidney or CV benefit is recommended for patients with T2DM, DKD, and eGFR ≥20mL/min/1.73m2. Once initiated, the SGLT2i can be continued at lower levels of eGFR.1

A glucagon-like peptide 1 receptor agonist with proven CV benefit is recommended for patients with T2DM and DKD who do not meet their individualised glycaemic target with metformin and/or an SGLT2i, or who are unable to use these agents.1

A non-steroidal mineralocorticoid receptor antagonist with proven kidney and CV benefit is recommended for patients with T2DM, eGFR ≥25mL/min/1.73 m2, normal serum potassium concentration, and albuminuria (albumin-to-creatinine ratio ≥30mg/g) despite the maximum tolerated dose of the renin-angiotensin-aldosterone-system (RAAS) inhibitor.1

Current strategies do not halt progression to ESRD

Although the blockade of RAAS is effective in slowing the progression of CKD, it does not halt the development of end-stage renal disease (ESRD). Similarly, while SGLT2i has proven glycaemic control benefits and has been shown to improve kidney outcomes in CV safety trials, it also does not halt renal decline in all patients living with DKD.3,4

Therefore, there is a need for new strategies to improve kidney function, delay the progression of the disease, and eventually improve kidney survival in patients living with DKD, according to Donate-Correa et al.3

The authors argue that the development of new pharmacotherapies takes time and is expensive and propose drug repurposing, a concept that has been investigated since the early 1990s.  The idea behind drug repurposing stems from the fact that different diseases share common molecular pathways and target the same cells. In essence, it means that instead of developing new pharmacotherapies, the indications of existing drugs can potentially be extended.4

In the field of kidney disease, pentoxifylline, a non-selective phosphodiesterase inhibitor with anti-inflammatory, anti-proliferative, and anti-fibrotic properties, has garnered attention over the past two decades. Pentoxifylline was approved by the American Food and Drug Administration to treat intermittent claudication resulting from peripheral vascular disease more than 30 years ago.3,4

Studies show that pentoxifylline diminishes blood viscosity, reduces erythrocyte aggregation, alleviates erythrocyte rigidity, and mitigates platelet aggregation. The enhancement of flexibility and deformability in red blood cells results in ameliorated blood circulation.3

Coupled with its ability to potentially lower intra-glomerular pressure, sparked initial enthusiasm for pentoxifylline as a potential therapeutic intervention in kidney and other diseases including brain ischaemia and non-alcoholic fatty liver diseases, as well as preserving skeletal muscle function.3,4

 Renoprotective effects of pentoxifylline

 Several studies have demonstrated the renoprotective effects of pentoxifylline when added to the RAAS blockade. The agent has shown promise in improving kidney function and delaying disease progression in patients living with DKD.4,5-13

 According to Donate-Correa et al, the most important randomised controlled study to date evaluating the renoprotective effects of pentoxifylline in DKD is the Pentoxifylline for Renoprotection in Diabetic Nephropathy (PREDIAN) study.4,14

Navarro-Gonzalez et al conducted an open-label, prospective, randomised trial to determine whether pentoxifylline used in addition to RAAS blockade, can slow the progression of renal disease in patients living with T2DM and stages 3-4 DKD.14

Participants were assigned to receive pentoxifylline (1200mg/d) (n=82) or to a control group (n=87) for 24 months. All patients received similar doses of RAAS inhibitors. At the end of the study period, eGFR had decreased by a mean of 2.1±0.4ml/min per 1.73 m2 in the pentoxifylline group compared with 6.5±0.4ml/min per 1.73m2 in the control group, with a between-group difference of 4.3ml/min per 1.73m2 in favour of pentoxifylline.14

The proportion of patients with a rate of eGFR decline greater than the median rate of decline (0.16ml/min per 1.73m2 per month) was lower in the pentoxifylline group than in the control group (33.3% versus 68.2%). Percentage change in urinary albumin excretion was 5.7% in the control group and -14.9% in the pentoxifylline group.14

Urine tumour necrosis factor-alpha (TNF-α) decreased from a median of 16ng/g to 14.3ng/g in the pentoxifylline group, with no changes in the control group. In this population, the addition of pentoxifylline to RAAS inhibitors resulted in a smaller decrease in eGFR and a greater reduction of residual albuminuria.14

Donate-Correa et al conclude that studies have consistently shown that pentoxifylline was associated with a decrease in proteinuria and, in some instances, the preservation or enhancement of GFR. Furthermore, studies have also identified a notable reduction in inflammatory markers.4

The reduction in proteinuria has been linked to lowered levels of TNF-α. Studies involving patients living with DKD - particularly those in stages 3 and higher - reported stabilised renal function and reduced TNF-α, fibrinogen, and C-reactive protein levels following pentoxifylline treatment.4

The PREDIAN trial showed that pentoxifylline slowed disease progression, accompanied by decreased proteinuria and urinary TNF-α levels after two years. Meta-analyses reinforced the role of reduced proinflammatory cytokine production, particularly TNF-α, in explaining the anti-proteinuric effects of pentoxifylline in patients living with DKD.4

Furthermore, the positive impact of pentoxifylline on kidney health may extend beyond inflammation control. Soluble Klotho, a protein linked to renal health, has shown promise as a biomarker for renal impairment in patients living with T2DM, and pentoxifylline treatment has been associated with increased Klotho levels.4

The mechanisms behind this stimulation have not been fully elucidated, but the anti-inflammatory properties of pentoxifylline and potential direct effects on Klotho expression have been proposed. In vitro studies further support pentoxifylline's positive influence on Klotho expression.4

Conclusion

Several studies have demonstrated the preservation, and the renoprotective effects of pentoxifylline in patients living with diabetes, marked by reduced proteinuria, potential GFR preservation, and lowered inflammatory markers. The positive influence on Klotho levels adds a novel dimension to its potential benefits in kidney health.4

In South Africa, pentoxifylline is approved for the symptomatic relief of intermittent claudication, associated with chronic occlusive arterial disorders of the limbs and trophic ulcers. Pentoxifylline may improve function as well as provide symptomatic relief. It is also approved for the treatment of Raynaud’s syndrome.15

According to Donate-Correa et al, two long-term studies are currently underway to evaluate the effects of pentoxifylline in patients living with DKD. These include the Veterans Affairs PTXRx (NCT03625648) and the Pentoxifylline Effect in Patients with Diabetic Nephropathy (NCT03664414) studies.4

References

  1.  De Boer IH, et al. Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Kidney International, 2022. [Internet]. 2022. Available at: https://kdigo.org/wp-content/uploads/2018/03/ADA-KDIGO-Consensus-Report-Diabetes-CKD-KI-2022.pdf
  2. Kidney Disease: Improving Global Outcomes (KDIGO). 2022 Clinical practice guideline for diabetes management in chronic kidney disease. Kidney International, 2022. [Internet]. Available at: https://www.kidney-international.org/action/showPdf?pii=S0085-2538%2822%2900507-5
  3. Donate-Correa J, et al. Pentoxifylline for Renal Protection in Diabetic Kidney Disease. A Model of Old Drugs for New Horizons. J Clin Med, 2019.
  4. Donate-Correa J, et al. Repurposing drugs for highly prevalent diseases: pentoxifylline, an old drug and a new opportunity for diabetic kidney disease. CKJ Review, 2022.
  5. Blagosklonnaia IAV, et al. Effect of trental on indices kidney function in diabetes mellitus. Probl Endokrinol, 1982.
  6. Doherty GM, et al. Pentoxifylline suppression of tumor necrosis factor gene transcription. Surgery, 1991.
  7. Navarro JF, et al. Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration. Am J Kidney Dis, 1999.
  8. Aminorroaya A, et al. Comparison of the effect of pentoxifylline and captopril on proteinuria in patients with type 2 diabetes mellitus. Nephron Clin Pract, 2005.
  9. Rodriguez-Moran M, Guerrero-Romero F. Pentoxifylline is as effective as captopril in the reduction of microalbuminuria in non-hypertensive type 2 diabetic patients-A randomized, equivalent trial. Clin Nephrol, 2005.
  10. Navarro JF, et al. Additive antiproteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin II receptor blockade: a short-term, randomized, controlled trial. J Am Soc Nephrol, 2005.
  11. Rodriguez-Moran M, et al. Effects of pentoxifylline on the urinary protein excretion profile of type 2 diabetic patients with microproteinuria: a double-blind, placebo-controlled randomized trial. Clin Nephrol, 2006.
  12. Badri S, et al. Effect of add-on pentoxifylline on proteinuria in membranous glomerulonephritis: a 6-month placebo-controlled trial. Clin Drug Investig, 2013.
  13. Wen WX, et al. Repurposing pentoxifylline for the treatment of fibrosis: an overview. Adv Ther, 2017.
  14. Navarro-Gonzalez JF, et al. Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial. J Am Soc Nephrol, 2015.
  15. Professional Information. Dyna Pentoxifylline. [Internet]. 2022. Available at: https://pi-pil-repository.sahpra.org.za/wp-content/uploads/2023/02/Approved-PI-Dec-2022-1.pdf

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