Exploring the role of pentoxifylline as a renal protector in diabetic kidney disease: a comprehensive review

Abstract

Diabetic Kidney Disease (DKD) is a leading cause of chronic kidney disease and end-stage renal disease, significantly impacting global public health. Despite the availability of conventional treatments like renin-angiotensin system (RAAS) inhibitors, disease progression remains a challenge. Pentoxifylline, an anti-inflammatory and immunomodulatory agent, has emerged as a promising adjunctive therapy for DKD. This review explores pentoxifylline’s mechanisms of action, including its effects on inflammation, oxidative stress, fibrosis, and renal function, supported by clinical and preclinical evidence. Studies indicate that pentoxifylline can reduce proteinuria, improve glomerular filtration rate, and protect against kidney fibrosis in DKD, offering a multifaceted approach to disease management. By addressing several key pathways in DKD progression, pentoxifylline may provide an essential addition to existing therapeutic strategies, especially in patients with advanced disease.

Trial registration

This is a review article, therefore it does not require any trial registration.

Introduction

Diabetic kidney disease (DKD) is a prevalent and serious complication of diabetes mellitus, representing a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) worldwide [1]. Affecting nearly 40% of diabetic patients, DKD is associated with considerable morbidity and mortality, as well as significant healthcare costs. The progression of DKD is characterized by a gradual decline in kidney function, driven by a complex interplay of metabolic, hemodynamic, and inflammatory processes [2]. Persistent hyperglycemia initiates a cascade of damaging effects, including oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and production of pro-inflammatory cytokines, all of which contribute to glomerular and tubular injury [3].

Current therapeutic approaches for DKD primarily focus on managing blood glucose and blood pressure, as well as inhibiting the RAAS using agents such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) [4]. While these treatments have been shown to reduce albuminuria and slow the decline in renal function, they are often insufficient to halt disease progression, particularly in patients with advanced stages of DKD. Consequently, there is a pressing need for additional therapies that can target the multifactorial mechanisms underlying DKD to improve renal outcomes and overall patient survival [5].

Pentoxifylline, a xanthine derivative initially developed as a treatment for peripheral vascular diseases, has emerged as a potential therapeutic option for patients with DKD. Its unique pharmacological profile includes anti-inflammatory, immunomodulatory, and hemorheological properties, making it well-suited to address the complex pathophysiology of DKD [6]. Pentoxifylline reduces blood viscosity and improves microvascular perfusion, thereby enhancing oxygen delivery to tissues. Moreover, it exerts potent anti-inflammatory effects by inhibiting the production of key pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α) and interleukins, as well as suppressing the activation of nuclear factor-kappa B (NF-κB), a critical transcription factor involved in inflammation and fibrosis [7].

Clinical studies have demonstrated that pentoxifylline can significantly reduce albuminuria, a hallmark of DKD, and slow the decline in the estimated glomerular filtration rate (eGFR). These findings suggest that pentoxifylline may offer additive benefits when used in conjunction with standard treatments, particularly in patients with persistent inflammation or progressive disease despite optimized conventional therapy [8]. Furthermore, the tolerability and safety profile of pentoxifylline make it an attractive candidate for long-term use in managing DKD.

This review aims to explore the role of pentoxifylline as a renoprotective agent in the context of DKD, with a focus on its mechanisms of action, evidence from clinical studies, and potential place in therapy. By addressing the critical pathways involved in DKD progression, pentoxifylline holds promise as an adjunctive treatment option to improve outcomes for patients with diabetes-related kidney disease.

Mechanisms of kidney protection by pentoxifylline

Pentoxifylline, a derivative of methylxanthine, exhibits multiple effects, including the non-selective inhibition of phosphodiesterases (PDEs). This inhibition influences the balance of intracellular cyclic adenosine-3,5-monophosphate (cAMP), a critical intracellular signaling messenger [9]. The regulation of cAMP levels depends on two primary enzymes: adenylyl cyclase, which is responsible for its synthesis, and PDEs, which hydrolyze it. By inhibiting PDEs, pentoxifylline prevents the breakdown of cAMP, leading to its accumulation. Elevated cAMP levels activate protein kinase A (PKA), which subsequently phosphorylates various effectors and inhibits signaling pathways associated with proteinuria and renal fibrosis [10].

PDEs have been identified as promising targets for pharmacological intervention in CKD progression. Mammalian cells express 11 PDE gene families (PDE1–PDE11), with each family containing 1–4 distinct genes, resulting in more than 20 genes encoding over 60 PDE isoforms [9, 11]. Pentoxifylline specifically inhibits PDE3 and PDE4 isoforms in vitro through a PKA-dependent mechanism. These isoforms are predominantly expressed in monocytes and neutrophils, making them therapeutic targets in various inflammatory diseases, such as asthma, chronic obstructive pulmonary disease, and rheumatoid arthritis [12]. The anti-inflammatory properties mediated by PDE inhibition support pentoxifylline’s potential application in protecting the kidneys of diabetic patients.

In experimental models, pentoxifylline modulates inflammatory pathways triggered by cytokines. It has been shown to inhibit endotoxin-induced TNF-α synthesis in macrophage models, as well as reduce TNF-α production in the serum and cultured cells of treated mice [12, 13]. In a rat model of crescentic glomerulonephritis, pentoxifylline demonstrated anti-inflammatory and immunomodulatory effects by reducing the expression of renal TNF-α, ICAM-1, MCP-1, and other pro-inflammatory markers. Similarly, in diabetic rat models, pentoxifylline decreased TNF-α and IL-6 expression, which ameliorated renal hypertrophy and sodium retention [14].

Clinical trials have also demonstrated pentoxifylline’s anti-inflammatory effects in non-diabetic patients, reducing inflammatory cytokine production in coronary artery disease and atherosclerosis. Additionally, the drug decreased TNF-α and interferon-gamma T-cell expression in patients with ESRD [15].Randomized controlled trials evaluating pentoxifylline in diabetic patients have shown kidney-protective effects, such as reduced proteinuria and, in some cases, preservation of glomerular filtration rate (GFR). These effects are often accompanied by decreases in inflammatory markers [16]. For example, the PREDIAN trial demonstrated that adding pentoxifylline to RAS blockade therapy in DKD patients reduced proteinuria, slowed disease progression, and decreased TNF-α levels. Meta-analyses have highlighted the reduction of pro-inflammatory cytokines as a key factor in the antiproteinuric effects of pentoxifylline in these patients [17].

Pentoxifylline may also promote kidney health by increasing the expression of Klotho, an anti-aging protein mainly found in kidney tubular cells. Klotho levels decline in CKD and DKD, contributing to disease progression [18]. Pentoxifylline has been shown to prevent Klotho downregulation and even increase its expression, likely due to its anti-inflammatory properties and direct effects on tubular cells. This action suggests that Klotho upregulation may play a role in the kidney-protective effects of pentoxifylline [19].

Overall, pentoxifylline’s mechanisms of kidney protection involve anti-inflammatory, immunomodulatory, and antifibrotic effects. By inhibiting PDEs, increasing cAMP levels, and modulating key signaling pathways, pentoxifylline represents a promising therapeutic option for CKD and DKD patients.

In vitro studies of pentoxifylline for renal protection in diabetic kidney disease (DKD)

In various in vitro studies (as shown in Table 1), pentoxifylline (PTX) demonstrated significant reno-protective effects in diabetic kidney disease (DKD).

Table 1.

In vitro studies of Pentoxifylline for renal protection in diabetic kidney disease (DKD)

Study/Reference	Model Used	Key Findings	Mechanisms Identified	Relevance to DKD
Donate-Correa et al. (2019)	RAW 264.7 macrophages	PTX inhibits TNF-α production induced by endotoxins.	Increased cAMP → PKA activation → NF-κB inhibition → suppression of pro-inflammatory cytokine synthesis.	Reduced inflammation and cytokine-mediated renal damage.
Wang et al. (2020)	Renal tubular epithelial cells	PTX suppresses TGF-β expression and reduces ECM deposition.	Inhibition of the Smad signaling pathway downstream of TGF-β.	Mitigates renal fibrosis and glomerulosclerosis in DKD.
Liu et al. (2018)	Mesangial and tubular cells	PTX reduces ROS production and oxidative stress-induced apoptosis.	Inhibition of NADPH oxidase, reducing ROS levels and preserving cell function.	Protects tubular cells from oxidative damage, a key factor in DKD progression.
Huang et al. (2022)	Tubular epithelial cells	PTX prevents Klotho downregulation induced by high glucose and albumin.	Direct upregulation of Klotho expression; possible anti-inflammatory and anti-fibrotic mechanisms.	Enhances renoprotective effects by increasing Klotho levels, crucial for renal health in DKD.
Navarro-González et al.(1999)	Cultured renal cells	PTX reduces TNF-α and IL-6 production under pro-inflammatory conditions.	Inhibition of NF-κB signaling, leading to reduced expression of pro-inflammatory cytokines.	Controls inflammation, a major driver of DKD progression.
Navarro-González et al. (2015)	Endothelial cells	PTX decreases expression of VCAM-1 and ICAM-1 under hyperglycemic conditions.	Downregulation of adhesion molecules prevents leukocyte adhesion and endothelial dysfunction.	Prevents inflammatory cell infiltration and vascular complications in DKD.
Donate-Correa et al. (2019)	Tubular epithelial cells	PTX reduces albuminuria-induced MCP-1 and ICAM-1 expression.	Suppresses NF-κB-mediated activation of inflammatory and fibrotic pathways.	Reduces proteinuria and prevents progression of renal fibrosis.
Donate-Correa et al. (2022)	RAW 264.7 macrophages	PTX enhances Klotho levels in cultured cells exposed to inflammatory stimuli.	Direct stimulation of Klotho expression, possibly through anti-inflammatory effects or albuminuria prevention mechanisms.	Suggests a dual protective role by modulating inflammation and increasing Klotho expression.

In vivo studies of Pentoxifylline for renal protection in diabetic kidney disease (DKD)

In various in vivo studies (as shown in Table 2), pentoxifylline (PTX) has shown significant renal protective effects in diabetic kidney disease (DKD) models. These studies collectively highlight PTX’s potential to reduce inflammation, fibrosis, and oxidative damage, making it a promising therapeutic agent to prevent or slow the progression of DKD.

Table 2.

In vivo studies of Pentoxifylline for renal protection in diabetic kidney disease (DKD)

Study/Reference	Model Used	Key Findings	Mechanisms Identified	Relevance to DKD
Donate-Correa et al. (2015)	STZ-induced diabetic rats	Reduced renal hypertrophy, proteinuria, and glomerulosclerosis	Inhibited TNF-α, IL-6, oxidative stress, and fibrosis markers	Mitigated early kidney damage and inflammation in DKD progression.
Dai et al. (2019)	STZ-induced diabetic rats	Reduced proteinuria, albuminuria, and preserved GFR	Inhibition of TNF-α and reduction in kidney fibrosis via NF-κB	Prevented diabetic kidney injury and preserved kidney function.
Mora-Fernández et al. (2015)	STZ-induced diabetic rats	Improved renal function, reduced proteinuria and serum creatinine	Modulated the RAS and decreased pro-inflammatory cytokines	Reduced hyperfiltration, a key feature of DKD, preventing disease progression.
Zhang et al. (2016)	STZ-induced diabetic mice	Reduced mesangial expansion, albuminuria, and improved renal function	Reduced oxidative stress, promoted anti-inflammatory cytokines	Reversed pathological features of DKD, including fibrosis.
Wang et al. (2020)	STZ-induced diabetic rats	Reduced proteinuria, improved kidney histology	Inhibited TNF-α and TGF-β signaling, reduced glomerulosclerosis	Prevented kidney fibrosis, halting DKD progression.
Li et al. (2021)	Type 2 diabetic rat model	Reduced kidney injury, enhanced renal Klotho expression	Anti-inflammatory, antifibrotic effects, and Klotho upregulation	Klotho upregulation provides renal protection in DKD.
Patel et al. (2020)	Zucker diabetic fatty (ZDF) rats	Reduced kidney fibrosis and improved renal function markers	Reduced oxidative stress and inflammation, improved renal blood flow	Protected both kidneys and vasculature, slowing DKD progression.

Pharmacokinetics

Absorption

Pentoxifylline is rapidly absorbed after oral administration, with peak plasma concentrations typically reached within 1–2 h. The drug has a bioavailability of approximately 50%, which can be affected by food intake (slightly delayed absorption) [20].

Distribution

Pentoxifylline is widely distributed in the body, including in tissues such as the kidneys, liver, and lungs. It is highly protein-bound, around 96%, which influences its pharmacological activity. Pentoxifylline also crosses the blood-brain barrier to some extent, and its metabolites can be detected in urine [21].

Metabolism

Pentoxifylline is extensively metabolized in the liver, primarily through the cytochrome P450 enzyme system. It undergoes demethylation to form active metabolites such as 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (M1), which retains pharmacological activity. These metabolites have a longer half-life than the parent compound [22].

Excretion

The elimination half-life of pentoxifylline is approximately 1–2 h, but its metabolites have a longer half-life. Pentoxifylline and its metabolites are excreted primarily in the urine. The drug is cleared via both renal and hepatic pathways. Renal function can influence the clearance of pentoxifylline, and dosage adjustments may be necessary in patients with impaired kidney function [22].

Pharmacodynamics and therapeutic potential of pentoxifylline in DKD

Pentoxifylline protects the diabetic kidney through four complementary mechanisms. It dampens inflammation by blocking NF-κB activity and lowering cytokines such as TNF-α and IL-6, curbs oxidative stress by reducing NADPH oxidase–driven free radical formation, and slows fibrosis by interrupting TGF-β/Smad signaling and limiting matrix deposition [23–25]. In addition, it restores levels of Klotho, a renal protein with anti-aging and protective properties that is often reduced in chronic kidney disease [26]. Acting together, these effects help reduce proteinuria, preserve kidney structure, and stabilize glomerular filtration rate. Clinical studies reinforce these findings, showing that pentoxifylline improves inflammatory markers and slows disease progression, particularly when combined with renin–angiotensin system inhibitors [24, 25, 27].

Dosing and recommendations of pentoxifylline in DKD

Pentoxifylline appears to be most beneficial in moderate to advanced stages of diabetic kidney disease, particularly CKD stages 3–4 where eGFR ranges between 15 and 59 mL/min/1.73 m², with the strongest evidence in those with eGFR 15–45 [28]. The PREDIAN trial and other studies have shown that in this group, pentoxifylline significantly slows the decline in kidney function and reduces albuminuria when added to standard therapy. In contrast, its role in early disease remains uncertain; patients with preserved kidney function (eGFR >60) and only microalbuminuria derives little additional benefit, indicating limited effectiveness in the early stages of DKD.

Clinical initiation should be guided by clear parameters: persistent albuminuria >30 mg/24 hours (or proteinuria >150 mg/24 hours in some studies) despite optimized renin–angiotensin system blockade with ACE inhibitors or ARBs, established type 2 diabetes of several years’ duration, and stable kidney function without recent acute injury or cardiovascular events. Optimal blood pressure and glycemic control should be ensured before starting therapy. Dosage needs adjustment according to renal function, with 1200 mg/day providing the most consistent trial data. Regular monitoring of eGFR, urine protein or albumin excretion, complete blood count, and gastrointestinal tolerance is essential. Clinical benefits generally emerge after 6–12 months of consistent therapy, underscoring the need for long-term treatment and close follow-up [29, 30].

Clinical studies and human trials

Clinical studies and human trials on pentoxifylline in diabetic kidney disease (DKD) have demonstrated its therapeutic potential in improving renal outcomes (as shown in Table 3). The PREDIAN trial, a significant study involving patients with type 2 diabetes and stage 3–4 chronic kidney disease, showed that pentoxifylline, when used alongside renin-angiotensin system (RAS) inhibitors, significantly reduced proteinuria and stabilized glomerular filtration rate (GFR) [29, 31]. Additionally, pentoxifylline lowered levels of inflammatory markers such as TNF-α, emphasizing its anti-inflammatory effects. Meta-analyses have further confirmed that pentoxifylline consistently reduces proteinuria and improves kidney function in DKD patients, especially when combined with RAS inhibitors. Few Studies also demonstrated that pentoxifylline effectively reduced pro-inflammatory cytokines and improved renal function, with the reduction of proteinuria being a key outcome. Overall, these clinical studies support pentoxifylline as a promising adjunctive therapy in DKD, offering benefits in terms of inflammation reduction, proteinuria management, and preservation of kidney function [20].

Table 3.

Clinical studies and human trials of Pentoxifylline for renal protection in diabetic kidney disease (DKD)

Study/Reference	Design	Patient Population (N, CKD Stage)	Intervention (Dose, Duration)	Key Outcomes (Change in eGFR, Change in Albuminuria)	Key Findings/Limitations
PREDIAN Trial [29]	Open-label RCT	169 patients with T2DM, CKD stages 3–4, on RAS blockade	PTX 1200 mg/day vs. Control for 2 years	eGFR: Decline of 2.1 vs. 6.5 ml/min/1.73 m² (p < 0.001). Albuminuria: -14.9% change vs. +5.7% change (p = 0.001).	Landmark trial showing significant slowing of eGFR decline with long-term use. Limitation: Open-label design.
Navarro et al., 2015 (Follow-up)[32]	Post-hoc long-term follow-up of an RCT	91 patients with CKD (diabetic and non-diabetic)	PTX 800 mg/day vs. Control for 7 additional years	Renal Events: 11 events in PTX group vs. 24 in control group (p = 0.016). CV Mortality: 2 deaths in PTX group vs. 10 in control group (p = 0.024).	Suggests long-term benefits on hard renal and cardiovascular outcomes. Limitations: Small sample size, post-hoc analysis.
Shan et al., 2012 (Meta-analysis) [33]	Meta-analysis of 17 RCTs	991 patients with DKD	PTX vs. Placebo or routine treatment	Serum Creatinine: MD -0.10 mg/dL. Albuminuria: SMD − 2.28. Proteinuria: MD -428.58 µg/min.	Confirms significant reduction in proteinuria/albuminuria. No significant effect on CrCl. Limitation: Included studies were of low methodological quality.
McCormick et al., 2008 (Meta-analysis) [31]	Meta-analysis of 10 RCTs	476 patients with DKD	PTX vs. Placebo or usual care	eGFR: No significant change. Proteinuria: WMD − 278 mg/day (p < 0.001); effect more robust in overt proteinuria (-502 mg/day).	Confirms anti-proteinuric effect, especially in macroalbuminuria. No effect on GFR in shorter-term studies. Limitation: Significant heterogeneity among studies.

Effectiveness of pentoxifylline and other complementary therapies in DKD

A comparative table of Mechanism/Outcome of PTX Vs other DKD Therapies has been tabulated (as shown in Table 4).

Table 4.

Pentoxifylline versus other complementary therapies for renal protection in Diabetic Kidney Disease (DKD)

Drug Class	Effect on Proteinuria	Effect on eGFR Decline	Effect on ESKD/Renal Death	Effect on MACE	Effect on All-Cause Mortality	Key Trials
Pentoxifylline	Significant Reduction	Inconsistent / Some evidence of slowing	No Data	No Data	No Data	Multiple small trials, meta-analyses [34]
SGLT2 Inhibitors	Significant Reduction	Significant Slowing	Significant Reduction	Significant Reduction	Significant Reduction	CREDENCE, DAPA-CKD, EMPA-KIDNEY [35, 36]
GLP-1 Receptor Agonists	Significant Reduction	Significant Slowing	Significant Reduction	Significant Reduction	Neutral / Trend to Reduction	LEADER, SUSTAIN-6, FLOW [37]
ns-MRAs (Finerenone)	Significant Reduction	Significant Slowing	Significant Reduction	Significant Reduction	Neutral	FIDELIO-DKD, FIGARO-DKD [38]

Positioning and outcome of pentoxifylline and other complementary therapies for renal protection in Diabetic Kidney Disease (DKD)

A comparative table of degree of Renal Outcome and Positioning as per current guidelines for PTX and other DKD Therapies has been tabulated (as shown in Table 5).

Table 5.

Positioning and outcome of pentoxifylline and other complementary therapies for renal protection in diabetic kidney disease (DKD)

Drug Class	Renal/Proteinuria Benefit	Outcome Data	Positioning (Current Guidelines)
SGLT2 inhibitors	Strong	Renal, Cardiovascular System	First-line for DKD with/without T2D [1]
Finerenone	Moderate-Strong	Renal, Cardiovascular System	Add-on for high-risk patients, with SGLT2i [2]
GLP-1 receptor agonists	Modest	Cardiovascular System	Add-on/alternative for glycemic/CV targets [1]
Pentoxifylline	Modest (proteinuria)	Surrogates	Add-on, not guideline-recommended [33]

Although pentoxifylline may be used temporarily as an alternative or adjunctive treatment for diabetic kidney disease (DKD), updated clinical guidelines now recommend more recent standard-of-care medications, such as finerenone, SGLT2 inhibitors, and GLP-1 receptor agonists (GLP1RAs), as first-line and foundational treatments [1]. Standard-of-Care Agents In recent network meta-analyses, SGLT2 inhibitors outperformed finerenone and GLP1RAs in terms of risk reduction and are thought to be the current cornerstone of DKD management. They offer strong reductions in renal events, particularly when combined with background renin-angiotensin system blockade [4]. Because it has a better side-effect profile and has been shown to have cardiovascular and renal benefits than previous MRAs, finerenone, a non-steroidal mineralocorticoid receptor antagonist, is particularly advised for additional risk reduction when SGLT2 inhibitors are currently being used or in combination GLP1RAs are only used in those for whom SGLT2 inhibitors are not suitable or as supplementary medication to further decrease blood sugar and improve cardiovascular health [1, 4].

When used in conjunction with background RAS inhibitor medication, pentoxifylline, a nonspecific phosphodiesterase inhibitor, reduces proteinuria and some inflammatory indicators in DKD. It also has mild anti-inflammatory and antiproteinuric properties [4]. Due to a lack of strong trial data, pentoxifylline is not yet advised by major guidelines, despite evidence that it improves surrogate renal outcomes but not hard outcomes (such as time to ESKD or mortality) [30].

In patients with progressive DKD who have had the most standard-of-care treatments, its usage may be appropriate as an adjuvant, particularly when inflammation is thought to be a pathogenic factor or when more recent medications are not accessible or are not recommended [6].

Potential benefits of combining pentoxifylline with complementary or alternative therapies

The combination of pentoxifylline with complementary therapies, such as antioxidants or folic acid, provides additional therapeutic advantages in diabetic kidney disease (DKD). Evidence from clinical studies, including the PREDIAN trial, demonstrates that pentoxifylline added to ACEI/ARB therapy significantly slows eGFR decline and reduces proteinuria. These benefits are largely attributed to its anti-inflammatory and anti-fibrotic actions, which appear to be enhanced when combined with antioxidants like vitamin E, leading to further reductions in cytokines such as TNF-α, hs-CRP, and IL-6. Adjunctive use with folic acid has also been associated with improvements in biochemical markers of kidney function and reduced fatigue, thereby contributing to better quality of life and, in some cases, allowing dose minimization without loss of efficacy [39].

The use of pentoxifylline (PTX) in combination with renin–angiotensin system (RAS) inhibitors has emerged as a valuable therapeutic approach in the management of diabetic kidney disease (DKD). Multiple randomized controlled trials and meta-analyses consistently demonstrate that this combination achieves an additive and synergistic reduction in proteinuria. Although RAS inhibitors reduce proteinuria, many patients continue to show residual albuminuria. The addition of PTX has been shown to further lower urinary protein and albumin excretion, even in those maintained on stable doses of ACE inhibitors or ARBs. This effect is particularly relevant for patients who do not reach optimal proteinuria control with RAS inhibition alone [30].

In addition to proteinuria reduction, the combined regimen contributes to slowing the decline in glomerular filtration rate (GFR) and, in some cases, stabilizing renal function. The PREDIAN trial and supporting studies demonstrated that PTX use was associated with a significantly smaller decline in eGFR over a two-year follow-up compared with RAS blockade alone [29]. Patients on combination therapy also showed a lower risk of progression to end-stage renal disease, a delayed need for dialysis, and better long-term renal survival in both early and advanced CKD [28]. These benefits are linked to PTX’s anti-inflammatory, anti-fibrotic, and anti-proliferative properties, particularly its ability to reduce levels of TNF-α, MCP-1, and other pro-inflammatory mediators that drive DKD progression, mechanisms not fully addressed by RAS inhibition [40]. Taken together, the evidence supports that while PTX and RAS inhibitors are effective individually, their combined use provides superior outcomes, making PTX a valuable adjunctive option for patients with DKD and persistent proteinuria despite optimized RAS therapy.

Future perspectives

The potential for pentoxifylline as a cornerstone in DKD treatment could expand through further research on its combination with other therapeutic modalities, including dietary modifications. Future studies should focus on large-scale, long-term clinical trials to confirm its efficacy across diverse populations and DKD stages. Additionally, exploration of pentoxifylline’s impact on other diabetic complications, such as cardiovascular disease, would be valuable. Investigating its use in early-stage DKD or preventive treatment may also offer significant clinical benefits, further solidifying its role in improving patient outcomes and quality of life.

Limitations and barriers to consider for pentoxifylline therapy in DKD

While pentoxifylline has shown promise in the treatment of DKD with evidence supporting its role in reducing proteinuria and slowing renal function decline, there are several limitations to consider. Drug–drug interactions remain important, as PTX can potentiate hypoglycemic agents, increase bleeding risk with anticoagulants or antiplatelets, and elevate theophylline levels, making polypharmacy a concern. Gastrointestinal side effects such as nausea, dyspepsia, and diarrhea are common, and caution is required in patients with recent cerebral or retinal hemorrhage due to the potential for worsening bleeding.

Dosing and pharmacokinetics present additional challenges. In patients with moderate renal impairment, dose reduction is required, and PTX is contraindicated in severe kidney dysfunction. Current guidelines suggest reducing the dose to 400 mg/day in patients with creatinine clearance below 30 mL/min, and the renoprotective benefits of PTX generally require 6–12 months of sustained therapy and evidence beyond two years remains limited.

Clinical trial limitations also hinder its widespread adoption. Existing studies are heterogeneous, with variability in DKD stages, comorbidities, glycemic control, and background therapies, which reduces comparability and generalizability. Different dosing regimens and treatment durations make it difficult to design standardized protocols. Most trials are small, short-term, and reliant on surrogate outcomes such as proteinuria or eGFR changes rather than hard endpoints like ESRD progression, dialysis initiation, or mortality.

Finally, regulatory and research gaps contribute to limited acceptance in guidelines. As an off-patent drug originally approved for peripheral artery disease, PTX has received little industry-driven support for large-scale, robust trials in DKD. This has restricted evidence development, leaving its long-term efficacy, safety, and optimal dose unresolved.

Conclusion

Pentoxifylline shows significant promise in the treatment of Diabetic Kidney Disease (DKD) by targeting various underlying mechanisms of the disease, including inflammation, oxidative stress, fibrosis, and impaired renal function. While Pentoxifylline in combination with complementary therapies (such as RAS Inhibitors) holds meaningful potential for renoprotection and symptom management in DKD, its clinical role is constrained by interaction risks, gastrointestinal intolerance, dosing uncertainties in renal impairment, heterogeneity of trial data, and further requires large multicenter studies with definitive endpoints. Therefore, Careful patient selection, individualized dosing, and close monitoring are essential until stronger evidence clarifies its place in routine DKD management.

Author contributions

M.A researched the literature and conceived the idea of the review, edited and critically revised the final manuscript. B.K.B designed the review and collected, analysed the data and wrote the manuscript. All the authors contributed to the development of the article and approved the submitted version.

Funding

Open access funding provided by SRM Institute of Science and Technology for SRMIST – Medical & Health Sciences. Funding was supported by SRM Medical and Health Sciences, SRM Institute of Science and technology, Kattankulathur, Chengalpattu, Tamilnadu, India.

Data availability

This is a review article so no data was collected.

Declarations

Ethics statement and informed consent

This review article is based on previously conducted studies and does not involve any human participants or animals, beyond their involvement in the previously published articles we cite. Therefore, no ethical approval and informed consent is required for this study.

Permissions

No third- party contents were used in our review article.

Publication enhancement

No publication enhancement materials were used.

Competing interests

The authors declare no competing interests.