Effect of pentoxifylline on inflammatory markers in non-diabetic chronic kidney disease patients: A prospective, interventional, open label

Abstract

BACKGROUND

Pentoxifylline (PTX), a methylxanthine derivative, has been shown to exert notable anti-inflammatory and antiproteinuric actions in diabetic kidney disease, contributing to improved sodium handling, attenuation of renal hypertrophy, and reductions in tumour necrosis factor-alpha (TNF-α), interleukin-6 levels, and albuminuria.

AIM

To determine the impact of PTX on inflammatory biomarkers and the progression of chronic kidney disease (CKD) in non-diabetic patients.

METHODS

This prospective, interventional, open label, randomized controlled clinical study was conducted on 42 participants aged 18 years or older, of both genders, with CKD stages 3 or 4 and proteinuria < 1 g/24 hours. Participants were placed into two equal groups. Group 1 had standard therapy, including angiotensin-converting enzyme inhibitors (ACEIs; ramipril 1.25 mg), calcium acetate (700 mg), alfacalcidol (0.25 µg), antihypertensives, and diuretics. Group 2 had the same standard therapy plus PTX 400 mg (Trental^®) two times per day for six consecutive months.

RESULTS

There was no significant relationship between TNF-α and high-sensitivity C-reactive protein (hs-CRP) and participants’ gender in both groups. An essential direct correlation was observed between TNF-α and creatinine in both groups. A critical direct correlation was observed between hs-CRP and calcium in group B. There was a significant inverse correlation between the change in TNF-α and estimated glomerular filtration rate, as well as between the change in TNF-α and the urinary protein-to-creatinine ratio. The change in protein creatinine ratio noted in group 2 was mainly due to changes in mean arterial pressure, followed by changes in TNF-α.

CONCLUSION

In non-diabetic CKD patients, adjunctive treatment with PTX was associated with significant decreases in C-reactive protein levels and proteinuria. The reduction in proteinuria was mainly explained by changes in mean arterial pressure, followed by changes in TNF-α, indicating that hemodynamic factors may play a more prominent role than inflammatory modulation in mediating this effect.

Key Words: Pentoxifylline; Inflammatory marker; Non-diabetic; Chronic kidney disease; Tumour necrosis factor-alpha

Core Tip: This randomized controlled study evaluated the effect of pentoxifylline (PTX) on inflammation and disease progression in non-diabetic chronic kidney disease (CKD) stages 3-4. Adding PTX to standard therapy significantly reduced C-reactive protein and proteinuria compared with standard treatment alone. Changes in tumour necrosis factor-alpha were inversely correlated with estimated glomerular filtration rate and urinary protein-to-creatinine ratio, highlighting a link between inflammation and renal function decline. PTX may offer additional anti-inflammatory and renoprotective benefits in non-diabetic CKD.

INTRODUCTION

Chronic kidney disease (CKD) is a gradually worsening disorder impacting over 10% of the global population, representing more than 800 million individuals as of 2017. It has become one of the leading contributors to mortality and morbidity in the 21^st century[1].

CKD is primarily diagnosed through laboratory evaluations, typically involving the estimated glomerular filtration rate (eGFR) via serum creatinine or cystatin C as filtration markers within established equations. Additionally, urine assessments for albuminuria, proteinuria, or both are commonly employed to support the diagnosis[2].

Proteinuria reflects damage to the glomerular filtration barrier and serves as an important predictor of cardiovascular morbidity, mortality, and progression of kidney disease, even at sub-nephrotic level[3].

The antiproteinuric action of pentoxifylline (PTX) is attributed to its ability to suppress the production of pro-inflammatory cytokines as CKD is associated with a state of chronic, low-grade systemic inflammation. Emerging evidence highlights the pivotal role of inflammation in mediating the interplay between cardiovascular disease (CVD) and kidney dysfunction[4].

Inflammation is a central contributor to the accelerated development of atherosclerosis. Systemic microinflammation influences the degree of vascular endothelial injury, a critical probable determinant for both acute coronary syndrome and the gradual worsening of CKD. Moreover, glomerular filtration rate exhibits a graded and independent association with CVD outcomes[5].

In CKD, inflammatory macrophages infiltrate the renal tissue, triggering the release of pro-inflammatory cytokines, including interleukin (IL)-1β, tumour necrosis factor-alpha (TNF-α), IL-6, and IL-23[6].

PTX exerts its anti-inflammatory and antioxidant effects by reducing the levels of TNF-α and IL-6[7]. TNFα and IL6, pivotal cytokines involved in both acute and chronic inflammatory responses, have been linked to population-level cardiovascular morbidity and mortality, as well as in individuals undergoing predialysis and dialysis[8].

Although PTX has been shown to possess anti-inflammatory and antiproteinuric properties and has been investigated in various CKD populations, evidence regarding its effects on inflammatory markers and renal outcomes in non-diabetic CKD patients remains limited. In particular, the relationship between PTX-induced changes in inflammatory mediators, such as TNF-α and high-sensitivity C-reactive protein (hs-CRP), and their impact on proteinuria and kidney function progression has not been well established. Therefore, this study aimed to address this gap by evaluating the effect of PTX on inflammatory markers and CKD progression in non-diabetic patients.

After thorough research of the literature, studies assessing the effect of PTX on inflammatory markers in non-diabetic CKD patients are lacking. So, the objective of this study was to investigate the impact of PTX on the modulation of inflammatory markers and the progression of CKD in non-diabetic individuals.

MATERIALS AND METHODS

This prospective, interventional, open label, randomized controlled clinical study was conducted on 42 participants aged 18 years or older, of both genders, with CKD stages 3 or 4 and proteinuria < 1 g/24 hours. The study was conducted from February 2023 to August 2023, following authorization from the Research Ethics Committee of Ain Shams University, Cairo, Egypt (Approval No. FMASU MS 53/2023) and registered at ClinicalTrial.gov (https://clinicaltrials.gov/). The registration identification number is NCT07302464 (date: December 24, 2025). The study was conducted in accordance with good clinical practice guidelines and the ethical principles outlined in the Declaration of Helsinki. An informed written consent was gathered by the participants.

Exclusion criteria were patients who were terminally ill, those with diabetes mellitus, or with proteinuria more than 1 gm, individuals with a history of hemodialysis, patients with active infection, hospitalized patients, patients with recent cerebral and/or retinal hemorrhage, patients receiving warfarin or theophylline-containing drugs, also females using oral contraceptives, pregnant or lactating individuals, participants with a record of complications to PTX, individuals with polycystic kidney disease, and those with obstructive uropathy.

An online randomization program (http://www.randomizer.org) was used to generate a random list and each patients’ code will be kept in an opaque sealed envelope. Patients were randomly allocated with 1:1 allocation ratio into two groups in a parallel manner: The first group (group 1) received their standard therapy. The routine standard consisted of angiotensin-converting enzyme inhibitor (ACEI; ramipril 1.25 mg), a calcium-based phosphate binder (calcium acetate 700 mg, containing 180 mg of calcium), alfacalcidol (0.25 µg), antihypertensive medications, and diuretics. The initial dose of ramipril (1.25 mg) was selected to minimize the risk of hypotension and adverse effects in CKD patients; dose titration was permitted based on blood pressure (BP), renal function, and patient tolerance, according to standard clinical practice. The final doses were individualized and adjusted during follow-up visits. The second group (group 2) received a dose of one capsule of PTX 400 mg, manufactured by Sanofi and marketed as trental, administered twice daily for a duration of 6 months, in addition to the participants’ standard therapy. This study is open label due to different techniques. The PTX dose in this study was determined according to the PREDIAN trial, which noted gastrointestinal tract side effects at a daily dose of 1200 mg[9].

All participants underwent a comprehensive history taking, laboratory tests [haemoglobin, white blood cells (WBCs), platelet counts, serum phosphorus, potassium, calcium, magnesium, sodium, creatinine and blood urea nitrogen (BUN), and urinary protein/creatinine ratio].

Oxidative stress and inflammatory responses were evaluated by quantifying hs-CRP and TNF-α levels in both groups, measured before and after the intervention. Before sample collection, subjects remained seated for 5 minutes in a quiet room. BP was determined in a sitting position using mercury sphygmomanometers. BP was taken on each visit at least twice, with a 30-60 seconds interval.

Laboratory measurements

Blood samples were obtained from both groups at the study's outset and upon its completion using Vacutainer^® SST^TM tubes (serum separator tubes). The samples were centrifuged at 3000 rpm for 10 minutes at 4 °C to isolate the serum, which was then preserved at -80 °C until biochemical analysis of hs-CRP and TNF-α was performed. TNF-α concentrations were determined using a human TNF-α enzyme-linked immunosorbent assay (ELISA) kit (Cat. No. E0082Hu; Bioassay Technology Laboratory, BT LAB, China). The hs-CRP was quantified using an ELISA kit from Diagnostic Biochem Canada, Inc. All ELISA assays were conducted according to the manufacturer’s protocols and read using a BioTek Epoch 2 Microplate Reader with Gen6 software. Additionally, spot urine samples were collected, and total urine protein was determined via a colourimetric method using pyrogallol red, while urine albumin was measured through an immunoturbidimetric assay.

Determination of TNF-α

This assay is an ELISA in which the microplate was pre-coated with a human TNF-α-specific antibody. TNFα interacts with the antibodies coated on the wells. A biotinylated human TNF-α antibody was subsequently added, binding to the captured TNF-α. Streptavidin-horseradish peroxidase (HRP) was then applied, which binds specifically to the biotinylated antibody. After incubation, unbound streptavidin-HRP was removed by washing. A substrate solution was then added, resulting in a colour change proportional to the TNF-α concentration in the sample. The reaction was terminated using an acidic stop solution, and absorbance was measured at 450 nm.

Determination of C-reactive protein

The enzyme immunoassay utilises a standard two-step capture, or “sandwich”, format. Two particular monoclonal antibodies are employed: One antibody against C-reactive protein (CRP) is immobilised on the microwell plate, while a second antibody, recognising a different epitope of CRP, is conjugated to HRP. CRP present in the samples or standards binds to the plate-bound antibody, followed by washing and incubation with the HRP-conjugated antibody. After a second wash, the enzyme substrate is added, and the reaction is terminated with a stop solution. Absorbance is measured at 450 nm using a plate reader, with the colour intensity directly proportional to the CRP concentration in the samples.

The primary outcome of this study was hs-CRP, after 6 months of treatment. Secondary outcomes included assessing changes in other inflammatory markers, as well as evaluating the impact of PTX on renal function parameters such as serum creatinine and eGFR, and proteinuria levels.

Sample size calculation

The sample size calculation was done by G*Power 3.1.9.2 (Universitat Kiel, Germany). We performed a pilot study (5 cases in each group), and we found that the hs-CRP was 3.48 ± 0.66 mg/L in group 1 and 2.5 ± 1.23 mg/L in group 2. The sample size was based on the following considerations: 0.943 effect size, 95% confidence limit, 80% power of the study, group ratio 1:1, and 2 cases were added to each group to overcome dropout. Therefore, we recruited 21 patients in each group.

Statistical analysis

The analysis was conducted using SPSS v26 (IBM Inc., Chicago, IL, United States). Quantitative variables were presented as mean ± SD and compared between the two groups using an unpaired Students’ t-test (or repeated measures ANOVA). Qualitative variables were presented as n (%) and analysed using the χ² or Fisher’s exact test when appropriate. The correlation among various variables was calculated using the Pearson product-moment correlation equation. Multivariate regression was also applied to determine the relationship between a dependent variable and multiple independent variables. A two-tailed P value < 0.05 was statistically significant.

RESULTS

Demographic data were not significantly different between the two groups. A significant reduction in systolic BP was observed in group 1 (P = 0.009) after 6 months of treatment, whereas no significant difference was noted in group 2. No significant difference was noted when comparing diastolic BP or mean arterial pressure in both groups during the study period, either at enrollment or after 6 months (Table 1).

Table 1 Demographic data and vital signs of the studied groups, n (%) or mean ± SD.

		Group 1 (n = 21)	Group 2 (n = 21)	t value1	P value
Age (year)		52.476 ± 6.720	50.667 ± 8.593	0.760	0.452
Sex	Male	11 (52.38)	12 (57.14)	χ2 = 0.096	0.757
	Female	10 (47.62)	9 (42.86)
Vital signs
SBP	Baseline	153.095 ± 17.991	146.905 ± 17.922	1.117	0.271
	After 6 months	142.857 ± 11.019	140.000 ± 12.247	0.795	0.431
	Differences	-10.238 ± 16.239	-6.905 ± 18.873
	Paired test	0.009a	0.109
DBP	Baseline	77.143 ± 5.141	79.762 ± 5.585	-1.581	0.122
	After 6 months	75.952 ± 6.637	78.571 ± 6.353	-1.306	0.199
	Differences	-1.190 ± 9.862	-1.190 ± 8.201
	Paired test	0.586	0.514
MAP	Baseline	102.419 ± 7.284	102.114 ± 7.801	0.131	0.897
	After 6 months	98.214 ± 5.438	99.014 ± 5.588	-0.470	0.641
	Differences	-4.205 ± 9.373	-3.100 ± 10.251
	Paired test	0.053	0.181

^aP value < 0.05.

¹Students’ t-test.

SBP: Systolic blood pressure; DBP: Diastolic blood pressure; MAP: Mean arterial pressure.

Routine laboratory investigations revealed a significant difference in BUN levels between the two groups (P < 0.009). The hs-CRP and protein-to-creatinine ratios were no significant difference at baseline between groups and were highly significant between groups after 6 months, with group 2 showing a marked reduction after treatment (P < 0.05), with both groups demonstrating highly significant reductions over time; however, the decline was more pronounced in group 2. No significant differences were found in eGFR pre- and post-treatment. Both groups demonstrated a marked significant decrease in TNF-α after 6 months (P < 0.001), with a more pronounced reduction in group 2 (Table 2).

Table 2 Laboratory tests of the studied groups, mean ± SD.

		Group 1 (n = 21)	Group 2 (n = 21)	t value1	P value
BUN (mg/dL)		39.762 ± 4.158	43.238 ± 4.098	-2.729	0.009a
Cr (mg/dL)		1.447 ± 0.068	1.486 ± 0.091	0.000	1.000
Na (meq/L)		139.429 ± 3.789	138.381 ± 4.642	0.801	0.428
K (meq/L)		4.448 ± 0.368	4.343 ± 0.379	0.909	0.369
Ca (mg/dL)		8.743 ± 0.578	8.700 ± 0.483	0.261	0.795
PO4 (mg/dL)		4.810 ± 0.397	4.657 ± 0.514	1.074	0.289
PTH (pg/mL)		107.190 ± 8.675	105.095 ± 7.842	0.821	0.416
Hb (gm/dL)		11.114 ± 0.795	11.286 ± 0.857	-0.672	0.506
WBCs (× 103/μL)		7.048 ± 1.024	7.048 ± 0.740	0.000	1.000
Platelet (× 103/μL)		273.714 ± 65.293	303.524 ± 86.458	-1.261	0.215
hs-CRP (mg/L)	Baseline	3.071 ± 0.898	4.790 ± 0.774	-6.644	< 0.001a
	After 6 months	3.119 ± 0.789	2.510 ± 0.744	2.575	0.014a
	Differences	0.048 ± 1.172	-2.281 ± 1.114
	Paired test	0.854	< 0.001a
UPCR (mg/mg)	Baseline	372.381 ± 28.444	388.571 ± 14.243	-2.332	0.025a
	After 6 months	193.333 ± 26.520	150.000 ± 18.439	6.148	< 0.001a
	Differences	-179.048 ± 22.114	-238.571 ± 25.157
	Paired test	< 0.001a	< 0.001a
eGFR (mL/minute/1.73 m2)	Baseline	51.048 ± 7.625	50.714 ± 7.163	-0.146	0.885
	After 6 months	51.667 ± 4.282	52.381 ± 4.566	0.523	0.604
	Differences	0.619 ± 6.704	1.667 ± 7.358
	Paired test	0.677	0.312
TNF-α (ng/L)	Baseline	174.762 ± 69.326	174.524 ± 70.156	0.011	0.991
	After 6 months	77.429 ± 28.046	66.286 ± 25.767	1.341	0.188
	Differences	-97.333 ± 43.510	-108.238 ± 44.983
	Paired test	< 0.001a	< 0.001a

^aP value < 0.05.

¹Students’ t-test.

BUN: Blood urea nitrogen; Cr: Creatinine; Na: Sodium; K: Potassium; Ca: Calcium; PO₄: Phosphorus; PTH: Parathyroid hormone; WBC: White blood cell; Hb: Haemoglobin; hs-CRP: High-sensitivity C-reactive protein; UPCR: Urinary protein-to-creatinine ratio; eGFR: Estimated glomerular filtration rate; TNF-α: Tumour necrosis factor-alpha.

No significant correlation was observed between TNF-α and the demographic data of the groups studied. A significant direct correlation was observed between TNF-α and creatinine in both groups (r = 0.477, P = 0.029; r = 0.579, P = 0.006). Moreover, a significant positive correlation was observed among TNF-α and WBCs in group 1 (r = 0.487, P = 0.025). There was a significant inverse correlation between TNF-α and eGFR in group 2 (r = -0.440, P = 0.046). There was no significant correlation between hs-CRP and demographic data, urinary protein-to-creatinine ratio (UPCR), and eGFR. A significant direct correlation was observed between hs-CRP and calcium in group B (r = 0.454, P = 0.039). No significant correlation was found between hs-CRP and the studied groups (Table 3).

Table 3 Correlation among tumour necrosis factor-alpha and high-sensitivity C-reactive protein and participants’ age, blood pressure and laboratory parameters of the studied groups.

	TNF-α (ng/L) after 6 months				hs-CRP (mg/L) after 6 months
	r value1 (group 1)	P value (group 1)	r value1 (group 2)	P value (group 2)	r value1 (group 1)	P value (group 1)	r value1 (group 2)	P value (group 2)
Age	0.100	0.667	-0.052	0.823	0.238	0.298	0.128	0.579
SBP after 6 months	0.072	0.756	0.304	0.180	0.237	0.302	0.049	0.832
DBP after 6 months	0.078	0.738	0.318	0.160	0.082	0.723	0.145	0.530
MAP after 6 months	0.112	0.629	0.020	0.933	0.094	0.685	0.073	0.754
Laboratory parameters
Hb (gm/dL)	-0.040	0.864	0.101	0.663	0.327	0.148	-0.102	0.659
WBCs (× 103/μl)	0.487	0.025a	0.083	0.720	-0.113	0.627	0.172	0.457
Platelet (× 103/μl)	-0.127	0.585	-0.063	0.786	0.043	0.852	0.242	0.291
BUN (mg/dL)	0.262	0.250	0.301	0.186	0.364	0.105	-0.206	0.371
Cr (mg/dL)	0.477	0.029a	0.579	0.006a	0.143	0.535	-0.185	0.423
Na (meq/L)	0.115	0.619	-0.071	0.761	0.102	0.658	0.222	0.334
K (meq/L)	-0.279	0.222	0.193	0.402	-0.397	0.075	0.117	0.613
Ca (mg/dL)	-0.269	0.238	-0.100	0.666	-0.365	0.104	0.454	0.039a
PO4 (mg/dL)	0.126	0.586	0.041	0.861	0.269	0.239	0.005	0.983
Intact PTH (pg/mL)	0.104	0.655	0.179	0.439	-0.326	0.150	-0.184	0.424
hs-CRP (mg/L) after 6 months	0.223	0.331	0.143	0.537	-	-	-	-
UPCR (mg/g) after 6 months	0.110	0.634	0.084	0.717	0.236	0.304	-0.120	0.604
eGFR (mL/minute/1.73 m2) after 6 months	-0.134	0.562	-0.440	0.046a	-0.057	0.805	-0.062	0.789

^aP value < 0.05.

¹Pearson coefficients.

SBP: Systolic blood pressure; DBP: Diastolic blood pressure; MAP: Mean arterial pressure; BUN: Blood urea nitrogen; Cr: Creatinine; Na: Sodium; K: Potassium; Ca: Calcium; PO₄: Phosphorus; PTH: Parathyroid hormone; WBC: White blood cell; Hb: Haemoglobin; hs-CRP: High-sensitivity C-reactive protein; UPCR: Urinary protein-to-creatinine ratio; eGFR: Estimated glomerular filtration rate; TNF-α: Tumour necrosis factor-alpha.

No significant relation was documented between TNF-α and hs-CRP and participants’ gender in both groups (Table 4).

Table 4 Relation between tumour necrosis factor-alpha and C-reactive protein with patients’ gender in both groups, mean ± SD.

		Sex		t value1	P value
		Male	Female
Group 1	TNF-α (ng/L) after 6 months	73.273 ± 23.230	82.000 ± 33.226	-0.703	0.490
	hs-CRP (mg/L) after 6 months	2.836 ± 0.707	3.430 ± 0.789	-1.818	0.085
Group 2	TNF-α (ng/L) after 6 months	63.000 ± 24.812	70.667 ± 27.848	-0.665	0.514
	hs-CRP (mg/L) after 6 months	2.642 ± 0.765	2.333 ± 0.721	0.937	0.361

¹Students’ t-test.

hs-CRP: High-sensitivity C-reactive protein; TNF-α: Tumour necrosis factor-alpha.

There was insignificant negative correlation between the change in TNF-α and eGFR [group 1 (r = -0.04, P = 0.863) and group 2 (r = -0.012, P = 0.959)], as well as the change in TNF-α and UPCR [group 1 (r = 0.102, P = 0.662) and group 2 (r = 0.223, P = 0.331)]. Additionally, a positive correlation is observed between the change in TNF-α and hs-CRP [group 1 (r = 0.05, P = 0.828) and group 2 (r = 0.037, P = 0.874)], as well as the change in TNF-α and creatinine [group 1 (r = 0.102, P = 0.662) and group 2 (r = 0.223, P = 0.331); Table 5].

Table 5 Correlation among change in tumour necrosis factor-alpha over the 6 months of the study period and the change in high-sensitivity C-reactive protein, estimated glomerular filtration rate, urinary protein-to-creatinine ratio and creatinine.

	TNF-α (ng/L) change
	r value1 (group 1)	P value (group 1)	r value1 (group 2)	P value (group 2)
eGFR (mL/minute/1.73 m2)	-0.040	0.863	-0.012	0.959
Creatinine (mg/dL)	0.063	0.785	0.023	0.920
hs-CRP (mg/L)	0.050	0.828	0.037	0.874
Urinary protein creatinine ratio (mg/mg)	0.102	0.662	0.223	0.331

¹Pearson coefficients.

eGFR: Estimated glomerular filtration rate; hs-CRP: High-sensitivity C-reactive protein; TNF-α: Tumour necrosis factor-alpha.

The change in protein creatinine ratio noted in group 2 was mainly due to changes in mean arterial pressure, followed by changes in TNF-α (Table 6).

Table 6 Multiple regression of change in urinary protein creatinine ratio and change of mean arterial pressure, tumour necrosis factor-alpha, high-sensitivity C-reactive protein and estimated glomerular filtration rate, respectively, in group 2 over 6 months.

	Unstandardized coefficients		t value	P value
	β	SE
MAP	-1.933	0.896	-2.159	0.046a
hs-CRP (mg/L)	-2.909	4.734	-0.614	0.548
eGFR (mL/minute/1.73 m2)	-1.711	1.239	-1.381	0.186
TNF-α (ng/L)	-0.223	0.123	-1.817	0.088

^aP ≤ 0.05.

MAP: Mean arterial pressure; hs-CRP: High-sensitivity C-reactive protein; eGFR: Estimated glomerular filtration rate; TNF-α: Tumour necrosis factor-alpha.

DISCUSSION

PTX undergoes hepatic metabolism, yielding both active and inactive metabolites. In CKD individuals, an active metabolite of PTX (metabolite V) tends to accumulate, while the parent compound remains inactive.

In the sole investigation assessing PTX pharmacokinetics in CKD patients, Paap et al[10] advised lowering the dose from 600 mg twice daily to 400 mg twice daily for patients with moderate renal impairment, and further reducing it to 200-400 mg per day for individuals with severe renal impairment. These doses correspond to those recommended in established dosing guidelines by Bennett et al[11]. Badri et al[12] state that gastrointestinal upset was improved when the drug was taken with a meal, which offers another potential solution for this adverse effect.

The findings of this study demonstrated a significant reduction in hs-CRP levels in group 2 relative to group 1, and this decline was more evident in the PTX group than in group 1. Similarly, TNF-α demonstrated a significant decline in both group 1 and group 2. Therefore, the decrease in both hs-CRP and TNF-α in group 2 indicates a more pronounced reduction in systemic inflammation following the addition of PTX.

The anti-inflammatory effects of PTX can be attributed to its role as a non-selective phosphodiesterase inhibitor, leading to increased intracellular cyclic adenosine monophosphate levels. This, in turn, suppresses the transcription and release of pro-inflammatory cytokines, particularly TNF-α, IL-6, and other mediators involved in chronic inflammation. PTX has also been shown to inhibit nuclear factor kappa B activation, a key regulator of inflammatory gene expression[13].

Our findings are consistent, Goicoechea et al[14] demonstrated that hs-CRP mean levels were significantly decreased in subjects enrolled in the PTX group, from 4.7 mg/L to 2.0 mg/L. TNF-α levels decreased significantly in the PTX and control group at 12 months.

Our study found that TNF-α positively correlates with serum creatinine in both groups, consistent with the findings of Li et al[15] who suggest that TNF-α is a standard indicator of inflammation and kidney dysfunction across various kidney diseases. TNF-α also showed a positive correlation with WBCs, supporting its role as an inflammatory marker, and a significant inverse correlation with eGFR, implying that higher inflammation is associated with poorer kidney function.

Furthermore, the reduction in proteinuria observed in our study may be partially explained by these anti-inflammatory mechanisms. TNF-α is known to contribute to glomerular permeability and podocyte injury; therefore, its suppression by PTX may help preserve glomerular integrity and reduce protein leakage. This mechanistic link between inflammation and proteinuria is supported by the observed association between changes in TNF-α and urinary protein excretion in our results[16].

An important methodological consideration in the present study is the presence of baseline differences in UPCR and hs-CRP between the two groups. Although randomization was performed, the relatively small sample size may have contributed to this imbalance, which represents a potential confounding factor when interpreting treatment effects. Baseline variability in inflammatory markers and proteinuria may influence the magnitude of observed changes during follow-up, as patients with higher initial values may demonstrate greater absolute reductions independent of the intervention. Therefore, part of the observed improvement in hs-CRP and UPCR in the PTX group could be partially attributed to regression toward the mean rather than solely reflecting a pharmacological effect of PTX.

Regarding CKD progression, UPCR declined significantly in both groups, with a greater decline observed in group 2, suggesting a potential protective effect of PTX on proteinuria. No significant difference was documented in eGFR changes among the groups, indicating that PTX was not harmful to kidney function. Although not statistically significant, group 2 showed a slight improvement in eGFR. These findings align with previous research indicating the antiproteinuric impacts of PTX in individuals with non-diabetic CKD. Lin et al[17] demonstrated that the median proteinuria decreased from 1140 mg/g to 800 mg/g (a median change of -29.3%) in the PTX group, whereas it increased from 1410 mg/g to 1810 mg/g (a median change of 13.8%) in the control group. Based on a meta-analysis performed by Liu et al[18] the combination of PTX with RAS blockade has been found to decrease proteinuria and attenuate the decline in renal function in individuals with CKD stages 3-5. Another study that proves the renoprotective effect of PTX is a comprehensive analysis of a nationwide administrative dataset by Wu et al[16], which revealed that the group receiving PTX had a decreased probability of developing end-stage kidney disease (ESKD). This study provides the initial evidence supporting the potential of PTX in mitigating the likelihood of ESKD, even in individuals with late-stage CKD.

Data for this population-based cohort study was derived from the extensive and comprehensive NHI Research Database. Researchers retrospectively identified adults (≥ 20 years) with CKD who received erythropoiesis-stimulating agents between 2000 and 2010, dividing them into PTX users and matched nonusers using 1:1 propensity scoring. A total of 7366 individuals were enrolled in each group, with additional documentation of concurrent medications such as diuretics, ACEIs, and angiotensin II receptor blockers (ARBs). Using Cox proportional hazard models, the study found that PTX significantly decreased the risk of ESKD and composite renal outcomes, though it did not affect overall mortality. PTX alone provided renoprotection comparable to combined RAAS inhibitor therapy and was more effective than RAAS inhibitor monotherapy. Overall, the data indicates that PTX can slow the progression to ESKD in individuals with predialysis stage 5 CKD. Building upon the findings of Goicoechea et al[14], it was indicated that the potential protective impact of PTX was only observed in patients with albuminuria. Significant differences in renal survival were observed between the two groups, with PTX demonstrating a protective effect in individuals with albuminuria. However, no significant differences in renal survival were documented in non-albuminuric individuals. Furthermore, when the results were analysed based on the presence of diabetes mellitus, the renoprotective influence of PTX was comparable between the two groups.

Chen et al[19] evaluated the nephroprotective effect of adding PTX in 661 stage 3B-5 CKD individuals with proteinuria (≥ 1 g/gCr) already on ACEIs or ARBs. Patients were grouped into PTX users and nonusers, with renal survival and subgroup analyses based on proteinuria levels. While mortality and cardiovascular events did not differ between groups, PTX use was associated with significantly better renal outcomes, with the most substantial benefit seen in patients with higher proteinuria.

In the multivariate Cox regression analysis, PTX use was associated with improved renal outcomes, resulting in a lower hazard ratio (HR = 0.705; 95%CI: 0.498-0.997; P = 0.048). This protective effect was even more pronounced in the subgroup with elevated proteinuria (HR = 0.602; 95%CI: 0.413-0.877; P = 0.008). Overall, the investigation by Chen et al[19] demonstrated that the addition of PTX resulted in a better renal outcome in individuals with high proteinuria, suggesting that proteinuria may predict individual patient responsiveness to PTX. In our study, a multiple regression model analysis was applied to examine the relationship between changes in urinary protein-to-creatinine levels in group 2 and various parameters. It was found that the reduction in UPCR levels (from 388.57 ± 14.24 to 150 ± 18.43, P < 0.001) was primarily influenced by the changes in mean arterial pressure with a secondary contribution from alterations in TNF-α levels. This observation underscores the clinical importance of rigorous BP management as a potential prerequisite or synergistic factor for optimizing the antiproteinuric efficacy of PTX. In essence, while PTX exerts renoprotective effects through modulation of inflammatory pathways, adequate control of BP appears essential to fully realize its therapeutic benefits. These findings support the concept that PTX should be employed as an adjunctive therapy alongside standard antihypertensive regimens rather than as a monotherapy for proteinuria reduction in non-diabetic CKD. High BP often leads to kidney damage, resulting in the gradual development of proteinuria over a period of several years. This condition can eventually progress to ESRD[20]. Elevated BP directly harms the nephrons and results in the passage of micro- or macro-proteins (proteinuria) through the glomerulus, contributing to the development of nephropathy. Additionally, the decline in UPCR was influenced by changes in TNF-α; therefore, the benefit of pentoxyfilline as an antiproteinuric agent is evident, as evidenced by its impact on TNF-α levels over the 6-month study period.

The study had several limitations, including a relatively small sample size, a single-centre design, and a short period of patient follow-up. Additionally, baseline differences in hs-CRP and UPCR between the study groups may represent a potential source of confounding and should be considered when interpreting the magnitude of the observed treatment effects.

CONCLUSION

In non-diabetic CKD patients, the addition of PTX to standard therapy resulted in a moderate decrease in CRP levels, TNFα and proteinuria, suggesting its potential as an adjunctive treatment to mitigate inflammation and proteinuria. Similarly, changes in eGFR were not substantial, though a modest increase was observed in group 2. Overall, PTX contributed to a decrease in proteinuria and stabilization of renal function, as evidenced by the nonsignificant change in eGFR over the six-month study period. Further studies are warranted to clarify the underlying mechanisms and to optimise the clinical application of PTX in CKD management.