Table 2.
Studies examining the efficacy of PTX on diabetic proteinuria
| Investigators, years [Ref.] | Patients, number | Study design | PTX dose, duration | Background RAS blockade | Main outcome findings | Safety profiles |
|---|---|---|---|---|---|---|
| Original investigation | ||||||
| Aminorroaya et al., 2005 [39] | Hypertensive type 2 diabetes with proteinuria >300 mg/day, CKD stages 1 to 3, N = 40 | Randomized, open-label, crossover PTX ➔captopril (n = 20) Captopril ➔ PTX (n = 19) 1 dropped-out |
1200 mg/day (400 mg three times daily), 8 weeks | Captopril 25 mg thrice a day | Both PTX and captopril reduced macroalbuminuria. (PTX: 1.4 to 1.0 g/day; Captopril: 1.3 to 0.8 g/day) | PTX and captopril treatment was well tolerated, although 1 (5%) patient on the captopril arm withdrew due to the development of dry cough. |
| Rodriguez-Morán et al., 2005 [40] | Normotensive type 2 diabetes with microalbuminuria, N = 130 | Randomized, open-label, equivalent PTX (n = 65) 1 dropped-out Captopril (n = 65) 3 dropped-out |
1200 mg/day (400 mg three times daily), 6 months | Captopril 25 mg thrice a day | Both PTX and captopril reduced microalbuminuria. (PTX: 101.1 to 23.1 μg/min; Captopril: 102.0 to 23.9 μg/min) |
One (1.5%) patient in the PTX group and 3 (5%) patients in the captopril group withdrew from the study due to headache and dry cough, respectively. |
| Navarro et al., 2005 [41] | Normotensive type 2 diabetes, persistent albuminuria >400 mg/day, CKD stage 1, N = 61 | Randomized, open-label controlled PTX plus ARB (n = 30) ARB (n = 31) |
1200 mg/day (600 mg twice daily), 4 months | Recommended dose of ARB | Add-on PTX reduced albuminuria (900 to 791 mg/day), whereas ARB did not (910 to 900 mg/day). Add-on PTX decreased serum and urinary levels of TNF-α, but only the change of urinary TNF-α correlated with the change of albuminuria. |
Four (13%) patients developed dizziness, and 3 (10%) patients complained of dyspepsia in the PTX group. These were all transient, and no patient withdrew from the study as a result of PTX adverse effects. |
| Rodriguez-Morán et al., 2006 [42] | Normotensive type 2 diabetes with microalbuminuria, N = 40 | Randomized, double-blind, placebo controlled PTX (n = 20) Placebo (n = 20) |
1200 mg/day (400 mg three times daily), 4 months | No RAS blockade | PTX reduced urinary excretion of both high- & low- molecular weight proteins in comparison with the placebo. | No subjects dropped out, nor were there serious adverse events or side effects. Four (13%) patients receiving PTX experienced mild headache in the first month that did not require treatment. |
| Roozbeh et al., 2010 [45] | Type 2 diabetes with overt proteinuria (> 500 mg/day), CKD stage 1, N = 74 | Randomized, open-label controlled Captopril (n = 37) 2 dropped-out PTX + captopril (n = 37) 2 dropped-out |
1200 mg/day (400 mg three times daily), 6 months | Captopril (25 mg thrice a day) | PTX plus captopril led to greater reduction in proteinuria than captopril group. (PTX: 2.9 to 1.3 g/day; Captopril: 2.8 to 2.0 g/day) |
One (3%) patient receiving PTX withdrew from the study due to nausea. |
| Oliaei et al., 2011 [43] | Type 2 diabetes with UPCR >500 mg/day; CKD stages 1 to 2, N = 56 | Randomized, double-blind, placebo controlled PTX (n = 28) Placebo (n = 28) |
1200 mg/day (400 mg three times daily), 3 months | ACEI and/or ARB | The use of PTX led to reduction of proteinuria, compared to the placebo group | No adverse effects or intolerance to drug were found during the period of treatment. |
| Ghorbani et al., 2012 [44] | Type 2 diabetes with persistent proteinuria >150 mg/day; CKD stages 1 to 3, N = 100 |
Randomized, double-blind, controlled PTX plus ACEI + ARB (n = 50), 6 dropped-out ACEI + ARB (n = 50) |
400 mg/day, 6 months | ACEI (enalapril) plus ARB (losartan) | Add-on PTX additively reduced proteinuria after 3 months, independently of BP or metabolic control | In the PTX group, 1 (2%) patient with chest pain and dyspnea, 1 (2%) patient with retinal hemorrhage and 4 (8%) patients with intractable nausea and vomiting withdrew from the study. |
| Han et al., 2015 [46] | Type 2 diabetes with CKD stages 1 to 3, N = 174 | Randomized double-blind, placebo controlled PTX + ARB (n = 52) 35 dropped-out Placebo + ARB (n = 70) 17 dropped-out |
1200 mg/day (400 mg three times daily), 6 months | ARB | By using per protocol analysis, add-on PTX reduced proteinuria and improved glucose control and insulin resistance without decreasing serum TNF-α levels. | The frequency of adverse effects (dyspepsia, nausea, vomiting, gastric reflux, diarrhea and headache).was higher in the PTX group. Thirteen (15%) patients in the PTX group and 5 (6.5%) patients in placebo group withdrew from the study due to adverse effects. |
| Shahidi et al., 2015 [49] | Type 2 diabetes with microalbuminuria CKD stages 1 to 2, N = 50 |
Randomized double-blind, placebo-controlled PTX + usual care (n = 25), 5 dropped-out Placebo + usual care (n = 25), 5 dropped-out |
1200 mg/day (400 mg three times daily), 6 months | Usual care with ACEI and/or ARB plus protein intake <0.8 g/kg/day and HbA1c < 8% | PTX plus usual care failed to reduce albuminuria compared with placebo plus usual care. | Ten patients (5 (20%) patients each in placebo and PTX groups) withdrew from the study due to gastrointestinal problems. |
| Meta-analysis, systematic review | ||||||
| McCormick et al., 2008 [50] | DKD, N = 476 | Systematic review (10 RCTs searched as of March 2006) | 7: 1200 mg/day 1: 600 mg/day 2: 400 mg/day Treatment duration: 2 to 12 months (median 6 months) |
ACEI and/or ARB (60%) or usual care | Compared with placebo or usual care, PTX may decrease proteinuria | Four patients stopped pentoxifylline therapy because of adverse effects (most common: digestive symptoms and dizziness). In the control arms, 5 patients withdrew because of adverse effects (cough due to captopril). |
| Shan et al., 2012 [51] | Type 1 and/or type 2 DKD, at CKD stages 3 to 4 (micro- or macro-albuminuria) N = 991 | Cochrane systematic review (17 studies with 16 of them being RCTs, searched as of July 2009) | 16: 400–1200 mg/day 1: 100 mg/day Treatment duration: 21 days to 12 months |
Routine treatment plus ACEI or ARB (18%) | Evidence to support the use of PTX in reducing albuminuria & proteinuria was insufficient | Adverse effects associated with PTX were reported in nine included studies. The most common adverse effects reported were headache, dizziness, nausea and dyspepsia of mild degree. |
| Tian et al., 2015 [52] | Type 2 DKD, N = 587 | Meta-analysis (8 RCTs searched as of December 2014) | 5: 1200 mg/day 1: 600 mg/day 2: 400 mg/day Treatment duration: 21 days to 2 years (median 5 months) |
ACEI and/or ARB | Add-on PTX to RAS blockade additively reduced proteinuria, albuminuria and urinary TNF-α. The benefits occurred independently from the decrease in BP or improvement in glycemic control. | The most frequent adverse effects in the PTX groups were transient digestive symptoms (9.4%) and dizziness (2.3%), only six participants withdrew due to intractable nausea and vomiting. |
| Jiang et al. 2016 [53] | CKD of various etiology, N = 613 | Systematic review & meta-analysis (12 studies as of January 2015) - 9 RCTs: DKD 1 crossover: membranous GN 2 non-RCTs: mixed diabetic & non-diabetic kidney disease |
The dose of PTX ranged from 400 to 1200 mg/day Treatment duration: 2 to 24 months |
ACEI and/or ARB (one-third) | PTX decreased proteinuria compared to placebo or no-treatment groups, but the decrease was not significant compared to captopril treatment | In the pooled analysis, there was no significant difference in the risk of any adverse events between the PTX and control arms. |
BP blood pressure, CRP C-reactive protein, DKD diabetic kidney disease, RCT randomized controlled trial, UPCR urinary protein-creatinine ratio