Table 2 Studies examining the efficacy of PTX on diabetic proteinuria

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.

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.