Table 3.

Trials evaluating the efficacy of PTX on renal progression with at least 1 year follow-up

Investigators, years [Ref.]	Patients, number	Study design	PTX dose, duration	Background RAS blockade	Main outcome findings	Safety profiles
Meta-analysis, systematic review
Leporini et al., 2016 [57]	CKD of various etiology, N = 1518	Systematic review & meta-analysis (26 studies as of 2015) - 24: diabetic patients 2: non-diabetic or mixed CKD patients	15: 1200 mg/day 5: 800 mg/day 1: 600 mg/day 5: 400 mg/day Treatment duration: 21 days to 24 months.	15 RCTs: compared to placebo or standard therapy. 11 RCTs: compared to RAS blockade.	Lack of conclusive evidence proving the usefulness of this agent for improving renal outcomes in subjects with CKD	Mild gastrointestinal intolerance represented the most frequently reported adverse event. In a pooled meta-analysis of 10 RCTs (786 pts), PTX was associated with an almost 3-fold higher risk of gastrointestinal symptoms than control treatment.
Liu et al., 2017 [58]	CKD of various etiology, N = 705	Meta-analysis (11 RCT as of July 30, 2015) -8: diabetic patients 3: non-diabetic or mixed CKD patients	6: 1200 mg/day 1: 800 mg/day 1: 600 mg/day 1: 400/800 mg/day 2: 400 mg/day Treatment duration: 7: ≦6 months 4: 9 to 24 months.	11 RCTs: compared to ACEI and/or ARB	Combination of a RAS blockade and PTX reduces proteinuria & ameliorates eGFR decline in patients with CKD stages 3 to 5.	Six studies that included 218 participants reported adverse events, and the proportion was 39/218 (17.9%).
Randomized clinical trials
Diskin et al., 2007 [65]	Insulin-dependent adult onset diabetic patients with proteinuria >1.5 g/day, N = 14	Open-label, controlled PTX plus ACEIs/ARBs (n = 7) ACEIs/ARBs alone (n = 7)	800 mg/day (CCr > 50 mL/min); 400 mg/day (CCr < 50 mL/min), 12 months	Maximum doses of ACEI plus ARB	Add-on PTX showed no significant benefit in proteinuria reduction or preservation of CCr.	No adverse reactions were recorded. Nevertheless, the rate of CCr decline >11 mL/min per year raises concern about the quality of patient care or the use of background maximum doses of ACEI and ARB.
Lin et al., 2008 [47]	CKD stages 3 or higher with proteinuria >0.5 g/gCr (DM 28%), N = 56	Randomized, open-label controlled PTX + losartan (n = 27) 0 dropped-out Losartan (n = 29) 2 dropped-out	800 mg/day (CKD stage 3); 400 mg/day (CKD stage 4), 12 months	Losartan (100 mg/day)	PTX treatment additively reduced proteinuria, which occurred in conjunction with changes in urinary TNF-α and MCP-1. eGFR remained stable in the PTX group but declined in the control group.	Two (7%) patients in the PTX group discontinued treatment. One patient withdrew due to recurrent gastric ulcer bleeding (at 6 months); another one withdrew due to newly diagnosed breast cancer (at 3 months) which was not related to the use of PTX.
Perkins et al., 2009 [63]	CKD stages 3 to 4 with proteinuria >1 g/day (DM 61%), N = 40	Randomized, double-blind, placebo controlled PTX + RAS blockade (n = 22) 5 dropped out Placebo + RAS blockade (n = 18) 2 dropped-out	800 mg/day, 12 months	ACEI and/or ARB	Rate of eGFR decline had been slowed in the PTX but not the control group. No effect on proteinuria was observed in the PTX group.	One participant in each group had bleeding complications and withdrew from the study. Seven (32%) participants in the PTX group and 5 (28%) in the placebo group were hospitalized for nonselective indications during the study period. No hospitalization was determined to be related to PTX.
Goicoechea et al., 2012 [64]	Type 2 diabetes with persistent proteinuria >150 mg/day; CKD stages 3 or higher, N = 91	Randomized, double-blind, controlled PTX (n = 46) 12 dropped-out Control (n = 45) 9 dropped-out (7 lost to follow-up)	800 mg/day (400 mg twice daily), 12 months	Usual therapy including ACEI and/or ARB (PTX: 80% Control: 82%)	PTX did not decrease proteinuria; eGFR declined in the usual therapy but not in the PTX group. Reduction of serum TNF-α, fibrinogen and hsCRP in the PTX group, although the control group also showed reduction of serum TNF-α levels.	Eight (17%) patients receiving PTX withdrew from the study because of gastrointestinal symptoms. Incomplete follow-up in both arms, particularly in the control group (16%).
Navarro-González et al., 2015 [48]	DKD at CKD stages 3 to 4, N = 169	Randomized, open-label controlled PTX + ARB (n = 82) 4 dropped-out ARB (n = 87) 5 dropped-out	1200 mg/day, 24 months	ARB	PTX group showed greater reduction of albuminuria and lower decrease in eGFR. Reduction of urinary TNF-α in the PTX group.	The most frequent adverse effects in patients treated with PTX were gastrointestinal symptoms (abdominal discomfort, flatus, dyspepsia, nausea, and vomiting), which were significantly more frequent than in the control group (21.9% versus 10.3%). In most cases these symptoms were self-limited and disappeared during the first month. Only one case in the PTX group discontinued treatment due to the adverse effect. Cardiovascular and cerebrovascular events and the number of hospitalizations did not differ between groups.
Observational cohort study
Investigators, years [Ref.]	Patients, number	Study design	PTX dose, duration	Background RAS blockade	Main outcome findings	Safety profiles
Chen et al., 2014 [60]	CKD stages 3B-5 before ESRD, N = 661	PTX nonusers (n = 242, DM 44.6%) PTX users (n = 419, DM 54.2%)	Most patients (stages 4–5) received a PTX dose of 400 mg/day; patients in stage 3B received 800 mg/day. Median follow-up period was 2.25 years	ACEI and/or ARB	In the advanced stages of CKD, patients treated with a combination of PTX and ACEI or ARB had a better renal outcome than those treated with ACEI or ARB alone. Renoprotective effect was more prominent in patients with higher proteinuria (> 1 g/gCr).	Not available
Wu et al., 2015 [61]	CKD stage 5 (serum Cr > 6 mg/dL) plus ESA, not treated with dialysis during 6 months before and 3 months after the first prescription of ESA. N = 14,732	PTX nonusers (n = 7366, DM 39.5%) PTX users (n = 7366, DM 39.6%)	One-fifth to one DDD of PTX is sufficient for renoprotection. The median time from the first prescription of ESA to the initiation of dialysis and death was 1.05 years and 3.61 years, respectively.	ACEI and/or ARB (64.8%)	PTX nonusers showed an increased risk of ESRD; PTX users were protective from ESRD, compared to the nonusers who received RAS blockade monotherapy.	Not available
Kuo et al., 2015 [62]	CKD stage 5 (serum Cr > 6 mg/dL) plus prescription of ACEI or ARB within 90 days after ESA use N = 8742	PTX nonusers (n = 6354, DM 59.2%) PTX users (n = 2118, DM 58.9%)	No specific PTX doses or dose ranges were mentioned. Mean follow up was 11.4 months in PTX users and 12.1 months in non-users	ACEI and/or ARB	PTX exhibited a protective effect in reducing the risk for the composite outcome of long-term dialysis or death.	Not available

CCr creatinine clearance, Cr creatinine, DDD defined daily dose, DM diabetes mellitus, ESA erythropoiesis-stimulating agent, ESRD end-stage renal disease