Pentoxifylline for diabetic kidney disease

Abstract

Background

Diabetic kidney disease (DKD) is associated with increased morbidity and mortality, mostly relating to cardiovascular complications. The relevance of inflammation in the pathogenesis of DKD has been investigated in recent years, and it has been shown that inflammatory markers are higher in people with DKD compared with the wider population. Pentoxifylline is a methylxanthine phosphodiesterase inhibitor with favourable anti‐inflammatory effects and immunoregulatory properties. The anti‐inflammatory effects conferred by pentoxifylline may be beneficial in the management of DKD.

Objectives

To assess the benefits and harms of pentoxifylline for treating people with DKD.

Search methods

We searched the Cochrane Renal Group's specialised register (January 2012), CENTRAL (Issue 12, 2011), MEDLINE, EMBASE and four Chinese biomedical literature databases (CBM‐disc, 1979 to July 2009), Chinese Science and Technique Journals Database (VIP, until July 2009), China National Knowledge Infrastructure (CNKI, until July 2009) and WanFang database (until July 2009).

Selection criteria

All randomised controlled trials (RCTs) and quasi‐RCTs studying the benefits and harms of pentoxifylline for DKD.

Data collection and analysis

Data were extracted independently by two authors. Meta‐analyses were performed when more than one study provided data on a comparable outcome in sufficiently similar patients. Results of dichotomous outcomes were expressed as risk ratios (RR) with 95% confidence intervals (CI). Mean differences (MD) were calculated to assess the effects of treatment where outcomes were expressed on continuous scales, and standardised mean differences (SMD) calculated where different scales were used. Data was pooled using the random effects model. Adverse effects were assessed using descriptive techniques and where possible, risk differences (RD) with 95% CI.

Main results

We identified 17 studies that included a total of 991 participants with DKD which met our inclusion criteria. Overall, the methodological quality of included studies was low: 4/17 reported the method of randomisation, 13/17 did not; no study described the method of random allocation; 4/17 studies were considered to be at high risk of bias and 13/17 were considered to have unclear risk for incomplete outcome data reporting; 9/17 studies were at low risk bias and in 8/17 the risk of bias was unclear for selective outcome reporting.

Compared with placebo, pentoxifylline significantly reduced serum creatinine (SCr) (MD ‐0.10 mg/dL, 95% CI ‐0.17 to ‐0.03), albuminuria (SMD ‐2.28, 95% CI ‐3.85 to ‐0.70) and overt proteinuria (MD ‐428.58 µg/min, 95% CI ‐661.65 to ‐195.50), but there was no difference in creatinine clearance (CrCl) (MD ‐5.18 mL/min, 95% CI ‐15.55 to 5.19). When compared with routine treatment alone, pentoxifylline did not significantly reduce SCr (MD 0.00 mg/dL, 95% CI ‐0.06 to 0.07) or blood pressure (systolic (SBP): MD ‐0.28 mm Hg, 95% CI ‐2.20 to 1.63; diastolic (DBP): MD ‐0.15 mm Hg, 95% CI ‐1.44 to 1.14), but did significantly reduce albuminuria (SMD 0.62, 95% CI 0.18 to 1.07) and proteinuria (MD 0.46 g/24 h, 95% CI 0.17 to 0.74). There was no significant difference in SCr (MD 0.00 mg/dL, 95% CI ‐0.08 to 0.07), albuminuria (MD ‐8.79 µg/min, 95% CI ‐27.18 to 9.59), proteinuria (MD ‐0.01 g/24 h, 95% CI ‐0.03 to 0.01) or blood pressure (SBP: MD 1.46 mm Hg, 95% CI ‐0.57 to 3.50; DBP: MD 1.37 mm Hg, 95% CI ‐0.23 to 2.98) between pentoxifylline and the active comparator (captopril or clonidine/methyldopa) for patients with type 1 and type 2 DKD. CrCl was significantly increased when pentoxifylline was compared to clonidine/methyldopa (MD 10.90 mL/min, 95% CI ‐1.40 to 20.40) but not with captopril (MD 3.26 mL/min, 95% CI ‐1.05 to 7.59). No data were available on the incidence of end‐stage kidney disease (ESKD), time to ESKD, quality of life, or all‐cause mortality. The adverse events of pentoxifylline were mild; no serious adverse events were reported in any of the included studies.

Authors' conclusions

From the available evidence, pentoxifylline seems to offer some beneficial effects in renal function improvement and reduction in albuminuria and proteinuria, with no obvious serious adverse effects for patients with DKD. However, most studies were poorly reported, small, and methodologically flawed. Evidence to support the use of pentoxifylline for DKD was insufficient to develop recommendations for its use in this patient population. Rigorously designed, randomised, multicentre, large scale studies of pentoxifylline for DKD are needed to further assess its therapeutic effects.

Plain language summary

Pentoxifylline for diabetic kidney disease

Kidney disease develops in 25% to 40% of diabetic patients, usually 20 to 25 years after the onset of diabetes. Approximately one third of those with diabetic kidney disease (DKD) will progress to end‐stage kidney disease (ESKD) and will require long‐term dialysis or possibly receive a kidney transplant. Many patients however may die from associated coronary artery disease or other cardiovascular causes before the onset of ESKD. Pentoxifylline has been described as offering properties that may be beneficial for patients with DKD. We reviewed 17 randomised controlled studies, enrolling 991 patients with DKD, which compared pentoxifylline with placebo, routine treatment or antihypertensive drugs.

Compared with placebo, pentoxifylline significantly reduced serum creatinine (SCr), albuminuria, and overt proteinuria, but not creatinine clearance (CrCl). When compared with routine treatment alone, pentoxifylline did not reduce SCr or blood pressure, but did significantly reduce albuminuria and proteinuria. Compared to captopril or clonidine/methyldopa there was no significant difference in SCr, albuminuria, proteinuria or blood pressure for patients with type 1 and type 2 DKD. CrCl was significantly increased when pentoxifylline was compared to clonidine/methyldopa but not with captopril. No data were available on the incidence of ESKD, time to ESKD, quality of life, or all‐cause mortality. The adverse events of pentoxifylline were mild; no serious adverse events were reported in any of the included studies.

Pentoxifylline seemed to have some beneficial effects in improving kidney function and reducing albuminuria and proteinuria (which can indicate kidney health) for patients with DKD, and was not associated with any major adverse effects. However, the current evidence on the effects of pentoxifylline for patients with DKD was insufficient to formulate therapeutic recommendations. More large, high‐quality randomised studies are needed to better inform clinical decision making about the use pentoxifylline for patients with DKD.

Background

Diabetic kidney disease (DKD) occurs in 30% to 40% of patients with type 1 diabetes mellitus (DM), 20 to 25 years after disease onset, and in an increasing percentage (up to 25%) of type 2 diabetes patients, after a variable number of years (Ritz 1999a). DKD is the major cause of end‐stage kidney disease (ESKD) in most western nations and is associated with increased morbidity and mortality compared with other causes of kidney disease (KDOQI 2007; Middleton 2006; Ritz 1999b). There has been a continuous increase in the incidence of DKD, predominantly among patients with type 2 diabetes (Collins 2005; KDOQI 2007; USRDS 2009). The present population of patients whose ESKD was caused by diabetes (which tripled between 1990 and 2000) is expected to increase ten‐fold by 2030 to 1.3 million patients (Collins 2005). In the USA, diabetes now accounts for 45% of prevalent kidney failure, up from 18% in 1980 (KDOQI 2007). DKD is particularly common among elderly and non‐Caucasian (African‐American, Asian, and Native American) populations. A similar trend has become evident in other developed countries, which has created global concern about the need to address this major health issue (Ritz 1999a). 
 
 DKD is a major contributor of microvascular complications in patients with diabetes. It is commonly assumed that type 1 and type 2 diabetes share similar pathogenic and clinical stages of kidney damage (Mogensen 1997). Patients with diabetes typically experience several characteristic stages in the development of kidney disease: kidney hypertrophy and hyperfiltration, microalbuminuria (incipient kidney disease; urine albumin excretion (UAE) rate 30 to 300 mg/d), macroalbuminuria (overt kidney disease or overt proteinuria; UAE > 300 mg/d) and ESKD. Progression through these stages is accompanied by a high incidence of cardiovascular complications, which account for most deaths among these patients (Collins 2005; KDOQI 2007; USRDS 2009). 
 
 Once ESKD occurs, patient survival is very limited (Chantrel 1999; Ritz 1999a). In Germany and Australia, the five‐year survival rates are 6% and 27% respectively (Ritz 1999a). Patients with DKD who develop ESKD enter the highest known cardiovascular risk‐state (McCullough 2004). However, more people with DKD will die from complications related to cardiovascular disease than progress to ESKD (Collins 2005; KDOQI 2007; USRDS 2009; USRDS 2011). Data from 2011 United States Renal Data System (USRDS) show that the total Medicare costs of reported ESKD was about USD 12.2 billion in 2000 and this figure rapidly rose to USD 24.7 billion in 2009 (USRDS 2011). These factors justify intensive efforts to prevent and treat DKD.

Management of DKD is typically undertaken at three levels. Patients with no clinical and biochemical signs of kidney damage are targeted for primary prevention of DKD. Clinical and biochemical assessments to establish patients' status in relation to risk of developing DKD are: UAE < 30 mg/d, adherence to strict glycaemic control achieved with oral antidiabetic agents or insulin, blood pressure (BP) stable at less than 130/85 mm Hg, and obligatory use of angiotensin‐converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) (Ritz 2006). Secondary prevention aims to prevent or delay progression from microalbuminuria to macroalbuminuria (overt proteinuria). BP and glycaemic controls are first‐line therapies. At this stage, antihypertensive agents in addition to ACEi or ARB may be necessary to achieve optimal BP levels (Strippoli 2005a). Tertiary prevention aims to reduce the rate of progression to kidney failure by controlling BP, reducing dietary protein intake and controlling dyslipidaemia in the presence of a (non‐fundamental) euglycaemic state. However, these measures are not wholly effective (KDOQI 2007; Robertson 2007; Strippoli 2005b; Tonolo 2006). Achieving strict metabolic control is clinically challenging, and this has stimulated identification of additional and alternative treatment options to manage DKD.

Interest in inflammation in diabetes and its role in the pathogenesis of diabetic complications, including nephropathy, has increased in recent times. Results from several studies have indicated that serum levels of inflammatory markers and UAE levels are higher in patients with diabetes compared with normoalbuminuric individuals (Chen 1996; Festa 2000; Navarro 2003b). Moreover, some studies have shown that inflammatory marker levels increase as kidney disease progresses (Bruno 2003; Festa 2000). Inflammation has therefore become an important mechanism in the pathogenesis of kidney injury in diabetes (Navarro 2003b; Navarro 2003c; Navarro‐Gonzalez 2008; Rivero 2009).

Pentoxifylline is a methylxanthine phosphodiesterase inhibitor with favourable effects on microcirculatory blood flow as a result of its haemorrheologic properties (Ward 1987). Recent studies have shown that pentoxifylline also carries anti‐inflammatory and immunoregulatory properties. In vivo studies have demonstrated beneficial effects of pentoxifylline in different models of kidney disease, including murine lupus nephritis (Segal 2001), crescentic glomerulonephritis (Chen 2004), and mesangial proliferative glomerulonephritis (Chen 1999). Animal models of DKD have demonstrated significant effects of pentoxifylline in modulating inflammation, cell proliferation, and fibrosis (Han 2010; Lin 2002; Navarro 2006). Pentoxifylline administration attenuated interstitial inflammation, down‐regulated monocyte chemoattractant protein‐1 gene expression, reduced expression of mitogenic and profibrogenic genes, and suppressed proliferation of interstitial fibroblast and glomerular mesangial cells (Han 2010; Lin 2002; Navarro 2006).

Clinical studies in patients with DKD have also shown that pentoxifylline alone or combined with ACEi or ARB attenuates proteinuria (Aminorroaya 2005b; Guerrero‐Romero 1995b; Leyva‐Jimenez 2009; Navarro 2003d; Navarro 2005b; Tripathy 1993) and reduces inflammatory effects (Navarro 1999b; Navarro 2005b). A significant limitation of this evidence is that most studies enrolled small numbers of participants.

McCormick 2008 conducted a meta‐analysis that assessed the effect of pentoxifylline on proteinuria in patients with DKD that included 10 RCTs of 476 adult patients who received oral pentoxifylline. The analysis was limited to articles published before the first quarter of 2006 and predominantly looked at the effect of pentoxifylline on proteinuria in DKD patients. The report of the meta‐analysis indicated that pentoxifylline may be responsible for decreasing proteinuria in patients with DKD.

The most important goal of DKD treatment is to reduce or delay onset of cardiovascular events and ESKD, and ultimately to prolong survival and improve quality of life. This systematic review of pentoxifylline for DKD aimed to investigate clinically important outcomes at long‐term follow‐up and provide the best available evidence for clinical practice and further research.

Objectives

This review aimed to investigate the benefits and harms of pentoxifylline for treating people with DKD.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) and quasi‐RCTs (studies in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) that assessed the benefits and harms of pentoxifylline for treating DKD were included. The first periods of randomised cross‐over studies were also included.

Types of participants

Inclusion criteria

• Diagnosis of diabetes: Diagnosis of diabetes confirmed according to the prototypes from ADA 1997 and WHO 1999 (fasting plasma glucose ≥ 7.0 mmol/L, and 2 hour plasma glucose ≥ 11.1 mmol/L).

• Diagnosis of DKD: The diagnosis and staging of DKD are based on UAE rate measured by 24 or 48 hour urine collection or albumin/creatinine ratio (ACR). Definitions applied were:

  • Normoalbuminuria: ACR < 30 mg/g or UAE < 30 mg/d (< 20 µg/min)

  • Microalbuminuria: ACR between 30 and 300 mg/g or UAE between 30 and 300 mg/d (20 to 200 µg/min)

  • Macroalbuminuria (overt proteinuria): ACR > 300 mg/g or UAE > 300 mg/d (> 200 µg/min) on a timed specimen confirmed with three serial measurements for six months

  • DKD: albumin excretion rate ≥ to 30 mg/d (≥ 20 µg/min) or ACR ≥ 30 mg/g on a timed specimen confirmed with three serial measurements for six months (KDOQI 2007)

  • Proteinuria refers to all ranges of albuminuria. Overt proteinuria specifically relates to macroalbuminuria.

• Any type 1 or type 2 diabetes patients with DKD confirmed by the presence of microalbuminuria or macroalbuminuria.

Exclusion criteria

• Patients with kidney damage relating to diseases other than diabetes.

• Patients with kidney damage relating to types of diabetes other than type 1 or type 2, such as gestational diabetes.

• Patients in final stage DKD or ESKD were excluded. Final stage DKD was defined as the point at which dialysis or transplantation becomes necessary.

Types of interventions

Any pentoxifylline agents used for treating DKD, regardless of dosage, mode of administration or duration of treatment. The comparisons were:

• Pentoxifylline + routine treatment versus placebo + routine treatment

• Pentoxifylline + routine treatment versus routine treatment

• Pentoxifylline + routine treatment versus other drug + routine treatment.

Routine treatment included glycaemic, BP and lipid controls; anticoagulant/antiplatelet therapy; physical activity and diet control (protein, sodium and phosphate restriction). Other drugs administered could include ACEi, ARB, or calcium channel blockers (CCB).

Types of outcome measures

• Incidence of ESKD at end of treatment and follow‐up.

• Time to ESKD.

• Serum creatinine (SCr) (mg/dL, µmol/L) at the end of treatment or change in SCr between beginning and end of treatment.

• Doubling of SCr at end of treatment.

• Creatinine clearance (CrCl) or glomerular filtration rate (GFR) (any measure) at end of treatment or change in CrCl/GFR (any measure) between beginning and end of treatment.

• Change in GFR/year (mL/min/y).

• Change in renal plasma flow (mL/min) from the beginning to the end of treatment.

• Albuminuria (mg/d or µg/min), macroalbuminuria (overt proteinuria) (mg/d or µg/min) or proteinuria (all range of albuminuria) (mg/d) at the end of treatment or change between beginning and end of treatment.

• Urinary ACR (mg albumin/g creatinine).

• All‐cause mortality.

• Quality of life measured by any scale.

• Adverse events associated with pentoxifylline such as headache, dizziness, nausea, vomiting, dyspepsia, hypotension, cardiac arrhythmia, flush, hypersensitivity or allergic reaction.

• Change of BP (systolic (SBP); diastolic (DBP)) from beginning to end of treatment.

• Level of plasma fibrinogen at the end of treatment.

• Incidence of cardiovascular disease.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Renal Group's Specialised Register (10 January 2012) through contact with the Trials' Search Co‐ordinator using search terms relevant to this review.

The Cochrane Renal Group’s Specialised Register contains studies identified from:

1. Quarterly searches of the Cochrane Central Register of Controlled Trials CENTRAL;

2. Weekly searches of MEDLINE OVID SP;

3. Handsearching of renal‐related journals & the proceedings of major renal conferences;

4. Searching of the current year of EMBASE OVID SP;

5. Weekly current awareness alerts for selected renal‐journals;

6. Searches of the International Clinical Trials Register (ICTRP) Search Portal & ClinicalTrials.gov.

Studies contained in the specialised register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE, based on the scope of the Cochrane Renal Group. Details of these strategies as well as a list of handsearched journals, conference proceedings and current awareness alerts are available in the 'Specialised Register' section of information about the Cochrane Renal Group

See Appendix 1 for search terms used in strategies for this review.

We also searched the Chinese biomedical databases: China Biological Medicine (CBM‐disc, 1979 to July 2009), Chinese Science and Technique Journals Database (VIP, until July 2009), China National Knowledge Infrastructure (CNKI, until July 2009) and WanFang (until July 2009) were searched.

Searching other resources

1. Reference lists of nephrology textbooks, review articles and relevant studies.

Data collection and analysis

Selection of studies

Titles and abstracts of studies relevant to the review were screened independently by two authors, who discarded studies that were not applicable. However, studies and reviews that may have included relevant data or information were retained initially. Two authors independently assessed retrieved abstracts, and if necessary the full text, to determine which studies satisfied the inclusion criteria. Disagreements were resolved in consultation with a third author.

Data extraction and management

Data extraction was conducted independently by the same two authors using standardised data extraction forms. Studies reported in non‐English language journals were translated before assessment. Where more than one publication of one study existed, reports were grouped together and the publication with the most complete data was be used in the analyses. Where relevant outcomes were only published in earlier versions this data was used. Any discrepancies between published versions were to be highlighted. Where additional information was required from the original author, requests were made by written correspondence and any relevant information obtained in this manner was included in the review. Disagreements were resolved in consultation with a third author.

Assessment of risk of bias in included studies

The following items were assessed using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

• Was there adequate sequence generation (selection bias)?

• Was allocation adequately concealed (selection bias)?

• Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?

  • Participants and personnel

  • Outcome assessors

• Were incomplete outcome data adequately addressed (attrition bias)?

• Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

• Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (such as incidence of ESKD, all‐cause mortality) results were expressed as risk ratios (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess effects of treatment (such as SCr, GFR, proteinuria, and quality of life measures), the mean difference (MD) was used, or the standardised mean difference (SMD) if different scales were used. Adverse effects were tabulated and assessed using descriptive techniques because they were likely to differ among the various agents. Where possible, risk difference (RD) with 95% CI was calculated for each adverse effect, either compared with no treatment or to another agent.

Assessment of heterogeneity

Heterogeneity was analysed using a Chi² test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.

Assessment of reporting biases

Although we had planned to check for publication bias using funnel plots, the size of studies identified meant this was not feasible (Higgins 2011).

Data synthesis

Data were pooled using the random‐effects model but the fixed‐effect model was also applied to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis was conducted to explore possible sources of heterogeneity (such as participants, interventions and study quality). Heterogeneity among participants could be related to age, type of diabetes, stage of DKD, baseline presence or absence of hypertension, and renal pathology. Heterogeneity in treatments could be related to prior agent or agents used, dose, and duration of therapy. Heterogeneity among studies could be related to study quality.

Sensitivity analysis

Sensitivity analyses were performed to assess the effects of including:

• only those studies with adequate concealment of randomisation; and

• only those studies that used blinding techniques (that is, participants, investigators or outcome assessors were blinded) (Higgins 2011).

Results

Description of studies

Results of the search

We retrieved 33 potentially eligible studies for further assessment. Of these, 17 studies (991 participants) met our inclusion criteria (Aminorroaya 2005a; Gan 2003; Guerrero‐Romero 1995a; Harmankaya 2003; Leyva‐Jimenez 2009; Navarro 1999a; Navarro 2003a; Navarro 2005a; Pang 2003; Pantoja 2003; Rodriguez‐Moran 2005; Rodriguez‐Moran 2006; Solerte 1986; Solerte 1987; Sui 1999; Zang 1999; Zhang 2001). We excluded 16/33 potentially eligible studies based on methodological issues, wrong population, or the study was not an RCT. Details of the selection process for inclusion of studies are presented in Figure 1.

1.

Study flow diagram: pentoxifylline for diabetic kidney disease (DKD)

Included studies

Of the 17 included studies, all but one (Aminorroaya 2005a) were parallel RCTs. Studies were conducted in China (Gan 2003; Pang 2003; Sui 1999; Zang 1999; Zhang 2001), Spain (Navarro 1999a; Navarro 2003a; Navarro 2005a), Mexico (Guerrero‐Romero 1995a; Leyva‐Jimenez 2009; Rodriguez‐Moran 2005; Rodriguez‐Moran 2006), Turkey (Harmankaya 2003), Brazil (Pantoja 2003), Italy (Solerte 1986; Solerte 1987) and Iran (Aminorroaya 2005a). Participants' ages ranged from 20 to 77 years. There was a gender bias in most studies (male = 51% to 82.3% in 11 studies; two studies did not report participants' gender). Few studies reported diabetes diagnostic criteria, but those that did cited application of WHO 1999 criteria.

Most study participants had type 2 diabetes (Aminorroaya 2005a; Harmankaya 2003; Leyva‐Jimenez 2009; Navarro 2003a; Rodriguez‐Moran 2005; Rodriguez‐Moran 2006; Sui 1999; Zang 1999; Zhang 2001); three studies included people with type 1 diabetes (Navarro 1999a; Navarro 2005a; Solerte 1987); two included participants with types 1 and 2 diabetes (Guerrero‐Romero 1995a; Solerte 1986); and three studies did not report diabetes type (Gan 2003; Pang 2003; Pantoja 2003). Duration of diabetes diagnoses ranged from 2 to 20 years (13 studies), but four studies did not report duration (Aminorroaya 2005a; Navarro 1999a; Pantoja 2003; Zang 1999).

All study participants were in stage 3 or stage 4 of DKD (microalbuminuria or macroalbuminuria). None or the included studies reported duration of DKD.

Guerrero‐Romero 1995a included eight arms with four subgroups based around diabetes type and stage of DKD. Leyva‐Jimenez 2009 designed a study with four arms with two subgroups focused on DKD stage.

Five studies were conducted in outpatient settings (Guerrero‐Romero 1995a; Navarro 2003a; Rodriguez‐Moran 2005; Solerte 1986; Solerte 1987). One study was conducted in an inpatient setting (Sui 1999); four were conducted in both outpatient and inpatient settings (Aminorroaya 2005a; Gan 2003; Leyva‐Jimenez 2009; Pang 2003); and seven did not report study settings (Harmankaya 2003; Navarro 1999a; Navarro 2005a; Pantoja 2003; Rodriguez‐Moran 2006; Zang 1999; Zhang 2001).

Of the 17 included studies, four compared pentoxifylline plus routine treatment with placebo plus routine treatment (Guerrero‐Romero 1995a; Leyva‐Jimenez 2009; Rodriguez‐Moran 2006; Zang 1999). Nine studies compared pentoxifylline plus routine treatment with routine treatment alone (Gan 2003; Harmankaya 2003; Navarro 1999a; Navarro 2003a; Navarro 2005a; Pang 2003; Pantoja 2003; Solerte 1986; Sui 1999). Comparisons of pentoxifylline plus routine treatment with other drugs, such as an ACEi (captopril), were conducted in three studies (Aminorroaya 2005a; Rodriguez‐Moran 2005; Zhang 2001). Solerte 1987 investigated pentoxifylline plus conventional antihypertensive drugs (clonidine or methyldopa) plus routine treatment.

Pentoxifylline dose ranged from 400 mg/d to 1200 mg/d by oral administration (16 studies). Pentoxifylline was administered as 100 mg/d intravenously in one study (Pang 2003). Treatment duration varied from 21 days (Pang 2003) to one year (Solerte 1987). Routine treatment included glycaemic control (e.g. insulin injection, multiple oral hypoglycaemic drugs or both); antihypertensive drugs (ACEi, ARB, CCB); diets aimed at weight loss; and appropriate physical activities.

The most commonly reported outcomes were the mean value of proteinuria, albuminuria, SCr, CrCl and BP before and after treatment. None of the included studies provided ESKD incidence, time to ESKD, all‐cause mortality, quality of life, or incidence of cardiovascular disease data. Solerte 1987 reported plasma fibrinogen changes after treatment.

Adverse effects associated with pentoxifylline were reported in nine included studies (Aminorroaya 2005a; Guerrero‐Romero 1995a; Harmankaya 2003; Navarro 2005a; Pang 2003; Rodriguez‐Moran 2005; Rodriguez‐Moran 2006; Sui 1999; Zang 1999).The most common adverse effects reported were headache, dizziness, nausea and dyspepsia. Two studies indicated that one to three participants in pentoxifylline groups withdrew because of nausea and headache (Guerrero‐Romero 1995a; Rodriguez‐Moran 2005). Zang 1999 reported that two participants in the pentoxifylline arm withdrew because of dyspepsia. Sui 1999 reported three withdrawals from the pentoxifylline group due to unspecified side effects. Although there were no withdrawals associated with side effects in five studies, participants in pentoxifylline groups reported dizziness, headache and dyspepsia (Aminorroaya 2005a; Harmankaya 2003; Navarro 2005a; Pang 2003; Rodriguez‐Moran 2006).

Full details of included studies are presented in Characteristics of included studies.

Excluded studies

Fourteen studies (17 reports) were excluded. Participants in six studies (Cen 2005; Chua 1995; Diao 2003; Diskin 2007; Mooraki 2006; Paap 1996) were not randomised. Maiti 2007 included participants with unknown underlying kidney disease. Laczy 2009 enrolled patients with diabetic neuropathy, not DKD. Separate data for patients with DKD were not provided by five studies (Garg 1998; Lin 2008; Navarro 1998; Navarro 1999a; Perkins 2009). Gonzalez‐Espinoza 2008 included participants on haemodialysis and Demir 2007 included kidney transplant recipients.

Risk of bias in included studies

See Figure 2 and Figure 3 for summaries of the risk of bias findings.

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Overall, randomisation was poorly described in the included studies, and was unclear in 13 studies. Four studies applied a computer‐generated randomisation table for allocation (Navarro 2003a; Navarro 2005a; Rodriguez‐Moran 2005; Rodriguez‐Moran 2006). None of the included studies adequately described the allocation concealment methodologies that were applied.

Blinding

Reporting on blinding was inadequately addressed by most included studies. Fourteen studies did not report how or if blinding was applied. Participants and outcomes assessors were blinded in three studies (Leyva‐Jimenez 2009; Rodriguez‐Moran 2005; Rodriguez‐Moran 2006).

Incomplete outcome data

Four studies reported withdrawals, but the results were not analysed on an intention‐to‐treat basis (Guerrero‐Romero 1995a; Leyva‐Jimenez 2009; Sui 1999; Zang 1999). Thirteen studies were assessed to be low risk of attrition bias.

Selective reporting

Of the 17 included studies, nine reported on adverse events (Aminorroaya 2005a; Guerrero‐Romero 1995a; Harmankaya 2003; Navarro 2005a; Pang 2003; Rodriguez‐Moran 2005; Rodriguez‐Moran 2006; Sui 1999; Zang 1999).

Other potential sources of bias

Presented information was insufficient to determine if there were other potential sources of bias in the included studies.

Effects of interventions

None of the included studies presented data on the incidence of ESKD at treatment end or at follow‐up, or on the time to reach ESKD. Outcomes relating to all‐cause mortality and quality of life measured on any scale were not investigated or reported in any of the included studies.

Pentoxifylline plus routine treatment versus placebo plus routine treatment

Four studies (Guerrero‐Romero 1995a; Leyva‐Jimenez 2009; Rodriguez‐Moran 2006; Zang 1999) compared pentoxifylline plus routine treatment with placebo plus routine treatment.

Kidney function

Serum creatinine (mg/dL) at the end of treatment

Two studies (Rodriguez‐Moran 2006; Zang 1999) reported SCr at the end of treatment. There was a significant decrease in SCr among participants in the pentoxifylline group compared with the placebo group (Analysis 1.1 (2 studies, 117 participants): MD ‐0.10 mg/dL, 95% CI ‐0.17 to ‐0.03; I² = 0%).

1.1. Analysis.

Comparison 1 Pentoxifylline + routine treatment versus placebo + routine treatment, Outcome 1 Serum creatinine at end of treatment.

Leyva‐Jimenez 2009 did not report the standard deviation (SD) for change in SCr from baseline.

Creatinine clearance (mL/min) at the end of treatment

Two studies (Guerrero‐Romero 1995a; Leyva‐Jimenez 2009) reported CrCl, however Leyva‐Jimenez 2009 did not report end of treatment CrCl. Guerrero‐Romero 1995a reported no significant difference in CrCl improvement in patients with DKD regardless of diabetes type or baseline proteinuria between treatments (Analysis 1.2 (1 study, 94 participants): MD ‐5.18 mL/min, 95% CI ‐15.55 to 5.18). The four subgroups presented in Guerrero‐Romero 1995a were homogeneous (I² = 0%).

1.2. Analysis.

Comparison 1 Pentoxifylline + routine treatment versus placebo + routine treatment, Outcome 2 Creatinine clearance at end of treatment.

Albuminuria

Two studies (Rodriguez‐Moran 2006; Zang 1999) reported albuminuria. There was a significant decrease in albuminuria among patients with type 2 DKD in the pentoxifylline group compared with placebo (Analysis 1.3 (2 studies, 117 participants): SMD ‐2.28, 95% CI ‐3.85 to ‐0.70; I² = 90%). The very high heterogeneity may be attributable to differences in risk of bias, duration of diabetes and treatment periods. Rodriguez‐Moran 2006 reported blinding of participants and outcome assessors, duration of diabetes diagnosis (4 to 12 years) and treatment periods (four months). Zang 1999 did not report blinding or duration of diabetes diagnosis, but the treatment period in this study was six months.

1.3. Analysis.

Comparison 1 Pentoxifylline + routine treatment versus placebo + routine treatment, Outcome 3 Albuminuria at end of treatment.

Overt proteinuria (macroalbuminuria, µg/min)

One study (Guerrero‐Romero 1995a) reported overt proteinuria at the end of treatment. Compared to placebo, pentoxifylline significantly decreased overt proteinuria in all DKD patients (Analysis 1.4 (1 study, 46 participants): MD ‐428.58 µg/min, 95% CI ‐661.65 to ‐195.50) as well as those with type 2 DKD (Analysis 1.4.1 (1 study, 22 participants): MD: ‐552.00 µg/min, 95% CI ‐656.57 to ‐447.43) and type 1 DKD (Analysis 1.4.2 (1 study, 24 participants): MD: ‐314.00 µg/min, 95% CI ‐367.36 to ‐260.64).

1.4. Analysis.

Comparison 1 Pentoxifylline + routine treatment versus placebo + routine treatment, Outcome 4 Overt proteinuria at end of treatment.

Blood pressure (mm Hg) at the end of treatment

Two studies (Guerrero‐Romero 1995a; Rodriguez‐Moran 2006) reported BP at the end of treatment. In patients with type 2 microalbuminuria, pentoxifylline did not significantly decrease either SBP (Analysis 1.5.1 (2 studies, 62 participants): MD 10.15 mm Hg, 95% CI ‐15.27 to 35.58; I² = 90%) or DBP (Analysis 1.6.1 (2 studies, 62 participants): MD ‐3.17 mm Hg, 95% CI ‐7.98 to 1.64; I² = 0%) when compared to placebo. The high SBP heterogeneity may be attributable to inclusion and exclusion criteria differences. Rodriguez‐Moran 2006 described their inclusion and exclusion criteria, while Guerrero‐Romero 1995a did not report their inclusion and exclusion criteria in detail.

1.5. Analysis.

Comparison 1 Pentoxifylline + routine treatment versus placebo + routine treatment, Outcome 5 Systolic BP at end of treatment.

1.6. Analysis.

Comparison 1 Pentoxifylline + routine treatment versus placebo + routine treatment, Outcome 6 Diastolic BP at end of treatment.

In patients with type 2 proteinuria, pentoxifylline did not significantly decrease either SBP (Analysis 1.5.2 (1 study, 22 participants): MD 5.00 mm Hg, 95% CI ‐4.19 to 14.19) or DBP (Analysis 1.6.2 (1 study, 22 participants): MD ‐1.00 mm Hg, 95% CI ‐8.07 to 6.07) when compared with placebo.

There was a significant decrease in SBP (Analysis 1.5.3 (1 study, 18 participants): MD ‐6.00 mm Hg, 95% CI ‐11.08 to ‐0.92) and DBP (Analysis 1.6.3 (1 study, 18 participants): MD ‐9.00 mm Hg, 95% CI ‐14.55 to ‐3.45) in patients with type 1 microalbuminuria in the pentoxifylline group compared with placebo.

In patients with type 1 proteinuria, pentoxifylline significantly decreased SBP (Analysis 1.5.4 (1 study, 24 participants): MD ‐22.00 mm Hg, 95% CI ‐31.41 to ‐12.59) and DBP (Analysis 1.6.4 (1 study, 24 participants): MD ‐11.00 mm Hg, 95% CI ‐18.23 to ‐3.77) compared with placebo.

Adverse events

Three studies (Guerrero‐Romero 1995a; Rodriguez‐Moran 2006; Zang 1999) reported adverse events. Zang 1999 reported that seven patients experienced headache, dizziness or digestive problems, but did not indicate in which group they occurred. Guerrero‐Romero 1995a and Rodriguez‐Moran 2006 reported headaches, dizziness, and digestive problems such as vomiting and nausea in seven patients in the pentoxifylline group and one in the placebo group. Guerrero‐Romero 1995a reported that one patient in the control group died from myocardial infarction and one discontinued treatment because of headache.

There was no significant difference in the occurrence of any adverse events between the groups with moderate heterogeneity (Analysis 1.7 (2 studies, 73 participants): RD 0.10, 95% CI ‐0.10, 0.30; I² = 53%).

1.7. Analysis.

Comparison 1 Pentoxifylline + routine treatment versus placebo + routine treatment, Outcome 7 Any adverse events at end of treatment.

Pentoxifylline plus routine treatment versus routine treatment alone

Nine studies compared pentoxifylline plus routine treatment with routine treatment alone (Gan 2003; Harmankaya 2003; Navarro 1999a; Navarro 2003a; Navarro 2005a; Pang 2003; Pantoja 2003; Solerte 1986; Sui 1999).

Kidney function

Serum creatinine (mg/dL) at the end of treatment

Five studies (Harmankaya 2003; Navarro 1999a; Navarro 2003a; Navarro 2005a; Pantoja 2003) reported SCr levels at the end of treatment. There were no significant differences in SCr reduction between pentoxifylline and routine treatment (Analysis 2.1 (5 studies, 199 participants): MD 0.00 mg/dL, 95% CI ‐0.06 to 0.07; I² = 4%).

2.1. Analysis.

Comparison 2 Pentoxifylline + routine treatment versus routine treatment, Outcome 1 Serum creatinine at end of treatment.

Albuminuria (change from baseline)

Six studies (Gan 2003; Harmankaya 2003; Navarro 2005a; Pang 2003; Solerte 1986; Sui 1999) reported albuminuria, however data could not be extracted from Pang 2003 or Solerte 1986. Albuminuria was measured on different scales therefore SMD has been reported. Pentoxifylline significantly decreased albuminuria compared with routine treatment (Analysis 2.2 (4 studies, 220 participants): SMD 0.62, 95% CI 0.18 to 1.07; I² = 61%). There was significant heterogeneity which may be attributable to Gan 2003. Gan 2003 did not include a description of routine treatment, and accordingly, there was a possibility that co‐interventions differed. A sensitivity analysis excluding Gan 2003 reduced the heterogeneity to zero, however albuminuria was still significantly decreased in the pentoxifylline group (SMD 0.41, 95% CI 0.11 to 0.70).

2.2. Analysis.

Comparison 2 Pentoxifylline + routine treatment versus routine treatment, Outcome 2 Change in albuminuria.

Proteinuria (g/24 h) (change from baseline)

Six studies (Gan 2003; Navarro 1999a; Navarro 2003a; Pantoja 2003; Solerte 1986; Sui 1999) reported proteinuria, however data could not be extracted from Solerte 1986. Pentoxifylline significantly decreased proteinuria when compared to routine treatment (Analysis 2.3 (5 studies, 192 participants): MD 0.46 g/24 h, 95% CI 0.17 to 0.74; I² = 53%). There was moderate heterogeneity among studies.

2.3. Analysis.

Comparison 2 Pentoxifylline + routine treatment versus routine treatment, Outcome 3 Change in proteinuria.

Blood pressure (mm Hg) at the end of treatment

Five studies (Harmankaya 2003; Navarro 1999a; Navarro 2003a; Navarro 2005a; Pang 2003) reported BP. Pentoxifylline did not significantly decrease SBP (Analysis 2.4 (5 studies, 240 participants): MD ‐0.28 mm Hg, 95% CI ‐2.20 to 1.63; I² = 42%) or DBP (Analysis 2.5 (5 studies 240 participants): MD ‐0.15 mm Hg, 95% CI ‐1.44 to 1.14; I² = 12%) when compared to routine treatment.

2.4. Analysis.

Comparison 2 Pentoxifylline + routine treatment versus routine treatment, Outcome 4 Systolic BP at end of treatment.

2.5. Analysis.

Comparison 2 Pentoxifylline + routine treatment versus routine treatment, Outcome 5 Diastolic BP at end of treatment.

Adverse events

Four studies (Harmankaya 2003; Navarro 2005a; Pang 2003; Sui 1999) reported adverse events. Harmankaya 2003 reported that five participants developed headache, however treatment arm allocation for those patients was not reported.

There was no significant difference in side effects (including dizziness and dyspepsia) in the pentoxifylline group when compared to routine treatment (Analysis 2.6 (3 studies, 190 participants): RD 0.11, 95% CI ‐0.01 to 0.22; I² = 66%). Heterogeneity was moderate and may be attributable to differences in type and severity of side effects. Sui 1999 reported that all participants who experienced adverse events continued therapy except for three patients who developed severe side effects. The nature of the severe side effects was not reported.

2.6. Analysis.

Comparison 2 Pentoxifylline + routine treatment versus routine treatment, Outcome 6 Any adverse events at end of treatment.

Pentoxifylline plus routine treatment versus other drugs plus routine treatment

Three studies compared ACEi (captopril) plus routine treatment to pentoxifylline plus routine treatment (Aminorroaya 2005a; Rodriguez‐Moran 2005; Zhang 2001) and one study investigated conventional antihypertensive drugs (clonidine or methyldopa) plus routine treatment to pentoxifylline plus routine treatment (Solerte 1987).

Kidney function

Serum creatinine (mg/dL) at the end of treatment

Two studies (Aminorroaya 2005a; Rodriguez‐Moran 2005) reported SCr. There was no significant difference in SCr in the pentoxifylline group compared with those who received captopril (Analysis 3.1 (2 studies, 166 participants): MD 0.00 mg/dL, 95% CI ‐0.08 to 0.07; I² = 0%).

3.1. Analysis.

Comparison 3 Pentoxifylline + routine treatment versus other drugs + routine treatment, Outcome 1 Serum creatinine at end of treatment.

Creatinine clearance (mL/min) at the end of treatment

Three studies (Aminorroaya 2005a; Solerte 1987; Zhang 2001) reported CrCl. There was no significant difference in CrCl in the pentoxifylline group compared with captopril (Analysis 3.2.1 (2 studies, 145 participants): MD 3.26 mL/min, 95% CI ‐1.05 to 7.58; I² = 0%). There was a significant increase in CrCl in the pentoxifylline group compared to clonidine/methyldopa (Analysis 3.2.2 (1 study, 21 participants): 10.90 mL/min, 95% CI 1.40 to 20.40).

3.2. Analysis.

Comparison 3 Pentoxifylline + routine treatment versus other drugs + routine treatment, Outcome 2 Creatinine clearance at end of treatment.

Albuminuria (µg/min)

Two studies (Rodriguez‐Moran 2005; Zhang 2001) reported albuminuria. There was no significant difference in albuminuria in the pentoxifylline group compared to the captopril group (Analysis 3.3 (2 studies, 233 participants): MD ‐8.79 µg/min, 95% CI ‐27.18 to 9.59; I² = 84%). There was significant heterogeneity and this may be attributable to differences in racial background and methodological quality between studies. Zhang 2001 reported that all participants were Chinese, but blinding was not reported. Rodriguez‐Moran 2005 reported that all participants were Hispanic (Mexican), and that outcomes assessors were blinded.

3.3. Analysis.

Comparison 3 Pentoxifylline + routine treatment versus other drugs + routine treatment, Outcome 3 Albuminuria at end of treatment.

Proteinuria (g/24 h)

Two studies (Aminorroaya 2005a; Zhang 2001) reported proteinuria. There was no significant difference in proteinuria in the pentoxifylline group compared with the captopril group (Analysis 3.4 (2 studies, 145 participants): MD ‐0.01 g/24 h, 95% CI ‐0.03 to 0.01; I² = 0%).

3.4. Analysis.

Comparison 3 Pentoxifylline + routine treatment versus other drugs + routine treatment, Outcome 4 Proteinuria at end of treatment.

Blood pressure (mm Hg) at the end of treatment

Three studies (Aminorroaya 2005a; Rodriguez‐Moran 2005; Zhang 2001) reported BP. Pentoxifylline did not significantly decrease SBP (Analysis 3.5 (3 studies, 272 participants): MD 1.46 mm Hg, 95% CI ‐0.57 to 3.50; I² = 0%) or DBP (Analysis 3.6 (3 studies, 272 participants): MD 1.37 mm Hg, 95% CI ‐0.23 to 2.98; I² = 0%) compared with those who received captopril.

3.5. Analysis.

Comparison 3 Pentoxifylline + routine treatment versus other drugs + routine treatment, Outcome 5 Systolic BP at end of treatment.

3.6. Analysis.

Comparison 3 Pentoxifylline + routine treatment versus other drugs + routine treatment, Outcome 6 Diastolic BP at end of treatment.

Plasma fibrinogen (mg/dL) at the end of treatment

One study (Solerte 1987) reported plasma fibrinogen. There was a significant difference in plasma fibrinogen in the pentoxifylline group compared with those who received clonidine or methyldopa (Analysis 3.7 (1 study, 21 participants): MD ‐128.00 mg/dL, 95% CI ‐245.09 to ‐10.91).

3.7. Analysis.

Comparison 3 Pentoxifylline + routine treatment versus other drugs + routine treatment, Outcome 7 Plasma fibrinogen at end of treatment.

Adverse events

Two studies (Aminorroaya 2005a; Rodriguez‐Moran 2005) reported adverse events. Aminorroaya 2005a reported that one patient withdrew from the captopril arm of the study after developing a dry cough. Rodriguez‐Moran 2005 indicated that three patients in the pentoxifylline arm developed headache, and one participant withdrew. Adherence to treatment was not achieved in the control group; three participants developed intense dry cough and nasal congestion that lead to discontinuing captopril.

There was no significant difference in the occurrence of any adverse events in the pentoxifylline group compared with the captopril group (Analysis 3.8 (2 studies, 166 participants): RD ‐0.07, 95% CI ‐0.15, 0.01; I² = 0%).

3.8. Analysis.

Comparison 3 Pentoxifylline + routine treatment versus other drugs + routine treatment, Outcome 8 Adverse events at end of treatment.

Publication bias

It was not possible to check for publication bias by conducting funnel plot analysis because there were too few studies for each outcome.

Discussion

Summary of main results

This systematic review of pentoxifylline for DKD included 17 studies that enrolled 991 participants. The studies were conducted in China (five studies), Mexico (four studies), Spain (three studies), Italy (two studies), Turkey, Brazil and Iran (one study in each) and are representative of a wide range of racial, cultural and social groups. The results revealed that:

1. Compared with placebo, pentoxifylline reduced SCr, microalbuminuria and overt proteinuria in patients with type 1 and type 2 DKD. Pentoxifylline was no different to placebo in improving CrCl. Pentoxifylline significantly decreased SBP and DBP, but only in patients with type 1 DKD.

2. Compared with routine treatment, pentoxifylline did not reduce SCr or BP, but did reduce albuminuria and proteinuria in patients with DKD.

3. There was no significant difference in SCr, albuminuria, proteinuria or BP between pentoxifylline and active comparators (captopril and clonidine/methyldopa) for patients with type 1 or type 2 DKD. There was no significant difference in CrCl between pentoxifylline and captopril but there was significant increase when compared to clonidine/methyldopa.

4. The most commonly reported adverse effects associated with pentoxifylline were headache, dizziness, nausea and dyspepsia. No serious adverse events were reported.

5. There is no current evidence for the use of pentoxifylline when measured in terms of ESKD incidence, time to ESKD, all‐cause mortality, and quality of life in patients with type 1 or type 2 DKD.

Overall completeness and applicability of evidence

Proteinuria is an independent predictive factor for cardiovascular morbidity and mortality and progression to ESKD. Decreasing proteinuria is effective in delaying progression of chronic kidney disease (CKD), and decreasing cardiovascular morbidity and mortality (Eijkelkamp 2007; Olsen 2006). The most compelling evidence about therapies to delay disease progression points to drugs that intervene in the renin‐angiotensin‐aldosterone‐system (RAAS). RAAS intervention is a very effective strategy to decrease proteinuria (de Zeeuw 2007). Nevertheless, a substantial number of patients continue to exhibit proteinuria and progress to ESKD. RAAS intervention can only be prescribed selectively because of risk to patients of developing significant renal artery stenosis and refractory hyperkalaemia (ADA 2004; KDOQI 2004).

Pentoxifylline may be a worthwhile additional intervention to help decrease proteinuria in patients with DKD, especially those for whom the RAAS strategy cannot be applied.

Characteristics of participants

Age, diabetes type, stage of DKD, presence of hypertension at study baseline, and renal pathology influenced the effects of pentoxifylline in patients with DKD. We were unable to conduct prespecified subgroup analyses comparing patients with different types of diabetes, baseline proteinuria, BP and renal pathology for each outcome from the available evidence because:

1. the limited number of studies of pentoxifylline for the specific outcomes;

2. few studies reported diagnostic criteria for DM;

3. the diagnosis of DKD was mainly based on UAE rate. Few studies provided kidney biopsy data or investigated the presence of diabetic retinopathy in participants (a common complication of DM). It was therefore somewhat uncertain that kidney damage was secondary to diabetes; and

4. of variations in inclusion and exclusion criteria among studies.

After stratifying studies based on diabetes type and baseline proteinuria, subgroup analysis indicated that pentoxifylline significantly decreased SBP and DBP in patients with type 1 DKD. A recent meta‐analysis of pentoxifylline for DKD found no significant change in BP between pentoxifylline and control group participants (McCormick 2008). McCormick 2008 did not conduct subgroup analyses based on diabetes type and baseline proteinuria to assess the BP control properties of pentoxifylline.

We were unable to explain the positive effect in BP control conferred by pentoxifylline on patients with type 1 DKD. Results from the subgroup analyses should therefore be interpreted with caution.

Properties of interventions and comparisons

We were unable to conduct subgroup analyses comparing dose, administration, treatment period and co‐interventions for each outcome because there were very few studies of pentoxifylline for specific outcomes, and pentoxifylline was administered intravenously (100 mg/d) in only one study (Pang 2003). All other studies administered oral pentoxifylline.

There was a marked absence of blinding reported in the included studies. Bias may occur in the absence blinding ‐ observers can inadvertently (or not) make errors in measuring data toward an expected outcome, which often favours the treatment group. Placebo response is a related and important indicator in studies that apply subjective outcome measures, such as quality of life (Hrobjartsson 2001; Rochon 1999; Turner 1994; Walsh 2002). Our review included nine studies that compared pentoxifylline plus routine treatment with routine treatment, and four comparing pentoxifylline with placebo. We considered that these 13 studies may be prone to bias due to the absence of blinding, which could overestimate the effects of pentoxifylline.

Comparisons of pentoxifylline plus routine treatment with captopril did not report any significant differences in the outcomes of interest, and only CrCl was increased when pentoxifylline was compared to clonidine/methyldopa. It should be noted that these studies were not designed to show equivalence. Therefore, if study outcomes do not show statistical differences (P > 0.05) this does not indicate the existence of equal effectiveness of the studied drugs regarding these outcomes (Jones 1996).

Routine treatment was not clearly described in the majority of studies. Some routine treatments for diabetes and CKD, such as statin, thiamine and spironolactone, have beneficial effects on kidney function, mortality and proteinuria (Navaneethan 2009; Rabbani 2009; Ustundag 2008). If these variables were unevenly distributed between the study and control groups, results may be skewed.

Outcomes measures

Efficacy

The outlook for patients who have both diabetes and CKD is far worse than for either condition individually. DKD is a powerful predictor of major adverse cardiovascular events and death (KDOQI 2007). The principal goal of DKD management is to reduce and delay the onset of cardiovascular events and ESKD, and ultimately, to prolong survival and improve quality of life.

Evidence from the included studies focused chiefly on secondary outcomes ‐ SCr, CrCl, albuminuria, proteinuria, BP ‐ which acted as surrogate endpoints. There was a notable absence of data on clinically relevant outcomes such as ESKD incidence, time to ESKD, quality of life, cardiovascular events and mortality at long‐term follow‐up.

The lack of reliable evidence on primary outcomes meant that we were unable to offer conclusions about the influence of pentoxifylline on DKD.

Adverse events

Nine of the included studies reported adverse events. Adverse events associated with pentoxifylline for DKD were few in number and mild in severity. However, these results are not conclusive and care should be exercised in their interpretation. The pool of evidence was small and flawed: overall, studies were short in duration and included relatively few participants; follow‐up data were sparse; and adverse events were not reported in adequate detail.

Larger samples and long‐term follow‐up studies are needed to reliably assess and quantify the possibility of rare, but potentially devastating, adverse events.

Quality of the evidence

Overall, evidence appeared to show that pentoxifylline had beneficial effects in improving kidney function and reducing albuminuria and proteinuria with absence of serious adverse events for patients with type 1 or type 2 DKD. These results are however based on a small and methodologically flawed evidence base and should be interpreted with caution.

In general evidence quality was low. Randomisation methods were adequately reported in four studies (Rodriguez‐Moran 2005; Rodriguez‐Moran 2006; Navarro 2003a; Navarro 2005a), but allocation concealment was either absent or poorly reported in all studies. Blinding of participants and outcome assessors was reported in three studies (Leyva‐Jimenez 2009; Rodriguez‐Moran 2005; Rodriguez‐Moran 2006). Four studies were assessed to be at high risk of bias (Guerrero‐Romero 1995a; Leyva‐Jimenez 2009; Sui 1999; Zang 1999), and 13 studies presented unclear risk of bias.

It is generally accepted that methodologically flawed studies show larger differences between experimental and control groups than rigorously designed and executed studies (Kjaergard 1999; Moher 1998; Schulz 1995). An analysis of sources of bias reported that inadequate or unclear concealment netted higher estimates of treatment effects (P < 0.001) than studies that reported application of appropriate concealment methods. These effects were amplified when odds ratios were considered (Schulz 1995; Wood 2008). Odds ratios were amplified by 41% in studies that inadequately allocation concealment, and by 30% in studies in which allocation concealment was unclear (Schulz 1995).

The plausibility of evidence overall was not robust. Sensitivity analyses could not be conducted meaningfully because of study quality and power deficits. Definitive conclusions on the efficacy of pentoxifylline for DKD cannot be drawn from the current evidence.

Potential biases in the review process

The major limitations of this review are related to weaknesses inherent in the available published studies on pentoxifylline for DKD. Publication bias could not be assessed because of the limited numbers of studies for each outcome. Although we undertook extensive literature searches, we could not exclude the possibility that studies with negative findings remain unpublished.

Agreements and disagreements with other studies or reviews

Our review found that pentoxifylline for patients with DKD was associated with a significant decrease in albuminuria or proteinuria. This result was consistent with findings reported in a recent meta‐analysis that investigated the effect of pentoxifylline on proteinuria in patients with DKD (McCormick 2008). Our finding that beneficial effects were conferred by pentoxifylline on kidney function and BP control were not observed in the McCormick 2008 meta‐analysis. This inconsistency may be attributable to differences in included studies and analytical methods.

Our analysis, which stratified studies based on comparison type, found that compared to placebo (four studies), pentoxifylline significantly reduced SCr, microalbuminuria and overt proteinuria in patients with type 1 and type 2 DKD; and significantly decreased SBP and DBP, but only in patients with type 1 DKD, but this benefit was not observed in studies that compared pentoxifylline plus routine treatment with routine treatment alone (nine studies). McCormick 2008 reported pooled estimates of kidney function and BP that were derived from 10 studies that involved two comparisons: pentoxifylline plus routine treatment versus placebo plus routine treatment; and pentoxifylline plus routine treatment versus routine treatment.

Both reviews found that there was no difference between pentoxifylline and ACEi in decreasing proteinuria, preserving kidney function and controlling BP. The meta‐regression analysis presented in McCormick 2008 indicated that baseline proteinuria and study duration, but not pentoxifylline dose, were significantly associated with change in proteinuria.

Authors' conclusions

Implications for practice.

Although pentoxifylline may confer positive effects on kidney function, albuminuria and proteinuria levels, with a low adverse event profile. However the poor methodological quality of included studies, the small number of patients enrolled, and likelihood of publication bias, provided insufficient evidence to support the routine use of pentoxifylline for treating patients with type 1 and type 2 DKD.

Implications for research.

Promising results and a favourable side effects profile warrant further research in the use of pentoxifylline for DKD. Larger studies are needed to confirm the available evidence. Design and execution of methodological approach needs to ensure that studies are adequately powered, and protocols dictating randomisation, allocation and concealment are rigorously applied and reported in detail. Investigators should clearly describe their intention‐to‐treat rationale and analysis. Reasons for participants' withdrawal or discontinuation must be clearly described in detail. Participants' characteristics should be consistently collected, measured and reported, and include age, sex, diagnostic criteria applied to define DM and DKD, time since diagnosis, and any comorbid conditions.

Studies should be designed to examine the efficacy of pentoxifylline in different subgroups according to: age, type, stage and duration of DKD. In addition the should investigate the effect of different doses, administration (oral and IV) and duration of treatment. Adverse events should be critically assessed by standardised monitoring or an effective self‐report system. Attention should be paid to rare, severe adverse events relevant to pentoxifylline.

The importance of long‐term follow‐up should be emphasised. Clinically important outcome measures identified as part of long‐term follow‐up, such as ESKD incidence, time to ESKD, cardiovascular events, quality of life and mortality, should be collected, analysed and reported in detail.

What's new

Date	Event	Description
14 March 2013	Amended	Characteristics of included studies table amended

Notes

Data in Characteristics of included studies has been amended.

• Harmankaya 2003 – Pentoxifylline  600 mg/d (NOT 4 times daily) // lisinopril 10 mg/d (NOT 4 times daily)

• Navarro 1999a – Pentoxifylline  400 mg/d (NOT 4 times daily)

• Pang 2003 – Pentoxifylline  100 mg/d (NOT 4 times daily)

• Pantoja 2003 – Pentoxifylline 400 mg/d (NOT 4 times daily)

Appendices

Appendix 1. Electronic search strategies

Database	Search terms
CENTRAL	MeSH descriptor Pentoxifylline, this term only (oxpentifylline):ti,ab,kw in Clinical Trials (trental):ti,ab,kw in Clinical Trials (torental):ti,ab,kw in Clinical Trials (agapurin):ti,ab,kw in Clinical Trials (bl‐191):ti,ab,kw in Clinical Trials (pentoxifylline):ti,ab,kw in Clinical Trials (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7) MeSH descriptor Diabetes Mellitus explode all trees MeSH descriptor Diabetic Nephropathies, this term only (diabetic nephropath*):ti,ab,kw in Clinical Trials ((diabetic or diabetes) and (kidney* or renal or nephro* or nephritis* or glomerulo*)):ti,ab,kw in Clinical Trials (9 OR 10 OR 11 OR 12) (8 AND 13)
MEDLINE	Pentoxifylline/ oxpentifylline.tw. pentoxifylline.tw. trental.tw. torental.tw. BL‐191.tw. agapurin.tw. or/1‐7 exp Diabetes Mellitus/ Diabetic Nephropathies/ diabetic nephropath$.tw. ((diabetic or diabetes) and (kidney$ or renal$ or nephros$ or nephritis or glomerulo)).tw. or/9‐12 and/8,13
EMBASE	PENTOXIFYLLINE pentoxifylline.tw. oxpentifylline.tw. trental.tw. torental.tw. BL‐191.tw. agapurin.tw. or/1‐7 Diabetic Nephropathy/ diabetic nephropath$.tw. ((diabetic or diabetes) and (kidney$ or renal or nephro$ or nephritis or glomerulo$)).tw. or/9‐11 and/8,12

Appendix 2. Risk of bias assessment tool

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Data and analyses

Comparison 1. Pentoxifylline + routine treatment versus placebo + routine treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Serum creatinine at end of treatment	2	117	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.17, ‐0.03]
2 Creatinine clearance at end of treatment	1	94	Mean Difference (IV, Random, 95% CI)	‐5.18 [‐15.55, 5.18]
2.1 Type 2 microalbuminuria	1	30	Mean Difference (IV, Random, 95% CI)	‐12.0 [‐27.42, 3.42]
2.2 Type 2 proteinuria	1	22	Mean Difference (IV, Random, 95% CI)	‐1.0 [‐21.66, 19.66]
2.3 Type 1 albuminuria	1	18	Mean Difference (IV, Random, 95% CI)	2.0 [‐21.59, 25.59]
2.4 Type 1 proteinuria	1	24	Mean Difference (IV, Random, 95% CI)	1.0 [‐31.19, 33.19]
3 Albuminuria at end of treatment	2	117	Std. Mean Difference (IV, Random, 95% CI)	‐2.28 [‐3.85, ‐0.70]
4 Overt proteinuria at end of treatment	1	46	Mean Difference (IV, Random, 95% CI)	‐428.58 [‐661.65, ‐195.50]
4.1 Type 2 proteinuria	1	22	Mean Difference (IV, Random, 95% CI)	‐552.0 [‐656.57, ‐447.43]
4.2 Type 1 proteinuria	1	24	Mean Difference (IV, Random, 95% CI)	‐314.0 [‐367.36, ‐260.64]
5 Systolic BP at end of treatment	2	126	Mean Difference (IV, Random, 95% CI)	‐1.29 [‐11.80, 9.23]
5.1 Type 2 microalbuminuria	2	62	Mean Difference (IV, Random, 95% CI)	10.15 [‐15.27, 35.58]
5.2 Type 2 proteinuria	1	22	Mean Difference (IV, Random, 95% CI)	5.0 [‐4.19, 14.19]
5.3 Type 1 microalbuminuria	1	18	Mean Difference (IV, Random, 95% CI)	‐6.0 [‐11.08, ‐0.92]
5.4 Type 1 proteinuria	1	24	Mean Difference (IV, Random, 95% CI)	‐22.0 [‐31.41, ‐12.59]
6 Diastolic BP at end of treatment	2	126	Mean Difference (IV, Random, 95% CI)	‐5.75 [‐9.56, ‐1.94]
6.1 Type 2 microalbuminuria	2	62	Mean Difference (IV, Random, 95% CI)	‐3.17 [‐7.98, 1.64]
6.2 Type 2 proteinuria	1	22	Mean Difference (IV, Random, 95% CI)	‐1.0 [‐8.07, 6.07]
6.3 Type 1 microalbuminuria	1	18	Mean Difference (IV, Random, 95% CI)	‐9.0 [‐14.55, ‐3.45]
6.4 Type 1 proteinuria	1	24	Mean Difference (IV, Random, 95% CI)	‐11.0 [‐18.23, ‐3.77]
7 Any adverse events at end of treatment	2	83	Risk Difference (M‐H, Random, 95% CI)	0.10 [‐0.10, 0.30]

Comparison 2. Pentoxifylline + routine treatment versus routine treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Serum creatinine at end of treatment	5	199	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.06, 0.07]
2 Change in albuminuria	4	220	Std. Mean Difference (IV, Random, 95% CI)	0.62 [0.18, 1.07]
3 Change in proteinuria	5	192	Mean Difference (IV, Random, 95% CI)	0.46 [0.17, 0.74]
4 Systolic BP at end of treatment	5	240	Mean Difference (IV, Random, 95% CI)	‐0.28 [‐2.20, 1.63]
5 Diastolic BP at end of treatment	5	240	Mean Difference (IV, Random, 95% CI)	‐0.15 [‐1.44, 1.14]
6 Any adverse events at end of treatment	3	190	Risk Difference (M‐H, Random, 95% CI)	0.11 [‐0.01, 0.22]

Comparison 3. Pentoxifylline + routine treatment versus other drugs + routine treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Serum creatinine at end of treatment	2	166	Mean Difference (IV, Random, 95% CI)	‐0.00 [‐0.08, 0.07]
2 Creatinine clearance at end of treatment	3		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.1 Compared with ACEi	2	145	Mean Difference (IV, Random, 95% CI)	3.26 [‐1.05, 7.58]
2.2 Compared with clonidine or methyldopa	1	21	Mean Difference (IV, Random, 95% CI)	10.90 [1.40, 20.40]
3 Albuminuria at end of treatment	2	233	Mean Difference (IV, Random, 95% CI)	‐8.79 [‐27.18, 9.59]
4 Proteinuria at end of treatment	2	145	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.03, 0.01]
5 Systolic BP at end of treatment	3	272	Mean Difference (IV, Random, 95% CI)	1.46 [‐0.57, 3.50]
6 Diastolic BP at end of treatment	3	272	Mean Difference (IV, Random, 95% CI)	1.37 [‐0.23, 2.98]
7 Plasma fibrinogen at end of treatment	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
8 Adverse events at end of treatment	2	166	Risk Difference (M‐H, Random, 95% CI)	‐0.07 [‐0.15, 0.01]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Aminorroaya 2005a.

Methods	Study type: cross‐over RCT
Participants	Country: Iran Setting: one centre (hospital) Inclusion criteria: negative urine culture; no previous treatment; no serious intracranial or retinal haemorrhage, AMI or hypertension Number of patients randomised/analysed: 39/39 Age range: 34 to 75 years Males: 61% DM type: Type 2 DM duration: NS DKD stage: 4 (macroalbuminuria)
Interventions	Treatment group Pentoxifylline Dose: 400 mg; 3 times/d; oral Routine treatment Glycaemic control; antihypertensive drugs; weight management diet Duration: 2 months Control group Captopril Dose: 25 mg; 3 times/d; oral Routine treatment Glycaemic control; antihypertensive drugs; weight management diet Duration: 2 months
Outcomes	Change in kidney function: SCr, CrCl, proteinuria Adverse events BP
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study did not describe sequence generation process
Allocation concealment (selection bias)	Unclear risk	Study did not describe allocation concealment method
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study did not describe blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcomes data
Selective reporting (reporting bias)	Low risk	Free of selective reporting
Other bias	Unclear risk	Insufficient information provided

Gan 2003.

Methods	Study design: parallel RCT
Participants	Country: China Setting: inpatients and outpatients at one centre Number of patients randomised/analysed: 40/40 Age range: 49 to 71 years Males: 57% DM type: unclear DM duration: 6 to 18 years DKD stage: 3 and 4 (microalbuminuria and macroalbuminuria) Exclusion criteria: patients on dialysis; kidney transplantation wait lists
Interventions	Treatment group Pentoxifylline Dose: 100 mg; 4 times/d; oral Routine treatment: NS Duration: 6 months Control group Routine treatment: NS Duration: 6 months
Outcomes	Changes in kidney function: SCr, proteinuria/albuminuria
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study did not describe sequence generation process
Allocation concealment (selection bias)	Unclear risk	Study did not describe allocation concealment method
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study did not describe blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcomes data
Selective reporting (reporting bias)	Unclear risk	Insufficient information. Some clinically important outcomes, such as adverse events, not reported
Other bias	Unclear risk	Insufficient information provided

Guerrero‐Romero 1995a.

Methods	Study type: parallel RCT
Participants	Country: Mexico Setting: outpatients, 1 centre Number of patients randomised/analysed: 86/80 Age range: 20 to 71 years Males: 50% DM type: type 1 and type 2 DM duration: 2 to 18 years DKD stage: 3 and 4 (microalbuminuria or macroalbuminuria) Inclusion and exclusion criteria: not reported in detail
Interventions	Treatment group Pentoxifylline Dose: 400 mg; 3 times/d; oral Routine treatment Glycaemic control; weight maintaining diet Duration: 4 months Control group Placebo Routine treatment Glycaemic control; weight maintaining diet Duration: 4 months Patients were stratified based on DKD stage Type 1 microalbuminuria Type 1 overt proteinuria Type 2 microalbuminuria Type 2 overt proteinuria
Outcomes	Changes in kidney function: CrCl, proteinuria Adverse events BP
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study did not report sequence generation process
Allocation concealment (selection bias)	Unclear risk	Study did not report allocation concealment method
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study did not report blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	Participants randomised = 86, but number analysed = 80. ITT analysis not conducted
Selective reporting (reporting bias)	Low risk	Free of selective reporting
Other bias	Unclear risk	Insufficient information provided

Harmankaya 2003.

Methods	Study type: parallel RCT
Participants	Country: Turkey Setting: one centre Number of patients randomised/analysed: 50/50 Age range: 47 to 73 years Males: 62% DM: type 2 DM duration: 8 to 15 years DKD stage: 3 (microalbuminuria) Exclusion criteria: participants with history of MI, CVA and malignant hypertension
Interventions	Treatment group Pentoxifylline Dose: 600 mg/d; oral Routine treatment Lisinopril: 10 mg/d Glycaemic control Duration: 9 months Control group Routine treatment Lisinopril: 10 mg/d Glycaemic control Duration: 9 months
Outcomes	Change in kidney function: SCr, albuminuria Adverse events BP
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study did not report sequence generation process
Allocation concealment (selection bias)	Unclear risk	Study did not report allocation concealment method
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study did not report blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcomes data
Selective reporting (reporting bias)	Low risk	Free of selective reporting
Other bias	Unclear risk	Insufficient information provided

Leyva‐Jimenez 2009.

Methods	Study type: parallel RCT
Participants	Country: Mexico Setting: hospital, 1 centre Number of patients randomised/analysed: 37/34 Age range: 30 to 65 years Males: 82.3% DM: type 2 DM duration: > 7 years DKD stage: 3 or 4 (microalbuminuria or macroalbuminuria) Exclusion criteria: patients with hypertension and use of ACEi/ARB by the time of the study period or during the last 12 months
Interventions	Treatment group Pentoxifylline Dose: 400 mg; 3 times/d; oral Routine treatment Glycaemic control; diet control Duration: 12 months Control group Placebo Routine treatment Glycaemic control; diet control Duration:12 months Patients were stratified based on DKD stage Early DKD (microalbuminuria) Established DKD (macroalbuminuria or overt proteinuria)
Outcomes	Change in kidney function: UAE, CrCl
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study did not report sequence generation process
Allocation concealment (selection bias)	Unclear risk	Study did not report allocation concealment method
Blinding (performance bias and detection bias) All outcomes	Low risk	Participants and outcome assessors were blinded
Incomplete outcome data (attrition bias) All outcomes	High risk	Participants randomised = 37, but number analysed = 34. ITT analysis not conducted
Selective reporting (reporting bias)	Unclear risk	Insufficient information provided: adverse events not reported
Other bias	Unclear risk	Insufficient information provided

Navarro 1999a.

Methods	Study type: parallel RCT
Participants	Country: Spain Setting: NS Number of patients randomised/analysed: 24/24 Age range: 53 to 77 years Males: 67% DM: type 1 DM duration: NS DKD stage: 4 (macroalbuminuria) Exclusion criteria: patients had no other significant known diseases
Interventions	Treatment group Pentoxifylline Dose: 400 mg/d; oral Routine treatment Glycaemic control; antihypertensive drugs (not including ACEi); diet control Duration: 2 months Control group Routine treatment Glycaemic control; antihypertensive drugs (not including ACEi); diet control Duration: 2 months
Outcomes	Change in kidney function: SCr, proteinuria BP
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study did not report sequence generation process
Allocation concealment (selection bias)	Unclear risk	Study did not report allocation concealment method
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study did not report blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcomes data reported
Selective reporting (reporting bias)	Unclear risk	Insufficient information provided: e.g., adverse events were not reported
Other bias	Unclear risk	Insufficient information provided

Navarro 2003a.

Methods	Study type: parallel RCT
Participants	Country: Spain Setting: outpatient Number of patients randomised/analysed: 45/45 Age range: 53 to 75 years Males: 53% DM: type 2 DM duration: 7 to 16 years DKD stage: 3 (microalbuminuria) Exclusion criteria: current acute illness (including infectious diseases); severe proteinuria (urinary protein excretion > 3 g/24 h); UTI; renal insufficiency (SCr > 132.6 μmol/L); CVD history (cardiac, cerebral, or peripheral vascular disease)
Interventions	Treatment group Pentoxifylline Dose: 1200 mg/d; oral Routine treatment Glycaemic control (insulin injection); antihypertensive drugs; diet control Duration: 4 months Control group Routine treatment Glycaemic control (insulin injection); antihypertensive drugs; diet control Duration: 4 months
Outcomes	Change in kidney function: SCr, proteinuria BP
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	After basal measurements, patients with DM were randomly assigned using a computer‐generated random‐number table to either a control (no treatment) or pentoxifylline (treatment) group based on a 1:2 split
Allocation concealment (selection bias)	Unclear risk	Study did not report allocation concealment
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study did not report blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcomes data reported
Selective reporting (reporting bias)	Unclear risk	Insufficient information provided: e.g. adverse events were not reported
Other bias	Unclear risk	Insufficient information provided

Navarro 2005a.

Methods	Study type: parallel RCT
Participants	Country: Spain Setting: one centre Number of patients randomised/analysed: 61/61 Age range: 49 to 68 years Males: 51% DM: type 1 DM duration: 10 to 15 years Inclusion criteria: patients with no other kidney or urinary tract disease; presence of diabetic retinopathy; normal BP; normal kidney function (GFR ≥ 90 mL/min) and insufficient response to conventional therapy were included DKD stage: 4 (macroalbuminuria) Exclusion criteria: current acute illness (including infectious disease); CVD history (cardiac, cerebral, or peripheral vascular disease); history of cigarette smoking
Interventions	Treatment group Pentoxifylline Dose: 600 mg; twice/d; oral Routine treatment ARB; glycaemic control (insulin injection); diet control Duration: 4 months Control group Routine treatment ARB; glycaemic control (insulin injection); diet control Duration: 4 months
Outcomes	Change in kidney function: SCr, albuminuria Adverse events BP
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	After an initial 2 weeks run‐in period, patients were randomised using a computer‐generated random‐number table into a control group or an active treatment group
Allocation concealment (selection bias)	Unclear risk	Study did not report on allocation concealment
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study did not report on blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcomes data reported
Selective reporting (reporting bias)	Low risk	Free of selective reporting
Other bias	Unclear risk	Insufficient information provided

Pang 2003.

Methods	Study type: parallel RCT
Participants	Country: China Setting: inpatients and outpatients Number of patients randomised/analysed: 60/60 Age range: 28 to 64 years Males: 62% DM: NS DM duration: 6 to 20 years DKD stage: 3 (microalbuminuria) Exclusion criteria: NS
Interventions	Treatment group Pentoxifylline Dose: 100 mg/d; IV; gtt Routine treatment Glycaemic control; antihypertensive drugs; diet control Duration: 21 days Control group Routine treatment Glycaemic control; antihypertensive drugs; diet control Duration: 21 days
Outcomes	Change in kidney function: albuminuria Adverse events BP
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study did not report sequence generation process.
Allocation concealment (selection bias)	Unclear risk	Study did not report allocation concealment
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study did not report blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcomes data reported
Selective reporting (reporting bias)	Low risk	Free of selective reporting
Other bias	Unclear risk	Insufficient information provided

Pantoja 2003.

Methods	Study type: parallel RCT
Participants	Country: Brazil Setting: NS Number of patients randomised/analysed: 14/14 Age range: 38 to 62 years Males: 50% DM: NS DM duration: NS DKD stage: 4 (macroalbuminuria) Exclusion criteria: NS
Interventions	Treatment group Pentoxifylline Dose: 400 mg/d; oral Routine treatment Glycaemic control; antihypertensive drugs (furosemide, amlodipine, enalapril); diet control Duration: 6 months Control group Routine treatment Glycaemic control; antihypertensive drugs (furosemide, amlodipine, enalapril); diet control Duration: 6 months
Outcomes	Change in kidney function: SCr, proteinuria BP
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study did not report sequence generation process
Allocation concealment (selection bias)	Unclear risk	Study did not report allocation concealment method
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study did not report blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcomes data reported
Selective reporting (reporting bias)	Unclear risk	Study did not report some important clinical outcomes, such as possible adverse events of pentoxifylline
Other bias	Unclear risk	Insufficient information provided

Rodriguez‐Moran 2005.

Methods	Study type: parallel RCT
Participants	Country: Mexico Setting: outpatients Number of patients randomised/analysed: 130/130 Age range: 46 to 71 years Males: NS DM: type 2 DM duration: 2 to 16 years DKD stage: 3 (microalbuminuria) Exclusion criteria: hypertension and/or kidney failure and receiving ACEi or pentoxifylline
Interventions	Treatment group Pentoxifylline Dose: 400 mg; 3 times/d; oral Routine treatment 3 months before the study, all subjects received diet control and physical activity interventions, drug intervention included glibenclamide and metformin. Hypoglycaemic drug was not changed when the study began Duration: 6 months Control group Captopril Dose: 25 mg; 3 times/d Routine treatment 3 months before the study, all subjects received diet control and physical activity interventions, drug intervention included glibenclamide and metformin. Hypoglycaemic drug was not changed when the study began Duration: 6 months
Outcomes	Change in kidney function: SCr, albuminuria Adverse events BP
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random numbers were used to assign participants to pentoxifylline or captopril groups
Allocation concealment (selection bias)	Unclear risk	Study did not report allocation concealment
Blinding (performance bias and detection bias) All outcomes	Low risk	Outcomes assessors were blinded to group assignment
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcomes data reported
Selective reporting (reporting bias)	Low risk	Free of selective reporting
Other bias	Unclear risk	Insufficient information provided for assessment

Rodriguez‐Moran 2006.

Methods	Study type: parallel RCT
Participants	Country: Mexico Setting: NS Number of patients randomised/analysed: 40/40 Age range: 44 to 66 years Males: NS DM: type 2 DM duration: 4 to 12 years DKD stage: 3 (microalbuminuria) Exclusion criteria: hypertensive patients receiving ACEi, ARB and CCB, and those who previously received pentoxifylline; kidney failure or reduced kidney function; pregnancy; UTI; diuretic therapy; smoking
Interventions	Treatment group Pentoxifylline Dose: 400 mg; 3 times/d Routine treatment Glycaemic control; pretreatment serum glucose stabilisation 6 months before the study Duration: 4 months Control group Placebo Routine treatment Glycaemic control; pretreatment serum glucose stabilisation 6 months before the study Duration: 4 months
Outcomes	Change in kidney function: SCr, albuminuria Adverse events BP
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random numbers used to assign participants to pentoxifylline or placebo groups
Allocation concealment (selection bias)	Unclear risk	Study did not report allocation concealment
Blinding (performance bias and detection bias) All outcomes	Low risk	All participants and outcomes assessors were blinded to group assignment
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcomes data reported
Selective reporting (reporting bias)	Low risk	Free of selective reporting
Other bias	Unclear risk	Insufficient information provided for assessment

Solerte 1986.

Methods	Study type: parallel RCT
Participants	Country: Italy Setting: outpatients Number of patients randomised/analysed: 82/82 Age range: 26 to 52 years Males: 48% DM: types 1 and 2 DM duration: 2 to 5 years DKD stage: 3 and 4 (microalbuminuria and macroalbuminuria) Exclusion criteria: NS
Interventions	Treatment group Pentoxifylline Dose: 1200 mg/d; oral Routine treatment Glycaemic control including insulin injection, tolbutamide, glibenclamide, glicazide, metformin Duration: 6 months Control group Routine treatment Glycaemic control including insulin injection, tolbutamide, glibenclamide, glicazide, metformin Duration: 6 months
Outcomes	Change in kidney function: proteinuria, albuminuria
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study did not report sequence generation process
Allocation concealment (selection bias)	Unclear risk	Study did not report allocation concealment
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study did not report blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcomes data reported
Selective reporting (reporting bias)	Unclear risk	Insufficient information provided: e.g., adverse events were not reported
Other bias	Unclear risk	Insufficient information provided for assessment

Solerte 1987.

Methods	Study type: parallel RCT
Participants	Country: Italy Setting: outpatients: 1 centre Number of patients randomised/analysed: 21/21 Age range: 43 to 53 years Males: 38% DM: type 1 DM duration: 11 to 13 years DKD stage: 4 (macroalbuminuria) Exclusion criteria: NS
Interventions	Treatment group Pentoxifylline Dose:1200 mg/d; oral Routine treatment Glycaemic control: insulin injection Duration: 1 year Control group Other drugs Antihypertensive therapy Clonidine: 0.6 mg/d (8 patients) Methyldopa 1000 mg/d (3 patients) Routine treatment: Glycaemic control: insulin injection Duration: 1 year
Outcomes	Change in kidney function: CrCl Plasma fibrinogen
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study did not report sequence generation process
Allocation concealment (selection bias)	Unclear risk	Study did not report allocation concealment
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study did not report blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcomes data reported
Selective reporting (reporting bias)	Unclear risk	Insufficient information provided e.g. adverse events were not reported
Other bias	Unclear risk	Insufficient information provided for assessment

Sui 1999.

Methods	Study type: parallel RCT
Participants	Country: China Setting: inpatients Number of patients randomised/analysed: 72/69 Age range: 38 to 76 years Males: 51% DM type: 2 DM duration: 6 to 21 years DKD stage: 3 or 4 (microalbuminuria or macroalbuminuria) Exclusion criteria: NS
Interventions	Treatment group Pentoxifylline Dose: 400 mg; 3 times/d; oral Routine treatment: NS Duration: 4 months Control group Routine treatment: NS Duration: 4 months
Outcomes	Change in kidney function: proteinuria, albuminuria Pentoxifylline adverse events
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study did not report sequence generation process
Allocation concealment (selection bias)	Unclear risk	Study did not report allocation concealment
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study did not report blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	Participants randomised = 72, but number analysed = 69. ITT analysis not conducted
Selective reporting (reporting bias)	Low risk	Free of selective reporting
Other bias	Unclear risk	Insufficient information provided for assessment

Zang 1999.

Methods	Study type: parallel RCT
Participants	Country: China Setting: NS Number of patients randomised: 84/77 Age range: 34 to 51 years Males: 55% DM type: 2 DM duration: NS Stage of DKD: 3 (microalbuminuria) Exclusion criteria: hypertension; lipid disorders; hepatic; kidney function damage; infectious diseases; other primary and secondary kidney or urological diseases
Interventions	Treatment group Pentoxifylline Dose: 400 mg; 3 times/d Routine treatment Glycaemic control Duration: 6 months Control group Placebo Routine treatment Glycaemic control Duration: 6 months
Outcomes	Change in kidney function: SCr, albuminuria Adverse events BP (mean arterial pressure)
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study did not report sequence generation process
Allocation concealment (selection bias)	Unclear risk	Study did not report allocation concealment
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study did not report blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	Participants randomised = 84, but number analysed = 77. ITT analysis was not conducted
Selective reporting (reporting bias)	Low risk	Free of selective reporting
Other bias	Unclear risk	Insufficient information provided for assessment

Zhang 2001.

Methods	Study type: parallel RCT
Participants	Country: China Setting: NS Number of patients randomised/analysed: 106/106 Age range: 56 to 72 years Males: 57% DM type: 2 DM duration: 5 to 17 years DKD stage: 3 (microalbuminuria) Exclusion criteria: severe complications (heart, brain, lung, liver and kidney damage); bleeding and receiving anticoagulation therapy; ACEi
Interventions	Treatment group Pentoxifylline Dose: 400 mg; twice/d; oral Routine treatment Glycaemic control; antihypertensive drugs Duration: 6 months Control group Captopril Dose: 2.5 mg; 3 times/d Routine treatment Glycaemic control; antihypertensive drugs Duration: 6 months
Outcomes	Change in kidney function: CrCl, proteinuria/albuminuria BP
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study did not report sequence generation process
Allocation concealment (selection bias)	Unclear risk	Study did not report allocation concealment
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study did not report blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcomes data reported
Selective reporting (reporting bias)	Unclear risk	Insufficient information provided: e.g. adverse events were not reported
Other bias	Unclear risk	Insufficient information provided for assessment

ACEi: angiotensin converting enzyme inhibitors; AMI: acute myocardial infarction; ARB: angiotensin receptor blockers; BP: blood pressure; CCB: calcium channel blockers; CrCl: creatinine clearance; CVA: cardiovascular accident; DKD: diabetic kidney disease; DM: diabetes mellitus; GFR: glomerular filtration rate; gtt: guttae (drops); IV: intravenous; MI: myocardial infarction; NS: not stated; RCT: randomised controlled trial; SCr: serum creatinine; UAE: urinary albumin excretion; UTI: urinary tract infection

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Cen 2005	Questionable randomisation
Chua 1995	Questionable randomisation
Demir 2007	Participants were kidney transplant recipients with unknown underlying kidney diseases
Diao 2003	Questionable randomisation
Diskin 2007	Not RCT
Garg 1998	Participants Included diabetic retinopathy and/or DKD. Separate data not available for DKD
Gonzalez‐Espinoza 2008	Haemodialysis patients
Laczy 2009	Participants diagnosed with type 2 DM and diabetic neuropathy, not DKD
Lin 2008	Participants with moderate‐advanced CKD due to multiple causes. Separate data not available for DKD
Maiti 2007	Participants diagnosed with type 2 DM, not DKD
Mooraki 2006	Questionable randomisation
Navarro 1998	Participants diagnosed with advanced kidney failure due to multiple causes. Separate data not available for DKD
Paap 1996	Not RCT
Perkins 2009	Participants diagnosed with progressive CKD due to multiple causes. Separate data not available for DKD

CKD: chronic kidney disease; DKD: diabetic kidney disease; DM: diabetes mellitus; RCT: randomised controlled trial

Differences between protocol and review

The risk of bias assessment tool has been used in place of the quality assessment checklist in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Contributions of authors

• DS: Writing the draft review

• HMW: Search strategy development, resolution of disagreements, data analysis, protocol and review writing

• QYY: Study assessment, data extraction and entry

• RLZ: Study assessment, data extraction and entry

• JL: Methodological and clinical consultancy

• GJL: Statistical and methodological consultancy.

Sources of support

Internal sources

• Department of Geriatrics, West China Hospital, SiChuan University, China.

External sources

• None, Not specified.

Declarations of interest

• Dan Shan: None known

• Hong Mei Wu: None known

• Qi Yuan Yuan: None known

• Jun Li: None known

• Rong Le Zhou: None known

• Guan J Liu: None known

Edited (no change to conclusions)