Scolaris Content Display Scolaris Content Display

Base de datos Cochrane de Revisiones Sistemáticas Protocolo - Intervención

Pentoxifylline for diabetic kidney disease

Declaraciones de intereses de los autores

Versión publicada: 17 octubre 2007 Historial de versiones

https://doi.org/10.1002/14651858.CD006800

Esta versión no es la más reciente

ver la versión actual 15 febrero 2012
Contraer todo Desplegar todo

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

This review aims to look at the benefits and harms of pentoxifylline for treating DKD.

Background

Diabetic kidney disease (DKD) ‐ also called diabetic nephropathy ‐ occurs in 30% to 40% of type 1 diabetic patients, 20 to 25 years after disease onset, and in an increasing percentage (up to 25%) of type 2 patients after a variable number of years (Ritz 1999a). DKD is the major cause of end‐stage kidney failure (ESKF) in most western nations and is associated with increased morbidity and mortality as compared to other causes of kidney disease (Ritz 1999b). According to the most recent reports of the US Renal Data System (Collins 2005; Ritz 1999a; USRDS 1998), there has been a continuous increase in the incidence of DKD, predominantly those with type 2 diabetes. The proportion of patients with both end‐stage kidney disease (ESKD) and diabetes is now 55% (Collins 2005). DKD is particularly common among the elderly and non‐Caucasian (i.e. African‐American, Asians, and native Americans) populations. A similar trend has occurred in other developed countries, making ESKD patients with diabetes a medical problem of worldwide dimensions (Ritz 1999a).

DKD is one of the major microvascular complications in patients with diabetes mellitus. It is commonly assumed that type 1 and type 2 diabetics have similar pathogenetic and clinical stages of kidney damage, as outlined by Mogensen 1997. During the development of kidney disease, diabetic patients go through several characteristic stages, including kidney hypertrophy and hyperfiltration, microalbuminuria (incipient kidney disease)(urine albumin excretion rate (UAE) 30‐300 mg/d), macroalbuminuria (overt kidney disease)(UAE > 300 mg/d), and eventually reach ESKD if they have not died from cardiovascular complications which account for the majority of deaths (Collins 2005).

The survival of patients with DKD drops to extremely low levels once ESKD occurs (Chantrel 1999; Ritz 1999a). The five‐year survival rates are 6% in Germany and 27% in Australia (Ritz 1999a), and once ESKD is reached, patients enter the highest known cardiovascular risk‐state (McCullough 2004). However more people with DKD will die, primarily of cardiovascular disease, than progress to ESKD (Collins 2005). Furthermore, data from studies conducted in the USA show that the medical cost of ESKD was about US$12.7 billion in 1999 and is expected to increase to US$28 billion a year by 2010 (USRDS 2000; USRDS 2001). These factors justify intensive efforts to prevent and treat DKD.

Currently DKD can be approached on three different levels. Primary prevention is done in patients without clinical and biochemical signs of KIDNEY damage (UAE< 30 mg/d), represented by strict glycaemic control by oral antidiabetic agents or insulin, together with maintenance of blood pressure (BP) levels < 130/85 mm Hg, preferably using angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockade (ARB). Secondary prevention aims to prevent or delay the progression from micro‐ to macroalbuminuria. BP control is the first‐line approach, along with a strict glycaemic control. At this stage the use of other antihypertensive agents in addition to ACEI or ARB may be necessary to achieve optimal BP levels (Strippoli 2005a). Tertiary prevention addresses the reduction of the progression rate to kidney failure by optimal BP control, a slightly hypoproteic diet and the control of dyslipidaemia, in the presence of a (non‐fundamental) euglycaemic state. However, above‐mentioned measurements for preventing and delaying the progression of DKD are only partially effective (Strippoli 2005b; Tonolo 2006; Waugh 1997). Furthermore, strict metabolic control can be difficult. So the search for additional and alternative treatment options is needed.

There has been increasing interest in recent years in the relevance of inflammation in diabetes and its role in the pathogenesis of diabetic complications, including nephropathy. Several studies have reported that serum levels of inflammatory markers are higher in patients with diabetes and increased urinary albumin excretion when compared with normoalbuminuric individuals (Chen 1996; Festa 2000; Navarro 2003a). Moreover, some studies have shown that levels of these inflammatory markers increase as nephropathy progresses (Bruno 2003; Festa 2000). Therefore, inflammation emerges as a potential mechanism in the pathogenesis of kidney injury in type 2 diabetes (Navarro 2003a; Navarro 2003b).

Pentoxifylline is a methylxanthine phosphodiesterase inhibitor with favourable effects on microcirculatory blood flow as a result of its haemorrheologic properties(Ward 1987). In addition to its haemorrheologic activity, recent works have shown that PTF also possess anti‐inflammatory and immunoregulatory properties. In vivo studies have shown 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). One study in rats with a remnant kidney has demonstrated the significant effects of PTF in modulating inflammation, cell proliferation, and fibrosis (Lin 2002). In particular, PTF administration attenuated interstitial inflammation, down regulated monocyte chemoattractant protein‐1 gene expression, reduced the expression of mitogenic and profibrogenic genes, and suppressed the proliferation of interstitial fibroblast and glomerular mesangial cells. Parallel to these experimental studies, clinical trials in patients with DKD have also shown that PTF or combined with ACEI or ARB attenuates proteinuria (Aminorroaya 2005; Guerrero‐Romero 1995; Navarro 2003c; Navarro 2005; Tripathy 1993) and reduces inflammatory substances (Navarro 1999; Navarro 2005). But most of these trials have only enrolled small numbers of patients. Whether the existing evidence is scientifically rigorous and can be recommended for routine use of these agents in DKD is still unknown. Reviewing these data will be the aim of our study.

Objectives

This review aims to look at the benefits and harms of pentoxifylline for treating DKD.

Methods

Criteria for considering studies for this review

Types of studies

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

Types of participants

Inclusion criteria

  • Diagnosis of diabetes mellitus: fasting plasma glucose ≥ 7.0 mmol/L, and the two hour plasma glucose ≥ 11.1 mmol/L.

  • Diagnosis of DKD: The diagnosis and stages of DKD will be based on the UAE measured according to any one of the following methods; 24 hour urine collection or 8 hour urine collection or albumin/creatinine ratio (ACR). Normoalbuminuria is defined as an ACR <30 mg/g or UAE < 30 mg/d (< 20 ug/min); microalbuminuria as an ACR between 30‐300 mg/g or UAE between 30‐300 mg/d (20‐200 ug/min); and macroalbuminuria as ACR > 300 mg/g or UAE > 300 mg/d (>200 ug/min) on a timed specimen confirmed with three serial measurements. DKD was defined as an albumin excretion rate ≥ to 30 mg/d on a timed specimen confirmed with three serial measurements.

  • Any type 1 or type 2 diabetic patients with DKD (e.g. micro‐or macroalbuminuria).

Exclusion criteria

  • Patients with kidney damage due to other diseases rather than diabetes.

  • Patients with kidney damage due to other kinds of diabetes rather than type 1 or type 2 diabetes (e.g. gestational diabetes).

  • Patients with the final stage of DKD or ESKD will be excluded. The final stage of DKD is defined as the stage when treatment, such as 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 will be as follows:

  • Pentoxifylline + routine treatment versus placebo + routine treatment

  • Pentoxifylline + routine treatment versus routine treatment

  • Pentoxifylline + routine treatment versus other drug + routine treatment

The routine treatment includes glycaemic control, blood pressure control, and diet control (such as protein restriction, sodium and phosphate restriction).
Other drugs could include ACEI, ARB, calcium channel blockers (CCB).

Types of outcome measures

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

  • Time to ESKD.

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

  • Doubling of serum creatinine at end of treatment.

  • Creatinine clearance or GFR (any measure) at end of treatment or change in creatinine clearance/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/24 h or ug/min), macroalbuminuria (mg/24 h or ug/min) or proteinuria (mg/24 h) at the end of treatment or change between beginning and end of treatment.

  • Urinary ACR (mg albumin/mmol creatinine).

  • All‐cause mortality.

  • Quality of life measured by any scale.

  • Possible adverse events of pentoxifylline (e.g. headache, dizziness, nausea, vomiting, dyspepsia, hypotension, cardiac arrythmia).

  • Change of BP from beginning to end of treatment.

  • Level of plasma fibrinogen at the end of treatment.

  • Incidence of cardiovascular disease (CVD).

Search methods for identification of studies

1). The Cochrane Renal Groups specialised register and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (most recent issue) which will be searched using the following terms :
#1 Pentoxifylline, MESH
#2 (oxpentifylline):ti,ab,kw
#3 (trental):ti,ab,kw
#4 (torental):ti,ab,kw
#5 (agapurin):ti,ab,kw
#6 (bl‐191):ti,ab,kw
#7 (pentoxifylline):ti,ab,kw
#8 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)
#9 Diabetes Mellitus exp MESH
#10 Diabetic Nephropathies MESH
#11 (diabetic nephropath*):ti,ab,kw
#12 ((diabetic or diabetes) and (kidney* or renal or nephro* or nephritis* or glomerulo*)):ti,ab,kw
#13 (#9 OR #10 OR #11 OR #12)
#14 (#8 AND #13)

CENTRAL and the Renal Groups specialised register contain the handsearched results of conference proceedings from general and speciality meetings. This is an ongoing activity across the Cochrane Collaboration and is both retrospective and prospective (Master List 2007). Therefore we will not specifically search conference proceedings. Please refer to The Cochrane Renal Review Group's Module in The Cochrane Library for the most up‐to‐date list of conference proceedings.

2). MEDLINE (1966 to most recent) using the optimally sensitive strategy developed for the Cochrane Collaboration for the identification of RCTs (Dickersin 1994) together with the following search strategy developed with input from the Cochrane Renal Groups Trial Search Co‐ordinator.
1. Pentoxifylline/
2. oxpentifylline.tw.
3. pentoxifylline.tw.
4. trental.tw.
5. torental.tw.
6. BL‐191.tw.
7. agapurin.tw.
8. or/1‐7
9. exp Diabetes Mellitus/
10. Diabetic Nephropathies/
11. diabetic nephropath$.tw.
12. ((diabetic or diabetes) and (kidney$ or renal$ or nephros$ or nephritis or glomerulo)).tw.
13. or/9‐12
14. and/8,13

3). EMBASE (1980 to most recent) using a search strategy adapted from that developed for the Cochrane Collaboration for the identification of RCTs (Lefebvre 1996) together with the following search strategy developed with input from the Cochrane Renal Groups Trial Search Co‐ordinator.
1. PENTOXIFYLLINE/
2. pentoxifylline.tw.
3. oxpentifylline.tw.
4. trental.tw.
5. torental.tw.
6. BL‐191.tw.
7. agapurin.tw.
8. or/1‐7
9. Diabetic Nephropathy/
10. diabetic nephropath$.tw.
11. ((diabetic or diabetes) and (kidney$ or renal or nephro$ or nephritis or glomerulo$)).tw.
12. or/9‐11
13. and/8,12

4). The China biological medicine database (CBM disc 1979 to most recent) which is a database of Chinese biomedical research literature.
5). Reference lists of nephrology textbooks, review articles and relevant trials.
6). Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous trials.

Data collection and analysis

Included and excluded studies

The review will be undertaken by five authors (HM, QY, RL, JL and GJ). The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by (QY) and (RL), who will discard studies that are not applicable, however studies and reviews that might include relevant data or information on trials will be retained initially. Reviewers (QY) and (RL) will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria. Data extraction will be carried out independently by the same authors using standard data extraction forms. Studies reported in non‐English language journals will be translated before assessment. Where more than one publication of one trial exists, only the publication with the most complete data will be included. Where relevant outcomes are only published in earlier versions this data will be used. Any discrepancy between published versions will be highlighted. Any further information required from the original author will be requested by written correspondence and any relevant information obtained in this manner will be included in the review. Disagreements will be resolved in consultation with (HM).

Study quality

The quality of studies to be included will be assessed independently by (QY) and (RL) without blinding to authorship or journal using the checklist developed for the Cochrane Renal Group. Discrepancies will be resolved by discussion with HM. The quality items to be assessed are allocation concealment, blinding (participants, investigators, outcome assessors and data analysis), intention‐to‐treat analysis and completeness of follow‐up.

Quality checklist

Allocation concealment

  • Adequate (A): Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study.

  • Unclear (B): Randomisation stated but no information on method used is available.

  • Inadequate (C): Method of randomisation used such as alternate medical record numbers or unsealed envelopes; any information in the study that indicated that investigators or participants could influence intervention group.

Blinding

  • Blinding of investigators: Yes/No/not stated

  • Blinding of participants: Yes/No/not stated

  • Blinding of outcome assessor: Yes/No/not stated

  • Blinding of data analysis: Yes/No/not stated

The above are considered not blinded if the treatment group can be identified in > 20% of participants because of the side effects of treatment.

Intention‐to‐treat

  • Yes: Specifically reported by authors that intention‐to‐treat analysis was undertaken and this was confirmed on study assessment.

  • Yes: Not stated but confirmed on study assessment.

  • No: Not reported and lack of intention‐to‐treat analysis confirmed on study assessment. (Patients who were randomised were not included in the analysis because they did not receive the study intervention, they withdrew from the study or were not included because of protocol violation).

  • No: Stated but not confirmed upon study assessment.

  • Not stated.

Completeness of follow‐up

Per cent of participants excluded or lost to follow‐up.

Statistical assessment

For dichotomous outcomes (e.g. incidence of ESKD, all‐cause mortality) results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Data will be pooled using the random‐effects model but the fixed‐effect model will also be analysed to ensure robustness of the model chosen and susceptibility to outliers. Where continuous scales of measurement are used to assess the effects of treatment (e.g. serum creatinine, glomerular filtration rate, proteinuria, quality of life measures), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used. Heterogeneity will be analysed using a chi squared 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.

Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. participants, interventions and study quality). Heterogeneity among participants could be related to age, type of diabetes, stage of DKD, baseline presence/absence of hypertension and renal pathology. Heterogeneity in treatments could be related to prior agent(s) used and the agent, dose and duration of therapy. Heterogeneity among trials could be related to study quality. Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various agents used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent.