Heparin and related substances for preventing diabetic kidney disease

Abstract

Background

Diabetic kidney disease (DKD, also called diabetic nephropathy, DN) is the major cause of end‐stage kidney disease (ESKD) in many countries and is associated with increased morbidity and mortality as compared to other causes of kidney disease. One of the pathological changes of DKD is the thickening of the glomerular basement membrane, mesangial expansion and proliferation. The presence of the glycosaminoglycan side chains of heparan sulfate proteoglycan, an important constituent of the glomerular basement membrane, is decreased in DKD proportionally to the increasing degree of proteinuria. Research on animals has suggested that heparin and related substances may prevent glomerular membrane thickening. However, it is not known whether heparin and related substances can prevent the onset of DKD and, therefore, be recommended for primary prevention of this condition.

Objectives

To assess the benefits and harms of heparin and related substances for preventing the onset of DKD.

Search methods

We searched the Cochrane Renal Group's Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 2, 2009). We also searched MEDLINE (1966 to June 2009), EMBASE (1980 to June 2009), China Biological Medicine (CBM; 1979 to June 2009), VIP Chinese Science and Technique Journals Database (until June 2009), China National Infrastructure (CNKI) (until June 2009) and Wanfang database (until June 2009). Reference lists of nephrology textbooks, review articles and relevant studies were also searched.

Selection criteria

All relevant randomised controlled trials (RCTs) and quasi‐RCTs looking at the benefits and harms of heparin and related substances for preventing the onset of DKD were eligible.

Data collection and analysis

We planned for two authors to extract data independently using a self‐developed data extraction form and enter them into RevMan 5 software; for meta‐analyses to be performed when more than one study provided data on a comparable outcome on sufficiently similar patients; for random‐effects analyses to be performed whenever heterogeneity between results appeared to be present; and for standardised differences in mean outcome measures to be used due to the use of different scales and periods of treatment.

Main results

No studies met our inclusion criteria.

Authors' conclusions

Rigorously well‐designed, randomised, multi‐centre, large‐sample studies of heparin and related substances for preventing the onset of DKD are needed.

Plain language summary

There is currently no evidence of effects of heparin and related substances for preventing the onset of diabetic kidney disease (DKD)

Heparin and related substances, including glycosaminoglycans, chondroitin, low‐molecular‐weight heparin (LMWH), heparinoids, heparitin sulfate, hyaluronic acid and keratan sulphate, have been demonstrated a few positive effects on delaying the progression of diabetic kidney disease (DKD). This review looked for randomised studies assessing the effect of heparin and related substances on preventing the onset of DKD. No study was available. Well designed and high quality randomised studies that address this issue are needed.

Background

Diabetic kidney disease (DKD; also called diabetic nephropathy, DN) is one of the major microvascular complications in patients with diabetes mellitus (DM). It is commonly assumed that type 1 and type 2 diabetics have the 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 renal hypertrophy and hyperfiltration, microalbuminuric (incipient) kidney disease (urine albumin excretion rate, UAER 30 to 300 mg/d), macroalbuminuric (overt) kidney disease (UAER > 300 mg/d), and eventually reach end‐stage kidney disease (ESKD) if they do not die because of cardiovascular complications which account for the majority of deaths (Collins 2005).

DKD 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 ESKD 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 U.S. Renal Data System (Collins 2005; Ritz 1999a; USRDS 1998), there has been a continuous increase in the incidence of DKD, predominantly in those with type 2 diabetes. The population of existing patients whose ESKD is caused by diabetes, which tripled from 1990 to 2000, is expected to grow ten‐fold by 2030, to 1.3 million. The proportion of patients with both ESKD and diabetes is now 55% (Collins 2005). DKD is particularly common among the elderly and non‐Caucasian (i.e. Black, Asian, and Native American) populations. A similar trend has occurred in other developed countries as well, making ESKD in patients with diabetes a medical problem of worldwide dimensions (Ritz 1999a).

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) similar to the rates among patients with metastasising gastrointestinal carcinoma. Once ESKD is reached, patients enter the highest cardiovascular risk state known (McCullough 2004). However, more people with DKD will die primarily of cardiovascular disease (CVD) than progress to ESKD (Collins 2005). Furthermore, data from studies conducted in the USA show that the medical cost of ESKD was about USD 12.7 billion in 1999 and is expected to increase to USD 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 achieved in patients without clinical and biochemical signs of kidney damage (UAER < 30 mg/d), by strict glycaemic control using oral antidiabetic agents or insulin, as required, 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 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 2004). Tertiary prevention addresses the reduction of the progression rate to ESKD by optimal BP control, a slightly hypoproteic (reduced protein) diet and the control of dyslipidaemia, in the presence of a (non‐fundamental) euglycaemic state. However, the above mentioned measurements for preventing the onset and progression of DKD are only partially effective. Furthermore, strict metabolic control can be difficult. So the search for additional and alternative treatment options is needed.

One of the pathological changes of DKD is the thickening of the glomerular basement membrane, mesangial expansion and proliferation (Van der Pijl 1997). The presence of the glycosaminoglycan side chains of heparan sulfate proteoglycan, an important constituent of the glomerular basement membrane, is decreased in DKD proportionally to the increasing degree of proteinuria (Van der Pijl 1997). In DKD, increased urinary excretion of albumin has been associated with progression of disease and a more serious prognosis (Allen 2003). Biochemical studies in kidneys of insulin dependent diabetic mellitus (IDDM) patients with end‐stage DKD have shown a decreased content of proteoglycan molecules in glomerular basement membranes compared with nondiabetic subjects (Shinmomura 1987). Moreover, several studies of experimental diabetes in animals describe abnormalities of synthesis, sulfation, content, and/or proteoglycan matrix interaction of heparan sulfate molecules in diabetic glomerular basement membrane (Wu 1987; Wu 1989). Supporting these observations, it has been shown that heparan can prevent albuminuria and thickening of glomerular basement membranes in streptozotocin‐induced diabetic rats (Gambaro 1992); sulodexide can effectively lower the urinary albumin excretion rate, improve the ultrastructural renal pathologies and prevent glomerular basement membrane thickening in diabetic rats (Shu 2009). Parallel to these experimental studies, clinical studies have also demonstrated a few positive effects of heparin and related substances (heparin, low molecular weight heparin (LMWH), heparinoids, heparitin sulfate and sulodexide) on delaying the progression of DKD (Achour 2005; Gambaro 2002; Solini 1997; Tamsma 1996; Van der Pijl 1997; Van der Pijl 1999). However, whether heparin and related substances can prevent the onset of DKD and be recommended for routine use for primary prevention in DM is still unknown.

Objectives

To assess the benefits and harms of heparin and related substances for preventing the onset of DKD.

Methods

Criteria for considering studies for this review

Types of studies

We planned to include randomised controlled trials (RCTs) and quasi‐RCTS (in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) of heparin and related substances for preventing the onset of DKD. We also planned to include the first period of randomised cross‐over studies.

Types of participants

Inclusion criteria

We planned to include studies enrolling patients with the following characteristics.

1. Diagnosis of DM: The diagnosis of diabetes should be confirmed according to the prototypes from ADA 1997 and WHO 1999 (i.e. fasting plasma glucose ≥ 7.0 mmol/L, and 2 hour plasma glucose ≥ 11.1 mmol/L).

2. Any type 1 or type 2 diabetic patients without DKD (e.g. normoalbuminuria).

3. Diagnosis of DKD: The diagnosis and stages of DKD are based on the urine albumin excretion rate (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 UAER < 30 mg/d (or < 20 µg/min); microalbuminuria as an ACR between 30‐300 mg/g or UAER between 30‐300 mg/d (or 20‐200 µg/min); and macroalbuminuria as ACR > 300 mg/g or UAER > 300 mg/d (or > 200 µg/min) on a timed specimen confirmed with three serial measurements.

Exclusion criteria

Studies enrolling patients with other kinds of diabetes rather than type 1 or type 2 diabetes (e.g. gestational diabetes) were excluded.

Types of interventions

Heparin and related substances used for preventing the onset of DKD, regardless of dosage, mode of administration or duration of treatment, were to be included. Heparin and related substances are a group of glycosaminoglycans which are polysaccharides containing the same repeating disaccharide groups as heparin or the derivatives of heparin, including heparin, low molecular weight heparin (LMWH), heparinoids, heparitin sulfate, sulodexide, chondroitin, hyaluronic acid and keratan sulphate.

The comparisons were to be as follows:

1. heparin and related substances + routine treatment versus placebo + routine treatment;

2. heparin and related substances + routine treatment versus routine treatment;

3. heparin and related substances + routine treatment versus other drug + routine treatment.

Routine treatment includes glycaemic control, BP 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

Primary outcomes

1. Incidence/onset of microalbuminuria for patients without DKD at the end of treatment and follow‐up.

2. The change in kidney function measures (e.g. creatinine clearance (CrCl) or glomerular filtration rate (GFR) and serum creatinine (SCr)) for patients without DKD at the end of treatment and follow‐up.

3. All‐cause mortality.

Secondary outcomes

1. Quality of life measured by any scale.

2. Adverse events of interventions (e.g. chest distress, nausea, allergic reactions, gum bleeding, urticaria, anaphylaxis, any prolonged or unexplained bleeding, pain, ulceration at the injection site, hair loss, prolonged and painful erection and osteoporosis).

3. Other outcomes: change of BP from beginning to end of treatment, level of plasma fibrinogen at end of treatment, incidence of CVD.

Search methods for identification of studies

Electronic searches

1. The Cochrane Renal Group's Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, (issue 2, 2009). CENTRAL and the Renal Group's Specialised Register contain 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 2010). Therefore, we did not specifically search conference proceedings. Please refer to the Cochrane Renal Group's Module in The Cochrane Library for the most up‐to‐date list of conference proceedings (Renal Group 2010).

2. MEDLINE (January 1966 to June 2009) using the optimally sensitive strategy developed for the Cochrane Collaboration for the identification of RCTs (Lefebvre 2008) with specific search terms developed with input from the Cochrane Renal Groups Trial Search Co‐ordinator.

3. EMBASE (January 1980 to June 2009) using a search strategy adapted from that developed for the Cochrane Collaboration for the identification of RCTs (Lefebvre 2008) with specific search terms developed with input from the Cochrane Renal Groups Trial Search Co‐ordinator.

4. Four Chinese databases were searched: China Biological Medicine Database (CBM‐disc 1979 to June 2009); VIP Chinese Science and Technique Journals Database (until June 2009); China National Infrastructure (CNKI) (until June 2009); Wanfang database (until June 2009).

See Appendix 1 for search terms.

Searching other resources

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

2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

Using the search strategy described, we obtained titles and abstracts of studies that may have been relevant to the review. These titles and abstracts were screened independently by two authors (Li J and Zhang L), who discarded studies that were clearly not applicable. However, studies and reviews that might have included relevant data or information on published or ongoing studies were retained initially. The same two authors independently assessed retrieved abstracts and, if necessary, the full text of these studies to determine which ones satisfied the inclusion criteria. Studies reported in non‐English language journals were translated before assessment.

Data extraction and management

We planned for the same two authors to extract data, independently, using standard data extraction forms. Agreement between the two authors was to be tested using the statistic Kappa value. Where more than one publication of a study existed, we planned to group these reports together and include only the publication with the most complete data. Where relevant outcomes were only published in earlier versions, we planned to use these data. Disagreements were to be resolved in consultation with a third author (Wu HM).

Assessment of risk of bias in included studies

We planned for two authors (Li J, Zhang L) to independently assess the quality of studies to be included, without blinding to authorship or journal, using the risk of bias assessment tool. Discrepancies were to be resolved by discussion with a third author (Wu HM).

The following items were to be assessed using the risk of bias assessment tool (Higgins 2008) (seeAppendix 2).

• Was there adequate sequence generation?

• Was allocation adequately concealed?

• Was knowledge of the allocated interventions adequately prevented during the study?

• Were incomplete outcome data adequately addressed?

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

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

Measures of treatment effect

For dichotomous outcomes (e.g. all‐cause mortality) results were to be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (e.g. CrCl, SCr, quality of life measures), the mean difference (MD) was to be used, or the standardised mean difference (SMD) if different scales had been used.

Dealing with missing data

We planned to contact the original author by written correspondence for further information. We planned to include any relevant information obtained in this manner in the review.

Assessment of heterogeneity

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

Assessment of reporting biases

If sufficient RCTs were identified, an attempt was to be made to examine for publication bias using a funnel plot (Higgins 2008).

Data synthesis

We planned to pool data using the random‐effects model and the fixed‐effect model, to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

We planned to use subgroup analysis to explore possible sources of heterogeneity. Heterogeneity among participants could be related to age, type of diabetes, stage of diabetes, 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 studies could be related to study quality. Adverse effects were to be tabulated and assessed with descriptive techniques, as they were likely to be different for the various agents used. Where possible, the risk difference (RD) with 95% CI were to be calculated for each adverse effect, either compared to no treatment or to another agent.

Results

Description of studies

Through computerised searches, 74 potentially relevant studies were found. After title and abstract screening, 61 studies were excluded because they included patients who already had DKD; and two studies were excluded because no heparin or related substances were observed.

Eleven potentially eligible studies were retrieved for further assessment. Through the full text screening, these eleven studies were excluded because of the following reasons.

1. Patients who were observed in the studies already had DKD (five studies) (Achour 2005; Li 2007; Ma 2000; Piva 1985; Zalevskaia 1998).

2. Patients were not randomised to the treatment and control groups (three studies) (Ceriello 1993; Markoski 1977; Markovski 1977).

3. Patients without DM were included (one study) (Pisano 1986).

4. No data on the outcomes of interest were available (two studies) (Kalani 2007; Scroggie 2003).

Therefore, no eligible studies were included in this systematic review. Figure 1 shows the flow chart of the decision process for study selection.

1.

Flow chart of selection process for inclusion of studies on heparin and related substances for preventing DKD

Risk of bias in included studies

No studies met our inclusion criteria.

Effects of interventions

No studies met our inclusion criteria.

Discussion

No studies met our inclusion criteria.

Diabetes prevalence is increasing most rapidly in both the developed and developing countries. Despite substantial under diagnosis, worldwide, 171 million people have diabetes (KDOQI 2007). As the population of patients with diabetes of long duration grows, DKD becomes the leading cause of chronic kidney disease (CKD) in developed countries, and is rapidly becoming the leading cause in developing countries as a consequence of the global increase in type 2 diabetes and obesity (Zimmet 2001). The data from US Renal Data System indicated DKD accounts for 45% of prevalent kidney failure, up from 18% in 1980 (USRDS 2004). Management of DKD is costly not only in developed but also developing countries so a lot of focus has been put on the prevention and treatment of DKD. A growing body of evidence suggests that to reduce the risk or slow the progression of DKD, optimising glucose control and BP control are necessary. Reduction of protein intake in individuals with DKD may improve measures of kidney function and is recommended. There are clinical studies and guideline support that in the treatment of DKD, either ACEi or ARB should be used and can improve the prognosis of DKD. However, the above mentioned measures for preventing the onset and progression of DKD are only partially effective. Furthermore, strict metabolic control is difficult so additional and alternative treatment options are needed. Heparin and related substances may be promising in the prevention of DKD.

In our search for studies investigating heparin and related substances, no study focused on the prevention of incidence or onset of DKD, and we found no studies suitable for inclusion in this review. Therefore, we were not able to draw conclusions about whether heparin and related substances might prevent the incidence of DKD. Because of the severity and heavy burden of DKD, well‐designed RCTs are needed to guide clinical practice for the prevention of DKD.

Authors' conclusions

Implications for practice.

More focus should be put on the prevention of incidence or onset of DKD.

Implications for research.

Through the search and assessment, it was difficult to find studies concentrating on the prevention of DKD. Few studies observed the onset of microalbuminuria in patients with diabetes. More studies (such as Achour 2005; Li 2007) put their emphasis on the effect of heparin and related substances on progression from micro‐ to macroalbuminuria or regression from micro‐ to normoalbuminuria. Furthermore, some studies (Kalani 2007; Scroggie 2003), which observed the use of heparin and related substances in patients with diabetes, did not provide the data on the onset of DKD or microalbuminuria. Future research should concentrate on heparin and related substances for the prevention of DKD. Well‐designed RCTs are needed to guide clinical practice about the prevention of the incidence or onset of DKD.

History

Protocol first published: Issue 1, 2006
 Review first published: Issue 9, 2010

Date	Event	Description
5 October 2009	Amended	Change of title and new methods added

Appendices

Appendix 1. Electronic search strategies

Database	Search terms
CENTRAL	MeSH descriptor Glycosaminoglycans explode all trees (glycosaminoglycan* or glycoamin*):ti,ab,kw in Clinical Trials (chondroitin*):ti,ab,kw or (dermatan*):ti,ab,kw or (heparin*):ti,ab,kw or (LMWH):ti,ab,kw in Clinical Trials (dalteparin or tedelparin or fr‐860 or fragmin* or kabi‐2165):ti,ab,kw in Clinical Trials (enoxaparin or clexane or emt‐966 or emt‐967 or lovenox or "pk‐10 169" or pk‐10169 or pk10169 or klexane):ti,ab,kw in Clinical Trials (ardeparin or normiflo or wy90493 or "wy 90493"):ti,ab,kw in Clinical Trials (bemiparin or hibor or certoparin or sandoparin or "cy222"):ti,ab,kw in Clinical Trials (danaparoid or "kb 101" or kb101 or lomopar?n or orgaran):ti,ab,kw in Clinical Trials (embolex or fondaparinux or idraparinux):ti,ab,kw in Clinical Trials (parnaparin or fluxum or lohepa or lowhepa or "op 2123" or parvoparin):ti,ab,kw in Clinical Trials (nadroparin$ or cy‐216 or cy216 or fraxiparin or seleparin or tedegliparin or fraxiparin or seleparin or tedegliparin or tedelparin or antixarin or tinzaparin or reviparin or "rd 11885"):ti,ab,kw in Clinical Trials (heparitin sulfate* or heparitin sulphate*):ti,ab,kw in Clinical Trials (heparan or hyaluronic acid or keratan sulfate* or keratan sulphate*):ti,ab,kw in Clinical Trials (mucopolysaccharide* or polymucosaccharide*):ti,ab,kw in Clinical Trials (galactosaminoglycan* or perlecan or polysialic acid or proteoheparan* or sulodexide* or syndecan or trichosaccaride*):ti,ab,kw in Clinical Trials (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15) MeSH descriptor Diabetes Mellitus, this term only MeSH descriptor Diabetes Mellitus, Type 1 explode all trees MeSH descriptor Diabetes Mellitus, Type 2 explode all trees MeSH descriptor Diabetic Nephropathies, this term only (IDDM or NIDDM):ti,ab,kw in Clinical Trials ((diabetes or diabetic) and (kidney* or renal or nephro* or nephriti* or glomerulo*)):ti,ab,kw in Clinical Trials (17 OR 18 OR 19 OR 20 OR 21 OR 22) (16 AND 23)
MEDLINE	exp Glycosaminoglycans/ (glycosaminoglycan$ or glycoamin$).tw. chondroitin.tw. dermatan$.tw. heparin$.tw. LMWH.tw. (dalteparin or tedelparin or fr‐860 or fragmin$ or kabi‐2165).tw. (enoxaparin or clexane or emt‐966 or emt‐967 or lovenox or "pk‐10 169" or pk‐10169 or pk10169 or klexane).tw. (ardeparin or normiflo or wy90493 or "wy 90493").tw. (bemiparin or hibor or certoparin or sandoparin or "cy222").tw. (danaparoid or "kb 101" or kb101 or lomopar?n or orgaran).tw. (embolex or fondaparinux or idraparinux).tw. (parnaparin or fluxum or lohepa or lowhepa or "op 2123" or parvoparin).tw. (nadroparin$ or cy‐216 or cy216 or fraxiparin$ or seleparin$ or tedegliparin or fraxiparin$ or seleparin$ or tedegliparin$ or tedelparin$ or antixarin or tinzaparin or reviparin or "rd 11885").tw. (heparitin sulfate$ or heparitin sulphate$).tw. heparan$.tw. hyaluronic acid.tw. (keratan sulfate$ or keratan sulphate$).tw. (mucopolysaccharide$ or polymucosaccharide$).tw. (galactosaminoglycan$ or perlecan$ or polysialic acid$ or proteoheparan$ or sulodexide$ or syndecan$ or trichosaccaride$).tw. or/1‐20 diabetes mellitus/ or exp diabetes mellitus, type 1/ or exp diabetes mellitus, type 2/ Diabetic Nephropathies/ (IDDM or NIDDM).tw. ((diabetes or diabetic) and (kidney$ or renal or nephro$ or nephriti$ or glomerulo$)).tw. or/22‐25 and/21,26
EMBASE	exp Heparin Derivative/ exp Glycosaminoglycan/ (glycoamin$ or glycoaminoglycan$ or polymucosaccharide$ or mucopolysaccharide$).tw. (heparin or heparan or LMWH).tw. or/1‐4 Diabetes Mellitus/ Diabetic Nephropathy/ (IDDM or NIDDM).tw. ((diabetes or diabetic) and (kidney$ or renal or nephro$ or nephriti$ or glomerulo$)).tw. or/6‐9 and/5,10

Appendix 2. Risk of bias assessment tool

Potential source of bias	Assessment criteria
Was there adequate sequence generation?	Yes (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).
	No (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.
Was allocation adequately concealed?	Yes (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).
	No (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.
Was knowledge of the allocated interventions adequately prevented during the study?	Yes (low risk of bias): No blinding, but the review authors judge that the outcome and the outcome measurement are 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; either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non‐blinding of others unlikely to introduce bias.
	No (high risk of bias): No blinding or incomplete blinding, and the outcome or outcome measurement 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; either participants or some key study personnel were not blinded, and the non‐blinding of others likely to introduce bias.
	Unclear: Insufficient information to permit judgement of ‘Yes’ or ‘No'
Were incomplete outcome data adequately addressed?	Yes (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 standardised 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.
	No (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 standardised 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 of ‘Yes’ or ‘No'.
Are reports of the study free of suggestion of selective outcome reporting?	Yes (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).
	No (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 of ‘Yes’ or ‘No'.
Was the study apparently free of other problems that could put it at a risk of bias?	Yes (low risk of bias): The study appears to be free of other sources of bias.
	No (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 permit judgement of ‘Yes’ or ‘No'.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Achour 2005	Patients who were observed in the studies already had DKD
Ceriello 1993	Patients not randomised to the treatment and control groups
Kalani 2007	No data on the outcomes of interest were available
Li 2007	Patients who were observed in the studies already had DKD
Ma 2000	Patients who were observed in the studies already had DKD
Markoski 1977	Patients not randomised to the treatment and control groups
Markovski 1977	Patients not randomised to the treatment and control groups
Pisano 1986	No data on the outcomes of interest were available
Piva 1985	Patients who were observed in the studies already had DKD
Scroggie 2003	No data on the outcomes of interest were available
Zalevskaia 1998	Patients who were observed in the studies already had DKD

DKD ‐ diabetic kidney disease

Differences between protocol and review

This review was initially designed to investigate "Glycosaminoglycan for preventing and treating diabetic kidney disease" (Wu 2006). A similar review was being undertaken "Low molecular weight heparin for diabetic kidney disease" (Xie 2007) and the Cochrane Renal Group Editorial office merged and then split the reviews into two reviews "Heparin and related substances for preventing diabetic kidney disease" and "Heparin and related substances for delaying the progression of diabetic kidney disease" (Xie 2010).

The risk of bias assessment tool (Higgins 2008) has replaced the quality assessment checklist.

Contributions of authors

• JL: Study selection, quality assessment, data extraction, data entry, data analysis, writing of protocol and review.

• LC: Study selection, quality assessment, data extraction, data entry, data analysis, writing of protocol and review.

• HW: Dispute resolution, data analysis, writing of protocol and review.

• BZ: Statistical assistance.

• DB: Expertise on clinical knowledge, revising protocol and review.

Sources of support

Internal sources

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

• Chinese Cochrane Center, China.

External sources

• Chinese Medical Board of New York (Grant 98‐680), USA.

Declarations of interest

None known.

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