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Altered dietary salt intake for preventing and treating diabetic kidney disease

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Abstract

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

The objective of this review is to evaluate the effects of salt reduction on the prevention and progression of nephropathy in diabetes mellitus. It is unlikely that there are studies of sufficient duration to examine the effect on outcome measurements such as end stage renal failure or death. Therefore studies evaluating the effect of dietary salt modification on surrogate markers of diabetic nephropathy will be included.

Background

Diabetic kidney disease is the leading cause of end stage renal failure in the western world. With increasing prevalence of type 2 diabetes, chronic kidney disease secondary to diabetic nephropathy is likely to increase. Measures reducing the occurrence and progression of diabetic kidney disease are therefore vital. Increased 24 hour urinary sodium is an independent risk factor for the development of type 2 diabetes, implicating a possible role for dietary sodium in the aetiology or progression of type 2 diabetes (Hu 2005).

Salt reduction has several potential roles which could be beneficial in diabetic nephropathy. Dietary salt is important in blood pressure control (Denton 1995; He 2002; Intersalt 1988; Lifton 1996), with a meta‐analysis demonstrating dietary salt reduction improves blood pressure by 5 mm Hg in hypertensives and 3 mm Hg in normotensives. Diastolic blood pressure improved by 2 mm Hg and 1 mm Hg respectively (He 2002). In diabetics with blood pressure levels less than 130/80, reduction of GFR is similar to age matched healthy individuals (Giunti 2006). Interventions reducing blood pressure in diabetes slows the progression of diabetic nephropathy and improves survival (Schrier 2002). Therefore improving blood pressure by dietary salt modification would be expected to be protective in the development and progression of diabetic kidney disease.

Sodium intake influences the activity of the renin‐angiotensin system (RAS). High dietary salt suppresses the RAS however the RAS is less responsive in diabetes, increasing the salt sensitivity in diabetes. The effect of angiotensin II on renal haemodynamics is reduced (De'Oliveira 1997; Price 1999; Trujillo 1989). Furthermore, the antiproteinuric and antihypertensive effect of ACE inhibition is dependent on salt intake, i.e. a low‐salt intake enhances and a high‐salt intake abolishes the antiproteinuric effect of ACE inhibition (MacGregor 1987). The effect of salt induced changes in haemodynamic measurements are reversed with ACE inhibition (De'Oliveira 1997).

Urinary albumin excretion, a marker of diabetic nephropathy and significant independent risk factor for cardiovascular mortality (Hillege 2002), is reduced by lowering dietary salt (Allen 1997; Cianciaruso 1998; Swift 2005). Transforming growth factor ß (TGF ß) is increased in type II diabetes and is associated with chronic kidney disease (Sharma 1997). Experimental evidence suggest high dietary salt increases renal fibrosis and modulates renal production of the prosclerotic (TGF ß) (Houlihan 2002; Ying 1998a; Ying 1998b; Yu 1998). Changes in dietary salt may have a beneficial influence on TGF ß production, affecting the progression of diabetic kidney disease.

Many previous studies are of short duration and involve small patient numbers (Ames 2001; da Costa 1997; Dodson 1889; Vedovato 2004) and it is unlikely that there are any studies of sufficient duration to test the efficacy of salt reduction on outcome measurements such as end stage renal failure or death in patients with diabetes. Changes in salt intake on surrogate markers, including urinary albumin level, blood pressure and GFR will therefore be important in this review.

Objectives

The objective of this review is to evaluate the effects of salt reduction on the prevention and progression of nephropathy in diabetes mellitus. It is unlikely that there are studies of sufficient duration to examine the effect on outcome measurements such as end stage renal failure or death. Therefore studies evaluating the effect of dietary salt modification on surrogate markers of diabetic nephropathy will be included.

Methods

Criteria for considering studies for this review

Types of studies

Studies in this review will be limited to randomised controlled and quasi‐randomised trials.
All studies will need to satisfy the following criteria for inclusion:

  • Allocation to either a low or a high salt diet. Ideally a low salt diet will aim less than 6 g as compared to usual/high salt diet of 10‐12 g/day. Studies achieving a minimum difference in dietary salt of 2 g/day between the two groups will be considered.

  • Sodium intake estimated by 24 hour urinary sodium excretion.

  • Net reduction in 24 hour urinary sodium must be equal or greater than 34 mmol (2.0 g/day) of salt. Twenty four hour urinary sodium reduction will be calculated as U Na (high) ‐ U Na (low) in cross over studies, where U Na (low) is the 24 hour urinary sodium at the end of the reduced salt period and the U Na (high) is the 24 hour urinary sodium at the end of the high salt period. The 24 hour urinary sodium reduction in parallel studies will be calculated using [U Na(high) ‐ U Na(low)] low salt group ‐ [U Na(high) ‐ U Na(low)] control group

  • Studies with concomitant interventions, such as anti hypertensive medication or other dietary modifications used during the study period, will be included providing they are non randomised co‐interventions.

Types of participants

Any adult with type 1 or type 2 diabetes mellitus will be included, irrespective of ethnicity or gender. Studies looking at the treatment of diabetic kidney disease will have this confirmed by an albumin excretion rate of greater than 30 mg/24 h confirmed on three serial measurements. Studies of children and pregnant women will be excluded.

Types of interventions

The intervention is a reduction in dietary salt intake. Studies which involve concomitant interventions will be included if they are non randomised co‐interventions.

Types of outcome measures

It is unlikely that the studies will be of sufficient durations for primary outcome measurements such as end stage renal failure (ESRF) and therefore we will also include surrogate markers for the development and progression of diabetic kidney disease.

The following measurement will be extracted where available:

  1. Time to ESRF (renal replacement therapy (RRT) or transplantation)

  2. ESRF (RRT or transplantation)

  3. Death (any cause)

  4. Death (cardiovascular)

  5. Changes in urinary sodium excretion (mmol/24 h)

  6. Serum creatinine (mg/dL, μmol/L) at end of intervention or change in serum creatinine between the beginning and end of intervention

  7. Doubling of serum creatinine at end of treatment

  8. Creatinine clearance or GFR (any measure) or change in creatinine clearance/GFR (any measure) between beginning and end of intervention

  9. Change in GFR/year (mL/min/y)

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

  11. Albuminuria (mg/24 h or μg/min), macroalbuminuria (mg/24 h or μg/min) or proteinuria (mg/24 h) at the end of the intervention or between the beginning and end of the intervention

  12. Macroalbuminuria to microalbuminuria, microalbuminuria to normoalbuminuria at the end of the intervention

  13. Urinary albumin creatinine ratio (mg albumin/mmol creatinine)

  14. Blood pressure (mmHg) systolic, diastolic, mean arterial pressure at end of intervention or change between the beginning and end of intervention.

  15. Glycaemic control HbA1c %

  16. BMI kg/m²

Search methods for identification of studies

This search strategy has previously been developed with the trials search coordinator from the Cochrane Renal Group. It is based on previous search strategies used to identify studies of salt intervention and blood pressure.

Relevant studies will be obtained from the following sources:

1). The specialised registers of the Cochrane Renal Group, the Cochrane Metabolic Disorders and Endocrine Group and the Cochrane Hypertension Group, and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, (most recent) will be searched using the following terms:‐

  1. MeSH descriptor Sodium, Dietary explode all trees

  2. MeSH descriptor Diet, Sodium‐Restricted, this term only

  3. (dietary salt*) or (dietary sodium) in Clinical Trials

  4. (diet* and (salt* or sodium)) in Clinical Trials

  5. (salt* or sodium) and (restrict* or intak* or chang*) in Clinical Trials

  6. (#1 OR #2 OR #3 OR #4 OR #5)

  7. MeSH descriptor Diabetic Nephropathies, this term only

  8. MeSH descriptor Diabetes Mellitus, this term only

  9. MeSH descriptor Diabetes Mellitus, Type 1 explode all trees

  10. MeSH descriptor Diabetes Mellitus, Type 2 explode all trees

  11. MeSH descriptor Glucose Intolerance explode all trees

  12. MeSH descriptor Insulin Resistance explode all trees

  13. (diabetic nephropath* or diabetic kidney* or diabetic renal*) in Clinical Trials

  14. (IDDM or NIDDM) in Clinical Trials

  15. (insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.) in Clinical Trials

  16. (impaired glucose toleranc* ) or (glucose intoleranc*) in Clinical Trials

  17. (insulin resistanc*) in Clinical Trials

  18. (#7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17)

  19. (#6 AND #18)

CENTRAL and the Cochrane Review Groups specialised registers 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).

2). MEDLINE and Pre‐MEDLINE (1966 to most recent) using the optimally sensitive strategy developed for the Cochrane Collaboration for the identification of RCTs (Dickersin 1994) with a specific search strategy developed with input from the Cochrane Renal Groups Trial Search Co‐ordinator.

MEDLINE and Pre‐MEDLINE 1966‐present

  1. exp Sodium, Dietary/

  2. Diet, Sodium‐Restricted/

  3. (dietary salt or dietary sodium).tw.

  4. (diet$ and (salt$ or sodium)).tw.

  5. ((salt$ or sodium$) and (restrict$ or intake$ or chang$)).tw.

  6. or/1‐5

  7. diabetes mellitus/ or exp diabetes mellitus, type 1/ or exp diabetes mellitus, type 2/

  8. (IDDM or NIDDM).tw.

  9. Diabetic Nephropathies/

  10. diabetic nephropath$.tw.

  11. ((diabetic or diabetes) and (kidney$ or renal$ or nephro$ or nephritis or glomerulo$)).tw.

  12. (insulin dependent diabetes or non insulin dependent diabetes).tw.

  13. Glucose Intolerance/

  14. (impaired glucose toleranc$ or glucose intoleranc$).tw.

  15. exp Insulin Resistance/

  16. insulin resistanc$.tw.

  17. or/7‐16

  18. and/6,17

  19. randomised controlled trial.pt.

  20. controlled clinical trial.pt.

  21. randomised controlled trials/

  22. random allocation/

  23. double blind method/

  24. single blind method/

  25. or/19‐24

  26. animals/ not (animals/ and humans/)

  27. 25 not 26

  28. clinical trial.pt.

  29. exp clinical trials/

  30. (clinic$ adj25 trial$).ti,ab.

  31. cross‐over studies/

  32. (crossover or cross‐over or cross over).tw.

  33. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab.

  34. placebos/

  35. placebo$.ti,ab.

  36. random$.ti,ab.

  37. research design/

  38. or/28‐37

  39. 38 not 26

  40. 27 or 39

  41. and/18,40

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 a specific search strategy developed with input from the Cochrane Renal Groups Trial Search Co‐ordinator.

  1. Salt Intake/

  2. Sodium Intake/

  3. Sodium Restriction/

  4. (dietary salt or dietary sodium).tw.

  5. (diet$ and (salt$ or sodium)).tw.

  6. ((salt$ or sodium) and (restrict$ or intak$ or change$)).tw.

  7. or/1‐6

  8. Diabetic Nephropathy/

  9. diabetic nephropath$.tw.

  10. ((diabetic or diabetes) and (kidney$ or renal$ or nephro$ or nephritis or glomerulo$)).tw.

  11. (IDDM or NIDDM).tw.

  12. diabetes mellitus/ or impaired glucose tolerance/ or insulin dependent diabetes mellitus/ or non insulin dependent diabetes mellitus/

  13. (insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus).tw.

  14. Glucose Intolerance/

  15. (impaired glucose toleranc$ or glucose intoleranc$).tw.

  16. Insulin Resistance/

  17. insulin resistanc$.tw.

  18. or/8‐17

  19. and/7,18

  20. exp clinical trial/

  21. evidence based medicine/

  22. outcomes research/

  23. crossover procedure/

  24. double blind procedure/

  25. single blind procedure/

  26. prospective study/

  27. major clinical study/

  28. exp comparative study/

  29. placebo/

  30. "evaluation and follow up"/

  31. follow up/

  32. randomisation/

  33. or/20‐32

  34. controlled study/ not case control study/

  35. or/33‐34

  36. (clinic$ adj5 trial$).ti,ab.

  37. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ti,ab.

  38. random$.ti,ab.

  39. placebo$.ti,ab.

  40. or/36‐39

  41. 35 or 40

  42. limit 41 to human

  43. and/19,42

4).Conference proceedings from nephrology meetings: (ISN, European Renal Association (ERA‐EDTA), American Society of Nephrology and renal association) and hypertension meetings (ISH, ESH, AHA, ASH)
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

Selection of trials

This review will be undertaken by three reviewers (RS, FH, GM). The search strategy will be used to obtain titles and abstracts of studies relevant to the review. These will be screened independently by two reviewers (RS and FH) and full articles will be retrieved if the initial assessment suggests that studies or reviews might include relevant data. These abstracts and, if necessary, the full text will be independently assessed by the same reviewers to identify studies which meet the inclusion criteria. Studies in non English language will be translated before assessment. Disagreements will be resolved in consultation with the third reviewer (GM).

Data extraction will be performed by the same reviewers independently using standard data extraction forms. Where there is more than one publication of a study, the publication with the most complete data will be used. Further information will be requested from the original author by written correspondence.

Methodological quality

Allocation concealment

  • Adequate (A): The randomisation method described would not allow participants and investigators to foresee assignment.

  • Unclear (B): randomisation method is stated but no information of the method used is described.

  • Inadequate (C): Method of randomisation allows participants and investigators to foresee assignment e.g. unsealed envelopes or alternate medical record numbers.

Blinding

We will distinguish studies by the method of blinding

  • Blinding of the investigator: Yes/no/not stated

  • Blinding of the participant: Yes/no/not stated

  • Blinding of the outcome assessor: Yes/no/not stated

  • Blinding of the data analysis: Yes/no/not stated

Intention to treat analysis

  • Yes: specifically reported by authors that intention to treat analysis was undertaken and this is confirmed on study assessment

  • Yes: Not specifically reported but confirmed on study assessment

  • No: not reported and lack of intention to treat analysis confirmed on study assessment

  • No: stated but not confirmed upon study assessment

  • Not stated

Completeness of follow‐up

We will record the percentage of participants excluded or to follow‐up.

Statistical assessment

The treatment effect for each trial will be calculated. For dichotomous outcomes the results will be expressed as risk ratio (RR) with 95% confidence intervals. For continuous variables e.g. microalbuminuria, serum creatinine, GFR, blood pressure the mean difference will be calculated.

In crossover trials, the mean difference in outcomes will be the changes between the end of the reduced salt period and usual salt period. For parallel trials the treatment effect will be the difference between the two measurement groups in the changes in outcomes from baseline to the end of the trial.

Mean difference (MD) for continuous measurements e.g. systolic blood pressure, microalbuminuria, will be calculated by random‐effects model. Fixed effect model will also be analysed to ensure robustness of the model chosen and susceptibility to outliers. Standardised mean difference (SMD) will be calculated if different scales have been used.

Heterogeneity will be examined using the I² and Q statistics. I² describes the percent variation across studies that results from heterogeneity rather than chance (Higgins 2003). If there is a significant heterogeneity between studies, the sources of heterogeneity will be explored by meta‐regression analysis or subgroup analysis (e.g. ethnicity, study design, amount of salt reduction, type of diabetes, nephropathy).