Study characteristics

Methods

Study design

• Parallel RCT

Duration of study/recruitment

• Not reported

Duration of treatment

• 5 to 7 days

Duration of follow‐up

• 2 weeks from start of treatment

Participants

Study characteristics

• Setting: single centre

• Country: USA

• Inclusion criteria: ≥ 30 years; NIDDM; onset > 30 years; no diabetic ketoacidosis episodes; fasting blood glucose ≥ 140 mg/dL or 2‐hour blood glucose level in standard GTT ≥ 200 mg/dL; hypertension ≥ 140/90 mm Hg

• Exclusion criteria: azotaemia or gross proteinuria

Baseline characteristics

• Number: intervention group (9); control group (10)

• Mean age ± SEM (years): intervention group (56 ± 3); control group (55 ± 2)

• Sex (F/M): intervention group (7/2); control group (9/1)

• Ethnicity: Caucasian (17); African American (2)

• Mean BMI ± SEM ( kg/m²): intervention group (28.9 ± 1.5); control group (31.6 ± 1.7)

• Mean MAP ± SEM (mm Hg): intervention group (102 ± 3); control group (102 ± 6)

• Mean cholesterol ± SEM (mg/dL): intervention group (234 ± 17); control group (143 ± 10)

• Diabetes

  • Mean NIDDM duration ± SEM: 7 ± 1 years

  • Mean fasting blood sugar ± SEM (mg/dL): intervention group (181 ± 23); control group (162 ± 23)

  • Mean 2‐hour oral GTT ± SEM: 319 ± 26 mg/dL

• Mean SCr ± SEM (mg/dL): intervention group (1.16 ± 0.05; control group (1.21 ± 0.06)

• Mean uric acid ± SEM (mg/dL): intervention group (5.8 ± 0.7); control group (7.0 ± 0.7)

• CKD definition: not reported

Interventions

Pre‐randomisation/run‐in period

• Isocaloric diet: 10 mmol NaCl + 100 mmol K⁺ + 2000 mL water

• Duration: 5 to 7 days

Intervention group

• Low salt diet

  • NaCl: 10 mmol/day

  • K⁺: 100 mmol

  • Water: 2000 mL

• Duration: 5 to 7 days

 Control group

• High salt diet

  • NaCl: 200 mmol/day

  • K⁺: 100 mmol

  • Water: 2000 mL

• Duration: 5 to 7 days

 Co‐interventions

• Anti‐hypertensive agents ceased 2 weeks before the study. Participants did not receive ACEi or ARBs during the study

Outcomes

Outcomes reported / outcomes relevant to this review*

• MAP*

• ERPF*

• eGFR*

• BMI*

• Fasting blood glucose

• Cholesterol

• Uric acid

• SCr*

• 24‐hour UNa excretion*

• PRA

• Plasma aldosterone

• FF

Notes

Additional information

• Exclusions post‐randomisation but pre‐intervention: none

• Stop or end point/s: not reported

• Additional data requested from authors: yes, but no response to our request

• Completeness of follow‐up

  • Analysed: 100%

  • Per cent followed: 100%

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "9 subjects were randomized to remain in the low‐salt diet ... the other 10 were switched to ... 200 mmol NaCl".

Comment: insufficient detail was provided about how the randomisation methods were undertaken

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding the concealment of allocation to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: unblinded study

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: unblinded study

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition not reported. Unclear what the final attrition rate is. ITT analysis was not performed

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori published protocol or trial registration details

• Trial registration: not reported

• A priori published protocol: provided in appendix but not published earlier

Funding source

Low risk

Quote: "this work was supported in part by the National Institutes of Health grants T32 HL‐07609, NCRR GCRC M01RR026376, P01AC00059916, and 1 P50ML53000‐01 and in part by the Canadian Medical Research Council Fellowship Award (Dr. Donald Allan), and a Northern Ireland Council for Postgraduate Medical Education Award (Dr. John McKnight). Dr. Naomi Fisher and Deborah Price were supported by NIH Clinical Associate Physician Awards"

Comment: no industry funding

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

Low risk

Washout period: not applicable to parallel design

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Parallel RCT (followed by a cross‐over study Dodson_X 1989)

Duration of study (recruitment)

• Not clear

Duration of treatment

• 3 months

Duration of follow‐up

• At 3 months end of treatment

Participants

Study characteristics

• Setting: single centre

• Country: UK

• Inclusion criteria: type 2 DM; mild hypertension (SBP > 160 mm Hg or DBP > 95 mm Hg)

• Exclusion criteria: past or current treatment with insulin; CKD due to diabetes or hypertensive kidney disease (proteinuria or raised SCr); cardiac failure; pregnancy

Baseline characteristics

• Number: intervention group (17); control group (17)

• Mean age ± SD (years): intervention group (61.9 ± 7.5); control group (61.1 ± 6.3)

• Sex (F/M): intervention group (12/5); control group (11/6)

• Body weight (% of ideal body weight): intervention group (126.6 ± 20.2); control group (127.5 ± 24.9)

• Mean BP SBP/DBP (mm Hg): intervention group (179/98); control group (174/100)

• Hypertension

  • Duration of 'mild' hypertension (years): intervention group (4.1 ± 3.4); control group (6.5 ± 8.0)

  • Taking atenolol: intervention group (2/17); control group (2/17)

• Mean HbA1c ± SD (%): intervention group (10.2 ± 1.95); control group (10.4 ± 2.5)

• Diabetes

  • Type 2 DM

  • Mean duration of diabetes ± SD (years): intervention group (4.1 ± 5.2); control group (5.1 ± 3.4)

  • Taking hypoglycaemic agents: intervention group (2/17); control group (4/17)

• Mean 24‐hour UNa excretion (mmol/24 hours): intervention group (198.7 ± 65.9); control group (183.2 ± 62.3)

• Mean 24‐hour urinary potassium excretion (mmol/24 hours): intervention group (65.9 ± 25.4); control group (71.8 ± 27.0)

• CKD definition: not reported

Interventions

Pre‐randomisation/run‐in

• No changes, outcome measurements taken

• Duration: 7 weeks

Intervention group

• Dietary advice: moderate sodium restriction

• Duration: 3 months

Intervention group

• No advice: continue on normal diabetic diet (low carbohydrate, high fat, low fibre, added salt)

• Duration: 3 months

Co‐interventions

• None; participants did not receive ACEi or ARB

Outcomes

Reported outcomes (at 3 months)

• SBP*, DBP* (mm Hg)

• Body weight*

• 24‐hour UNa excretion*

• 24‐hour urinary potassium excretion

• Alcohol intake

• Smoking

• HbA1c* (%)

Notes

Additional information

• Stop or end point/s: not reported

• Per cent followed: 100%

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "the dietician randomly allocated patients either to receive advice on reducing sodium intake or to a control group"

Comment: insufficient information provided on how the randomisation methods were performed by the dietician

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding the concealment of allocation to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: unblinded parallel study

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: unblinded parallel study

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition not reported. Unclear what the final attrition rate is. ITT analysis was not performed

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori published protocol or trial registration details

• Trial registration: not reported

• A priori published protocol: not reported

Funding source

High risk

Quote: "we are grateful to CIBA (Horsham) for supplies of Slow Sodium and placebo"

Comment: pharmaceutical industry funding of study drugs

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

Low risk

Washout period for cross‐over trials: not applicable, parallel phase

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over study after parallel study (Dodson_P 1989)

Duration of study (recruitment)

• Not clear

Duration of treatment

• 1 month

Duration of follow‐up

• At end of treatment

Participants

Study characteristics

• Setting: single centre

• Country: UK

• Inclusion criteria: type 2 DM; mild hypertension (SBP > 160 mm Hg or DBP > 95 mm Hg)

• Exclusion criteria: past or current treatment with insulin; CKD due to diabetes or hypertensive kidney disease (proteinuria or raised SCr); cardiac failure; pregnancy

Baseline characteristics

• Number (randomised/analysed): 13/9

• Mean age ± SD: 62 ± 6.5 years

• Sex (M/F): 6/3

• Mean body weight ± SD: 77.7 ± 4.8 kg

• Mean SBP/DBP ± SD (mm Hg): 163.8 ± 15.9/95.3 ± 8.1

• Hypertension: 'mild'

• HbA1c%: not reported

• Diabetes

  • Type 2 DM

  • Mean duration: 5 years

• Co‐morbidities: not reported

• CKD definition: not reported

• 24‐hour UNa excretion: 141.5 ± 47.7 mmol/24 hours

• 24‐hour urinary potassium excretion: 72.3 ± 20.6 mmol/24 hours

Interventions

Pre‐randomisation

• 13 patients who just participated in 3 months of 'moderate dietary salt restriction diet' via dietician advice: from the treatment arm of Dodson_P 1989

• Washout period: no washout applied

Intervention group

• Continue on 'moderate dietary salt restriction diet' + placebo oral tablet

• Duration: daily, for 1 month

Control group

• Continue on 'moderate dietary salt restriction diet' + slow‐release sodium supplement oral tablet 80 mmol/day

• Duration: daily, for 1 month

Co‐interventions or additional treatments

• None; participants did not receive ACEi or ARB

Follow up details

• No follow‐up past the end of the treatment period (2 months in total)

Outcomes

Reported outcomes (at 3 months) / outcomes relevant to this review*

• SBP*, DBP* (mm Hg)

• Body weight*

• 24‐hour urinary sodium excretion*

• HbA1c* (%)

Notes

Additional information

• Stop or end point/s: not reported

• Per cent followed: 100%

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "six men and three women ... completed the randomised double‐blind crossover trial"

Comment: insufficient information provided on how the randomisation methods were undertaken

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding the concealment of allocation to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "six men and three women ... completed the randomised double‐blind crossover trial"

Comment: the study states to be double‐blind but there is insufficient information provided on how the blinding of either the participants or the study personnel was undertaken

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: no information provided regarding any blinding of the outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: all participants were accounted for from start to end of the trial

Comment: high attrition rate. 4 participants (attrition = 31%) withdrew due to adverse effects (from both sodium and placebo groups)

Comment: unclear if ITT analysis was performed or original participant sample (ITT = 13?) as group totals are not provided for final analysis

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori published protocol or trial registration details

• Trial registration: not reported

• A priori published protocol: not reported

Funding source

High risk

Quote: "we are grateful to CIBA (Horsham) for supplies of Slow Sodium and placebo".

Comment: pharmaceutical industry funding of study drugs

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

Unclear risk

Washout period for cross‐over trials: no washout period

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Parallel RCT, with cross‐over dietary salt

Duration of study

• 3 months

Duration of treatment

• 3 months

Duration of follow‐up

• At end of 3 months of treatment

Participants

Study characteristics

• Setting: multicentre (Austin and Repatriation Medical Centre diabetes clinic, and surrounding district)

• Country: Australia

• Inclusion criteria: 30 to 75 years; type 2 diabetes; hypertension: seated BP > 130/85 mm Hg; albuminuria (AER 10 to 200 µg/min); HbA1c < 11.0%; habitual 24‐hour UNa excretion > 100 mmol/24 hours

• Exclusion criteria: serious systemic illness; history of substance abuse; seated BP > 165/100 mm Hg; serum potassium > 5.5 mmol/L; SCr > 200 µmol/L; long term use of NSAIDs; recurrent UTIs (> 3/year); BMI > 35 kg/m²; cardiac failure; nitrate therapy; intolerance of ACEi

Baseline characteristics

• Number: 20

• Mean age ± SEM (years): losartan group (60.6 ± 3.7); control group (63.1 ± 3.9)

• Sex (M/F): losartan group (10/0); control group (9/1)

• Mean BMI ± SEM (kg/m²): losartan group (30.4 ± 2.1); control group (28.1 ± 1.6)

• Mean MAP ± SEM (mm Hg): losartan group (114 ± 3); control group (111 ± 3)

• Hypertension: hypertensive > 130/85 mm Hg

• Mean HbA1c ± SEM (%): 7.4 ± 0.4 losartan group (7.9 ± 0.5); control group (7.4 ± 0.4)

• Diabetes

  • Type 2 DM

  • Duration of diabetes: median 4.0 years (range 1 to 10)

• Co‐morbidities: none

• CKD definition: AER: 10 to 200 µg/min

• Mean AER ± SEM (µg/min): losartan group (26.6 ± 1.4); control group (32.6 ± 1.3)

• Mean SCr ± SEM (mmol/L): losartan group (97 ± 6.5); control group (92 ± 2.7)

Interventions

Pre‐randomisation/run‐in period

• Antihypertensives, including ACEi, ARBs and diuretics, stopped for at least 2 weeks before commencing study

Intervention group

• Losartan (oral): 50 mg/day

• Low sodium diet: 50 to 70 mmol/day

• Duration: 2 weeks

Control group

• Losartan (oral): 50 mg/day

• Regular sodium diet: > 100 mmol/day

• Duration: 2 weeks

Washout period

• 4 weeks washout between treatments (switch from low to regular and regular to low sodium diet)

Co‐interventions

• Losartan (ARB) for the entire 8 weeks 

Follow up details

• No follow‐up past the end of the treatment period (12 weeks in total)

Outcomes

Reported outcomes (at 2 and 4 weeks) / outcomes relevant to this review*

• 24‐hour ambulatory BP: SBP* and DBP*

• MAP*

• eGFR*

• ERPF*

• HbA1c* (%)

• Body weight* (kg)

• ACR on 24‐hour urine collection

• Plasma glucose

• Electrolytes

• PRA

• Angiotensin II

• Aldosterone

• Urinary electrolytes

• Urea

• SCr

• CrCl

Notes

Additional information

• Additional data requested from authors: yes; no response to our request

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "patients were randomly assigned in a double‐blind fashion to receive losartan ... or placebo"

Comment: insufficient information provided on how the randomisation methods were undertaken

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding the concealment of allocation to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "patients were randomly assigned in a double‐blind fashion to receive losartan ... or placebo"

Comment: insufficient information provided on how the blinding of either the participants or the study personnel was undertaken

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: no information provided regarding any blinding of the outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition rates are not reported. Unclear from the report what the final attrition rate is. Unclear whether an ITT analysis was performed

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori published protocol or trial registration details

• Trial registration: not reported

• A priori published protocol: not reported

Funding source

High risk

Quote: "this work was supported by a Merck medical school grant and an Apex Diabetes Australia Research grant. During the period of this work, CAH was supported by grants from the Austin Hospital Medical Research Foundation and the National Health and Medical Research Council"

Comment: pharmaceutical industry funding

Conflicts of interest

High risk

Quote: "MEC is on an advisory panel for Merck on diabetic nephropathy, he has received honoraria for speaking engagements for Merck, and his laboratory has received funding from Merck for studies on a new drug to treat retinopathy"

Comment: conflicted interests

Other bias

Low risk

Washout period for cross‐over studies: 4 weeks washout between treatment arms

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Parallel RCT, with cross‐over dietary salt

Duration of study

• 3 months

Duration of treatment

• 3 months

Duration of follow‐up

• At end of 3 months of treatment

Participants

Study characteristics

• Setting: multicentre (Austin and Repatriation Medical Centre diabetes clinic, and surrounding district)

• Country: Australia

• Inclusion criteria: 30 to 75 years; type 2 diabetes; hypertension: seated BP > 130/85 mm Hg; albuminuria (AER 10 to 200 µg/min); HbA1c < 11.0%; habitual 24‐hour UNa excretion > 100 mmol/24 hours

• Exclusion criteria: serious systemic illness; history of substance abuse; seated BP > 165/100 mm Hg; serum potassium > 5.5 mmol/L; SCr > 200 µmol/L; long term use of NSAIDs; recurrent UTIs (> 3/year); BMI > 35 kg/m²; cardiac failure; nitrate therapy; intolerance of ACEi

Baseline characteristics

• Number: 20

• Mean age ± SEM (years): losartan group (60.6 ± 3.7); control group (63.1 ± 3.9)

• Sex (M/F): losartan group (10/0); control group (9/1)

• Mean BMI ± SEM (kg/m²): losartan group (30.4 ± 2.1); control group (28.1 ± 1.6)

• Mean MAP ± SEM (mm Hg): losartan group (114 ± 3); control group (111 ± 3)

• Hypertension: hypertensive > 130/85 mm Hg

• Mean HbA1c ± SEM (%): 7.4 ± 0.4 losartan group (7.9 ± 0.5); control group (7.4 ± 0.4)

• Diabetes

  • Type 2 DM

  • Duration of diabetes: median 4.0 years (range 1 ‐ 10)

• Co‐morbidities: none

• CKD definition: AER: 10 to 200 µg/min

• Mean AER ± SEM (µg/min): losartan group (26.6 ± 1.4); control group (32.6 ± 1.3)

• Mean SCr ± SEM (mmol/L): losartan group (97 ± 6.5); control group (92 ± 2.7)

Interventions

Pre‐randomisation/run‐in period

• Antihypertensives, including ACEi, ARBs and diuretics, stopped for at least 2 weeks before commencing study

Intervention group

• Losartan placebo

• Low sodium diet: 50 to 70 mmol/day

• Duration: 2 weeks

Control group

• Losartan placebo

• Regular sodium diet: > 100 mmol/day

• Duration: 2 weeks

Washout period

• 4 weeks washout between treatments

Co‐interventions

• Placebo oral tablet for the entire 8 weeks

Follow up details

• No follow‐up past the end of the treatment period (12 weeks in total)

Outcomes

Reported outcomes (at 2 and 4 weeks) / outcomes relevant to this review*

• 24‐hour ambulatory BP: SBP* and DBP*

• MAP*

• eGFR*

• ERPF*

• HbA1c* (%)

• Body weight* (kg)

• ACR on 24‐hour urine collection

• Plasma glucose

• Electrolytes

• PRA

• Angiotensin II

• Aldosterone

• Urinary electrolytes

• Urea

• SCr*

• CrCl*

Notes

Additional information

• Additional data requested from authors: yes; no response to request

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "patients were randomly assigned in a double‐blind fashion to receive losartan ... or placebo"

Comment: insufficient information provided on how the randomisation methods were undertaken

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding the concealment of allocation to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "patients were randomly assigned in a double‐blind fashion to receive losartan ... or placebo"

Comment: insufficient information provided on how the blinding of either the participants or the study personnel was undertaken

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: no information provided regarding any blinding of the outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition rates are not reported. Unclear from the report what the final attrition rate is. Unclear whether an ITT analysis was performed

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori published protocol or trial registration details

• Trial registration: not reported

• A priori published protocol: not reported

Funding source

High risk

Quote: "This work was supported by a Merck medical school grant and an Apex Diabetes Australia Research grant. During the period of this work, CAH was supported by grants from the Austin Hospital Medical Research Foundation and the National Health and Medical Research Council"

Comment: pharmaceutical industry funding

Conflicts of interest

High risk

Quote: "MEC is on an advisory panel for Merck on diabetic nephropathy, he has received honoraria for speaking engagements for Merck, and his laboratory has received funding from Merck for studies on a new drug to treat retinopathy"

Comment: conflicted interests

Other bias

Low risk

Washout period for cross‐over trials: 4 weeks washout between treatment arms.

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• 4 weeks

Duration of treatment

• 1 week

Duration of follow‐up

• No follow‐up past the end of the treatment period (approximately 4 weeks in total)

Participants

Study characteristics

• Setting: single centre (hospital inpatient centre)

• Location: Japan

• Inclusion criteria: type 2 DM with simple retinopathy (divided into microalbuminuria and normoalbuminuria) and normal BP

• Exclusion criteria: history of non‐diabetic kidney disease; history of heart disease; history of UTI; SCr ≥ 97.4 µmol/L; needing antihypertensive drugs; found to have hypertension at study entry (4)

Baseline characteristics (microalbuminuria group)

• Microalbuminuria: 28.8 to 288 mg/24 hours

• Number (randomised/analysed): 12/8

• Mean age ± SD: 59 ± 10 years

• Sex (M/F): 7/5

• BMI: 24.4 ± 4.4 kg/m²

• Mean BP ± SD (mm Hg): SBP (136 ± 9); DBP (82 ± 6)

• Mean HbA1c ± SD (%): 8. 1 ± 1.8

• Diabetes

  • Type 2 DM

  • Simple diabetic retinopathy: 100%

• Co‐morbidities: not reported

• CKD definition: microalbuminuria 20 to 200 µg/min

• Mean SCr ± SD: 60.4 ± 13.5 mmol/L

Interventions

Pre‐randomisation/run‐in

• Plasma glucose levels were brought under control during ≥ 2 weeks of hospitalisation

Intervention group

• Microalbuminuria

• Low sodium diet: ≈ 80 mmol/day

• Duration: 7 days

Control group

• Microalbuminuria

• Regular sodium diet: ≈ 200 mmol/day

• Duration: 7 days

Washout

• No washout; immediately switched to other group, with no time intervening

Co‐interventions or additional treatments

• None

Follow up details

• No follow‐up past the end of the treatment period (approximately 4 weeks in total, including run‐in)

Outcomes

Reported outcomes (at 7 days) / outcomes relevant to this review*

• SBP*, DBP*

• CrCl*

• UAE*

• BMI*

• Fasting plasma glucose

• HbA1c* (%)

• SCr*

• ERPF*

• PRA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "the patients were put on a diet ... in random order"

Comment: insufficient information provided on how randomisation methods were undertaken

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding concealment of the allocation to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: unblinded study

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: unblinded study

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition rates are not reported. Unclear from the report what the final attrition rate is. Unclear whether an ITT analysis was performed

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori published protocol or trial registration details

• Trial registration: not reported

• A priori published protocol: provided but not published

Funding source

Low risk

Quote: "This study was supported by the Hohansha Foundation (Osaka, Japan) and a grant from the Osaka City General Hospital for medical research"

Comment: no industry funding

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

High risk

Washout period for cross‐over trials: no washout period applied, participants immediately switched to the other group, "with no time intervening"

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• 4 weeks

Duration of treatment

• 1 week

Duration of follow‐up

• No follow‐up past the end of the treatment period (approximately 4 weeks in total)

Participants

Study characteristics

• Setting: single centre (hospital inpatient centre)

• Location: Japan

• Inclusion criteria: type 2 DM with simple retinopathy (divided into microalbuminuria and normoalbuminuria) and normal BP

• Exclusion criteria: history of non‐diabetic kidney disease; history of heart disease; history of UTI; SCr ≥ 97.4 µmol/L; needing antihypertensive drugs; found to have hypertension at study entry (3)

Baseline characteristics (normoalbuminuria group)

• Normoalbuminuria: < 28.8 mg/24 hour

• Number (randomised/analysed): 11/8

• Mean age ± SD: 61 ± 10 years

• Sex (M/F): 5/6

• BMI: 22.0 ± 2.1 kg/m²

• Mean BP ± SD (mm Hg): SBP (132 ± 11); DBP (73 ± 7)

• Mean HbA1c ± SD (%): 8.6 ± 1.1

• Diabetes

  • Type 2 DM

  • Simple diabetic retinopathy: 100%

• Co‐morbidities: not reported

• CKD definition: UAE < 20 µg/min

• Mean SCr ± SD: 53.8 ± 13.9 mmol/L

Interventions

Pre‐randomisation/run‐in

• Plasma glucose levels were brought under control during 2 or more weeks of hospitalisation

Intervention group

• Normoalbuminuria

• Low sodium diet: ≈ 80mmol/day

• Duration: 7 days

Control group

• Normoalbuminuria

• Regular sodium diet: ≈ 200 mmol/day

• Duration: 7 days

Washout

• No washout; immediately switched to other group, with no time intervening

Co‐interventions or additional treatments

• None

Follow up details

• No follow‐up past the end of the treatment period (approximately 4 weeks in total, including run‐in)

Outcomes

Reported outcomes (at 7 days) / outcomes relevant to this review*

• SBP*, DBP*

• CrCl*

• UAE*

• BMI*

• Fasting plasma glucose

• HbA1c* (%)

• SCr*

• ERPF*

• PRA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "the patients were put on a diet ... in random order"

Comment: insufficient information provided about how the randomisation methods were undertaken

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding concealment of the allocation to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: unblinded study

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: unblinded study

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition rates are not reported. Unclear from the report what the final attrition rate is. Unclear whether an ITT analysis was performed

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori published protocol or trial registration details

• Trial registration: not reported

• A priori published protocol: provided but not published

Funding source

Low risk

Quote: "this study was supported by the Hohansha Foundation (Osaka, Japan) and a grant from the Osaka City General Hospital for medical research"

Comment: no industry funding

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

High risk

Washout period for cross‐over trials: no washout period applied, participants immediately switched to the other group, "with no time intervening"

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• October 2009 to December 2012

Duration of treatment periods

• 6 weeks

Duration of follow‐up

• No follow‐up past the end of the total treatment period (30 weeks in total, including a 6‐week run‐in)

Participants

Study characteristics

• Setting: multicentre (3 sites; University Medical Center Groningen, ZGT Hospital Almelo, and Medical Center Leeuwarden)

• Country: The Netherlands

• Inclusion criteria: ≥ 18 years; type 2 DM; DKD; albuminuria present at screening and after run in period > 30 mg/day; urinary albumin concentration > 20 mg/L; or urinary ACR > 2.5 mg/mmol for men and > 3.5 mg/mmol for women; CrCl ≥ 30 mL/min with < 6 mL/min decline in previous year

• Exclusion criteria: BP ≥ 180/110 mm Hg; overt nephrotic syndrome at baseline; second primary kidney disease in addition to DKD; type 1 diabetes; renovascular hypertension; cardiovascular or cerebrovascular events within 3 months before study; serum potassium ≥ 6.0 mmol/L; transplantation or immunosuppressive treatment; contraindication for the use of lisinopril or hydrochlorothiazide; pregnancy or lactation; poor compliance with medication

Baseline characteristics (both groups)

• Number: 45

• Mean age ± SD: 65 ± 9 years

• Sex (M/F): 38/7

• Ethnicity (white): 100%

• Mean BMI ± SD: 32 ± 5 kg/m²

• BP (SBP/DBP): < 180/110 mm Hg

• Mean HbA1c ± SD (%): 7.1 ± 0.9

• Diabetes: type 1

• Co‐morbidities: macrovascular disease

• CKD definition: CrCl ≥ 30 mL/min; with < 6 mL/min decline in previous year

• CKD diagnosis: stages 2 to 5

• Albuminuria (mg/day), geometric mean (95% CI): 711 (485 to 1043)

• Mean CrCl ± SD: 101 ± 47 mL/min

• Mean eGFR ± SD: 65 ± 25 mL/min/1.73 m²

Interventions

Pre‐randomisation/run‐in period

• Patients titrated to maximum dose of ACEi (lisinopril 40 mg/day)

• All other RAS blockers and diuretics discontinued

• Duration: 6 weeks

Intervention group

• Hydrochlorothiazide: maximum dose 50 mg/day

• Dietary change: target 50 mmol dietary sodium/day

• Duration: 6 weeks

Control group

• Hydrochlorothiazide: maximum dose 50 mg/day

• Dietary change: target 200 mmol dietary sodium/day

• Duration: 6 weeks

Washout period

• Placebo phase of 6 weeks in between dietary change periods considered to be sufficient washout time

Co‐interventions or additional treatments

• Hydrochlorothiazide oral tablet, maximum dose 50 mg/day, for 6 weeks

Follow up details

• No follow‐up past the end of the treatment period (30 weeks in total)

Outcomes

Reported outcomes (at end of each 6‐week period) / outcomes relevant to this review*

• 24‐hour UAE*

• SBP*, DBP*

• CrCl*

• eGFR*

• SCr*

• Body weight*

• Serum sodium

• Serum potassium

• Serum urea

• Serum albumin

• Serum glucose

• Total cholesterol

• Urinary excretion of protein, urea and potassium

• Urinary ACR

• Urinary PCR

Notes

Additional information

• Compliance with sodium restriction assessed by 24‐hour UAE at the middle and end of each 6‐week period

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “an independent pharmacist used a computer program to randomise patients in blocks of two. No stratification was needed as the trial has a crossover design. An independent pharmacist randomised treatment sequences. Patients were sequentially enrolled according to moment of recruitment"

Allocation concealment (selection bias)

Low risk

Quote: "the randomisation code remained a secret during the entire trial"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

DIETARY COMPONENT

Comment: the dietary component (regular sodium or sodium restriction) was not possible to blind. Open‐label

Quote: “the drug intervention was double blind, whereas the dietary intervention was open label”

DRUG COMPONENT

Comment: the drug component (hydrochlorothiazide or placebo) was blinded within each cross‐over phase

Quote: “all patients, investigators, and health‐care providers were masked, apart from the pharmacist who did the randomisation"

Quote: "on completion of the trial, the principal investigator (AJK) provided the pharmacist and the medical ethics committee with a written statement that the trial was completed, after which masking ended”

Blinding of outcome assessment (detection bias)
All outcomes

High risk

DIETARY COMPONENT

Comment: the dietary component (regular sodium or sodium restriction) was not possible to blind. Open‐label

Quote: “the drug intervention was double blind, whereas the dietary intervention was open label”

DRUG COMPONENT

Comment: the drug component (hydrochlorothiazide or placebo) was blinded within each cross‐over phase

Quote: “all patients, investigators, and health‐care providers were masked, apart from the pharmacist who did the randomisation"

Quote: "on completion of the trial, the principal investigator (AJK) provided the pharmacist and the medical ethics committee with a written statement that the trial was completed, after which masking ended”

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: all participants were accounted for from start to end of the trial. Only 2 participants (attrition rate = 4%) withdrew. ITT analysis was performed for the original participant sample, including those 2 withdrawals (ITT: N = 45)

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori published protocol or trial registration details

• Trial registration: not reported

• A priori published protocol: provided online as supplementary materials but not published prior to trial

Comment: baseline BP and bodyweight are not recorded in Table 1. However, the difference is mentioned (unclear if the baseline data is before or after run‐in period)

Funding source

Low risk

Quote: "the sponsor of this trial is the University Medical Center Groningen, Groningen, The Netherlands. The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. No funding was received for this trial"

Conflicts of interest

Low risk

Quote: "we declared that we have no competing interests"

Other bias

High risk

Washout period for cross‐over trials: no washout applied, possible carryover effects

Quote: "to prevent systematic errors resulting from the crossover design, the different treatment periods were done in random order. The trial protocol (appendix) did not include a washout period between treatment periods because of the randomisation procedure and the short half‐life of both interventions"

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• October 2009 to December 2012

Duration of treatment periods

• 6 weeks

Duration of follow‐up

• No follow‐up past the end of the total treatment period (30 weeks in total, including a 6‐week run‐in)

Participants

Study characteristics

• Setting: multicentre (3 sites; University Medical Center Groningen, ZGT Hospital Almelo, and Medical Center Leeuwarden)

• Country: The Netherlands

• Inclusion criteria: ≥ 18 years; type 2 DM; DKD; albuminuria present at screening and after run in period > 30 mg/day; urinary albumin concentration > 20 mg/L; or urinary ACR > 2.5 mg/mmol for men and > 3.5 mg/mmol for women); CrCl ≥ 30 mL/min with < 6 mL/min decline in previous year

• Exclusion criteria: BP ≥ 180/110 mm Hg; overt nephrotic syndrome at baseline; second primary kidney disease in addition to DKD; type 1 diabetes; renovascular hypertension; cardiovascular or cerebrovascular events within 3 months before study; serum potassium ≥ 6.0 mmol/L; transplantation or immunosuppressive treatment; contraindication for the use of lisinopril or hydrochlorothiazide; pregnancy or lactation; poor compliance with medication

Baseline characteristics (both groups)

• Number: 45

• Mean age ± SD: 65 ± 9 years

• Sex (M/F): 38/7

• Ethnicity (white): 100%

• Mean BMI ± SD: 32 ± 5 kg/m²

• BP (SBP/DBP): < 180/110 mm Hg

• Mean HbA1c ± SD (%): 7.1 ± 0.9

• Diabetes: type 1

• Co‐morbidities: macrovascular disease

• CKD definition: CrCl ≥ 30 mL/min; with < 6 mL/min decline in previous year

• CKD diagnosis: stages 2 to 5

• Albuminuria (mg/day), geometric mean (95% CI): 711 (485 to 1043)

• Mean CrCl ± SD: 101 ± 47 mL/min

• Mean eGFR ± SD: 65 ± 25 mL/min/1.73 m²

Interventions

Pre‐randomisation/run‐in period

• Patients titrated to maximum dose of ACEi (lisinopril 40 mg/day)

• All other RAS blockers and diuretics discontinued

• Duration: 6 weeks

Intervention group

• Placebo

• Dietary change: target 50 mmol dietary sodium/day

• Duration: 6 weeks

Control group

• Placebo

• Dietary change: target 200 mmol dietary sodium/day

• Duration: 6 weeks

Washout period

• Placebo phase of 6 weeks in between dietary change periods considered to be sufficient washout time

Co‐interventions or additional treatments

• Placebo oral tablet, for 6 weeks

Follow up details

• No follow‐up past the end of the treatment period (30 weeks in total)

Outcomes

Reported outcomes (at end of each 6 week period) / outcomes relevant to this review*

• 24‐hour UAE*

• SBP*, DBP*

• CrCl*

• eGFR*

• SCr*

• Body weight*

• Serum sodium

• Serum potassium

• Serum urea

• Serum albumin

• Serum glucose

• Total cholesterol

• Urinary excretion of protein, urea and potassium

• Urinary ACR

• Urinary PCR

Notes

Additional information

• Compliance with sodium restriction assessed by 24‐hour UAE at the middle and end of each 6‐week period

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “an independent pharmacist used a computer program to randomise patients in blocks of two. No stratification was needed as the trial has a crossover design. An independent pharmacist randomised treatment sequences. Patients were sequentially enrolled according to moment of recruitment"

Allocation concealment (selection bias)

Low risk

Quote: "the randomisation code remained a secret during the entire trial"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

DIETARY COMPONENT

Comment: the dietary component (regular sodium or sodium restriction) was not possible to blind. Open‐label

Quote: “the drug intervention was double blind, whereas the dietary intervention was open label”

DRUG COMPONENT

Comment: the drug component (hydrochlorothiazide or placebo) was blinded within each cross‐over phase

Quote: “all patients, investigators, and health‐care providers were masked, apart from the pharmacist who did the randomisation"

Quote: "on completion of the trial, the principal investigator (AJK) provided the pharmacist and the medical ethics committee with a written statement that the trial was completed, after which masking ended”

Blinding of outcome assessment (detection bias)
All outcomes

High risk

DIETARY COMPONENT

Comment: the dietary component (regular sodium or sodium restriction) was not possible to blind. Open‐label

Quote: “the drug intervention was double blind, whereas the dietary intervention was open label”

DRUG COMPONENT

Comment: the drug component (hydrochlorothiazide or placebo) was blinded within each cross‐over phase

Quote: “all patients, investigators, and health‐care providers were masked, apart from the pharmacist who did the randomisation"

Quote: "on completion of the trial, the principal investigator (AJK) provided the pharmacist and the medical ethics committee with a written statement that the trial was completed, after which masking ended”

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: all participants were accounted for from start to end of the trial. Only 2 participants (attrition rate = 4%) withdrew. ITT analysis was performed for the original participant sample, including those 2 withdrawals (ITT: N = 45)

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori published protocol or trial registration details

• Trial registration: not reported

• A priori published protocol: provided online as supplementary materials but not published prior to trial

Comment: baseline BP and body weight are not recorded in Table 1. However, the difference is mentioned (unclear if the baseline data is before or after run‐in period)

Funding source

Low risk

Quote: "the sponsor of this trial is the University Medical Center Groningen, Groningen, The Netherlands. The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. No funding was received for this trial"

Conflicts of interest

Low risk

Quote: "we declared that we have no competing interests"

Other bias

High risk

Washout period for cross‐over trials: no washout applied, possible carryover effects

Quote: "to prevent systematic errors resulting from the crossover design, the different treatment periods were done in random order. The trial protocol (appendix) did not include a washout period between treatment periods because of the randomisation procedure and the short half‐life of both interventions"

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• Not reported

Duration of treatment

• 7 days

Duration of follow‐up

• No follow‐up past the end of the treatment period (2 weeks in total)

Participants

Study characteristics

• Setting: single centre (diabetes outpatient clinic)

• Country: UK

• Inclusion criteria: 10 to 55 years; IDDM; normal BP (< 140/90 mm Hg); normoalbuminuria (< 20 µg/min 4 to 6 months preceding study); < 31 years old at diagnosis of diabetes; body weight within 20% of ideal range (scale not mentioned); regular isocaloric diet (25% protein, 25% fat, 50% carbohydrate)

• Exclusion criteria: no other medications other than insulin; evidence of endocrinologic, hepatic, cardiac, or kidney disease; oral contraceptives or oestrogens; hypertension

Baseline characteristics

• Number: 10

• Mean age ± SD (years): 30 ± 3 years

• Sex (M/F): 7/3

• Diabetes: IDDM

• Co‐morbidities: none

• CKD definition: CKD not inclusion criteria

Interventions

Pre‐randomisation/run‐in period

• None reported

Intervention group

• Patients' own regular salt diet: ≈ 100 mmol sodium/day

• Duration: 7 days

Control group

• Regular salt diet: ≈ 100 mmol sodium/day

• Sodium chloride 0.5 g oral capsules (32 taken/day to elevate salt intake to ≈ 300 mmol/day

• Duration: 7 days

Washout period

• 7 days interval between diets

Co‐interventions

• Potassium intake fixed in both groups to approximately 79 to 80 mmol/day

• No participant received ACEi or ARB

Follow up details

• No follow‐up past the end of the treatment period (2 weeks in total)

Outcomes

Reported outcomes / outcomes relevant to this review*

• Compliance with diets: urinary electrolyte excretion (days 5, 6, and 7)

• BP* (days 5, 6, and 7)

• Body weight* (days 5, 6, and 7)

• Mean 24‐hour urinary sodium excretion (daily)

• Plasma sodium

• Urinary potassium

• Sodium p‐amino‐hippurate (every 24 hours)

• Polyfructosane

• HCT

• Blood glucose

• HbA1c* (%)

• Electrolytes

• eGFR*

• Increased RPF

• MAP*

• PRA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "the order of sodium intake was randomized ... between the two diets"

Comment: insufficient information provided about how the randomisation methods were undertaken

Allocation concealment (selection bias)

High risk

Comment: open‐label. All participants knew they were starting on the 'regular salt' first before changing to 'higher salt' capsules week. No placebo appears to have been provided for the first week

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: open‐label. All participants and personnel knew which week they had to change tablets from low salt to high salt

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: open‐label. No information provided regarding the blinding of the outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition are not reported. Unclear what final attrition is and no ITT analysis was performed

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori published protocol or trial registration details

• Trial registration: not reported

• A priori published protocol: not reported

Funding source

Unclear risk

Comment: funding sources are not clearly stated

Conflicts of interest

Low risk

Quote: "JLdF and RF were recipients of scholarships from Conselho National de Pesquisa, Brazil. SdC was a visiting research assistant from Ospedale Casa Sollievo della Sofferenza, Italy"

Other bias

Low risk

Washout period for cross‐over trials: 7 days interval between diets

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• Not reported

Duration of treatment

• 7 days

Duration of follow‐up

• No follow‐up past the end of the treatment period (2 weeks in total)

Participants

Study characteristics

• Setting: single centre (University Hospital Department)

• Country: The Netherlands

• Inclusion criteria: type 1 DM (age of onset < 35 years); HbA1c < 8.0% (for adequate metabolic control, average of 61 ± 18 units insulin during days before trial start); normotensive (< 140/85 mm Hg); normoalbuminuria (< 30 mg/24 hours)

• Exclusion criteria: not reported

Baseline characteristics

• Number: 24

• Mean age ± SD: 28.2 ± 6 years

• Sex (M/F): 15/9

• Mean BMI ± SD (kg/m²): intervention group (23.5 ± 2.2); control group (23.7 ± 2.2_

• Hypertension: normotensive

• Diabetes:

  • Type 1 DM, ketosis prone (mean age of onset 15.8 ± 6.5 years)

• Co‐morbidities: none reported

• CKD definition: CKD not inclusion criteria

Interventions

Pre‐randomisation/run‐in period

• None reported

Intervention group

• Dietary changes: 50 mmol sodium/day, via dietary changes, as advised by a dietician

• Duration: 7 days

Intervention group

• Dietary changes: 200 mmol sodium/day, via dietary changes, as advised by a dietician

• Duration: 7 days

Washout period

• 10 to 17 days

Co‐interventions or additional treatments

• No participants received ACEi or ARB

Follow up details

• No follow‐up past the end of the treatment period (2 weeks in total)

Outcomes

Reported outcomes (various time points) / outcomes relevant to this review*

• eGFR*

• ERPF*

• Serum electrolytes

• SCr*

• Serum liver enzymes

• Blood count

• Plasma glucose concentration

• HbA1c*

• SBP*, DBP*

• Albuminuria

• Urinary ACR*

• CrCl*

• BMI*

• Body weight*

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "the sequence of the diet was randomized by drawing an allocation number from closed envelopes"

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding concealment of the allocation to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: open‐label. All participants and personnel knew which week they had to change their diet to low salt and then one week on high salt

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: open‐label. No information provided regarding the blinding of the outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition are not reported. Unclear what final attrition is. ITT analysis was not performed

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori published protocol or trial registration details

• Trial registration: not reported

• A priori published protocol: not reported

Funding source

Low risk

Quote: "this work was supported by grants from the Dutch Kidney Foundation and Diabetes Fonds Nederland (Diabetes Research fund)"

Comment: no industry funding

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

Low risk

Washout period for cross‐over trials: "Crossover to treatment groups was separated by 10 ‐ 17 days to rule out any carryover effects"

Comment: no other sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• Not reported

Duration of treatment

• 7 days

Duration of follow‐up

• No follow‐up past the end of the treatment period (2 weeks in total)

Participants

Study characteristics

• Setting: single centre (Clinical Investigation Unit of Toronto Hospital)

• Country: Canada

• Inclusion criteria: insulin‐dependent diabetic males

• Exclusion criteria: orthostatic hypertension; retinopathy; increased creatinine or evidence of microalbuminuria; signs of autonomic neuropathy

Baseline characteristics

• Number: 9

• Mean age ± SE: 25.6 ± 1.5 years

• Sex (M/F): 9/0

• Mean body weight ± SEM (kg): intervention group (80 ± 4); control group (81 ± 4)

• Body fat: non‐obese

• Smoker: non‐smokers

• Mean MAP ± SE (mm Hg): intervention group (78 ± 2); control group (79 ± 1)

• Hypertension: normotensive

• Mean HbA1c ± SE (%): 8.2 ± 1.6

• Diabetes

  • IDDM, diagnosed within 5 years of the study

  • Mean duration of diabetes: 3.5 ± 0.5 years (range 2 to 5 years)

• Co‐morbidities: none

• CKD definition: CKD not a criteria

• Albumin (microalbuminuria): 8.5 ± 1.3 µg/min

• Mean CrCl ± SE: 120 ± 12 mL/min

• Mean 24‐hour UNa excretion ± SE (mmol/day): intervention group (15 ± 2); control group (247 ± 22)

• Mean 24‐hour urinary potassium excretion SE (mmol/day): intervention group (77 ± 15); control group (68 ± 7)

Interventions

Pre‐randomisation/run‐in period

• None reported

Intervention group

• Dietary changes: restriction to 10 to 20 mmol sodium/day, as advised by a dietician

• Duration: 7 days

Control group

• Dietary changes: increase to 200 mmol sodium/day, as advised by a dietician

• Duration: 7 days

Washout

• Not reported, appears no washout period was applied

Co‐interventions or additional treatments

• No participants received ACEi or ARB

Follow up details

• No follow‐up past the end of the treatment period (2 weeks in total)

Outcomes

Reported outcomes (7 days) / outcomes relevant to this review*

• HbA1c*

• 24‐hour UNa excretion*

• 24‐hour urine potassium excretion

• Central venous pressure

• CrCl*

• Microalbuminuria

• MAP*

• Heart rate (bpm)

• PRA

• Plasma norepinephrine

• Forearm vascular response

• Aldosterone

• HCT

Notes

Additional information

• Additional non‐diabetic control group not included in this review

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Quote: "diets were randomly determined by the research dietician"

Comment: investigator randomisation is not true randomisation, and no further details are provided about the methods used by the dietician to randomise participants

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding concealment of the allocation to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: open‐label. All participants knew which week they had to change their diet to low salt, and then one week on high salt

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "investigators were blinded to the diets"

Comment: no further details are provided about how the investigators were kept blind. It is also unclear whether the 'investigators' are the study personnel or the outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition are not reported. Unclear what final attrition is. ITT analysis was not performed

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori published protocol or trial registration details

• Trial registration: not reported

• A priori published protocol: not reported

Funding source

Low risk

Quote: "This work was supported by Grant 92‐27 from the physicians of Ontario through the Physicians Services Inc. Foundation. JA Miller is the recipient of a Research Scholarship from the Kidney Foundation of Canada"

Comment: no industry funding

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

High risk

Washout period for cross‐over trials: not mentioned, appears no washout period was applied. Possible carryover effects

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• Not reported

Duration of treatment

• 7 days

Duration of follow‐up

• No follow‐up past the end of the treatment period (2 weeks in total)

Participants

Study characteristics

• Setting: single centre (Clinical Investigation Unit of Toronto Hospital)

• Country: Canada

• Inclusion criteria: early IDDM; males

• Exclusion criteria: orthostatic hypertension; retinopathy; decreased creatinine or evidence of microalbuminuria; signs of autonomic neuropathy

Baseline characteristics

• Number: 12

• Age ± SE: 23 ± 2 years

• Sex (M/F): 12/0

• Mean body weight ± SE (kg): intervention group (79 ± 3); control group (80 ± 2)

• Mean MAP ± SE (mm Hg): intervention group (79 ± 2); control group (80 ± 1)

• Hypertension: normotensive (< 140/90 mm Hg)

• HbA1c: < 10%

• Diabetes

  • Early IDDM

  • Duration of diabetes: 2.8 ± 0.4 years

• Co‐morbidities: none

• CKD definition: CKD not a criteria

• Mean Na⁺ excretion ± SE (mmol/day): intervention group (19 ± 2); control group (201 ± 10)

• Mean UNa excretion ± SE (µmol/min): intervention group (124 ± 33); control group (254 ± 34)

Interventions

Pre‐randomisation/run‐in period

• None reported

Intervention group

• Dietary changes: 20 mmol sodium/day, as advised by a dietician

• Duration: 7 days

Intervention group

• Dietary changes: 200 mmol sodium/day, as advised by a dietician

• Duration: 7 days

Washout

• 2 weeks of normal diet between each treatment period

Co‐interventions or additional treatments

• No participants received ACEi or ARBs

Follow up details

• No follow‐up past the end of the treatment period (2 weeks in total)

Outcomes

Reported outcomes (at 7 days) / outcomes relevant to this review*

• Body weight*

• 24‐hour urine sodium

• 24‐hour UNa excretion*

• 24‐hour urine potassium excretion

• 24‐hour urea excretion

• MAP* (mm Hg)

• Heart rate (bpm)

• PRA

• Plasma norepinephrine

• eGFR*

• Aldosterone

• HCT

Notes

Additional information

• Additional non‐diabetic control group not included in this review

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Quote: "the sequence was randomly determined"

Comment: appears to be investigator randomisation which is no true randomisation, and no further details are provided about the methods used by the investigators to properly randomise

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding concealment of the allocation to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: open‐label. All participants knew which week they had to change their diet to low salt, and then one week on high salt

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: open‐label. No information provided regarding the blinding of the outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition are not reported. Unclear what final attrition is. ITT analysis was not performed

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori published protocol or trial registration details

• Trial registration: not reported

• A priori published protocol: not reported

Funding source

Low risk

Quote: "this work was supported by Grant 92‐27 from the physicians of Ontario through the Physicians Services Inc. Foundation. JA Miller is the recipient of a Research Scholarship from the Kidney Foundation of Canada"

Comment: no industry funding

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

Low risk

Washout period for cross‐over trials: 2 weeks of normal diet between each treatment period

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Parallel RCT

Duration of study

• Not reported

Duration of treatment

• 1 month

Duration of follow‐up

• No follow‐up past the end of the treatment period (4 weeks in total)

Participants

Study characteristics

• Setting: multicentre (3 sites)

• Country: Germany

• Inclusion criteria: 18 to 60 years; IDDM on intensified insulin therapy; diabetes duration > 5 years; increased proteinuria (> 60 mg/24 hours); stable renopathy

• Exclusion criteria: UTI; other drugs or oral contraception (except insulin); pregnancy; untreated SBP ≥ 140 < 160 mm Hg and/or DBP ≥ 85 < 100 mm Hg

Baseline characteristics

• Number: intervention group (8); control group (8)

• Mean age ± SD (years): intervention group (35 ± 11); control group (27 ± 9)

• Sex (M/F): intervention group (5/3); control group (7/1)

• Mean BMI ± SD (kg/m²): intervention group (27 ± 9); control group (25.2 ± 3.1)

• Hypertension: 'hypertensive'

• Mean HbA1c ± SD (%): intervention group (8 ± 1); control group (7.5 ± 0.7)

• Diabetes

  • IDDM

  • Mean duration of diabetes ± SD (years): intervention group (23 ± 5); control group (22 ± 10)

• Co‐morbidities: none reported

• CKD definition: not inclusion criteria for this trial

Interventions

Pre‐randomisation/run‐in period

• 4 weeks usual diet

• 2 weeks of dietary training to reduce sodium intake to about 90 mmol/day

Intervention group

• Placebo (oral): lactose 1 g, 6 times/day

• Diet changes: keep at a maximum 90 mmol/day

• Duration: 4 weeks

Control group

• Sodium supplement (oral): 100 mmol/day

• Diet changes: keep at a maximum 90 mmol/day

• Duration: 4 weeks

Co‐interventions or additional treatments

• None, other than keeping diet at a maximum 90 mmol/day

• No participants received ACEi or ARBs

Follow up details

• Not reported

Outcomes

Reported outcomes (at 4 weeks) / outcomes relevant to this review*

• Body weight*

• Energy intake (calories/kg/day)

• Dietary sodium intake (mmol/day)

• UNa excretion (mmol/day)*

• Urinary potassium excretion (mmol/day)

• Protein intake (g/kg)

• HbA1c*

• Insulin dosage (IU/kg/day)

• Serum cholesterol (mmol/L)

• HDL‐cholesterol (mmol/L)

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "eight patients were randomised to receive ..."

Comment: insufficient details provided about how the randomisation methods were carried out, and by whom

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding concealment of the allocation to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "all relevant laboratory results of the blinded study period, including excretion of urinary electrolytes, were kept blinded to patients and investigators until the last patient had finished the study"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "all relevant laboratory results of the blinded study period, including excretion of urinary electrolytes, were kept blinded to patients and investigators until the last patient had finished the study"

Comment: implies that the outcome assessors were probably also kept blind

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition are not reported. Methods state that 2 participants withdrew during the run‐in period (before receiving treatment), but the results and analysis includes 8 participants per group. Unclear what the final attrition is

ITT analysis was not performed

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori published protocol or trial registration details

• Trial registration: not reported

• A priori published protocol: not reported

Funding source

High risk

Quote: "the coated tablets were kindly provided by Cassella‐Riedel (Frankfurt, Germany)". "The study has been supported by Cassella Riedel, Frankfurt, Germany, and by the E Klockner Stiftung, Duisburg, Germany"

Comment: pharmaceutical industry funding

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

Low risk

Washout period for cross‐over trials: not applicable for parallel design

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• Not reported

Duration of treatment

• 6 days

Duration of follow‐up

• No follow‐up past the end of the treatment period (12 days in total)

Participants

Study characteristics

• Setting: single centre (diabetes hospital clinic)

• Location: Italy

• Inclusion criteria: IDDM; known history of persistent microalbuminuria (urinary AER: 20 to 200 µg/min); non‐obese (BMI < 27 kg/m²); untreated seated BP < 140/90 mm Hg (normotensive)

• Exclusion criteria: smoker; endocrine liver or non‐DKD; oral contraceptives

Baseline characteristics (microalbuminuria group)

• Number: 7

• Mean age ± SE: 38 ± 5 years

• Sex (M/F): 6/1

• Ethnicity (Caucasian): 100%

• Mean BMI SE: 23 ± 1 kg/m²

• Smoker: non‐smokers

• Mean BP ± SE (mm Hg): SBP (125 ± 6); DBP (78 ± 5)

• Hypertension: normotensive

• Mean HbA1c ± SE (%): 9.2 ± 0.6

• Diabetes

  • IDDM

  • Mean duration of diabetes ± SE: 24 ± 4 years

• Co‐morbidities: none

• CKD definition: none

• Urinary AER (µg/min): 77.3 (39 to 198)

Interventions

Pre‐randomisation/run‐in

• None reported

Intervention group

• Dietary changes: aimed at 25 mmol NaCl/day

• Duration: 6 days

Intervention group

• Dietary changes: aimed at 250 mmol NaCl/day, given as 500 mg NaCl tablets

• Duration: 6 days

Washout period

• None, consecutive diets

Co‐interventions or additional treatments

• Day 5 IV insulin to achieve plasma glucose concentrations 5 to 7 mmol/L

• No participants received ACEi or ARBs

Follow up details

• No follow‐up past the end of the treatment period (12 days in total)

Outcomes

Reported outcomes / outcomes relevant to this review*

• UNa excretion* (mmol/day)

• Urinary potassium (mmol/day)

• PRA (ng/mL/hour)

• Aldosterone (pmol/L)

• Atrial natriuretic peptide (pmol/L)

• eGFR*

• ERPF*

• FF

• AER (µg/min)

• BMI*

• Body weight*

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "All subjects underwent two … diets … in random order"
Comment: insufficient details provided about how the randomisation methods were carried out and by whom

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding concealment of the allocation to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: unblinded trial. All participants knew which week they had to change their diet to low salt, and then one week on high salt

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: no information provided regarding the blinding of outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition not reported. Unclear what final attrition is. Appears ITT analysis was performed, but totals numbers are unclear

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori trial registration or published protocol

• Trial registration: not reported

• Protocol registered/published: not reported

Funding source

Low risk

Quote: "This work was supported by Consiglio Nazionale delle Ricerche Grants 9603475CT04 and 9504361CT04"
Comment: no industry funding

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

High risk

Washout period for cross‐over trials: no washout applied, "All subjects underwent two consecutive 6‐day diets"

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• Not reported

Duration of treatment

• 6 days

Duration of follow‐up

• No follow‐up past the end of the treatment period (12 days in total)

Participants

Study characteristics

• Setting: single centre (diabetes hospital clinic)

• Location: Italy

• Inclusion criteria: IDDM; known history of persistent microalbuminuria (urinary AER: 20 to 200 µg/min); non‐obese (BMI < 27 kg/m²); untreated seated BP < 140/90 mm Hg (normotensive)

• Exclusion criteria: smoker; endocrine liver or non‐DKD; oral contraceptives

Baseline characteristics (normoalbuminuria group)

• Number: 9

• Mean age ± SE: 42 ± 4 years

• Sex (M/F): 6/3

• Ethnicity (Caucasian): 100%

• Mean BMI ± SE: 22 ± 1 kg/m²

• Smoker: non‐smokers

• Mean BP ± SE (mm Hg): SBP (120 ± 7); DBP (72 ± 2)

• Hypertension: normotensive

• Mean HbA1c ± SE (%): 8.9 ± 0.9

• Diabetes

  • IDDM

  • Mean duration of diabetes ± SE: 22 ± 4 years

• Co‐morbidities: none

• CKD definition: none

• Urinary AER (µg/min): 7.5 (2 to 12)

Interventions

Pre‐randomisation/run‐in

• None reported

Intervention group

• Dietary changes: aimed at 25 mmol NaCl/day

• Duration: 6 days

Intervention group

• Dietary changes: aimed at 250 mmol NaCl/day, given as 500 mg NaCl tablets

• Duration: 6 days

Washout period

• None, consecutive diets

Co‐interventions or additional treatments

• Day 5 IV insulin to achieve plasma glucose concentrations of 5 to 7 mmol/L

• No participants received ACEi or ARBs

Follow up details

• No follow‐up past the end of the treatment period (12 days in total)

Outcomes

Reported outcomes / outcomes relevant to this review*

• UNa excretion* (mmol/day)

• Urinary potassium (mmol/day)

• PRA (ng/mL/hour)

• Aldosterone (pmol/L)

• Atrial natriuretic peptide (pmol/L)

• eGFR*

• ERPF*

• FF

• AER (µg/min)

• BMI*

• Body weight*

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "all subjects underwent two … diets … in random order"
Comment: insufficient details provided about how the randomisation methods were carried out and by whom

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding concealment of the allocation to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: unblinded trial. All participants knew which week they had to change their diet to low salt, and then one week on high salt

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: no information provided regarding the blinding of outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition not reported. Unclear what final attrition is. Appears ITT analysis was performed, but totals numbers are unclear

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori trial registration or published protocol

• Trial registration: not reported

• Protocol registered/published: not reported

Funding source

Low risk

Quote: "this work was supported by Consiglio Nazionale delle Ricerche Grants 9603475CT04 and 9504361CT04"
Comment: no industry funding

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

High risk

Washout period for cross‐over trials: no washout applied, "All subjects underwent two consecutive 6‐day diets"

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• Not reported

Duration of treatment

• 7 days

Duration of follow‐up

• No follow‐up past the end of the treatment period (2 weeks in total)

Participants

Study characteristics

• Setting: multicentre (Diabetes Clinics at Padova University Hospital and Bergamo Hospital)

• Country: Italy

• Inclusion criteria: type 2 DM; BP < 140/90 mm Hg (in the absence of antihypertensives); normal or slightly increased UAE

• Exclusion criteria: not reported

Baseline characteristics (microalbuminuria group)

• Number: 20

• Mean age ± SEM: 57 ± 1 years

• Sex (M/F): 15/5

• Mean BMI SEM: 29 ± 2 kg/m²

• Mean BP ± SEM (mm Hg): SBP (130 ± 2); DBP (80 ± 2)

• Hypertension: normotensive

• Mean HbA1c ± SEM (%): 8.2 ± 0.6

• Diabetes

  • Type 2 DM

  • Mean duration of diabetes ± SEM: 9 ± 2 years

• Co‐morbidities: none reported

• CKD definition: none

• Urinary AER (µg/min): 91 (43 to 180)

Interventions

Pre‐randomisation/run‐in

• None reported

Intervention group

• Dietary changes: aimed at 25 mmol NaCl/day

• Duration: 7 days

Control group

• Dietary changes: aimed at 250 mmol NaCl/day, as 500 mg sodium chloride oral tablets

• Duration: 7 days

Washout period

• None, consecutive diets

Co‐interventions or additional treatments

• None

• No antihypertensive agents given so presumed not to receive ACEi or ARB

Follow up details

• None, only follow‐up at the end of treatment period (2 weeks in total)

Outcomes

Reported outcomes / outcomes relevant to this review*

• SBP*, DBP*, MAP*

• Insulin sensitivity

• Mean 24‐hour UNa excretion*

• Mean 24‐hour urinary potassium excretion

• Aldosterone

• PRA

• Body weight*

• Urinary AER* (µg/min)

• eGFR*

• ERPF*

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "all subjects underwent, in random order, two consecutive 7‐day diet periods"
Comment: insufficient details provided about how the randomisation methods were carried out and by whom

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding concealment of allocation to randomised treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: unblinded trial. All participants knew which week they had to change their diet to low salt, and then one week on high salt

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: no information provided regarding the blinding of outcome assessors. Unblinded trial so unlikely to be done

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition not reported. Unclear what final attrition is. Appears ITT analysis was performed, but unclear

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori trial registration or published protocol

• Trial registration: not reported

• Protocol registered/published: not reported

Funding source

Low risk

Quote: "this study was supported by a research grant from the University of Padua, Italy".
Comment: no industry funding

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

High risk

Washout period for cross‐over trial: no washout applied, "Two consecutive 7‐day diet periods"
Comment: no other sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• Not reported

Duration of treatment

• 7 days

Duration of follow‐up

• No follow‐up past the end of the treatment period (2 weeks in total)

Participants

Study characteristics

• Setting: multicentre (Diabetes Clinics at Padova University Hospital and Bergamo Hospital)

• Country: Italy

• Inclusion criteria: type 2 DM; BP < 140/90 mm Hg (in the absence of antihypertensives); normal or slightly increased UAE

• Exclusion criteria: not reported

Baseline characteristics (normoalbuminuria group)

• Number: 21

• Mean age ± SEM: 60 ± 2 years

• Sex (M/F): 16/5

• Mean BMI ± SEM: 29 ± 2 kg/m²

• Mean BP ± SEM (mm Hg): SBP (130 ± 2); DBP (80 ± 2)

• Hypertension: normotensive

• Mean HbA1c ± SEM (%): 8.2 ± 0.6

• Diabetes

  • Type 2 DM

  • Mean duration of diabetes ± SEM: 9 ± 2 years

• Co‐morbidities: none reported

• CKD definition: none, not inclusion criteria for this review, but must be normoalbuminuria

• Urinary AER (µg/min): 10 (3 to 18)

Interventions

Pre‐randomisation/run‐in

• None reported

Intervention group

• Dietary changes: aimed at 25 mmol NaCl/day

• Duration: 7 days

Control group

• Dietary changes: aimed at 250 mmol NaCl/day, as 500 mg sodium chloride oral tablets

• Duration: 7 days

Washout period

• None, consecutive diets

Co‐interventions or additional treatments

• None

• No antihypertensive agents given so presumed not to receive ACEi or ARB

Follow up details

• None, only follow‐up at the end of treatment period (2 weeks in total)

Outcomes

Reported outcomes / outcomes relevant to this review*

• SBP*, DBP*, MAP*

• Insulin sensitivity

• Mean 24‐hour UNa excretion*

• Mean 24‐hour urinary potassium excretion

• Aldosterone

• PRA

• Body weight*

• Urinary AER* (µg/min)

• eGFR*

• ERPF*

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "All subjects underwent, in random order, two consecutive 7‐day diet periods"
Comment: insufficient details provided about how the randomisation methods were carried out and by whom

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding concealment of allocation to randomised treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: unblinded trial. All participants knew which week they had to change their diet to low salt, and then one week on high salt

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: no information provided regarding the blinding of outcome assessors. Unblinded trial so unlikely to be done

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: withdrawals and study attrition not reported. Unclear what final attrition is. Appears ITT analysis was performed, but unclear

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori trial registration or published protocol

• Trial registration: not reported

• Protocol registered/published: not reported

Funding source

Low risk

Quote: "This study was supported by a research grant from the University of Padua, Italy".
Comment: no industry funding

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

High risk

Washout period for cross‐over trial: no washout applied, "Two consecutive 7‐day diet periods"
Comment: no other sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• Not reported

Duration of treatment

• 7 days

Duration of follow‐up

• No follow‐up past the end of the treatment period (2 weeks in total)

Participants

Study characteristics

• Setting: single centre

• Country: Japan

• Inclusion criteria: type 2 DM; advanced albuminuria (UAE > 144 mg/24 hours)

• Exclusion criteria: history of heart disease; non‐diabetic CKD; UTI; SCr > 1.0 mg/dL; treated currently or previously with antihypertensive agents or with BP > 160/95 mm Hg

Baseline characteristics (advanced albuminuria group)

• Number: 4

• Mean age ± SE: 61 ± 7 years

• Sex (M/F): 11/4 (study total)

• Mean BMI ± SE: 23.3 ± 1.9 kg/m²

• Mean BP ± SE (mm Hg): SBP (131 ± 4); DBP (75 ± 4)

• Hypertension: must be < 160/95 mm Hg

• Mean HbA1c ± SE (%): 8.1 ± 0.5

• Diabetes

  • Type 2 DM

  • Mean duration of diabetes ± SE: 12 ± 3 years

• Co‐morbidities: none reported

• CKD definition: none

• Mean UAE ± SE (range): 479 ± 91 mg/24 hours (309 to 635)

Interventions

Pre‐randomisation/run‐in

• Standard diet with ordinary salt (170 mEq sodium/day)

• Duration: for at least 2 weeks until plasma glucose had been controlled

Intervention group

• Dietary changes: low salt diet 85 mEq sodium/day

• Duration: 7 days

Control group

• Dietary changes: low salt diet 225 mEq sodium/day

• Duration: 7 days

Washout period

• None, no time intervening

Co‐interventions or additional treatments

• None

• Participants on antihypertensive agents or previously receiving these agents were excluded

Follow up details

• Not reported

Outcomes

Reported outcomes / outcomes relevant to this review*

• eGFR*

• MAP*

• UNa excretion* (mEq/24 hours)

• PRA (ng/mL/hours)

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "the order of these diets was random"
Comment: insufficient details provided about how the randomisation methods were carried out and by whom

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding concealment of allocation to randomised treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: unblinded trial. All participants knew which week they had to change their diet to low salt, and then one week on high salt

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: no information provided regarding the blinding of outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: all participants are accounted for from start to end of trial. No participants dropped out, 0% attrition. Unclear whether ITT analysis was performed

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori trial registration or published protocol

• Trial registration: not reported

• Protocol registered/published: not reported

Funding source

Unclear risk

Comment: not reported

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

High risk

Washout period for cross‐over trials: none applied, "No time intervening"

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• Not reported

Duration of treatment

• 7 days

Duration of follow‐up

• No follow‐up past the end of the treatment period (2 weeks in total)

Participants

Study characteristics

• Setting: single centre

• Country: Japan

• Inclusion criteria: type 2 DM; microalbuminuria (UAE 28.8 to 144 mg/24 hours)

• Exclusion criteria: history of heart disease; non‐diabetic CKD; UTI; SCr > 1.0 mg/dL; treated currently or previously with antihypertensive agents or with BP > 160/95 mm Hg

Baseline characteristics (microalbuminuria group)

• Number: 7

• Mean age ± SE: 55 ± 4 years

• Sex (M/F): 11/4 (study total)

• Mean BMI ± SE: 23.8 ± 1.8 kg/m²

• Mean BP ± SE (mm Hg): SBP (133 ± 6); DBP (75 ± 4)

• Hypertension: must be < 160/95 mm Hg

• Mean HbA1c ± SE (%): 8.0 ± 0.5

• Diabetes

  • Type 2 DM

  • Mean duration of diabetes ± SE: 12 ± 3 years

• Co‐morbidities: none reported

• CKD definition: none

• Mean UAE ± SE (range): 65 ± 13 mg/24 hours (31 to 122)

Interventions

Pre‐randomisation/run‐in

• Standard diet with ordinary salt (170 mEq sodium/day)

• Duration: for at least 2 weeks until plasma glucose had been controlled

Intervention group

• Dietary changes: low salt diet 85 mEq sodium/day

• Duration: 7 days

Control group

• Dietary changes: low salt diet 225 mEq sodium/day

• Duration: 7 days

Washout period

• None, no time intervening

Co‐interventions or additional treatments

• None

• Participants on antihypertensive agents or previously receiving these agents were excluded.

Follow up details

• Not reported

Outcomes

Reported outcomes / outcomes relevant to this review*

• eGFR*

• MAP*

• UNa excretion* (mEq/24 hours)

• PRA (ng/mL/hour)

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "the order of these diets was random"
Comment: insufficient details provided about how the randomisation methods were carried out and by whom

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding concealment of allocation to randomised treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: unblinded trial. All participants knew which week they had to change their diet to low salt, and then one week on high salt

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: no information provided regarding the blinding of outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: all participants are accounted for from start to end of trial. No participants dropped out, 0% attrition. Unclear whether ITT analysis was performed

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori trial registration or published protocol

• Trial registration: not reported

• Protocol registered/published: not reported

Funding source

Unclear risk

Comment: not reported

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

High risk

Washout period for cross‐over trials: none applied, "no time intervening"

Comment: no other potential sources of bias identified

Study characteristics

Methods

Study design

• Cross‐over RCT

Duration of study

• Not reported

Duration of treatment

• 7 days

Duration of follow‐up

• No follow‐up past the end of the treatment period (2 weeks in total)

Participants

Study characteristics

• Setting: single centre

• Country: Japan

• Inclusion criteria: type 2 DM; normoalbuminuria (UAE < 28.8 mg/24 hours)

• Exclusion criteria: history of heart disease; non‐diabetic CKD; UTI; SCr > 1.0 mg/dL; treated currently or previously with antihypertensive agents or with BP > 160/95 mm Hg

Baseline characteristics (normoalbuminuria group)

• Number: 8

• Mean age ± SE: 65 ± 3 years

• Sex (M/F): 11/4 (study total)

• Mean BMI ± SE: 22.1 ± 0.8 kg/m²

• Mean BP ± SE (mm Hg): SBP (134 ± 5); DBP (72 ± 1)

• Hypertension: must be < 160/95 mm Hg

• Mean HbA1c ± SE (%): 8.8 ± 0.4

• Diabetes

  • Type 2 DM

  • Mean duration of diabetes ± SE: 12 ± 3 years

• Co‐morbidities: none reported

• CKD definition: none

• Mean UAE ± SE (range): 16 ± 7 mg/24 hours (8 to 27)

Interventions

Pre‐randomisation/run‐in

• Standard diet with ordinary salt (170 mEq sodium/day)

• Duration: for at least 2 weeks until plasma glucose had been controlled

Intervention group

• Dietary changes: low salt diet 85 mEq sodium/day

• Duration: 7 days

Control group

• Dietary changes: low salt diet 225 mEq sodium/day

• Duration: 7 days

Washout period

• None, no time intervening

Co‐interventions or additional treatments

• None

• Participants on antihypertensive agents or previously receiving these agents were excluded.

Follow up details

• Not reported

Outcomes

Reported outcomes / outcomes relevant to this review*

• eGFR*

• MAP*

• UNa excretion* (mEq/24 hours)

• PRA (ng/mL/hour)

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "the order of these diets was random"
Comment: insufficient details provided about how the randomisation methods were carried out and by whom

Allocation concealment (selection bias)

Unclear risk

Comment: no information provided regarding concealment of allocation to randomised treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: unblinded trial. All participants knew which week they had to change their diet to low salt, and then one week on high salt

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: no information provided regarding the blinding of outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: all participants are accounted for from start to end of trial. No participants dropped out, 0% attrition. Unclear whether ITT analysis was performed

Selective reporting (reporting bias)

High risk

Comment: all outcomes planned in the methods were reported in the results. However, no access to an a priori trial registration or published protocol

• Trial registration: not reported

• Protocol registered/published: not reported

Funding source

Unclear risk

Comment: not reported

Conflicts of interest

Unclear risk

Comment: not reported

Other bias

High risk

Washout period for cross‐over trials: none applied, "No time intervening"

Comment: no other potential sources of bias identified