The Modification of Diet in Renal Disease Study

Study Overview
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Brief Summary
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The Modification of Diet in Renal Disease Trial is a multicenter randomized clinical trial for men and women aged 18-70 years with chronic renal disease who are not on dialysis and who have not had a kidney transplant. Study participants are randomized in a 2 × 2 factorial design to diets containing different amounts of protein and phosphorus and to two levels of blood pressure control. The prescribed modifications differ depending on the level of a patient's kidney function. The primary outcome variable to compare diet or blood pressure groups is each patient's slope (or the change) in glomerular filtration rate (GFR) with time.

Detailed Description
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Selection of patients is conducted in two periods: a screening period for initial determination of eligibility and a 3-month baseline period. The baseline period is used to instruct patients about study procedures; to assess GFR and dietary protein intake; and to control blood pressure according to standard medical practice. GFR, dietary protein, and urinary protein must meet the eligibility criteria at the end of the baseline period before an individual can be randomized. Two different strata or studies are used depending on the level of an individual's GFR at the end of the baseline period. Study A is for individuals with a GFR from 25 to 55 ml/min/1.73 m^2 and a usual dietary protein intake of at least 0.90 g/kg/day, where kg are standard body weight. Study B is for persons with a baseline GFR from 13 to 24 ml/min/1.73 m^2 and no specification of protein intake. Individuals who are randomized in the trial are prescribed one of three diets and one of two target mean arterial blood pressure goals (MAP). MAP is a weighted average of the diastolic and systolic blood pressures (two-thirds diastolic plus one-third systolic). The goals depend on the person's age. The moderate goal of 107 mm Hg is equivalent to a blood pressure of 140/90 mm Hg, the usual limits of normal blood pressure. The low-MAP goal of 92 mm Hg is a more strict level of control than usually achieved, equivalent to, for example, 125/75 mm Hg.

Official Title
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The Modification of Diet in Renal Disease Study

Conditions
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Chronic Renal Disease

Intervention / Treatment
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* Other: Usual Protein Diet
* Other: Low Protein Diet
* Other: Very Low Protein Diet
* Drug: Medications needed to maintain usual blood pressure
* Drug: Medications needed to maintain low blood pressure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Increased serum creatinine: Men: 1.4-7.0 mg/dl, Women: 1.2-7.0 mg/dl, or other objective evidence of kidney disease Mean arterial blood pressure <=125 mm Hg GFR 13-55 ml/min/1.73 m^2 Urinary protein excretion <10 g/day Protein intake >0.90 g/kg/day if GFR 25-55 ml/min/1.73 m^2 Exclusion Criteria: Insulin-dependent diabetes or fasting serum glucose >200 mg/dl Patient on dialysis Kidney transplant recipient Lactating or pregnant woman or woman planning to become pregnant within the time frame of the study Doubtful compliance Body weight <80% or >160% of standard body weight Serum albumin <3.0 g/dl Selected renal disorders: Upper or lower urinary tract obstruction, Renal artery stenosis, Branched or staghorn calculi, Cystinuria Serious medical conditions: Malignancy (excluding skin cancer) within 1 year, Heart failure, New York Heart Association class 3 or 4, Lung disease, Liver disease, Gastrointestinal disease, Chronic systemic infections, including AIDS, Collagen vascular disease (other than rheumatoid arthritis), Frequent hospitalizations or disability Drugs: Immunosuppressive agents, Corticosteroids in excess of replacement dosage for 2 months per year or more, Gold or penicillamine within past month, Salicylates: more than 20 tablets per week, Other nonsteroidal antiinflammatory agents more than 3 times per week in past 2 months, Investigational drugs Allergy to iothalamate or iodine Inability or unwillingness to give consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Study A Usual Protein Usual Pressure<br>Study A Usual Protein and Usual Pressure | Other: Usual Protein Diet<br>* The usual protein diet contains 1.30 g/kg/day protein and 16-20 mg/kg/day of Phosphorus<br>Drug: Medications needed to maintain usual blood pressure<br>* The MAP goal for the usual blood pressure group is <=107 mm Hg for ages 18-60 and <=113 for ages 61+. Pharmacological and non-pharmacological therapies will be used to achieve the desired blood pressure values. The recommended anti-hypertensive regimen is a angiotensin-converting-enzyme inhibitor with or without a diuretic agent; a calcium-channel blocker or other medications can be added as needed.<br>|
| Experimental: Study A Usual Protein Low Pressure<br>Study A Usual Protein and Low Pressure | Other: Usual Protein Diet<br>* The usual protein diet contains 1.30 g/kg/day protein and 16-20 mg/kg/day of Phosphorus<br>Drug: Medications needed to maintain low blood pressure<br>* The MAP goal for the low blood pressure group is <=92 mm Hg for ages 18-60 and <=98 for ages 61+. Pharmacological and non-pharmacological therapies will be used to achieve the desired blood pressure values. The recommended anti-hypertensive regimen is a angiotensin-converting-enzyme inhibitor with or without a diuretic agent; a calcium-channel blocker or other medications can be added as needed.<br>|
| Experimental: Study A Low Protein Usual Pressure<br>Study A Low Protein and Usual Pressure | Other: Low Protein Diet<br>* The low protein diet contains 0.575 g/kg/day protein and 5-10 mg/kg/day of Phosphorus<br>Drug: Medications needed to maintain usual blood pressure<br>* The MAP goal for the usual blood pressure group is <=107 mm Hg for ages 18-60 and <=113 for ages 61+. Pharmacological and non-pharmacological therapies will be used to achieve the desired blood pressure values. The recommended anti-hypertensive regimen is a angiotensin-converting-enzyme inhibitor with or without a diuretic agent; a calcium-channel blocker or other medications can be added as needed.<br>|
| Experimental: Study A Low Protein Low Pressure<br>Study A Low Protein and Low Pressure | Other: Low Protein Diet<br>* The low protein diet contains 0.575 g/kg/day protein and 5-10 mg/kg/day of Phosphorus<br>Drug: Medications needed to maintain low blood pressure<br>* The MAP goal for the low blood pressure group is <=92 mm Hg for ages 18-60 and <=98 for ages 61+. Pharmacological and non-pharmacological therapies will be used to achieve the desired blood pressure values. The recommended anti-hypertensive regimen is a angiotensin-converting-enzyme inhibitor with or without a diuretic agent; a calcium-channel blocker or other medications can be added as needed.<br>|
| Active Comparator: Study B Low Protein Usual Pressure<br>Study B Low Protein and Usual Pressure | Other: Low Protein Diet<br>* The low protein diet contains 0.575 g/kg/day protein and 5-10 mg/kg/day of Phosphorus<br>Drug: Medications needed to maintain usual blood pressure<br>* The MAP goal for the usual blood pressure group is <=107 mm Hg for ages 18-60 and <=113 for ages 61+. Pharmacological and non-pharmacological therapies will be used to achieve the desired blood pressure values. The recommended anti-hypertensive regimen is a angiotensin-converting-enzyme inhibitor with or without a diuretic agent; a calcium-channel blocker or other medications can be added as needed.<br>|
| Experimental: Study B Low Protein Low Pressure<br>Study B Low Protein and Low Pressure | Other: Low Protein Diet<br>* The low protein diet contains 0.575 g/kg/day protein and 5-10 mg/kg/day of Phosphorus<br>Drug: Medications needed to maintain low blood pressure<br>* The MAP goal for the low blood pressure group is <=92 mm Hg for ages 18-60 and <=98 for ages 61+. Pharmacological and non-pharmacological therapies will be used to achieve the desired blood pressure values. The recommended anti-hypertensive regimen is a angiotensin-converting-enzyme inhibitor with or without a diuretic agent; a calcium-channel blocker or other medications can be added as needed.<br>|
| Experimental: Study B Very Low Protein Usual Pressure<br>Study B Very Low Protein and Usual Pressure | Other: Very Low Protein Diet<br>* The very low protein diet contains 0.28 g/kg/day or protein, mg/kg/day of Phosphorus and a keto acid mixture.<br>Drug: Medications needed to maintain usual blood pressure<br>* The MAP goal for the usual blood pressure group is <=107 mm Hg for ages 18-60 and <=113 for ages 61+. Pharmacological and non-pharmacological therapies will be used to achieve the desired blood pressure values. The recommended anti-hypertensive regimen is a angiotensin-converting-enzyme inhibitor with or without a diuretic agent; a calcium-channel blocker or other medications can be added as needed.<br>|
| Experimental: Study B Very Low Protein Low Pressure<br>Study B Very Low Protein and Low Pressure | Other: Very Low Protein Diet<br>* The very low protein diet contains 0.28 g/kg/day or protein, mg/kg/day of Phosphorus and a keto acid mixture.<br>Drug: Medications needed to maintain low blood pressure<br>* The MAP goal for the low blood pressure group is <=92 mm Hg for ages 18-60 and <=98 for ages 61+. Pharmacological and non-pharmacological therapies will be used to achieve the desired blood pressure values. The recommended anti-hypertensive regimen is a angiotensin-converting-enzyme inhibitor with or without a diuretic agent; a calcium-channel blocker or other medications can be added as needed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in GFR slope | Slopes will be calculated on the basis of the final baseline GFR and all follow-up values without adjustment for body surface area | Up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dialysis or kidney transplantation | Time to first dialysis or kidney transplantation | 3 years | 
| Death from any cause | Time to death from any cause | 3 years | 
| Time to kidney failure | The onset of kidney failure was ascertained from the US Renal Data System (USRDS) and included starting dialysis or undergoing kidney transplant | Up to 10 years | 
| Time to kidney failure or death | The onset of kidney failure was ascertained from the US Renal Data System (USRDS) and included starting dialysis or undergoing kidney transplant. Data for death were obtained from the National Death Index | Up to 10 years |