CKD: Dietary Protein (2001)

Citation:

Levey AS, Adler S, Caggiula AW, England BK, Greene T, Hunsicker LG, Kusek JW, Rogers NL, Teschan PE. Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study. Am J Kidney Dis. 1996; 27:652-663.

Worksheet created prior to Spring 2004 using earlier ADA research analysis template.
PubMed ID: 8629624
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:

The purpose of this secondary analysis of the MDRD Study was to determine the relationship between achieved in addition to prescribed, protein intake and the progression of kidney disease.

Inclusion Criteria:

1. 18 to 70 years of age

2. Serum creatinine: 1.2 to 7.0 mg/dL (women) or 1.4 to 7.0 mg/dL (men) or CrCl <70 ml/min/1.73 m2.

3. Mean arterial blood pressure (MAP): <125 mm Hg

Exclusion Criteria:

1. Systemic disease

2. Diabetes mellitus requiring insulin

3. Urine protein > 10 g/day

4. Body weight <80% or >160% of standard body weight

Description of Study Protocol:

Recruitment Subjects were recruited from 15 clinical centers in the US.

Design:

Randomized Controlled Trial. Randomization was stratified according to clinical center and average MAP during baseline.

Blinding (if applicable):  Not mentioned

Intervention (if applicable):

a. protein: subjects were randomly assigned to follow either a low protein diet, 0.58 g/kg/d (>0.35 g/kg/d as HBV protein) or a very low protein diet (0.28 g/kg/d) + a mixture of amino and keto acids (0.28 g/kg/d) which provided a total of 0.46 g protein/kg/d. (1 additional g of protein was allowed for each g of urinary protein)

 b. phosphorus: low protein diet (5 to 10 mg/kd/day or very low protein diet (4 to 9 mg/kg/day)

Statistical Analysis

Baseline characteristics were compared between groups using t-test, ANOVA or chi-square tests, as appropriate. hypothesis tests were regarded as statistically significant if P less than or equal to 0.05 (two-sided). The decline in GFE was compared between the diet groups using a one-slope informative censoring model .

Data Collection Summary:

Timing of Measurements

Dietitians at each clinical center provided nutrition education to enable subjects to follow the diet protocol during the baseline period.

Estimated dietary protein intake was determined monthly using urea nitrogen excretion (UUN): protein intake (g/d) = 6.25 x [UUN (g/d) + standard body weight (kg) x 0.03] (g/kg standard body weight)/d ]

Intake of protein, phosphorus, calories, and other nutrients was assessed monthly from 3-day food records. Blood pressure and weight were measured monthly. Blood samples were analyzed for hematologic and biochemical values every 2 months.

GFR was measured at baseline, 2 months, 4 months, and every 4 months thereafter as the renal clearance of 125I-iothalamate. Symptoms of uremai were assessed monthly by a self-administered questionnaire.

Dependent Variables

  • Rate of change of GFR (slope)
  • Serum creatinine
  • Creatinine clearance
  • UUN
  • Mean arterial pressure

Independent Variables

  • low protein diet, 0.58 g/kg/d (>0.35 g/kg/d as HBV protein), phosphorus:5 to 10 mg/kd/day
  • very low protein diet (0.28 g/kg/d) + a mixture of amino and keto acids (0.28 g/kg/d) which provided a total of 0.46 g protein/kg/d. (1 additional g of protein was allowed for each g of urinary protein), phosphorus 4 to 9 mg/kg/day.

Control Variables

Description of Actual Data Sample:

Initial N: 255 patients 

Attrition (final N): 121 reached kidney failure and 7 died prior to an administrative censoring date of June 15, 1993 ~5 months after the final follow-up visit.   GFR measurements at 1, 2 and 3 years in 219, 137 and 62 patients.

Age:  Ranged from18 to 70 years.

Ethnicity: not stated

Other relevant demographics:  Not stated

Anthropometrics  Not stated

Location: 15 clinical centers in the U.S.

 

Summary of Results:

Baseline Renal Function was similar in the low protein (LP) and very low protein (VLP) diet groups:

  LP VLP
GFR (ml/min/1.73 m2)

18.7+3.2

18.3+3.5

CrCl (ml/min/1.73 m2)

24.2+6.3

24.9+7.8

Serum creatinine (mg/dL)

3.5+0.9

3.4+0.9

Urine protein (g/d)

0.6+1.7*

0.5+1.8*

Estimated protein intake (g/kg/d)

0.9+0.2

0.9+0.2

* geometric mean

Other findings: 

 Inclusion of the amino acids in the supplement as a source of nitrogen in the very low protein diet group resulted in a mean total protein intake (food + supplements) of 0.66 g/kg/d which was slightly but significantly different from the low protein diet group (P<0.001) (a difference of 0.07 g/kg/d).

Rate of decline of GFR:

There was a significant inverse relationship between GFR and dietary protein intake (-2.94 and –4.32 mL/min/yr per g/kg/d without and with supplement respectively; P=0.026 and P=0.030).

In correlational analyses, we combined patients assigned to both diets and controlled for baseline factors associated with a faster progression of kidney disease. A 0.2 g/kg/d lower achieved total protein intake (food + supplement) was associated with a 1.15 mL/min/yr slower mean decline in GFR (P=0.011), equivalent to 29% of the mean GFR decline. After adjusting for achieved total protein intake, no independent effect of prescription of the keto acid-amino acid supplement to slow the GFR decline could be detected.

The mean follow-up protein intakes were 0.73 and 0.43 (food only) g/kg/day in the low and very low protein diet groups (P<0.001).
Author Conclusion:

The secondary analysis of the MDRD Study suggest that a lower protein intake, but not the keto-amino acid supplement, retards the progression of advanced kidney disease. .

It is difficult to compare the value of delaying the onset of kidney failure to the difficulty in long-term adherence to a low-protein diet. We believe, however, that appropriate counseling by physicians and dietitians will enable patients to make this assessment. For well-informed patients who choose to restrict dietary protein, we recommend a prescribed protein intake of 0.6 g/kg/day in patients with a GFR <25 ml/min/1.732 . The benefit of this level of protein restriction in those with a GFR >25 ml/min remains to be determined..

 

Funding Source:
Government: NIDDK
Reviewer Comments:

This study demonstrates how difficult it is to reduce dietary protein intake to prescribed levels. Subjects instructed to follow a diet containing 0.58 g/kg/d achieved 0.73 g/kg/d compared to a baseline intake of 0.9 g/kg/d. In this study, the subjects saw a dietitian monthly throughout the study.

Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? No
2. Was the selection of study subjects/patients free from bias? ???
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? No
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? ???
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? ???
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) No
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? Yes
5. Was blinding used to prevent introduction of bias? No
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? No
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? ???
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? Yes
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? ???
  10.2. Was the study free from apparent conflict of interest? Yes