CKD: Dietary Protein (2001)
The purpose of the reanalysis of the data from the MDRD feasibility study was to determine the effects of ketoacid- and aminoacid-supplemented very low protein diets on GFR.
1. 18 to 75 years of age
2. Serum creatinine 1.2 to 7.0 mg/dL in women or 1.4 to 7.0 mg/dL in men
3. Progressive increase in serum creatinine from 2 months to 3 years before study entry.
1. Pregnant
2. Compliance to study protocol doubtful
3. Abnormal nutritional status
4. Diabetes requiring insulin
5. Proteinuria >10 g/d
6. Uncorrected renal artery stenosis
7. Urinary tract obstruction or vesicoureteral reflux
8. Prior renal transplantation
9. Chronic medical conditions, eg. CHF, systemic infection
10. Receiving immunosuppressive or nonsteroidal anti-inflammatory drugs
Recruitment
Subjects from the MDRD study utilized.
Design: Randomized controlled trial; randomized by the nine Clinical Centers to the dietary treatment groups according to baseline GFR and prescribed levels of dietary protein and phosphorus intake.
Blinding used (if applicable): Not mentioned
Intervention (if applicable):
A. Study A: GFR: 25-80 ml/min/1.73 m2 and a baseline dietary protein intake of at least 0.9 g/kg/d randomized to one of the following:
1) Diet M: usual protein diet (1.2 g/kg/d) and 16-20 mg phosphorus/kg/d
2) Diet L: low protein diet (0.575 g/kg/d and 5-10 mg phosphorus/kg/d
3) Diet K: very low protein diet (0.28 g/kg/d + ketoacids) and 4-9 mg phosphorus/kg/d
B. Study B: GFR: 7.5-24 ml/min/1.73 m2 randomized to one of the following:
1) Diet L: low protein (0.575 g/kg/d and 5-10 mg phosphorus/kg/d
2) Diet K: very low protein (0.28 g/kg/d + ketoacids) and 4-9 mg phosphorus/kg/d
3) Diet J: very low protein (0.28 g/kg/d + aminoacids) and 4-9 mg phosphorus/kg/d.
Nutrition intervention and assessment: patients were instructed by Clinical Center dietitians to monitor the protein, phosphorus and energy content of their diets using food exchange lists that were based on the protein & phosphorus content of foods.
Statistical Analysis
Results were interpreted as post-hoc findings. For descriptive purposes in plots, changes in GFR were fit over time using a four-slope model with break points every four months. Regression analyses based on the one-slope informative censoring model in Study B and the two-slope mixed effects analysis in Study A were used to relate GFR decline to the achieved mean protein intake during follow-up.
Timing of Measurements
Dietary protein intake was estimated both from patient’s food records and 24-hr urinary urea nitrogen (UUN) excretion (6.25 [UUN (g/d) + 0.031 (g/kg/d) x SBW (kg)] where UUN is the UUN content of a 24-hr urine and SBW is read from the Metropolitan Height and Weight Tables, 1983.
Dietary protein intake was assessed during a 3 month baseline period and a follow-up period up to 22 months.
Renal function assessment: GFR was measured q 3 months as the renal clearance of subcutaneously injects 125-I iothalamate without epinephrine.
Dependent Variables:
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GFR decline
Independent Variables:
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Diet M: usual protein diet (1.2 g/kg/d) and 16-20 mg phosphorus/kg/d
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Diet L: low protein diet (0.575 g/kg/d and 5-10 mg phosphorus/kg/d
-
Diet K: very low protein diet (0.28 g/kg/d + ketoacids) and 4-9 mg phosphorus/kg/d
-
Diet L: low protein (0.575 g/kg/d and 5-10 mg phosphorus/kg/d
-
Diet K: very low protein (0.28 g/kg/d + ketoacids) and 4-9 mg phosphorus/kg/d
-
Diet J: very low protein (0.28 g/kg/d + aminoacids) and 4-9 mg phosphorus/kg/d.
Initial N: 30 patients with moderate renal failure (GFR 25-80 ml/min/1.73 m2)(Study A) and 66 patients with advanced renal disease (GFR 7.5-24 ml/min/1.73 m2) (Study B).
Attrition (final N): 28 patients in Study A and 63 patients in Study B
Age: Not stated
Ethnicity: Not stated
Other relevant demographics:
Anthropometrics:
Location: U.S.
Study A
Consistent with a hemodynamic effect, the mean GFR decline varied directly with the decrease in dietary protein intakes during the first 4 months (P=0.028) but thereafter did not differ among groups (P=0.76).
Study B
Diet L
Diet K
Diet J
Baseline
n=23
n=23
n=21
Protein intake (g/kg/d)
0.90(0.04)
0.85(0.02)
0.94(0.04)
GFR (ml/min)
15.8(0.88)
14.2(0.98)
15.1(1.05)
Follow-up (4 months)
n=23
n=21
n=19
Protein intake (g/kg/d)
1.04(0.04)
0.85(0.03)
0.54(0.05)
GFR decline (ml/min/month)
0.473(0.6)
–1.16(0.7)
–2.28(0.7)
GFR decline differed among the 3 diets (P=0.028); pair wise comparisons showed that the mean GFR (ml/min/month) was slower on diet K (very low protein diet +ketoacids)(-0.250+0.072) than diet J (very low protein diet + amino acids) (-0.533+0.074)(P=0.008)
Diet M | Diet L | Diet K | |
Baseline | n=11 | n=10 | n=9 |
Protein intake (g/kg/d) | 1.05(0.05) | 1.10(0.04) | 1.14(0.08) |
GFR (ml/min) | 37.2(3.00) | 36.5(2.65) | 37.5(2.83) |
Follow-up (4 months) | n=11 | n=9 | n=8 |
Protein intake (g/kg/d) | 1.04(0.04) | 0.85(0.03) | 0.54(0.05) |
GFR decline (ml/min/month) | 0.473(0.6) | –1.16(0.7) | –2.28(0.7) |
The results of these reanalysis of the MDRD feasibility study are consistent with earlier reports suggesting that the ketoacid-aminoacid supplement used in this study slows the progression of advanced renal disease more than the amino acid supplement. There is also a trend from a correlational analysis suggesting the possibility that the different composition of the ketoacid mixture used in the feasibility study may be more effective than the supplement used in the MDRD full-scale study.
However, the post-hoc nature of the reanalysis, the relatively small number of patients, and the limited duration of follow-up in the feasibility study preclude a definitive conclusion. Further studies with this ketoacid-aminoacid supplement in advanced renal disease are warranted in view of the potential clinical value of this treatment.
Government: | NIH, NIDDK |
University/Hospital: | John Hopkins University, Vanderbilt University, Cleveland Clinic Foundation, Washington University School of Medicine, New England Medical Center, Emory University, University of Iowa, Beth Israel Hospital, |
The benefit of the diet was shown for only the first 4 months in subjects with moderate renal failure, however, the sample size was small.
Quality Criteria Checklist: Primary Research
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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? | Yes | |
2. | Was the selection of study subjects/patients free from bias? | Yes | |
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? | No | |
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%.) | No | |
4.3. | Were all enrolled subjects/patients (in the original sample) accounted for? | No | |
4.4. | Were reasons for withdrawals similar across groups? | ??? | |
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? | N/A | |
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? | Yes | |
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? | N/A | |
6.6. | Were extra or unplanned treatments described? | N/A | |
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)? | No | |
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? | Yes | |
10.2. | Was the study free from apparent conflict of interest? | Yes | |