CKD: Dietary Protein (2001)
Teschan PE, Beck GJ, Dwyer JT, Greene T, Klahr S, Levy AS, Mitch WE, Snetselaar LG, Steinman TI, Walser M. Effect of a ketoacid-amino acid-supplemented very low protein diet on the progression of advanced renal disease: a reanalysis of the MDRD feasibility study. Clin Nephrology. 1998;50:273-283.
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.
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
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.
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.
Diet M: usual protein diet (1.2 g/kg/d) and 16-20 mg phosphorus/kg/d
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:
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).
Protein intake (g/kg/d)
Follow-up (4 months)
Protein intake (g/kg/d)
GFR decline (ml/min/month)
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|
|Protein intake (g/kg/d)||1.05(0.05)||1.10(0.04)||1.14(0.08)|
|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.
|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
|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|
|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|