EAL

CKD: Dietary Protein (2001)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

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.

Inclusion Criteria:

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.

Exclusion Criteria:

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

Description of Study Protocol:

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.

Data Collection Summary:

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:

GFR decline

Independent Variables:

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.

Description of Actual Data Sample:

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.

Summary of Results:

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

Mean (SE) protein intake and renal function at baseline and follow-up:
	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)

Mean (SE) protein intake and renal function at baseline and follow-up:
	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)

Author Conclusion:

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.

Funding Source:

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,

Reviewer Comments:

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
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