CKD: Dietary Protein (2001)


Walser M, Hill SB, Ward L, Madger L.  A crossover comparison of progression of chronic renal failure: Ketoacids versus amino acids. Kidney International 1993;43:933-9.

PubMed ID: 8479131
Study Design:
Randomized Crossover Trial
A - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:
The purpose of this study was to investigate the effects of ketoacid supplements in slowing the progression of chronic renal failure compared with amino acid supplements to the same low protein diet.
Inclusion Criteria:
  • Chronic renal failure: defined by a subnormal GFR in the absence of acute renal failure.
Exclusion Criteria:
  • Age less than 18 or over 75 years
  • Pregnant or planning to become pregnant
  • Compliance doubtful owing to drug abuse, alcohol abuse, psychiatric illness, poor understanding of study, limited motivation, transient residence, or unsuitable home environment
  • Impaired nutrition as evidenced by body weight less than 85% or more than 150% of standard weight, serum albumin less than 3.5g/dl or serum transferrin les than 180mg/dl
  • Proteinuria greater than 10g/day
  • Presence of urinary tract obstruction, vesicoureteral reflux grade III or worse, branched or staghorn calculi, kidney transplant or cystinuria
  • Chronic serious medical conditions such as nalignancy, severe heart failure, collagen vascular disease or any other condition that leads to frequent hospitalization
  • Immunosuppressive drugs
  • Inability to empty the bladder
Description of Study Protocol:

Recruitment Not mentioned

Design :Randomized crossover study

Blinding used (if applicable) Not used - lab tests

Intervention (if applicable)

Patients were prescribed mixed quality protein at .3g/kg ideal body weight receiving a 10g dose of amino acids per day, providing 1.1g N/day or receiving 2.8g/ nearest 10kg of ideal body weight of keto acids. Caloric intake was 35 kcal/kg of actual body weight, except that in case where weight loss was desirable, total intake was reduced by 500 to 1000 calories per day. Phosphorus was prescribed at 7 to 9 mg per kg ideal body weight.

Statistical Analysis

The GFR progression outcomes were calculated using least squares regression. Patient specific estimates were then analyzed by standard methods (t-test, Wilcoxon signed rank test). In a second approach to the analysis, linear random effects model was postulated and restricted maximum likelihood estimates were found using “EM” algorithm.


Data Collection Summary:

Timing of Measurements

Patients were seen monthly, although the interval between visits varied from three to six weeks. At each visit patients brought in a 24-hr urine collection. Body weight, blood pressure, and GFR was measured at each visit. Blood samples for routine chemical and hematological determinations were performed. 100 µCi 99mTc-labeled diethylenetriamine-pentaacetic acid was injected intravenously and 60 min. later, three timed urine collections with blood samples at the beginning and end of each period were obtained.

Dependent Variables

  • Chronic renal disease progression as measured by GFR
  • Blood pressure 

Independent Variables

  • Low protein diet with 10g amino acids
  • Low protein diet with 2.8g/ nearest 10kg IBW keto acids

Control Variables


Description of Actual Data Sample:

Initial N: 21 patients; 7 female and 14 male

Attrition (final N): 16 patients, dropout rate of 24%

Age: mean age 51.8 years, range 31 - 79

Ethnicity: 2 black and 19 caucasian

Other relevant demographics:

Anthropometrics (e.g., were groups same or different on important measures)

Location: U.S.-Baltimore, Maryland


Summary of Results:




95% Confidence limits

Rate of progression on ketoacid


-0.36, 0.09

Rate of progression on amino acid


 -0.91, -0.41

Change in GFR during first month  (KA to AA)


 -0.82, 1.08

Change in GFR during first month  (AA to KA)


-0.77, 1.02

Other Findings

GFR, serum urea N, and serum creatinine did not differ between amino acids (AA) and keto acid (KA). The rate of change of GFR during KA averaged -0.15ml/min/month, while the rate of change of GFR during AA averaged -.67ml/min/month. Mean period-to-period differences in progression rates, KA-AA, were all of the same sign but failed to achieve statistical significance individually.

The expected progression rate during AA periods was estimated as -.66ml/min/month (95% confidence interval -0.91, -0.42). The expected progression rate during KA periods was estimated as -0.14 ml/min/month (95% confidence interval -0.36, 0.09).

Mean arterial pressure averaged 107mm Hg during KA supplementation and 105mm Hg during AA supplementation. These values do not differ significantly, nor do values for mean systolic or diastolic pressure.

Author Conclusion:

In the 16 subjects who completed the protocol, mean progression rate on ketoacid is only 22% of that on amino acids. This difference would predict postponment of the need for dialysis for many years. However, patients were only followed for a few months and it is hard to extrapolate the data.

There is a highly significant correlation between the treatment effect of KA and the progression rate on AA. Thus more rapidly progression subjects exhibit a larger treatment effect of KA.

Funding Source:
Government: NIH
Foundation associated with industry:
Reviewer Comments:
Study does not make mention of how were recruited nor did it mention where they were recruited.  Dropout rate of 24%.
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? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? N/A
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  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? ???
  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%.) ???
  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? N/A
5. Was blinding used to prevent introduction of bias? ???
  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? No
  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)? No
  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