Citation:

Mircescu G, Garneata L, Stancu SH, Capusa C. Effects of a supplemented hypoproteic diet in chronic kidney disease. J. Renal Nutr. 2007; 17(3): 179-188.

PubMed ID: 17462550
 
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:

To study the effects of severe hypoproteic diet supplemented with ketoanalogues (SVLPD) on nitrogen waste products accumulation, calcium-phosphorus metabolism disturbances, acid-base disorders, nutritional status and the compliance with the prescribed diets in nondiabetic patients with stage four CKD for 48 weeks.

Inclusion Criteria:

Chronic kidney disease (CKD) with an estimated glomerular filtration (eGFR) rate of less than 30ml per minute per 1.73m2; adult age; Modification of Diet in Renal Disease  (MDRD) formula; stable renal function at least 12 weeks before enrollment (reduction in eGFR less than or equal to 4.0ml per minute per year); proteinuria less than 1.0g per gL urinary creatinine; good nutritional status (SGA score A/B and serum albumin more than 3.5g per gL) and anticipated good compliance with the prescribed diet for at least 12 weeks before enrollment. The prescribed diet was 0.6g per kg of ideal body weight and a daily energy intake of 30cal per kg per day three months before the inclusion. The compliance with the conventional LPD was assessed every two weeks during the three-month period and considered to be good if both the achieved protein and energy intake were in the range of +10% of the recommended values.

Exclusion Criteria:

Patients with poorly controlled arterial blood pressure (more than 145/85mm Hg); relevant comorbid conditions such as diabetes mellitus, heart failure, active hepatic disease, digestive diseases with malabsorption, inflammation/anti-inflammatory therapy; uremic complications (pericarditis and polyneuropathy) or feeding inability (anorexia, nausea).

Also excluded from the analysis were patients from the SVLPD (1) and patients from the low-protein diet (LPD) group. Seven dropped out from the study due to renal replacement treatment.

Description of Study Protocol:

Recruitment

Recruitment took place between January 15, 2004 and February 15, 2005. Out of 114 patients enrolled, 27 patients refused to participate, seven did not meet the inclusion criteria and 16 were enrolled in other clinical trials. Only 53 patients were randomized, but later eight patients initiated renal replacement treatment.  

Design

Prospective, randomized controlled clinical trial for 48 weeks; eligible patients entered a 12-week baseline phase. At the end of this phase, patients were randomized to receive either 0.3g per kg per day of vegetable proteins and one capsule for every 5.0kg per IBW per day ketonalogues of essential amino acids (SVLPD group) or continued with their conventional LPD (control group) with 0.6g per kg per day. Both groups received 30cal per kg per day. All patients received calcium and water-soluble vitamin supplement, as required. Intravenous iron sucrose was received by the patients based upon their level of serum ferritin. All the inclusion and exclusion criteria were analyzed at the enrollment, after four weeks and at randomization. To evaluate protein intake, urinary urea excretion was used to assess the protein intake using Mitch-Maroni's formula. Energy daily intake was estimated using the three-day food diary. 

Intervention

  • Severe hypoproteic diet supplemented with ketoanalogues of amino acids (SVLPD): 0.3g per kg per day plus one capsule per 5kg per IBW per day
  • Low protein diet (0.6g per kg per day): Control group. 

Statistical Analysis

Student T-test, chi-square and nonparametric tests were used to determine differences in baseline parameters between study groups. Mean and SD used for parameters with normal distribution and median and interquartile range for skewed data. eGFR was only analyzed from week 16 to 48 when the creatinine was stabilized after patients switched to a meat-restricted diet.

 

Data Collection Summary:

Timing of Measurements

The anthropometrics parameters and SGA were evaluated at enrollment, at randomization and every three months thereafter. The compliance with the prescribed diet was assessed weekly for the first month, every four weeks during the next eight weeks and every 12 weeks thereafter. Biochemical samples were recorded at weeks -12, -8, -4, and zero, and monthly thereafter. The blood pressure levels, drug therapy requirements for hypertension and occcurrence of adverse events were recorded monthly. 

Dependent Variables 

  • eGFR (ml per minute per 1.73m2)
  • SGA: Score A/B
  • BMI (kg/m2)
  • Tricipital skinfold (cm)
  • Mid-arm muscular circumference (cm)
  • Serum albumin (g per dL)
  • C-reactive protein
  • Serum urea and creatinine
  • Urinary urea nitrogen
  • Proteinuria
  • Calcium-phosphorus
  • Serum bicarbonate 
  • Blood pressure.

Independent Variables

SVLPD vs. LPD control diet. 

Control Variables

  • Age
  • Gender
  • Primary renal diseases (primary glomerular nephropathies, tubulointerstitial diseases)
  • Angiotensin-converting enzyme inhibitor and anigotensin receptor blocker.

 

Description of Actual Data Sample:

 

  • Initial N: 53; 27 (SVLPD group), 26 (LPD group)
  • Attrition (final N): 45; 26 (SVLP group), 19 (LPD group) [excluded from the primary end-point analysis: one (SVLPD) and seven (LPD)]
  • Age: Mean age, 55 (SVLP group) and 54 (LPD group)
  • Other relevant demographics: At baseline there was more males in both groups, with a slight increase in number of males in the SVLPD group compared with the LPD (63% vs. 58%). Some patients were receiving angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers. eGFR included only the data from weeks 16 to 48 from individuals with significant variations in dietary intake.
  • Anthropometrics: At baseline age, BMI, SGA, serum albumin, C-reactive protein and albumin were well matched
  • Location: Dr Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania.

 

Summary of Results:

 

Variables

SVLPD LPD
Metabolic and renal function parameters Baseline 48 weeks Baseline  48 weeks
eGFR (ml per minute per 1.73m2) 18.3±4.6 15.4±5.0 17.9±4.3 13.4±5.1*
Serum urea (mg per dL) 157±33 121±28* 135±24 144±26
Serum creatinine (mg per dL) 4.1±1.3 4.8±1.5 3.9±1.4 5.0±1.7*
Serum bicarbonate (mEq per L) 18.1±1.5 23.4±2.1* 18.3±1.3 17.6±1.9
Serum phosphate(mg per dL) 5.9±2.1 4.5±1.7* 5.7±2.3 6.0±1.9
Serum calcium (mg per dL) 4.0±0.6 4.4±0.7* 4.1±0.9 3.9±0.5
Anthropometric markers    
BMI (kg)  23.9±3.1  23.8±2.4  23.2±4.4  23.4±4.4
Tricipital skinfold (cm) 19.9±3.3 20.1±3.0 19.2±4.3 19.3±4.6
Mid-arm muscular circumference(cm) 23.2±2.7 23.1±2.5 22.9±3.8 23.0±4.0
Serum albumin (g per dL)  3.9±0.3  4.2±0.6  4.1±0.4  4.0±0.5
SGA (A, %)  87  87  90  90
Protein intake (g per kg per day)  0.31±0.09  0.32±0.007  0.62±0.1 0.59±0.08 
Energy intake (kcal per day)  31.2±2.3  31.8±2.1  32.3±2.1  31.0±1.9
Blood Pressure        
systolic (mm Hg) 125.2±27.1 123.1±16.9 125.3±24.5 129.8±14.9
diastolic (mm Hg) 74.6±15.7 70.9±12.4 70.8±14.0 70.5±10.2
*Statistically significant vs. baseline.

 Other Findings:

  • Percentage of patients with declining renal function: It was similar in the two groups during the 12-week periods before the enrollment but only a significantly smaller percentage of patients in the SVLDPgroup had a reduction during the assessment phase (63% vs. 88.5% in the control group)
  • Only a significantly lower percentage of patients in the SVLDP group required RRT initiation during the study  compared with the LPD group (4% vs. 27%)
  • Compliance was considered good. See results in the table.
  • Ketoanalogues was well tolerated.

 

Author Conclusion:

Severe hypoproteic diet supplemented with ketoanalogues seems to ameliorate the nitrogen waste products retention, acid-base and calcium-phosphorus metabolism disturbances, nutritional status preservation and postpone renal replacement therapy in non-diabetic patients with stage four CKD.

Funding Source:
Reviewer Comments:

Overall the study had a lot of flaws, making it difficult to interpret the outcomes. The small size sample increases the possibility of type two error and cannot determine whether the SVLPD changes the rate of progression of renal insufficiency. Patients who initiate RTT during the follow-up were excluded from the analysis, which can bring bias to the effectiveness of the intervention. Statistical significances were not established for the analysis.

Differential dropout rate: 4% SVPD group, 27% LPD group.

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) ???
  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) ???
 
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? No
  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? No
  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? No
3. Were study groups comparable? No
  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? No
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  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? 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? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? ???
  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? 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? No
  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? N/A
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? No
  8.1. Were statistical analyses adequately described and the results reported appropriately? No
  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? No
  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? No
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
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