EAL

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To evaluate the concomitant long-term effects of recombinant human erythropoietin (rHuEPO) and ketoacids on the metabolism of amino acids proteins and lipids in chronic renal failure patients treated with a low-protein diet during 36 months.

Inclusion Criteria:

Chronic renal failure
Creatinine clearance of 22.36ml per minute per 1.73m²
Signs of renal anemia (11.5g per dL of hemoglogin and hematocrit below 32%)
Good compliance and adherence to diet in previous outpatient follow-up.

Exclusion Criteria:

Not mentioned.

Description of Study Protocol:

Design

Prospective, randomized clinical trial for 36 months.

In the beginning of the study, chronic renal patients received a standard low-protein diet with 35kcal per kg per day. They were randomized in three groups: Group 1 received low-protein diet (LPD) with ketoacid supplement (KA) and rHuEPO, Group 2 had LPD plus rHuEPO and Group 3 (control) only LPD. rHuEPO was given twice a week along with oral iron supplementation three times a day. The doses were individualized to keep hemoglobin within 11.0g to 12.0g per dL and hematocrit within 32% to 34%. In the beginning of the study all patients were on balance follow-up for five days in a clinical department. Biochemistry and nutritional parameters, as well the nutrition questionnaire, were evaluated every six months. Compliance was determined using 24 hours of urinary urea and phosphorus excretion. The patients were on follow-up on an outpatient basis at four-week intervals througout the study.

Blinding Used

None, lab test.

Intervention

Group 1: Low-protein diet (0.6g per kg per day) with ketoacid supplementation (100mg per kg per day) plus rHuEPO
Group 2: Low-protein diet (0.6g per kg per day) plus rHuEPO
Group 3 (control group): Low-protein diet (0.6g per kg per day).

Low-protein diet containing an average of 0.6g or protein per kg BW per day per animal: Vegetable protein ratio (1.1), 1.3g per kg BW per day of lipids, 4.9g per kg BW per day of carbohydrates and 35 kcal per kg W per day of energy. The diet contained, as standard, about 100mmol Na (2,300mg), 50mmol K (1,950mg), and 30mmol P (930 mg).

Statistical Analysis

ANOVA
Regression analysis
Student's paired and unpaired T-tests with Bonferri correction.

Data Collection Summary:

Timing of Measurements

The anthropometric and biochemistry parameters as well as the nutrition questionnaire were evaluated at six, 12, 18, 20, 24, 30 and 36 months.

Dependent Variables

Creatinine clearance
Inulin clearance
Serum albumin
Triglycerides
Total, LDL and HDL cholesterol
Serum and urine aminogram by HPLC
24-hour proteinuria by photometry.

Independent Variables

LPD+KA+rHuEPO vs. LPD+rHuEPO vs. LPD control diet.

Control Variables

Age
Gender
Primary renal disease (tubulo interstitial nephritis, chronic glomerunephritis, polycystic kidney disease, malignant nephrosclerosis).

Description of Actual Data Sample:

Initial N: 105
- LDL+KA+rHuEPO (17 male, 18 female)
- LDL+rHuEPO (17 male, 19 female)
- LDL (16 male, 18 female)
Attrition (final N): 105
- LDL+KA+rHuEPO (17 male, 18 female)
- LDL+rHuEPO (17 male,19 female)
- LDL (16 male, 18 female).
Age: Mean age 54+7 (26 to 78 years)
Other relevant demographics:
- Fifty patients had chronic tubulointersticial nephritis, 44 had chronic glomerulonephritis, three had chronic polycystic disease and eight patients had malignant nephrosclerosis. Hypolypidemic and immunosuppressives drugs were not given to the patients.
- All patients had a stable blood pressure (140/85mm Hg) throughout the study
Location: Department of Nephrology, Transplant Center, Prague, Czech Republic.

Summary of Results:

Renal Function

The glomerular filtration rate measured by creatinine clearence decreased slightly during the study but it was significantly different between Group 1 (from 26.4+2.2ml to 23.2+2.1ml per minute) in relation to Group 2 (from 26.0+3.2ml to 20.1+2.6ml per minute) and Group 3 (from 27.1+2.8ml to 19.4+3.0ml per minute); P<0.01.

Metabolic Status

The urinary urea output per 24 hours was significantly decreased in all patients (Group 1 vs. Groups 2 and 3); P<0.05 to 0.01
The serum level of leucine increased significantly in Group 1 (P<0.01 to 0.02) and Group 2 (P<0.05), while only Group 1 showed the fractional excretion of leucine decreased (P<0.01). A significant difference was noted between groups (P<0.05 to 0.01).

Nutritional Status

The albumin was increased in LPD+KA+rHuEPO patients compared with the patients in other regimens; P<0.02
BMI was slightly increased in Group 1 compared to Groups 2 and 3 during metabolic follow-up, which remained unaltered or declined non-significantly; P<0.02 to 0.05.

Lipid Metabolism

Triglycerides levels decreased significantly in Group 1 during follow up; P<0.01
Total cholesterol and LDL-cholesterol decreased in Groups 1 and 2 at month 12 of follow-up; P<0.02 (for both)
However, HDL cholesterol increased significantly after six months of the study only in Group 1; P<0.02-0.01.

Author Conclusion:

Concomitant administration of low-protein diet with ketoacids and recombinant human erythropoietin constitutes an effective alternative to conservative management of chronic kidney disease delaying progression of renal insufficiency and correction of metabolic parameters including proteinuria.

Funding Source:

Government:

Grant Agency of the Czech Republic

Reviewer Comments:

The design is not well reported, making it difficult to follow the randomization process and follow-up. Patients' characteristics at baseline are not complete. No data of BMI and albumin. No information about the exclusion criteria.

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)	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?		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?	No
	2.2.	Were criteria applied equally to all study groups?	???
	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?	No
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)	No
	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.)	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?		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?	???
	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?	No
	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?	???
	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?	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?	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?	No
9.	Are conclusions supported by results with biases and limitations taken into consideration?		No
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	No
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