EAL

CKD: Nutrition Assessment and Best Predictors of CKD (2001)

Citation:

Study Design:

Class:

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Quality Rating:

Research Purpose:

The purpose of this study was to determine if treatment of metabolic acidosis in chronic kidney disease would prevent protein catabolism while following a restricted protein diet.

Inclusion Criteria:

1. CKD

2. Chronic metabolic acidosis (serum bicarbonate <21 mmol/L) for >6 months prior to study inclusion.

3. Weight and anthropometric data stable for 6 months prior to study.

Exclusion Criteria:

1. History of thyroid disorder, diabetes mellitus, myopathy, nephrotic range proteinuria, severe anemia (Hg <9.0 g/dL), hypertension requiring medications.

2. Clinical evidence of salt and water retention.

3. No regular use of medications except for phosphate binders (aluminum hydroxide and/or calcium carbonate).

Description of Study Protocol:

Recruitment: Informed consent obtained. Other recruitment details not provided.

Design: This nonrandomized crossover study was conducted in 3 parts of 2 weeks each.

Blinding used: none

Intervention:

Part 1: (14 days) Baseline study - unrestricted diet continued, metabolic acidosis not treated.

Part 2: (14 days) Low protein study - subjects instructed on 0.6 g protein/kg/day, with a total intake equivalent to previous diet of at least 35 kcal/kg/day for nitrogen equilibrium, metabolic acidosis not treated.

Part 3: (14 days) Low protein diet contined, sodium bicarbonate supplement (1 mEq/kg/day) to correct metabolic acidosis.

Statistical analysis: results expressed as mean + SEM, paired Student's t-test to compare values obtained in same patient. P<0.05 considered significant.

Data Collection Summary:

Timing of measurements:

Dietary intake was monitored throughout study using daily diet record sheets and interviews. Details of collection methods not provided.

Diets were designed to be free of 3-methyl histidine (3-MEH; ie animal protein free) for 72 hours prior to the 24-hr urine collection at the end of each study period. For this reason, protein and calorie supplement drinks were provided during each of these 3-day periods to maintain protein and kcal intakes.

For each study period, the subjects were admitted to the clinical research center at 8:30 a.m. after an overnight fast.

Urine was collected (and refrigerated as possible) for 24-hr prior to admission for analysis of electrolytes, total protein, urate, urea, total nitrogen and urinary 3-MEH.
Biochemical: venous blood samples were taken for electrolytes, urea, creatinine, glucose, urate, cholesterol, TG, liver function. Arterial blood sample was taken for blood gas analysis.
GFR was determined by measuring the clearance of 51Cr-EDTA over a 4-hr period after a peripheral venous injection.
Weight, mid-arm circumference, and triceps skinfold thickness were measured at each study period. Subjects were clinically examined for evidence of salt and water retention. Lying and standing blood pressures were recorded.

S1=measurements obtained on morning following Part 1.

S2=measurements obtained on morning following Part 2.

S3=measurements obtained on morning following Part 3.

Dependent variables:

urinary nitrogen excretion
urinary 3-MEH:creatinine ratio as an index of skeletal muscle protein degradation.

Independent variables:

Dietary compliance
Sodium bicarb therapy compliance
Sodium or fluid retention, changes in MAP
GFR
Anthropometric measurements

Control variables:

serum creatinine, urinary creatinine and exogenous 3-MEH to control for measures of skeletal muscle protein degradation.

Description of Actual Data Sample:

Initial N: n=6 (4 male, 2 female).

Attrition (Final N): 6

Age: the mean age was 60+5.3 yr (range 43-75).

Ethnicity: not mentioned

Other relevant demographics:

Anthropometrics: see results section

Location: study performed in Leicester, England.

Summary of Results:

Mean characteristics of study subjects:
	S1	S2	S3
	usual protein	low pro	low pro + NaHC03
Dietary protein, g/d	82.2 a, b	38.3	39.2
Kcal/kg/d	38.3	39.8	37.8
Weight, kg	69.4	69.1	69.4
MAC, cm	28.5	28.4	28.1
TSF, mm	17.2	17.4	17.8
Serum albumin g/L	38.8	37.8	38.5
Hemoglobin, g/dL	11.0	10.9	10.6
Serum creatinine, umol/L	465.5	487.3	486.8
MAP, mm Hg	118.2 b	114.0	110.3
Arterial pH	7.28 b	7.31 d	7.35
NaHCO3, mmol/L	17.0 b	18.3 d	24.3
GFR, ml/min	12.8	13.2	13.6
Urine pH	5.5 c	5.8 d	6.8
Urine K, mmol/24 hr	70.3 a	56.3	65.8
Urine creatinine, mmol/24 hr	8.8	8.5	8.5
Urine urate mmol/24 hr	2.2 e	1.7	1.7
serum urea, mmol/L	22.7 e	17.6 d	15.2
Urine urea mmol/24 hr	231.5 e	163.3 f	134.5
a P<0.01 S1 vs. S2
b P<0.01 S1 vs S3
c P<0.05 S1 vs S3
d P<0.01 S2 vs. S3
e P<0.05 S1 vs S2
f P<0.05 S2 vs. S3

Dietary compliance, assessed to be good throughout the study.
Sodium bicarb therapy compliance, assessed to be good, based on weekly tablet count.
No clinical evidence of salt or water retention, significant decrease in MAP.
GFR constant throughout study.
No changes in anthropometric measurements throughout study.

The major response to the low protein diet was a significant change in nitrogen metabolism, indicated by significant decreases in serum urea, urine urea, and total urinary nitrogen excretion (S1: 264.4±17.9 mmol/d vs S2: 196±17.6 mmol/d, P<0.003). This was due to significantly decreased excreation of both urea nitrogen and non-urea nitrogen (primarily ammonia).

Correcting metabolic acidosis resulted in increased excretion of sodium and potassium and further significant changes in nitrogen metabolism. Serum urea and urine urea excretion decreased significantly. Total nitrogen excretion decreased further from S2 measures (S3: 146.7+16 mmol/day, P<0.02), again due to significantly decreased excretion of both urea nitrogen and non-urea nitrogen.

The fractional degradation rate of skeletal muscle myofibrillar proteins, as measured by the 3-MEH:creatinine ratio per 24 hours, increased during the low protein diet (S1: 20.33±1.0 µmol/mmol vs S2: 23.5 ±1.09 µmol/mmol, P<0.01). Treatment of metabolic acidosis while on the low protein diet significantly decreased skeletal muscle degradation (S3:18.67±1.2 µmol/mmol, P<0.01). This decline is also significantly less that the muscle protein degradation observed at S1 (P=0.05).

Author Conclusion:

Even though the adaptive responses to the introduction of a low protein diet in patients with mild CKD appear to be normal, these diets are more frequently prescribed for patients with more advanced kidney impairment, often complicated by metabolic acidosis. This study demonstrates that in such patients, the metabolic adaptation to low protein diets is impaired. Such patients should not be prescribed a protein restricted diet without correction of acidosis. If a low protein diet is prescribed in these circumstances, not only is it likely to be less efficient in achieving its primary objective, it could also simultaneously expose the patient to the risk of accelerated loss of lean body mass.

Funding Source:

Reviewer Comments:

Although a dietitian instructed the patients to follow the low protein (0.6 g protein/kg/d) the amount of time that the dietitian spent with the subjects was not reported. This study suggests following CO2 in subjects with CKD and treating metabolic acidosis will help prevent protein malnutrition.

Despite the small study sample, CKD subjects on a low protein diet significantly improved nitrogen balance and exhibited less muscle protein degradation when metabolic acidosis was corrected.

Small study population, but meticulous methods and results described in detail add emphasis to reported outcomes. Extended discussion section adds rationale to interpretation of results.

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?		???
	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?		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?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	N/A
	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?	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?	Yes
	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?	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?	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?	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)?	N/A
	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