EAL

CKD: Physical Activity (2008)

Citation:

Castaneda C, Gordon PL, Parker RC, Uhlin KL, Roubenoff R, Levey AS. Resistance training to reduce the malnutrition-inflammation complex syndrome of chronic kidney disease. Am J Kidney Dis. 2004; 43 (4): 607-616.

PubMed ID: 15042537

Study Design:

Randomized Controlled Trial

Class:

A - Click here for explanation of classification scheme.

Quality Rating:

POSITIVE: See Quality Criteria Checklist below.

Research Purpose:

To evaluate whether 12 weeks of resistance training in patients with chronic kidney disease without dialysis and consuming a low-protein diet (0.6g per kg per day) reduces systemic inflammation in association with the improvement of nutritional status and muscle strength.

Inclusion Criteria:

Chronic kidney disease (CKD)
Creatinine concentration from 1.5mg to 5.0mg per dL
Prescription of low-protein diet (0.6g per kg per day).

Exclusion Criteria:

Body weight loss more than 25% from the beginning of the study
Hospitalization
Precluding exercise
Need for dialysis or transplant
Biochemical signs of malnutrition.

Description of Study Protocol:

Recruitment

Clinical patients over 50 years old with moderately severe chronic kidney disease (median GFR, 27.5ml per minute per 1.73m²), not on dialysis therapy. (Note: Same patients as Castaneda, 2001.)

Design

Randomized clinical trial for 12 weeks
All patients consumed a diet with 0.6g per kg per day of protein for two to eight weeks before randomization
All were maintained on a low-protein diet after being assigned to resistance-exercise training group or control group without exercise
The dietitians monitored diet adherence and energy intake using three-day diet diary-assisted recalls.

Blinding Used

Dietitian and exercise trainer were not blinded.

Intervention

Resistance-exercise training: Three times a week with each section about 45 minutes, including a five-minute warm-up, 35 minutes resistance training and a five-minute cool-down
Control exercise: The same stretching and flexibility exercise as those used during cool-down in the intervention group
Protein diet: 0.6 per kg per day (both groups).

Statistical Analysis

T-test and linear regression analysis (variables with normal distribution) and Mann-Whitney test or median regression analysis (variable with non-normal distribution)
Spearman correlation to see the association between inflammatory markers and nutritional variables.

Data Collection Summary:

Timing of Measurements

Dietary intake, nutritional and functional parameters, blood and urine were collected at baseline and after 12 weeks.

Dependent Variables

Serum CRP and IL-6 determined using an enzyme immunoassay
Muscle mass measured by biopsy
Whole-body muscle strength assessed with 1MR testing
Body weight (kg) and body mass index (BMI)
Blood samples analyzed for serum creatinine, urea nitrogen concentration, albumin, transferrin, hematocrit and hemoglobin
Urine samples analyzed for urea.

Independent Variables

Resistance-exercise training vs. control exercise
Both groups were on a low-protein diet (0.6 per kg per day).

Control Variable

Cholesterol-lowering agents.

Description of Actual Data Sample:

Initial N: 26 (nine female, 17 male)
Attrition (final N): 26; 14 in the resistance training group and 12 in the control group
Age: Older than 50 years, mean 65 (resistance training) and 64 (control)
Other relevant demographics: Body weight higher in the resistance training group, with BMI slightly high in both groups
Anthropometrics: Matched at the baseline for age, body weight and biochemical variables. At screening, there was no difference in the renal function between the two groups.
Location: Greater Boston, MA, area.

Summary of Results:

Nutritional and Functional Parameters

	Exercise+Low-Protein Baseline	12 Weeks	Change	No-Exercise+Low-Protein Baseline	12 Weeks	Change	*P Group Effect
Body Weight (kg)	84.6±15.8	84.8±16.2	0.2±2.6	76.1±13.5	72.5±9.0	-3.6±1.5	0.049
BMI	29.3±6.6	29.3±6.6	0.0±0.8	26.8±2.7	25.7±2.1	-1.1±0.7	0.203
Type I Muscle Fiber Area (mcg m²)	3.887±1.566	4.821±1.411	934±1,486	4.578±1.524	3.960±998	-618±967	0.031
Type II Muscle Area (mcg m²)	3.626±1.216	4.578±1.524	811±1,479	3.957±988	3.399±814	-558±1,126	0.045
Muscle Strength (kg)	298±106	384±123	86±45	265±86	230±94	-35±62	0.001

All values expressed as means±SD. Variables adjusted for sex and baseline body weight.

*Treatment group effect on the change in each main outcome.

Systemic Inflammation

	Exercise+Low-Protein Baseline	12 Weeks	Change	No-Exercise+Low-Protein Baseline	12 Weeks	Change	*P Group Effect
CRP (mg per dL)	7.8(6.0)	6.1(6.0)	-1.7(0.0)	6.2(6.0)	7.7(6.9)	1.5(0.0)	0.049
IL-6 (pg per ml)	11.3(10.5)	6.9(6.5)	-4.2(-3.6)	7.7(6.9)	10.0(9.8)	2.3(3.0)	0.012
Transferrin (mg per dL)	178±32	258±52	80±25	175±34	177±37	2±34	0.042
Albumin (g per dL)	3.7±0.3	3.8±0.2	0.1±0.2	3.8±0.4	3.6±0.2	-0.2±0.2	0.091

All values expressed as means ±SD or geometric mean (median). Variables adjusted for sex, baseline body weight and each respective baseline inflammation marker (i.e. CPR or IL-6 level).

*Treatment group effect on the change in each main outcome.

Other Findings

Inversed association of muscle mass (determined by the Type I and II muscle fiber) and the inflammatory marker, IL-6, persisted in both groups (Type I muscle fiber: R=-0.58, P<0.02; Type II muscle fiber: R=0.68, P=0.005). The same association was found between IL-6 and muscle strength: R=-0.49, P=0.05.
CPR was correlated with the levels of IL-6 (R=0.46, P=0.04); however, there was only an inversed association between CPR with muscle strength (R=-0.45, P=0.03) and albumin (R=-0.47, P=0.05), but not with muscle mass.
There was a 24% reduction in protein intake in both groups at the end of the study, but the average intake of protein and calories was not different between the two groups. Calories were low in both group.

Author Conclusion:

Resistance training and low-protein diet reduced inflammation and improved nutritional status and muscle strength in patients with moderate chronic kidney disease
These data and few studies in patients with earlier stages of chronic kidney disease and under hemodialysis suggest a role for resistance training in increasing muscle mass and strength, therefore improving the quality of life for CKD patients.

Funding Source:

Government:

NIA, New England Medical Center Research Fund, USDA

Reviewer Comments:

Same patients as Castaneda, 2001
Well-designed and executed randomized clinical trial study
Limitations of the study, such as sample size and application of this therapy to other CKD patients who do not consume low-protein diet or are in different stages of the disease, were considered (recognized) by the authors
Results on the muscle strength may be biased because the exercise trainer was not blinded
Long-term interventions of resistance exercise should be investigated.

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
	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
	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
	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
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
	1.	Was the research question clearly stated?	Yes
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.1.	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
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
	1.3.	Were the target population and setting specified?	Yes
	2.	Was the selection of study subjects/patients free from bias?	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
	2.1.	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
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	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?	No
	2.4.	Were the subjects/patients a representative sample of the relevant population?	No
	3.	Were study groups comparable?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	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?	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	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
	3.4.	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
	3.5.	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
	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.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	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
	4.2.	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
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	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
	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.	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?	Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	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
	5.2.	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
	5.3.	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
	5.4.	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
	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.	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
	6.1.	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
	6.2.	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
	6.3.	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
	6.4.	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
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments 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
	6.7.	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
	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.	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
	7.1.	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
	7.2.	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
	7.3.	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
	7.4.	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
	7.5.	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
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	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.	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
	8.1.	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
	8.2.	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
	8.3.	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
	8.4.	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
	8.5.	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
	8.6.	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
	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.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	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.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes