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

Citation:

Ikizler TA, Greene JH, Wingard RL, Parker RA, Hakim RM. Spontaneous dietary protein intake during progression of chronic renal failure. J Am Soc Nephrol. 1995; 6:1386-1391.

Worksheet created prior to Spring 2004 using earlier ADA research analysis template.
PubMed ID: 8589313
 
Study Design:
Time Study
Class:
C - 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 identify the relationship between the progression of renal disease and spontaneous dietary protein intake (DPI) in patients with chronic renal failure (CRF).  Several commonly measured nutritional indices were monitored in an attempt to determine early markers of malnutrition.

Inclusion Criteria:

Patients being treated for CRF.  Causes of renal failure included diabetic nephropathy, chronic glomerulonephritis, hypertension, adult polycystic kidney disease, and other.

Exclusion Criteria:
  • treatment with corticosteroids and/or immunosuppressive agents.
  • previous participation in dietary intervention study or prior restrictions in dietary protein.
Description of Study Protocol:

Recruitment: Patients being regularly monitored by their nephrologist at the Renal Clinic at Vanderbilt University Medical Center between Aug 1990 to Aug 1994.

Design:  Prospective Time Series.  Patients evaluated by the same RD during the entire study period.

Blinding Used:  none mentioned - lab values.

Intervention:  no specific interventions except dietary management of elevated serum potassium (>6.0 mEq/L) and use of phosphate binders for elevated serum phosphorus.  Patients encouraged to eat to satiety.

Statistical Analysis

1. Initial approach - all data points for each subject used:

  • Nutritional parameters averaged, per category of creatinine clearance (>50, 50 - 25, 24 - 10, and <10 mL/min) and analyzed for trends.

  • Correlations between DPI and creatinine clearance (as a continuous function) using Pearson correlation coefficient.  Similar analyses done using either DPI or creatinine clearance as predictor (independent) variables, while other nutritional indices used as outcome (dependent) variable.

2. Mixed model approach - association between variables assessed for each individual, then averaged appropriately over all subjects, incorporating repeated measures with correlation decreasing over time.  Each subject had an initial level of outcome variable, allowing for random effect.  This model allows for other adjustments (control variables) to predict outcome.

3. Some simple correlations between specific variables reported.

Data Collection Summary:

Timing of Measurements: 

  • At each clinic visit:  vitals, weight, BUN, serum creatinine, total bicarbonate, glucose, serum albumin, cholesterol. 
  • Less frequently:  serum transferrin, prealbumin, IGF-1. 
  • 24-hour urine collection once every 4 weeks to 6 months, depending on rate of progression of renal disease.  Total daily urine creatinine, total protein, urea nitrogen obtained from these urine samples. 
  • Creatinine clearance (CrCl) and Dietary Protein Intake (DPI) calculated by formulas provided, using 24 hour urine creatinine data. 

Dependent Variables:  

  • weight
  • serum albumin
  • transferrin
  • prealbumin
  • cholesterol
  • creatinine excretion
  • IGF-1.

Independent Variables:  CrCl or DPI

  • CrCl (mL/min): [urine creatinine (mg/dL) x urine volume (mL/min)/serum creatinine (mg/dL)]
  • DPI: 6.25 x [24-h urine urea nitrogen (g/d) + 0.031 g of N/kg/d) x desirable body weight (kg)] + urine protein (if >5 g/d)

Control Variables: 

  • age (in decades)
  • gender
  • race (white vs nonwhite)
  • presence of diabetes
Description of Actual Data Sample:

Initial N:  90 patients, 46 male/44 female

Attrition (Final N):  90 patients

Age:  53 + 15 years

Ethnicity:  not mentioned

Other Relevant Demographics:  Major causes of renal failure in this study group were diabetic nephropathy (39%), chronic glomerulonephritis (26%), hypertension (8.9%).

Anthropometrics:

Location:  the Renal Clinic at Vanderbilt University Medical Center in Nashville, Tennesse.

Summary of Results:

The mean follow-up time for all subjects was 16.5±11.8 months (range 2 to 48 months).

Mean baseline values + SD

Serum creatinine, mg/dL

3.4±2.2

BUN, mg/dL

46±24

CrCl, mL/min

35.1±26.1

DPI, g/kg/d

0.82±0.28

Serum albumin, g/dL

3.8±0.45

Cholesterol, g/dL

240±73

Transferrin, mg/dL

282±34

Total CO2, mEq/L

22.5±4.41

  • Classification according to levels of renal function (CrCl >50, 50 - 25, 24 - 10, and <10 mL/min) found statistically significant (p<0.05 with standard regression) progressive decreases between groups for DPI, total daily creatinine excretion, cholesterol, total bicarbonate and transferrin.

Correlation with CrCl                
  DPI

Creatinine Excretion

Chol Alb CO2 Transferrin Prealb IGF-1
Correlation Coefficient 0.46 0.44 0.14 0.06 0.35 0.42 0.04 0.06
p value <0.0001 <0.0001 <0.01 >0.25 <0.0001 <0.01 >0.25 >0.25

 

Correlation with DPI                
  CrCl

Creatinine Excretion

Chol Alb CO2 Transferrin Prealb IGF-1
Correlation Coefficient 0.46 0.44 0.12 0.11 0.19 0.33 0.38 0.44
p value <0.0001 <0.0001 <0.05 <0.05 <0.001 <0.05 <0.01 >0.05

 

  • Results show a strong positive correlation between CrCl and DPI.  Decreases in both CrCl and DPI were significantly associated with decreases in total creatinine excretion.  Serum cholesterol and transferrin decreased as both CrCl and DPI decreased.  Stronger associations were found with CrCl than DPI.
  • Using mixed model analysis, rate of decrease of DPI was not substantially changed by gender, race, and diabetic status.
  • Using mixed model analysis, rate of decrease of CrCl was associated with percent decrease of baseline weight (p<0.01) and with transferrin levels (p<0.01).  A significant association was suggested between decrease of CrCl and decrease of IGF-1 (p<0.05).  No association found between decrease of CrCl and changes in albumin, cholesterol and prealbumin.
Author Conclusion:

This study indicated that the spontaneous DPI of patients with CRF decreases significantly as renal function declines. This decrease was particularly notable at creatinine clearance <25 mL/min and was below the minimum daily protein requirement when creatinine clearance is <10 mL/min.

This study confirmed previous findings of decreased renal functions asociated with decreased protein intake in subjects not receiving specific dietary interventions.

These calculated low levels of protein intake were associated with the development of other indices of malnutrition, particularly weight, transferrin, cholesterol and 24 hour creatinine excretion.  Changes occurred progressivley, but parameters of malnutrition worsened when CrCl was <10 mL/min.

Results indicated a significant association between IGF-1 and creatinine clearance, making IGF-1 levels a potential early marker for declining nutritional status.  No relationship was found between serum albumin levels and changes in creatinine clearance, however, other studies have found an association.

Because of the large effect of malnutrition on subsequent survival, dietary protein restriction should be used with caution when creatinine clearance is <25 mL/min.

Early initiation of chronic dialysis therapy should be considered if dietary protein intake falls <0.7 g/kg/d in spite of adequate nutrition counseling.

Funding Source:
Government: NIH, FDA
Reviewer Comments:

It should be noted that the term "Dietary Protein Intake" (DPI) as used in this study represents a calculated value based on 24 hour urine urea nitrogen and does not represent actual diet intake.

The authors note that calculation of DPI assumes neutral nitrogen balance, therefore calculations in this study may overestimate actual protein intake.

Subjects followed in this study did not receive diet counseling, no diet assessment was made, and changes in body weight over the course of this study were not reported.  Therefore, calculated decreases in DPI cannot be directly correlated to recommended protein intakes for this population at large.  The authors' caution in regards to dietary protein restrictions might be reworded to advise "ensuring adequate" protein intake for this population.

The authors make a leap between the measured decreases in renal function and decreases in nutritional parameters because they do not have diet records or diet intervention as part of their study design.  Therefore their results only apply to patients with CRF that do not receive any diet intervention during the course of their disease.

Interesting statistical approach and discussion of data.

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) ???
  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
  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) N/A
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) N/A
 
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? ???
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
  2.1. 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? ???
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
  3. Were study groups comparable? N/A
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
  3.1. 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
  3.2. 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
  3.3. 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
  3.4. 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? ???
  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
  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? N/A
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  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? N/A
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  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? ???
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? ???
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? No
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? No
  6.6. Were extra or unplanned treatments 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
  6.7. 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? ???
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? ???
  7.5. Was the measurement of effect at an appropriate level of precision? ???
  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? 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