EAL

CKD: Protein Requirements (2010)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To examine the short-term renal, hormonal and nutritional responses to dietary protein in patients with biopsy-proven chronic renal transplant rejection.

Inclusion Criteria:

Transplant biopsy showing histologic evidence of rejection or transplant glomerulopathy without evidence for acute rejection or recurrence of the original disease
Proteinuria of 2.0±0.6g per day and serum creatinine of 1.5mg and 5.0mg per dL at the time of entry into the study
Bilateral nephrectomy of the native kidneys or the absence of proteinuria on urinalysis one month post-transplant
Stable immunosuppressive treatment and no therapy with an angiotensin-converting enzyme inhibitor for the two months preceding the study.

Exclusion Criteria:

None except not meeting all inclusion criteria.

Description of Study Protocol:

Recruitment

Subjects were recruited from the renal transplant population at the University of Minnesota.

Design

Randomized crossover study. The study consisted of two 11-day periods during which all subjects were in-patients at the GCRC. By random assignment, seven patients were started on the low-protein diet (0.55g per kg per day) and seven on the high-protein diet (2.0g per kg per day). Diets were supplemented gram for gram by the 24-hour urinary protein loss measured prior to entry into the study. The diets were controlled for sodium, potassium, phosphorus and calories at 35kcal per kg per day. A constant research diet was employed with a two-day cycle menu. The food products were weighed and prepared according to standardized food preparation procedures for research diets. The two periods diets were separated by an interval of one to four weeks. Prior to the start of each dietary period, 24-hour urine was collected for comparison of the regular home diet to those at the end of the low-protein and high-protein diets period at GCRC. Weight, blood pressure and blood sugars (only for diabetic patients) were measured. At the end of each diet period renal clearance studies were performed, 24-hour urine collected at home and all biochemistry and nutritional parameters were analyzed.

Blinding Used

No. Lab tests.

Intervention

Low-protein diet (0.55g per kg per day) vs. high-protein diet (2.0g per kg per day).

Statistical Analysis

Student's paired T-test or Wilcoxon signed run test were used to measure normal distributed variables and non-normal distributed variables respectively (P<0.05).

Data Collection Summary:

Timing of Measurements

Weight was measured daily, blood pressure twice a day and blood sugars for diabetic subjects was measured at least twice a day. Renal clearance, RPF, biochemistry and nutritional parameters were measured at the end of each diet period. The serum urea nitrogen was measured at the beginning and at end of each dietary period.

Dependent Variables

GFR: Inulin
RPF: PAH
Filtration fraction
Urinary total protein: 24-hour urine
Urinary albumin: 24-hour urine
Urinary IgG: 24-hour urine
Urinary urea nitrogen
Hematocrit
Serum urea nitrogen
Serum creatinine
Serum albumin
Tranferrin
Weight
Plasma renin activity.

Independent Variables

Low-protein diet
High-protein diet.

Control Variables

Age
Sex
Primary renal disease
Immunosuppressive drugs
Time of the transplant
Antihypertensive drugs.

Description of Actual Data Sample:

Initial N: 14 (seven males and seven females)
Attrition (final N): 14 (seven males and seven females)
Age: Mean age 37+4.0
Other relevant demographics: All patients were on antihypertensive treatment. Drugs were not changed throughout the study, except by one patient. The mean time of transplant was 77.4+14.2 months. Primary renal diseases were chronic glomerulonephritis (eight), diabetic nephropathy (three) and unknown (three).
Location: University of Minnesota, USA.

Summary of Results:

Parameters were measured on the final day of each dietary period.

Variables	High-Protein Diet	Low-Protein Diet	Statistical Significance of Group Difference
Weight (kg)	69.0±3.5	70.0±3.4	NS
Serum urea nitrogen (mmol per L)	34.3±3.6	10.7±1.8	P<0.01
Urine urea nitrogen (mmol per day)	595±54	171±16	P<0.01
GFR (ml per minute per 1.73m²)	27±4	25±4	NS
RPF (ml per minute per 1.73m²)	121±14	102±11	NS
Filtration fraction	0.24±0.02	0.25±0.02	NS
Hematocrit	0.30±0.02	0.30±0.02	NS

Other Findings

The average daily protein intake for high-protein and low-protein diets was 41g and 145g respectively. The calorie content was 2,430 and 2,458 for low-protein and high-protein diets respectively.
Serum total protein, albumin and tranferrin were significantly lower at the end of low-protein diet compared to the high-protein diet. The calculated nitrogen balance on the final day of the low-protein and high-protein diet was +0.30±0.45 and +5.94±1.78g, respectively.
Creatinine was significantly higher on the high-protein diet
24-hour urinary excretion of total protein, albumin and IgG were significantly lower at the end of low-protein diet compared to the high-protein diet
Fractional clearance of albumin and IgG was significantly lower on the low-protein diet; 43% decrease in albumin(P<0.01) and 60% decrease in IgG (P<0.001)
The plasma renin activity was significantly higher on the high-protein diet (P<0.05).

Author Conclusion:

A low-protein diet reduces proteinuria and lowers plasma renin activity in patients with chronic rejection. Dietary protein restriction may improve the course of renal failure in chronic rejection partly by suppressing the renin-angiotensin system. Studies are needed to establish the safe level of dietary protein restriction in these patients and to assess the efficacy of such restriction in slowing the progression of renal failure.

Funding Source:

Government:

U.S Public Health Service Grants AM-31437

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

Overall the study is very well designed. However, the small number of subjects and short period of time are the main limitations of the study, which is recognized and considered by the authors. The efficacy of low-protein diet only applies for a short period of time in patients with chronic renal transplant rejection.

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?		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
	2.3.	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?		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
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	No
	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%.)	N/A
	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?		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.)	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
	5.5.	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?	N/A
	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)?	N/A
	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?		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