EAL

DM: Protein (2007)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The purpose of this study was to determine the mechanisms responsible for the faster initial decline in the GFR in patients with type 1 diabetes and diabetic nephropathy when following a low protein diet.

Inclusion Criteria:

1. Diagnosis of diabetic nephropathy (albuminuria >300 mg/24-h in 2 of 3 urine samples, duration of type 1 diabetes for >=10 yr, presence of diabetic retinopathy).

2. GFR >=25 ml/min/1.73m²

3. 18-60 yr of age

Exclusion Criteria:

1. Malignant hypertension

2. History of CHF

3. History of MI

4. Coronary bypass surgery within the last 3 months.

Description of Study Protocol:

Recruitment: consecutive patients seen at the clinic and meeting inclusion criteria were recruited into the study

Design: subjects were randomized to 1 of 2 study diets for 4 wk, (phase I) followed by 4 wk on usual diets (phase II, recovery). Subjects continued with prescribed anti-hypertensive medications.

Blinding Used (if applicable): not specified

Intervention Used (if applicable):

Diets:

subjects were randomized to either a low protein diet (LPD)(0.6 g/kg) or normal protein diet (NPD)(1.1 g/kg).
Patients excreting >=2 g urine albumn/24 hr were allowed 1 g dietary protein/extra g of urinary protein.
subjects randomized to LPD were provided frozen meals to take home for lunch and dinner from a hospital kitchen and planned by a dietitian.
3-d diet records were completed at each study period: baseline, 4 wk and 8 wk.

Statistical Analysis

clinical characteristics at baseline gven as mean ± SEM or median
follow-up values for urinary excretionof albumin, sodium, and fractional clearance of albumin were logarithmetically transformed before statistical analyis because of their positively skewed distribution
95% confidence intervals for changes between visits
unpaired t test used to compare baseline data and changes in nutritional data, GFR, albumiuria, and blood pressure between the LPD group and the NPD group during phases I and II, except baseline data of albuminuria, which was tested by the Mann-Whitney U-test.
Spearman's rank correlation used to analyze data for connections.

Data Collection Summary:

Timing of Measurements

24-h dietary protein intake was estimated using 3 consecutive 24-h urine collections at baseline, wk 4, and wk 8 using the urinary excretion of urea nitrogen as a marker.
GFR measured after a single IV injection of 3.7 MBq⁵¹Cr-EDTA at 8 a.m. by determining the radioactivity in venous blood samples taken at 180, 200, 220 and 240 minutes after the injection. Results were standardized for 1.73 m²body surface area.
supine blood pressure, HbA1c, blood glucose, 24-hr urine albumin and sodium.

Dependent Variables

GFR
albuminuria
arterial blood pressure

Independent Variables

protein intake
- subjects were randomized to either a low protein diet (LPD)(0.6 g/kg) or normal protein diet (NPD)(1.1 g/kg).
- Patients excreting >=2 g urine albumn/24 hr were allowed 1 g dietary protein/extra g of urinary protein.
- subjects randomized to LPD were provided frozen meals to take home for lunch and dinner from a hospital kitchen and planned by a dietitian.
- 3-d diet records were completed at each study period: baseline, 4 wk and 8 wk.

Control Variables: not specified

Description of Actual Data Sample:

Initial N: 30 15 subjects were randomized to each study diet but 1 subject randomized to the LPD group dropped out of the study after randomization and was not included in the data analysis.

Final N: 29

Ethnicity: White

Age, Other Relevant Demographics, Anthropometrics:

	LPD n=14	NPD n=15
Age, yr	47±3	44±2
Duration of Diabetes, yr	29±2	29±2
Duration: diabetic Nephropathy, yr	9±2	10±2
BMI	25±1	25±1
HbA1c, %	8.4±0.3	8.6±0.3
Dietary protein (g/kg)	1.2±0.1	1.1±0.1
GFR	94±6	92±6
Urine albumin, mg	397	438
MAP, mm Hg	95±2	100±3

Location: Steno Diabetes Center, Copenhagen, Denmark.

Summary of Results:

At baseline, the LPD group and the NPD group were comparable regarding dietary protein intake, GFR, albuminuria, and MAP.

Significant differences by study group and study period:

Phase I:

	LPD (CI)	NPD (CI)	Significance
protein intake, g/kg	-0.4 (-0.3 to-0.5)	0.0(-0.2 to 0.1)	(P<0.0001)
GFR, ml/min	-8.6 (-3.2 to -13.9)	-2.5 (-6.8 to 1.8)	(P=0.07)
Urine albumin, %	-28.7(-14 to-40.9)	0.0(- 23.5 to 20.1)	(P<0.05)

Phase II:

	LPD (CI)	NPD (CI)	Significance
protein intake, g/kg	0.3 (0.2 to 0.5)	0.0(-0.2 to 0.1)	(P<0.0001)
GFR, ml/min	5.9 (0.8 to 11.0)	-2.9(-6.4 to 0.6)	(P<0.01)
Urine albumin, %	25(4.5 to 49.6)	2.9(-18.3 to 29.7)	(P<0.16)

Author Conclusion:

Dietary protein restriction for 4 wk induces a reversible decrease in GFR and albuminuria in individuals with type 1 diabetes with diabetic nephropathy, whereas systemic blood pressure remains unchanged.

Our data render some support of the hypothesis that the initial faster reduction in GFR after initiating the LPD in those patients is due to a local intrarenal hemodynamic effect achieved by improved autoregulation of GFR.

We have confirmed and extended the previously reported reversible decrease in albuminuria during a LPD in diabetic nephropathy. This antiproteinuric effect of LPD is present during antihypertensive treatment.

Funding Source:

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

This study shows the importance of looking at initial changes in renal function in studies using low protein diets to evaluate the effect on renal function. In addition, this study shows the importance of having a study long enough to account for the initial changes in renal function with a decrease in dietary protein.

Good monitoring of dietary protein intake with 24-h urine nitrogen.

It would have been helpful if actual values (e.g. grams of protein) rather than percent change was reported in the 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?		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?	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
	3.2.	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
	3.4.	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?	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?	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)?	No
	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?	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