EAL

CKD: Anemia (2010)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To evaluate the rate of decline of renal function and the duration of the predialysis period in patients treated with rHuEpo.

Inclusion Criteria:

Serum creatinine > 300 micromol/L and/or creatinine clearance < 15 mol/min/1.73 m²

Exclusion Criteria:

None noted.

Description of Study Protocol:

Recruitment

67 adult predialysis CRF patients followed at Necker Hospital between January 1990 and December 1999.

Design: Cohort Study

rHuEpo therapy given for hemoglobin level <9 g/dl (13 cases) or between 9 and 10 g/dl with poorly tolerated anemia (11 patients): "Epo+"
all received identical care

Blinding used (if applicable)

Not applicable.

Intervention (if applicable): Protein restriction, oral vitamin supplementation, and recombinant human erythropoietin administered subcutaneously.

Statistical Analysis

mean + SD
inter-group comparisons: ANOVA and chi square test of Pearson
P value < 0.05 considered significant

Data Collection Summary:

Timing of Measurements

every 3 months before starting rHuEpo; monthly thereafter in both groups
serum cr, Hb, body wt, blood pressure each visit
creatinine clearance calculated via Cockcroft-Gault formula
rate of decline in creatinine clearance determined over 24 months preceding start of follow-up

Dependent Variables

change in creatinine clearance before treatment (ml/min/1.73 m²/month)
change in creatinine clearance after treatment (ml/min/1.73 m²/month)
duration to dialysis (months)
Hb at end (g/dl)
systolic blood pressure at end (mmHg)
diastolic blood pressure at end (mmHg)
MAP at end (mmHg)
creatinine clearance at end (ml/min/1.73 m²/month)

Independent Variables

Diet: 0.7-0.8 g/kg/day protein restriction

Oral vitamin supplementation:
- B1 and B6 (250 mg each, twice weekly)
- Vitamin B12 (1 mg twice weekly)
- Folic acid (5 mg three times/week). Increased to 5 mg daily with rHuEpo treated patients.
- Iron (80-120 mg elemental iron daily) from the time when creatinine clearance dropped below 25-30 ml/min/1.73 m²
Recombinant human erythropoietin administered subcutaneously for hemoglobin level <9 g/dl (13 cases) or between 9 and 10 g/dl with poorly tolerated anemia (11 patients): "Epo+" :
- 2000-4000 units/week in two injections, in order that the increase in Hb level did not exceed 1 g/dl/month
- Maintenance doses ranged from 1000-4000 units /week aimed at a taret Hb level of 11.5 + 0.5 g/dl.

Control Variables:

none reported

Description of Actual Data Sample:

Initial N: 67 subjects

Attrition (final N): 63 (94%), 45 males, 18 females. 4 patients started on rHuEpo treatment at advanced stage of chronic renal failure and who reached end stage renal disease were excluded from data analysis. 43 with less marked and asymptomatic anemia who did not require rHuEpo therapy until the start of dialysis constituted the control group: "Epo-"

Age: 67.1 + 9.2 for Epo +; 58.7 + 13.4 for Epo - (P <0.01)

Ethnicity: Caucasian

Other relevant demographics: Diabetes: Epo +: 0 Epo -: 5 (p <0.01)

Anthropometrics: The proportion of women was significantly higher, as well as the mean age of patients in the Epo + group, and there were no diabetics in the Epo + group. There were no significant differences between groups in the distribution of primary renal disease, Scr and Ccr values, blood pressure or the proportion of patients treated with ACE inhibitors.

Location: Necker Hospital, Paris, France

Summary of Results:

Variables	Treatment Group Measures and confidence intervals	Control group Measures and confidence intervals	Statistical Significance of Group Difference
change in creatinine clearance before treatment	0.36 + 0.16	0.55 + 0.48	P < 0.01
change in creatinine clearance after treatment	0.26 + 0.15	0.57 + 0.44	P < 0.01
Hb before HD initiation(g/dl)	11.3 + 0.9	9.5 + 0.9	P < 0.01
Duration time to dialysis (months)	16.3 + 12.7	10.6 + 6.1	P < 0.01

Other Findings

nonsignificant changes between groups for bloop pressure or creatinine clearance at the end of treatment
nonsignificant changes for treated groups in patients with slowed vs. unchanged rate of progression on rHuEpo therapy

Author Conclusion:

The data in this study provided conclusive evidence that rHuEpo therapy was associated with a partial correction of anemia in rHuEpo-treated patients when compared to untreated patients with a similar degree of renal failure.
The authors partially attribute favorable Hb levels to providing vitamin (B1, B6, B12, folic acid) and iron supplementation.
Supplementation of folic acid and iron may have contributed to the favorable response to rHuEpo therapy.
Moderate doses of rHuEpo in predialysis chronic renal failure patients achieve effective and sustained correction of anemia, without inducing worsening of blood pressure or adverse effects on renal function.
rHuEpo therapy resulted in a substantial delay in the need for renal replacement therapy in half of the study patients.
Authors unclear as to possible mechanisms for the slowing of CRF progression in some of the patients treated with rHuEpo, although may due to improved tissue oxygenation.
Recommend validation of these results in a large, prospective, randomized study.

Funding Source:

University/Hospital:

Necker Hospital (Paris, France)

Reviewer Comments:

Did not explain how protein intake recommendations were enforced or evaluated, although in the discussion, the authors state protein-caloric intake was carefully monitored.

Treatment group contained 20 patients vs 43 patients in control group (p value not reported).

No patients with diabetes were in the epo treatment group, while 5 were in the control group (p <0.01). This may affect findings and was not addressed by the authors in the discussion.

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?		No
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	No
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	No
	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?	No
	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?	Yes
	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?		No
	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.)	No
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	No
	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?		???
	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?	???
	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?	???
	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)?	No
	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?		???
	10.1.	Were sources of funding and investigators' affiliations described?	No
	10.2.	Was the study free from apparent conflict of interest?	???