EAL

CKD: Anemia (2001)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The purpose of this paper is to demonstrate the need for adequate folate when treating anemia in CRF with erythropoeitin.

Inclusion Criteria:

Patients with CRF and treated with rhEPO for 1-26 months without an adequate response to rHuEpo therapy.

Exclusion Criteria:

severe hyperparathyroidism
diseases of the bone marrow
infections
chronic blood loss
inflammatory disease
aluminum intoxication
iron deficiency

Description of Study Protocol:

Recruitment: Not clearly stated- 82 patients suffering from chronic renal diseases, treated with rhEPO for a time period of 1-26 months. 13 of these patients enrolled due to inadequate response to rhEPO treatment.

Design: Nonrandomized Clinical Trial

no protein restriction
patients encouraged to consume high protein diet
phosphorus and potassium restrictions (levels of restriction not indicated)
time frame for the study: 26 months

Blinding used (if applicable): not used

Intervention (if applicable):

all 13 patients received rhEPO, mean dose of 75 U/kg body weight
8 of these patients recieved folic acid 10 mg/day
hemoglobin concentrations of < 11 mg/ml and hematocrit of <30% recived rhEPO (Recormon)
rhEPO given subcutaneously 3 times a week for at least 12 weeks
normal iron status as determined by ferritin >100 ng/ml and ferritin saturation >20%; weekly ferrihydroxydisaccharide was given IV (equivalent to 100 mg metallic iron).
additional medication provided prn: digitoxin, enalapril, nifedipine, dihidralazinsulfate, calcitriol or calcium lactate
No methotrexate or other drug known to antagonize the effect of folic acid was administered

Statistical Analysis

All data expressed as means +/- standard deviation
Analyzed for statistical significance by analysis of variance and Student's t test for paired and unpaired samples where appropriate
p < 0.05 considered significant

Data Collection Summary:

Timing of Measurements:

rhEPO given subcutaneously 3 times a week for at least 12 weeks. 8 patients with imparied Hct response to rhEPO therapy and macrocytic anemia received folic acid for a mean period of 3.14 +- 1.1 months.

Dependent Variables:

hematological profile determined using a Coulter counter
serum ferritin: used a commerically available immunological dimming assay
iron saturation calculated using serum iron: Ferrozine assay
transferrin: nephelometric mearurement
B12 and folic acid measured simultaneously using a radioassay kit
aluminum concentration setermined by atom absorption spectrometry

Independent Variables:

folic acid supplementation
rhEPO

Control Variables:

Description of Actual Data Sample:

Initial N: 13 subjects who did not respond adequately to rhEPO. 69 patients with chronic renal disease with regular response to rhEPO served as controls.

Attrition (final N): 13 subjects, 4 male, 9 female

Age: mean, 65 years (54-78)

Ethnicity: not stated

Other relevant demographics:

9 patients on hemodialysis
4 were immediately before starting it

Anthropometrics: not stated

Location: Austria

Summary of Results:

Hematocrit response to rhEPO before study:
	Control		folate deficient
	n=68		n=13
		%
baseline	20+4.2		19+2.9
+rhEPO	31+4.5 P<0.001		23+3.8 NS

Before starting rhEPO in all patients, MCV, aluminium, B-12 and folic acid levels all WNL:

Hematological Profile Before Treatment
Item	Value	WNL
MCV	90.3 fl (80.8-96.6 fl)	Yes
Aluminium	< 2 micromol/L	Yes
B12	280 pmol/l (normal 118-720 pmol/l)	Yes
folic acid	15 nmol/l (normal 3.4 to 38 micromol/l)*	Yes

* nmol and micromol were stated in the text- ? error vs these are interchangeable terms

During treatment:

transferrin saturation was more than 20% after administration of iron
mean serum ferritin level during rhEPO treatment was 169+/- 38 ng/ml (normal reference value 10-150 ng/ml)

After rhEPO treatment period between 1 and 26 months (mean 6.5 months):

MCV of all 13 patients showed significant increase from 90.5 to 104.7 fl (p <0.05)

8 patients with imparied Hct response to rhEPO therapy and macrocytic anemia received folic acid for a mean period of 3.14 +- 1.1 months:

Patients who received folic acid
MCV decreased	12.989 +/- 9.2 fl	p < 0.05
Hct increased	23 +/- 3.3 to 30 +/- 4.2%	p<0.01
rhEPO dose decreased	from 75 U/kg to 60 U/kg	p value not reported
reticulocyte count increased	from 3-5% before folic acid supp to 12-24%	p <0.01

when MCV normalized, folic acid supplement stopped:

when rhEPO therapy continued, MCV again increased in 4 patients
- folic acid admin repeated
- MCV decreased (p value not reported)
no difference between those with preterminal renal failure vs those on hemodialysis

the other 5 patients were given rhEPO without folic acid supplement:

all had MCVs that remained high
Hcts were inadequate for rhEPO therapy (mean Hct 23 +/- 3.8%)

Author Conclusion:

The administration of rhEPO influences the metabolism of folic acid.
Although the patients in this study had vitamin B12 and folic acid serum levels before starting rhEPO, folic acid stores became exhausted during therapy.
Perhaps the enhanced erythropoiesis during rhEPO treatment is responsible for the increased need for folic acid.
The close observation of MCV is very important for the decision whether folic acid substitution is necessary or not.
In patients suffering from renal anemia, rhEPO therapy is sometimes accompanied by a distinctly increased MCV and decreased rhEPO response.
Uner these circumstances and after the exclusion of other interfering factors, the additional administration of folic acid could again normalize the erythrocyte parameters.
The need for folic acid does not exclusively depend on lowered serum folic acid levels, as macrocytic anemia with normal folic acid values also requires the administration of this vitamin.
The supplementation of folic acid after the exclusion of other interfering factors and independent of normal serum folic acid, could reduce the dosage of rhEPO, which would be helpful in minimizing the costs of this expensive therapy regime.

Funding Source:

University/Hospital:

University Clinic of Vienna (Austria)

Reviewer Comments:

This paper demonstrates the importance of considering folate and B-12 deficiency when hematocrit does not respond to ruEPO treatment in patients with CRF and anemia.

The authors measured serum folate that is a marker for recent folate intake, whereas RBC folate reflects body stores. Serum B-12 levels in the folate deficient subjects were low normal; since normal B-12 metabolism depends on adequate folate, the low values for B-12 would be expected. In addition, serum B-12 is not a good marker for B-12 status.

Measuring folic acid dietary intake of these vs. those who did respond to therapy would be useful to know.

Intervention group numbers quite small (8 and 5).

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?		???
	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?	???
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
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?	N/A
	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?		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?	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?	???
	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?		???
	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?	No
	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?	No
	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)?	???
	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?		No
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	No
10.	Is bias due to study's funding or sponsorship unlikely?		???
	10.1.	Were sources of funding and investigators' affiliations described?	???
	10.2.	Was the study free from apparent conflict of interest?	???