Racial variations in erythropoietic response to epoetin alfa in chronic kidney disease and the impact of smoking

Charlotte Jones-Burton1, Stephen L. Seliger1, Jeanine Brown2, Lucy Stackiewicz2, Van Doren Hsu3 and Jeffrey C. Fink1,2

1 Division of Nephrology, University of Maryland School of Medicine, 2 Early Renal Insufficiency Program, University of Maryland Medical Center and 3 Pharmaceutical Research Computing, University of Maryland School of Pharmacy, Baltimore, MD, USA

Correspondence and offprint requests to: Dr Jeffrey C. Fink, University of Maryland Medical System, Division of Nephrology, Room N3W143, 22 S. Greene St. Baltimore, MD. 21201, USA. Email: Jfink{at}medicine.umaryland.edu



   Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Of the known risk factors for chronic kidney disease (CKD), race represents one that is non-modifiable, while smoking is another that is modifiable. Moreover, smoking tends to increase red blood cell mass, which is frequently diminished in CKD. No studies have examined the interplay of race with smoking on anaemia management in patients with CKD.

Methods. We examined the effects of smoking on anaemia management in CKD and its variation across race in a previously conducted study of CKD patients (n = 1312) initiated on weekly epoetin alfa and followed for 16 weeks. Smoking status was classified as current vs non-smoker. Race was classified as African-American vs non–African-American. Changes in estimated glomerular filtration rate, urinary albumin excretion, and erythropoietic response to weekly epoetin alfa were examined.

Results. Overall, African-Americans had lower baseline Hb than non–African-Americans. African-American non-smokers did not mount an erythropoetic response comparable to other non-smokers by final Hb (mean 11.29 g/dl vs 11.64 g/dl, P<0.001) or week 16 Hb (mean 11.61 g/dl vs 11.86 g/dl, P = 0.02). However, African-American smokers had a more significant erythropoietic response than their non-smoking counterparts and were comparable to their smoking non-African-American counterparts. There was no effect of smoking on renal function or urinary protein excretion over the course of the study.

Conclusion. African-American non-smokers exhibit a diminished response to standard epoetin alfa dosing than non-smokers in other races. However, African-American smokers with CKD exhibit a response to epoetin alfa comparable to patients of other races. These findings may have implications for African-Americans who have CKD-related anaemia.

Keywords: anaemia; chronic kidney disease; epoetin alfa; race; smoking



   Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
There is growing recognition of a racial disparity in the chronic and end-stage renal disease (ESRD) population. Race, particularly the African-American race, is associated with an increased risk for chronic kidney disease (CKD) [1]. In fact, the prevalence of ESRD is 4.5 times higher for African-Americans than Caucasians [2]. Given the dismal outcome of patients with ESRD, there is an increasing emphasis on treating CKD in order to avert the rising incidence of ESRD.

It is well established, though often not practiced, that rigorous blood pressure and glycaemic control along with blockade of the renin–angiotensin system (RAS) are essential for slowing the progression of CKD to ESRD [3–4]. However, even with aggressive implementation of these therapies, most patients with CKD continue to lose renal function—African-Americans at a more rapid rate than Caucasians [5]. Thus, practitioners are faced with the reality of continued deterioration in renal function in most patients with CKD. To improve the outcome of those individuals with CKD who progress to ESRD, there is growing enthusiasm for treatment of the various sequelae of kidney disease, such as anaemia, secondary hyperparathyroidism, malnutrition, and left ventricular hypertrophy. Additionally, there has been new attention directed at modifiable risk factors for kidney disease that may play a role in disease progression.

Cigarette smoking is one such modifiable risk factor. Smoking is associated with progressive renal injury in both diabetic and non-diabetic populations [6–7]. More importantly, it has been shown that progressive renal injury in diabetic smokers with microalbuminuria can be abrogated with smoking cessation [7]. A countervailing finding is that, smoking has a tendency to increase red blood cell (RBC) mass [8,9]. The relevance of this interaction between smoking and RBC mass in persons with CKD is unknown.

Despite the extent of the evidence linking smoking with kidney disease, there have been few studies examining whether smoking accelerates loss of renal function in a population with moderate to advanced CKD [10,11]. Moreover, there are no studies examining the interaction between smoking and anaemia management in the CKD population. Furthermore, the impact of race on this interaction has not been examined. In this study, we conducted a retrospective analysis of a previously completed trial that evaluated once a week dosing of epoetin alfa in a cohort of patients with various stages of CKD and anaemia. Our primary goal was to determine the relationship between smoking and anaemia management.



   Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients
The ‘Clinical evaluation of PROCRIT® dosed once weekly in patients with anaemia due to early renal insufficiency, or ‘POWER’ study was a prospective, multi-centre, open-label, non-randomized study conducted between June 2000 and October 2001 evaluating the efficacy and safety of epoetin alfa given once a week (QW) for 16 weeks to patients with CKD [12]. Inclusion criteria included age ≥18 years of age, presence of CKD not receiving renal replacement therapy [defined as a serum creatinine (SCr) level of 1.5 to 6.0 mg/dl for females and 2.0 to 6.0 mg/dl for males at study enrollment], presence of anaemia [defined by a haemoglobin (Hb) level ≤10 g/dl at study enrollment] and a life expectancy ≥6 months. Exclusion criteria included uncontrolled hypertension, known hypersensitivity to mammalian cell-derived products or human albumin, diagnosis of anaemia due to iron, B12, or folate deficiencies, haemolysis, or gastrointestinal bleeding, severe congestive heart failure (New York Heart Association, Class IV), pregnancy, and treatment with epoetin alfa within 6 months prior to study enrollment.

Measurements
For this study, baseline assessments included patient demographics, weight, blood pressure, primary cause of CKD, and co-morbidities. Smoking status was determined at baseline. In the primary study, smoking history was defined as ‘yes’ or ‘no’, based on self-report. Individuals who reported ‘yes’ were asked to quantify packs per day and number of years smoked. For the current study, individuals were classified as current smokers if they responded ‘yes’ to smoking and associated a value >0 for packs per day; individuals with no packs per day recorded were classified as non-smokers. Race was classified as African-American and non-African-American (including Caucasians and others) based on self-reports. Required baseline clinical laboratory tests included: Hb, reticulocyte count, SCr, ferritin, transferrin saturation, and urine albumin concentration. Cumulative epoetin alfa dose was calculated for each patient for the duration of the study.

In the POWER study, the principal outcomes were haemoglobin (Hb), haematocrit (Hct) and blood pressure, which were monitored weekly until Hb and Hct became stable, and every 4 weeks thereafter. Transfusion utilization, SCr, blood–urea–nitrogen and urine albumin concentration were determined at baseline and every 4 weeks.

Dosage and drug administration
In the POWER study, 10 000 units (U) of epoetin alfa (PROCRIT®; Ortho Biotech Products, L.P.; Bridgewater, NJ) were initiated and administered weekly by subcutaneous (SC) injection. Patients received treatment for up to 16 weeks. If Hb did not increase by ≥1 g/dl after the first 4 weeks of therapy, then the epoetin alfa dose was increased to 20 000 U SC QW at week 5. If a patient did not respond to 20 000 U SC QW, the epoetin alfa dose could be increased at the discretion of the clinician. In patients whose Hb levels exceeded 13 g/dl during the course of the study, epoetin alfa treatment was withheld until their Hb levels decreased to 12 g/dl. Treatment was then resumed at 50% of the previous dose and titrated to maintain the desired Hb level. The dose was also reduced by 50% if Hb levels increased rapidly (>1.3 g/dl in any two-week period). Transfusions were administered at the discretion of the investigator. It was recommended that all patients receive adequate daily oral or intravenous (IV) iron supplementation during the study to maintain a transferrin saturation of at least 20% and a ferritin of at least 100 ng/ml.

Study analysis
This is a retrospective study of the previously conducted prospective POWER trial, to examine the effect of smoking on anaemia management. As a result of this analysis, we post-hoc elected to describe how this relationship varied across race. We restricted the cohort to those individuals who had complete baseline information on smoking, other demographic characteristics (e.g. age, sex, race), and serial measurements of Hb and SCr (n = 1312). The primary exposure of interest in this analysis was smoking. The primary outcome of interest was Hb at 16 weeks. For participants without an available Hb measurement at week 16, the last Hb measurement collected was used and labeled ‘final Hb’. To demonstrate similar results for both analyses, we present results for the final Hb and week 16 Hb. For each patient with available data, we estimated the glomerular filtration rate (eGFR) using the simplified Modified Diet in Renal Disease (MDRD) equation [13]. The Institutional Review Board (IRB) of the University of Maryland School of Medicine deemed the analysis of this secondary data exempt from review because the data was de-identified.

Baseline characteristics were summarized using descriptive statistics. Means and standard errors (SE) were obtained for continuous variables and frequencies, and percentages were obtained for categorical variables. To test the hypothesis, we utilized Student's t-test for univariate comparisons with an emphasis on smokers versus non-smokers and African-Americans versus non-African-Americans. Multiple regression was employed to assess the influence of potential confounding variables on the relationship between smoking and erythropoetic response. Variables included in the multivariate models were those that demonstrated significant variation across exposure groups as demonstrated in Tables 1 and 2. These variables were included whether or not they met absolute criteria for confounding, which requires a relationship with both exposure and outcome. We tested appropriate smoking-by-race interaction terms to evaluate the variable effect of smoking across race (SPSS, version 10 Chicago, IL).


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Table 1. Subject demographics and study characteristics by smoking status

 

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Table 2. Subject demographics and study characteristics by smoking status and race

 


   Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Characteristics of study population
Of the 1557 patients enrolled in POWER, data from 1312 patients met the criteria as described above and were analyzed as part of this cohort. A total of 245 patients were excluded from evaluation due to missing baseline Hb levels (32 patients), baseline Hb levels >10 g/dl (87 patients), baseline SCr levels outside the allowable range or with missing baseline values (121 patients), failure to fulfill all inclusion criteria (12 patients), and missing follow-up Hb values (25 patients); some patients failed more than one criterion. Table 1 depicts demographic and baseline characteristics of the study population classified by smoking status and Table 2 stratifies study participants by race within smoking status with comparisons made between races within smoking status classifications. The factors that significantly differed between groups included age and gender. Baseline Hb levels were not significantly different between smokers and non-smokers, but were lower among all African-Americans vs all non–African-Americans (9.05±0.03 vs 9.20±0.02, respectively, P<0.001, data not shown). African-Americans, as a group, had a significantly higher baseline serum ferritin than their non–African-American counterparts (248.0±15.1 vs 210.0±8.7, respectively, P = 0.02, data not shown). Baseline ferritin, reticulocyte count, transferrin saturation and cumulative epoetin alfa dose were not different between smokers and non-smokers. Likewise, there were no differences in these parameters when stratified by race and gender, except male non-smokers had a slightly higher baseline ferritin when compared to female non-smokers (269.0±18.3 vs 201.0±11.8, respectively, P<0.001). There was no difference in transfusion of RBC among smokers and non-smokers in either racial group.

Change in renal function parameters and blood pressure
Table 3 demonstrates the renal function parameters and blood pressures based on smoking status and Table 4 demonstrates the renal function parameters and blood pressure based on smoking status and stratified by race, at baseline and week 16. Urinary albumin excretion, eGFR and change in these values did not differ between current smokers and non-smokers; and likewise, there were no differences when smokers were stratified by race. Smokers had a higher urinary albumin excretion at baseline when compared to their non-smoking counterparts, but neither smokers nor non-smokers demonstrated a significant increase in urine albumin excretion between racial groups over the duration of the study. eGFR did not decrease significantly among smokers or non-smokers in either racial group during the 16 week study period, but as a group, African-Americans experienced a significant decline in eGFR when compared to non-African-Americans (–1.11±0.37 vs 0.003±0.271, P = 0.02, data not shown). Systolic and diastolic blood pressures at baseline and week 16 were higher in African-American smokers and non-smokers.


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Table 3. Renal function parameters for the study population at baseline and week 16

 

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Table 4. Renal function parameters for the study population at baseline and week 16 by smoking status and race

 
Effects of smoking on erythropoietic response
The variable effects of smoking on erythropoietic response to epoetin alfa in each racial group is shown in Figures 1A and 1B. Figure 1A depicts the mean Hb achieved at each study week over the duration of the study in non-African-American participants categorized by smoking status. In these non-African-American participants, there were no significant differences between smokers and non-smokers in Hb response at each week interval during the study. Figure 1B illustrates the mean Hb achieved at each study week over the duration of the study in African-American participants categorized by smoking status. As shown, anaemia management with epoetin alfa among African-American smokers and non-smokers in the study differed significantly at study weeks 13, 14, 15 and 16. African-American non-smokers had a lower erythropoietic response than their African-American smoking counterparts at study weeks 13, 14, 15 and 16. Furthermore, African-American non-smokers had a diminished erythropoetic response when compared to non-smokers of other races at study weeks 13 (mean Hb 11.63 g/dl vs 11.88 g/dl, P = 0.04), 14 (mean Hb 11.50 g/dl vs 11.83 g/dl, P = 0.01), 15 (mean Hb 11.56 g/dl vs 11.86 g/dl, P = 0.01), and 16 (mean Hb 11.61 g/dl vs 11.86 g/dl, P = 0.02). Erythropoetic response by gender and age was also examined without significant associations between these predictor variables and change in baseline Hb to week 16 or final Hb.



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Fig. 1. (A) Mean haemoglobin of non–African-American (non-AA) smokers (solid line with square) throughout the study. There is no significant difference in erythropoietic response to epoetin alfa treatment when comparing smokers to non-smokers (dashed line with triangle) in non-African-Americans. (B) Mean haemoglobin of African-American (AA) smokers (solid line with square) and non-smokers (dashed line with triangle) throughout the study. There is a significant difference (P<0.05) between African-American smokers in response to anaemia management with epoetin alfa as compared to African-American non-smokers at study weeks 13, 14, 15 and 16 (indicated by an asterisk).

 
Figure 2 depicts the adjusted mean differences in final Hb and week 16 Hb between smokers and non-smokers for all study participants, African-Americans, and non-African-Americans, controlling for age, gender, baseline weight, presence of diabetes mellitus, cumulative epoetin alfa dose, baseline Hb, baseline eGFR, baseline serum ferritin, and systolic and diastolic blood pressures. Among all study participants, there was no significant mean difference in final Hb and week 16 Hb between smokers and non-smokers in the entire study population. Similarly, among non-African-Americans, there was no significant mean difference between smokers and non-smokers in final Hb and week 16 Hb. However, among African-Americans, the adjusted mean difference in final Hb and week 16 Hb was significantly higher in smokers than in non-smokers. This indicates that race, particularly African-American race, modifies the effect of smoking on response to epoetin alfa (P = 0.03 for interaction term).



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Fig. 2. Mean difference in final haemoglobin (Hb) between smokers (gray bar) and non-smokers (black bar) for all participants, African-Americans, and non-African-Americans. There is a significant difference between African-American smokers and non-smokers not seen with non-African-Americans. Interaction term, P = 0.03. Mean Hb adjusted, see text. Final Hb refers to the last Hb recorded.

 


   Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Our secondary data analysis of the ‘POWER’ study found an important interaction between race and smoking status among persons with CKD who were receiving epoetin alfa for the anaemia associated with their kidney disease. While there was no difference in RBC mass at baseline between smokers and non-smokers, and erythropoietic response to epoetin alfa treatment was similar when comparing smokers to non-smokers among non-African-Americans, the erythropoietic response to epoetin alfa varied substantially between African-American smokers and non-smokers. Interestingly, African-American non-smokers did not mount an erythropoietic response comparable to other study participants, but African-American smokers did. Other findings from this study included a non-significant increase in urinary protein excretion among smokers in all racial groups over the 4 months duration of the study throughout the study. Despite this increase in proteinuria, there were no differences in eGFR in smokers vs non-smokers.

Recently, the national smoking rate among American adults was 22.6% [14]. We, along with others, demonstrated a high preponderance (35–60%) of current and past smokers with kidney disease [6,15]. It is well documented in the medical literature that smoking is associated with progressive renal injury in CKD patients, both diabetic and non-diabetic populations. Even though deterioration of renal function was not found in this study, this is not unusual given the limited follow-up period of the original study.

To our knowledge, there are no studies that report the interplay between smoking, anaemia and CKD. After adjusting for potential confounders, African-American non-smokers had a diminished response to anaemia management relative to African-American smokers and non-African-Americans, regardless of smoking status. Even though historical literature describes the effects of smoking on red blood cell mass [8,9], it is unlikely that smoking-related polycythaemia contributed to this differential response in our cohort. However, this observation raises the possibility that African-Americans differ in their mechanism of renal injury with a greater propensity for erythropoietin deficiency at any level of GFR. Under this hypothesis, the putative effect of cigarette smoking on oxygen carrying capacity of red blood cells may be most apparent in African-Americans due to their degree of erythropoietin deficiency. Perhaps cigarette smoking potentiates the response to epoetin alfa providing a plausible explanation for the similar erythropoetic response seen in non-African-Americans that African-American smokers exhibited. This differential response raises the possibility that African-Americans may require increased dosing of epoetin alfa, as with other drugs [16], to achieve a similar response to non-African-Americans. Likewise, the finding of similar cumulative epoetin alfa dosing across ethnic groups despite differential erythropoietic responses suggests that practice patterns should differ across these CKD sub-populations.

Retrospective analyses of existing studies have inherent shortcomings, which need to be considered when interpreting the reported findings. The original study design may not have accounted for all potential confounders and biases that could have affected our study findings. However, since the focus on anaemia management was the initial intent of the primary study, most relevant confounders were measured at baseline and adjusted for in our analysis. For those potential confounders that were not ascertained (i.e. concomitant use of RAS blockers), there is no reason to expect that they would be unequally distributed among the exposure groups. In fact, a recent prospective observational study found similar degrees of prescription of these agents in CKD patients regardless of underlying co-morbidities [17]. Given the large sample size in this study we believe this limitation is minimal. Another limitation of the study is that the measurement of smoking history at baseline in the primary study is not detailed and may not distinguish adequately between current and past smoking, lending to the possibility for misclassification bias and limiting the independent evaluation of current and prior exposure on the results. However, self-report of smoking is reasonably reliable [18]. More importantly, in individuals with existing renal injury, a prior history of cigarette use can have an enduring effect on the kidney similar to current use, therefore more detail would be unlikely to provide additional precision in exploring the association between smoking and anaemia management [19]. Lastly, the short duration of the study may have limited our ability to see a clinically significant difference in Hb or to discriminate the effects of smoking on kidney disease progression. Although, if this difference in Hb continued and there was no adjustment of medication, over time the difference could become compounded and clinically apparent. We concede that estimated GFR, given the short duration of this study, may fail to identify CKD progression, however we have focused our main analysis on the outcome that the primary study was designed to evaluate.

The findings of this study should in no way be interpreted as an endorsement of smoking in African-Americans as a vehicle to enhance the effects of epoetin alfa on anaemia management in kidney disease. We deduce from this analysis that African-Americans with CKD may have a sub-optimal response to epoetin alfa than individuals of other races. This observation may warrant altered dosing regimens to accommodate this effect, not previously described. More research is needed to evaluate racial variations in response to epoetin alfa given its widespread use.



   Acknowledgments
 
Ortho Biotech Products, LP provided support for the original POWER study, and full access to the data to conduct the analyses contained within this manuscript. This study was funded under the following grants: American Medical Association Seed Grant, Maryland Cigarette Restitution Fund, Excellence in Partnerships for Community Outreach, Research on Health Disparities and Training (PROJECT EXPORT), NIH P60 MD000532-01 and NIH NRSA (I F 32 DK69016-01).

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Received for publication: 20. 1.05
Accepted in revised form: 12. 8.05





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