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Erythropoiesis-Stimulating Protein Therapy and the Decline of Renal Function: a Retrospective Analysis of Patients With Chronic Kidney Disease

Posted on: Friday, 12 August 2005, 03:02 CDT

Key words: Chronic kidney disease * Disease progression * Erythropoiesis-stimulating protein * Renal function

ABSTRACT

Background/Aims: Previous studies have hinted at possible associations between anemia and progression of renal disease. The study objective was to determine whether treatment with erythropoiesis-stimulating proteins (ESPs) can curb the rate of decline in renal function in predialysis patients with chronic kidney disease (CKD).

Methods: Observational, before/after analysis using electronic medical records from the Veterans Administration (VA). Included patients had at least two measurements of serum creatinine levels before and after ESP treatment initiation. The Cockcroft-Gault formula was used to derive estimates of glomerular filtration rate (GFR). Rate of renal function decline prior to and following initiation of therapy were compared.

Results: One hundred and twenty two patients with renal impairment levels of Stage 3 (moderate) or Stage 4 (severe) at ESP treatment initiation were identified. Over 80% of patients initiated therapy with either Grade 1 or Grade 2 anemia. The rate of renal function decline was calculated as the slope of the least-squares linear regression line of the inverse serum creatinine over time during the pre-treatment initiation and post-treatment initiation time periods. Overall, patients experienced a slowing in the rate of renal function decline after treatment was initiated (mean pre- treatment initiation rate of -0.094 dL/mg/yr versus mean post- treatment initiation rate of -0.057 dL/mg/yr).

Conclusion: Renal function declined at a slower rate following ESP initiation. Results are consistent with prior studies indicating delayed dialysis initiation in patients treated with ESPs. Analyses were limited by the observational study design and lack of information regarding some potential confounders. Longer-term, prospective trials are needed to determine whether ESPs slow progression of renal disease and the potential magnitude of such an effect.

Introduction

Anemia is a common complication of chronic kidney disease (CKD), due to the inability of failing kidneys to produce adequate levels of erythropoietin, which in turn leads to decreased erythropoiesis. Use of erythropoiesis-stimulating proteins (ESPs) has become standard practice in treating anemic patients with end-stage renal disease, as that treatment greatly improves quality of life without the risks inherent in blood transfusion. Current practice is to administer sufficient doses of ESPs to achieve a partial correction of the anemia associated with renal failure; guidelines developed in Europe call for hemoglobin concentrations to be raised to ≥ 11 g/dL in at least 85% of patients with CKD1, while US clinical practice guidelines recommend hemoglobin target levels of 11-12 g/ dL in adult men and postmenopausal women2. ESP therapy has proven successful in increasing hemoglobin concentrations and ameliorating symptoms of anemia. Since anemia develops in parallel with a decline in renal function, earlier initiation of treatment for anemia may benefit patients with chronic kidney disease in whom dialysis is not indicated. Care for many of such patients, however, remains suboptimal3-6.

Treatment of anemia may slow the progression of renal failure in certain patients, for example those with severe resistant heart failure; or may affect a broader patient population7. Postulated mechanisms include the interruption of a cycle of anemia-induced worsening of heart and renal failure, which in turn worsen the anemia7. A recent study by Silverberg et al. found that the correction of mild anemia in patients with resistant congestive heart failure and mild-to-moderate CKD led to improved cardiac and renal function8. In other patients, the effect of correcting anemia on the progression of underlying renal disease is less clear, with arguments and evidence to support both beneficial and deleterious effects. Based on results from animal studies, it has been suggested that correction of anemia using ESPs might accelerate declines in renal function due to its blood-pressure-raising effects, though a review conducted several years ago found no compelling evidence to support this hypothesis9. Subsequent clinical studies in predialysis patients have also failed to note any detrimental effects on renal function, and some have suggested a beneficial effect10 and estimated its magnitude11.

Effects of anemia correction on the rate of renal function deterioration would be important from both clinical and economic perspectives. Even modest effects among patients with CKD could have a significant impact on the size of the dialysis population. In order to further clarify the association of anemia treatment and change in renal function, we studied changes in renal function in a group of patients with CKD treated with ESPs prior to initiation of dialysis.

Methods

Subject selection

We used electronic medical records maintained by the Veterans Integrated Service Networks (VISN 22) Data Warehouse from October 1998 to April 2002. The warehouse's records include all patients receiving treatment at outpatient facilities within the VA Greater Los Angeles Healthcare System. The Greater Los Angeles region includes VA hospitals and clinics located in West Hills, Sepulveda (San Fernando Valley), Long Beach, Los Angeles, Santa Barbara, and Gardena. All patients age 18 and older having at least one elevated serum creatinine measure (> 2.0mg/dL for males, > 1.5mg/dL for females) and receiving ESP treatments were identified. Institutional review board (IRB) approval was obtained covering both the VA Greater Los Angeles Healthcare System and the Cedars-Sinai Medical System prior to the start of the project.

Analyses related to disease progression were conducted on a subset of the larger sample. From the initial pool, patients were selected based on the availability of at least 2 measures of serum creatinine level prior to ESP therapy initiation and at least 2 measures of serum creatinine after the initiation of ESP therapy. Total length of follow up for each patient was equal to or greater than 1 year, with a minimum of 6 months separation between serum creatinine measurements required in both the pre-treatment initiation and post-treatment initiation time periods to allow for the measurement of changes in renal function. As this was an observational study based on patient records, data regarding patient compliance with treatment was unavailable or incomplete for most patients. We assumed that once ESP therapy was initiated (erythropoietin alfa, as this was the agent available during the study period), treatment continued on a consistent and regular basis. We only sampled patients who had at least 8 ESP treatments. Additionally, the time between the second serum creatinine measure in the pre-initiation period and the initiation of ESP therapy was not to exceed 90 days. No inpatient data were assessed in this analysis.

Study design and data collection

A before/after study design was employed to measure changes in the rate of renal function decline. Data collected for each individual included: demographic variables, patient vital signs, inpatient and outpatient visits, laboratory tests, ICD-9 codes, CPT codes, and pharmacy utilization. Patients were categorized by hemoglobin level using the World Health Organization (WHO) categorization, defined as Grade 0 (Hb ≥ 12g/dL), Grade 1 (Hb = 10-11.9g/dL), Grade 2 (Hb = 8-9.9g/dL) and combined Grades 3 and 4 (Hb ≤ 8 g/dL)12.

Use of angiotensin converting enzyme (ACE) inhibitors and angiotensin II (AII) receptor blockers

Since the use of ACE inhibitors and All receptor blockers may be associated with progression of disease, and their discontinuation may be associated with transient changes in serum creatinine levels, pharmacy data were used to determine whether one or more prescriptions for ACE inhibitors or All receptor blockers were dispensed during the pre-treatment initiation and post-treatment initiation time periods.

Renal function assessment at treatment initiation

We did not have direct glomerular filtration rate (GFR) measures, so we employed the Cockcroft-Gault formula for creatinine clearance to estimate GFR13, as recommended by the National Kidney Foundation14. This formula utilizes serum creatinine concentration and other patient-level variables, including age, body weight, and gender, to estimate a patient's creatinine clearance, which is expressed in milliliters per minute (mL/min/1.73m^sup 2^). Based on these values, patients were categorized into levels of renal impairment as defined by the K/DOQI guidelines14. This analysis focused on patients in Stage 3 ('moderate' impairment = GFR 30-59 mE/ min/1.73m^sup 2^) and Stage 4 ('severe' impairment = GFR ≤ 29 mL/min/1.73m^sup 2^) failure*.

Assessment of change in renal function and its correlates

The rate of progression of CKD was estimated as the slope of the ordinary least squares line of the inverses of the serum creatinine measurements over time. This measure has been shown to decline linearly with time in the majority of patients with renal disease15. Serum creatinine measurements during the pre-treatment initiation and post-treatment initia\tion time periods were used to calculate slopes for each patient. As noted earlier, patients were required to have at least two serum creatinine measurements separated by at least 6 months during the pre-treatment initiation and the post- treatment initiation time periods. Slopes for the inverses of the serum creatinine measurements and their variances were estimated separately for the period prior to initiation of ESP therapy and the period following treatment initiation.

To determine whether treatment with ESPs was associated with a difference in the rate of progression of CKD, the weighted mean difference between the slopes for the pre-treatment initiation and the post-treatment initiation time periods was evaluated. Inverse variance weighting was used to account for the variable number and timing of creatinine measurements for each patient. A description of the timing of ESP treatment during the course of the disease was developed, which compared the renal impairment level with the hemoglobin concentration at the time of ESP therapy initiation. A cross-tabulation of the proportion of patients within each renal impairment category and each hemoglobin level category at the time of ESP initiation was conducted. A chi-square test, across all groups, was used to test the independence of these 2 variables. In addition, the difference between the pre-treatment initiation and post-treatment initiation slopes for the inverse of serum creatinine was calculated for each category of renal impairment along with its 95% confidence interval.

The difference in the rate of progression of disease pre- treatment initiation and post-treatment initiation was also assessed in a secondary analysis conducted among the subset of patients with evidence of ACE inhibitor use during the pre-treatment initiation and post-treatment initiation time periods, to eliminate the possible confounding effects of ACE inhibitor discontinuation.

A regression model was developed to assess the association of the extent of renal impairment at the time of treatment initiation with treatment-associated changes in rates of renal function decline. The dependent variable for the model was the difference in the rates between the pre-treatment initiation and post-treatment time periods. Calculated creatinine clearance, as an estimate of GFR at the time of ESP treatment initiation, was used as an independent variable in the model to predict treatment-associated changes in renal function. The resulting coefficient for the inverse serum creatinine level at treatment initiation was used as a measure of association between the extent of renal impairment at treatment initiation and the change in rate of renal impairment following ESP treatment.

Other independent variables, such as age, gender, occurrence of hyperlipidemia, occurrence of myocardial infarction, hemoglobin concentration at time of ESP initiation, and use of ACE inhibitors and All receptor blockers were included in the model. The regression model was fit using weights for each observation equal to the inverse of the variance of the difference between the pre-treatment initiation and post-treatment initiation slopes; that variance was estimated as the sum of the variances of the pre-treatment and post- treatment slopes. Thus, results from patients with a greater number of serum creatinine measurements were given a greater weight than were measures from patients with fewer measurements.

Results

Demographics

Table 1 lists patient demographics. One hundred and twenty two patients met study inclusion criteria. The mean age of these patients was 72.0 years, while the mean weight was 85.4 kg. Approximately 98% were male. Hypertension, anemia, hyperlipidemia, and diabetes were the most frequent comorbidities. The average duration of follow-up was 19 months for both the pre-treatment initiation and post-treatment initiation time periods.

Table 1. Patient characteristics

Table 2. Use of ACE inhibitors and All receptor blockers in patients initiating ESP therapy (N = 122)

Use of ACE inhibitors and All receptor blockers

As expected, use of ACE inhibitors and All receptor blockers was widespread (Table 2). Use of at least one of these types of agents was somewhat more frequently documented during the period prior to initiation of ESP treatment than during the post-treatment initiation time period. Of 122 patients, 84 (69% of patients) had evidence of ACE inhibitor use before and after the initiation of ESP therapy.

Time of initiation of ESP therapy

Figure 1 illustrates the relationship between anemia grade and renal impairment level at the time of ESP initiation. With regard to the renal impairment level at the time of ESP therapy initiation, 58% (n = 71) of patients received ESP therapy when their CKD was Stage 3 (moderate) and 42% (n = 51) when their disease was Stage 4 (severe). Among all patients, most were classified as have Grade 1 or Grade 2 anemia (40% for each grade).

Rate of progression of chronic kidney disease

Table 3 shows the rates of progression of disease before and after the initiation of ESP therapy, stratified by the level of renal impairment at the time of ESP initiation. We assumed that as CKD progresses, the inverse of the serum creatinine level decreases in a linear fashion15. A negative slope indicates progression of renal disease (increase in serum creatinine). The difference in slopes was used to compare the rates of disease progression before and after ESP initiation. A greater negative value of the pre- treatment initiation slope as compared with the post-treatment initiation slope indicates that progression of disease slowed following treatment initiation.

Table 3 illustrates that patients who had Stage 3 (moderate) or Stage 4 (severe) levels of renal dysfunction had a significant decrease in the rate of disease progression. Although Stage 4 patients showed a slightly larger decrease in disease progression compared with Stage 3 patients, the difference between Stage 3 and Stage 4 patients was not significant (P > 0.05). The overall combined mean difference also showed a decrease in the decline of renal function (P < 0.05).

Figure 1. Grade of anemia and level of renal impairment at ESP initiation

Table 3. Weighted average difference in rate of change pre- treatment initiation and post-treatment initiation per year by level of renal impairment (measured in inverse serum creatinine)

As discontinuation of ACE inhibitors may result in transient decreases in serum creatinine levels suggesting a slowing of disease progression, a secondary analysis on the rate of disease progression was performed on those 84 patients with evidence of ACE inhibitor use before and after ESP treatment initiation. Results revealed a similar decrease in the rate of disease progression among Stage 3 and Stage 4 patients after ESP initiation.

Regression analysis was used to determine which factors predicted the difference in the rate of change of the inverse serum creatinine level before and after ESP initiation, controlling for other predictors of disease progression (Table 4). None of the independent variables examined had a significant effect on the rate of disease progression (P > 0.05). Creatinine clearance at the time of ESP initiation was not associated to a significant degree with change in rate of disease progression.

Discussion

Improvements in the treatment of patients with CKD whose disease has not progressed to the point of requiring dialysis are the focus of numerous initiatives and guideline development efforts. Given the projected rise in the number of patients requiring renal replacement therapy, interventions capable of delaying the onset of dialysis in patients with CKD are of considerable importance from both quality- of-life and economic perspectives.

Table 4. Predicting the difference in rate of change in the inverse of serum creatinine pre- and post-ESP treatment (change is per year) (N = 122)

Our results show that initiation of treatment with ESPs was associated with a reduction in the rate of renal function decline as measured by change in the inverse of the serum creatinine level, and we found little evidence that this association varied by degree of renal dysfunction (as measured by the estimated creatinine clearance) at the time of ESP initiation.

Rossert et al. discussed mechanisms by which treatment with ESPs might delay progression of CKD16. Potential mechanisms included increased oxygen delivery to tubular cells, thus decreasing; (1) the risk of hypoxia-induced tubular damage and nephron loss; (2) oxidative stress otherwise resulting from decreased oxygen consumption by damaged nephrons; and (3) apoptosis of tubular cells otherwise resulting from the production of reactive oxygen species.

In a review of reports of the association of renal disease progression and ESP treatment, Pinevich and Petersen concluded that there was little evidence to support a deleterious effect of ESP treatment on renal function in humans, despite results from animal studies suggesting such an effect9. Kuriyama et al. reported that renal disease progression was, on average, reduced in a group of CKD patients treated with ESPs as compared with an untreated group with an initially similar mean hematocrit10.

Our results are consistent with those reported for a group of patients with severe renal impairment in which it was estimated that the time interval from the start of the study to dialysis initiation was 5.6 months longer (16.2 vs. 10.6 months) in ESP-treated patients17. Assuming an initial creatinine clearance of 10mL/min/ 1.73m^sup 2^, a creatinine clearance at dialysis initiation of 7 mL/ min/1.73 m2 (approximately those reported by Jungers et al. for their study population17), age 72, male gender, and body weight of 85kg, our estimates for patients with severe renal impairment (0.0899/year for the pre-treatment initiation time period vs. 0.0416/ year for the post-treatmen\t initiation time period) imply time intervals from the start of the study to dialysis of approximately 7.4 and 16.1 months using pre-treatment initiation and post- treatment initiation rates, respectively. The Cockroft-Gault formula was used to estimate creatinine clearance. Given the error inherent in our estimates, our results are consistent with those reported by lungers et al.17.

Observational studies of treatment effects are subject to a variety of biases. Regression to the mean could bias the results of before/after studies if patients with high rates of decline were preferentially selected for inclusion. Though we did not use rate of renal function decline as a selection criterion, we did select subjects based on the availability of at least two serum creatinine measurements at least 6 months apart and it is possible that this criterion was associated with rate of renal function decline. Other factors affecting renal disease progression such as NSAID use, blood pressure, and proteinuria might confound these results but were not assessed in this analysis. Additionally, we could not determine the influence of treatments for dyslipidemia, hyperglycemia and hypertension, which may affect progression of renal disease. Treatment with ACE inhibitors and All receptor blockers has been shown to slow progression of CKD18-22. However, discontinuation of ACE and All therapies may produce transient decreases in serum creatinine levels. The effect of differences in discontinuation rates during the pre-treatment initiation and post-treatment initiation time periods would depend on the timing of the discontinuations. Potential bias should be evaluated in light of the modest differences in proportions of subjects using ACE inhibitors/ All blockers in the post-treatment time period, and results from the subgroup of subjects using these agents during both periods. Differences in the rate of progression of renal disease remained among those with Stage 3 renal functioning patients but not among those with Stage 4. In spite of this, the small sample size of this additional analysis limits the power to detect a difference between the measurements.

While we found that a large percentage of our study subjects were being treated with one or both of these agents and that this percentage declined modestly following ESP initiation, the intensity of the treatments might confound our results, as might treatments associated with initiation of ESPs, such as iron therapy. Since this is a before/after study, it is possible that newer treatments for disease progression may have been introduced or newer practices implemented such as more aggressive control of blood pressure, hypertension, dyslipidemia, or proteinuria (which present in approximately one fourth of our study subjects). Although it is possible that better control of blood pressure may have occurred during ESP treatment, it would seem unlikely given that blood pressure usually rises as renal failure progresses and hence, if anything, becomes more difficult to control.

We used the inverses of the serum creatinine measurements over time to estimate the rate of progression of CKD. The regression model we used assumed linearity over time and the inverse serum creatinine has been shown to decline linearly with time in the majority of patients with renal disease15. Similarly, investigators of the African-American study of kidney disease (AASK) concluded that remarkably similar results were seen when GFR was estimated by iothalamate or inverse serum creatinine23.

Ultimately, an adequately powered clinical trial is the only way to determine definitively whether or not treatment with ESPs slows progression of renal disease, and to accurately estimate the magnitude of such an effect if it exists. Given the magnitude of potential savings that might be realized with a substantial delay of dialysis onset and the observational results available to date, more studies furthering this investigation are warranted.

Acknowledgements

This research was supported by a grant from Amgen, Inc.

* In analyzing the entire database of VA patients with CKD receiving ESP, we found that those with Stage 2 renal impairment had very few ESP treatments (73.8% had only 1-3 ESP treatments while only 17.3% had 8 or more treatments and the median number of treatments was one). This is in contrast to patients in Stage 3 or Stage 4 renal impairment (34.9% of Stage 4 patients had 1-3 ESP treatments while 55.5% had 8 or more treatments).

References

1. European best practice guidelines for the management of anaemia in patients with chronic renal failure. Working Party for European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure. Nephrol Dial Transplant 1999;14(Suppl 5): 1-50

2. IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: update 2000. Am J Kidney Dis 2001;37(Suppl l):S182-238

3. Nissenson AR, Collins AJ, Hurley J, et al. Opportunities for improving the care of patients with chronic renal insufficiency: current practice patterns. J Am Soc Nephrol 2001;12:1713-20

4. Obrador GT, Ruthazer R, Arora P, et al. Prevalence of and factors associated with suboptimal care before initiation of dialysis in the United States. J Am Soc Nephrol 1999; 10:1793-800

5. Arora P, Obrador GT, Ruthazer R, et al. Prevalence, predictors, and consequences of late nephrology referral at a tertiary care center. J Am Soc Nephrol 1999; 10:1281 -6

6. Kausz AT, Khan SS, Abichandani R, et al. Management of patients with chronic renal insufficiency in the Northeastern United States. J Am Soc Nephrol 2001;12:1501-7

7. Silverberg DS, Wexler D, Blum M, et al. The correction of anemia in severe resistant heart failure with erythropoietin and intravenous iron prevents the progression of both the heart and the renal failure and markedly reduces hospitalization. CHn Nephrol 2002;58(Suppl l):S37-45

8. Silverberg DS, Wexler D, Blum M, et al. The effect of correction of anaemia in diabetics and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron. Nephrol Dial Transplant 2003;18:141-6

9. Pinevich AJ, Petersen J. Erythropoietin therapy in patients with chronic renal failure. West J Med 1992; 157:154-7

10. Kuriyama S, Tomonari H, Yoshida H, et al. Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron 1997; 77:176- 85

11. Jungers P, Hannedouche T, Itakura Y, et al. Progression rate to end-stage renal failure in non-diabetic kidney diseases: a multivariate analysis of determinant factors. Nephrol Dial Transplant 1995; 10:1353-60

12. Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999;91: 1616-34

13. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41

14. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;392(Suppl l):Sl-266

15. Mitch WE, Walser M, Buffington GA, Lemann Jr J. A simple method of estimating progression of chronic renal failure. Lancet 1976;2:1326-8

16. Rossert J, Fouqueray B, Boffa JJ. Anemia management and the delay of chronic renal failure progression. J Am Soc Nephrol 2003;14(Suppl 2):S173-7

17. Jungers P, Choukroun G, Oualim Z, et al. Beneficial influence of recombinant human erythropoietin therapy on the rate of progression of chronic renal failure in predialysis patients. Nephrol Dial Transplant 2001;16:307-12

18. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993;329:1456-62

19. Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med 2001; 135:73-87

20. Perico N, Remuzzi G. Angiotensin II receptor antagonists and treatment of hypertension and renal disease. Curr Opin Nephrol Hypertens 1998;7:571-8

21. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-9

22. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001 ;345: 851- 60

23. Lewis J, Greene T, Appel L, et al. Effects of interventions on outcomes based on serum creatinine in the African American Study of Kidney Disease (AASK). J Am Soc Nephrol 2002;13:423A [Program and Abstracts Issue]

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2973_3, Accepted for publication: 21 April 2005

Published Online: 23 May 2005

doi: 10.1185/030079905X49644

Bonnie B. Dean(a), Michelle Dylan(a), Anacleto Gano, Jr(a), Kevin Knight(a), Joshua J. Ofman(a,b) and Barton S. Levine(c,d)

a Cerner Health Insights, Beverly Hills, CA, USA

b Cedars-Sinai Departments of Medicine and Health Services Research, Los Angeles, CA, USA

c VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA

d David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

Address for correspondence: Anacleto Gano, Jr., MPH, Cerner Health Insights, 9100 Wilshire Blvd., Suite 655, East Tower Beverly Hills, CA 90212, USA. Tel.: +1-310-598-4546; Fax: +1-816-936-1946; email: agano@cerner.com

Copyright Librapharm Jul 2005

Source: Current Medical Research and Opinion

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