Ace inhibitors do not induce recombinant human erythropoietin resistance in hemodialysis patients

ACE Inhibitors Do Not Induce Recombinant Human Erythropoietin Resistance in Hemodialysis Patients Ali K. Abu-Alfa, MD, Dinna Cruz, MD, Mark A. Perazella, MD, Rex L. Mahnensmith, MD, David Simon, MD, and Margaret J. Bia, MD ● Angiotensin-converting enzyme (ACE) inhibitors may exacerbate anemia in patients with chronic renal failure, as well as in dialysis patients. To better answer this question, a prospective, crossover study was conducted to evaluate the effect of ACE inhibitors on recombinant human erythropoietin (rHuEPO) requirements in hemodialysis patients. Patients administered an ACE inhibitor when entering the study remained on this drug for the initial 4 months and were then switched to another antihypertensive agent for 4 more months. Patients not initially administered an ACE inhibitor were switched to lisinopril at 4 months. rHuEPO doses were adjusted using a sliding scale based on weekly laboratory hematocrit values. The inclusion criteria were met by 51 patients undergoing dialysis. Demographics were as follows: 61% were women, 64% were black, 46% had diabetes, average age was 53.2 ⴞ 13.3 years, and time on hemodialysis was 38.0 ⴞ 44.5 months. Thirty-three patients completed the study. Hematocrit averaged 32.7% ⴞ 1.9% while on ACE inhibitor therapy and 33.1% ⴞ 2.1% off ACE inhibitor therapy (P ⴝ 0.217). There was no difference in rHuEPO dose per treatment during each period (3,500 ⴞ 1,549 U on ACE inhibitor therapy versus 3,312 ⴞ 1,492 U off ACE inhibitor therapy; P ⴝ 0.300). No significant differences were found in degree of blood pressure control or various clinical and laboratory parameters that might be associated with rHuEPO resistance between the two periods. Similarly, no differences were found in hospitalization days, duration of infections, or transfusion requirements. These findings suggest that ACE inhibitors do not contribute to rHuEPO resistance in hemodialysis patients. 娀 2000 by the National Kidney Foundation, Inc. INDEX WORDS: Angiotensin-converting enzyme (ACE) inhibitor; erythropoietin; anemia; hemodialysis (HD); end-stage renal disease (ESRD).

A

NGIOTENSIN-CONVERTING enzyme (ACE) inhibitors have been observed to exacerbate anemia in patients with chronic renal insufficiency,1,2 those undergoing hemodialysis not administered exogenous recombinant human erythropoietin (rHuEPO),3-6 and renal transplant recipients.7 Furthermore, these drugs have been successfully used in correcting posttransplantation erythrocytosis.8-16 It is therefore possible that these drugs might also increase rHuEPO requirements in patients undergoing dialysis. We have previously shown, in a case-control study, no difference in rHuEPO requirements in hemodialysis patients administered ACE inhibitors versus those administered other antihyFrom the Department of Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT. Received July 26, 1999; accepted in revised form January 7, 2000. Supported in part by a research grant from Amgen, Thousands Oak, CA. Address reprint requests to Ali K. Abu-Alfa, MD, Department of Internal Medicine, Section of Nephrology, 333 Cedar St, LMP 2073, New Haven, CT 06520-8029. E-mail: [email protected]

娀 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3506-0009$3.00/0 doi:10.1053/ajkd.2000.7465 1076

pertensive medications.17 Although this finding was confirmed in some studies,18-22 other investigators have observed an increase in rHuEPO requirements with the use of ACE inhibitors.23-30 In an attempt to resolve this controversy, we performed a prospective, crossover study to examine whether the treatment of hypertension with ACE inhibitors was associated with erythropoietin resistance that would require an increased dosage of rHuEPO to maintain hematocrit in the target range. PATIENTS AND METHODS

Patient Population The study population was selected from all consenting adult hemodialysis patients being treated thrice weekly at the Yale–Gambro Healthcare dialysis center (New Haven, CT) between May and August 1996. Selection criteria included dialysis therapy for at least 3 months, baseline hematocrit of 30% or greater, and treatment requiring both rHuEPO (Epogen; Amgen, Thousand Oaks, CA) and at least one antihypertensive medication. Patients with intolerance to an ACE inhibitor, active infection, human immunodeficiency virus positivity, malignancy, recurrent or active gastrointestinal bleeding, iron deficiency (transferrin saturation ⬍20%), aluminum overload (aluminum ⬎100 µg/L), severe hyperparathyroidism (intact parathyroid hormone level ⬎600 pg/mL or severe symptomatic or radiologic bone disease), recurrent hyperka-

American Journal of Kidney Diseases, Vol 35, No 6 (June), 2000: pp 1076-1082

ACE INHIBITORS AND rHuEPO RESISTANCE

lemia (predialysis serum potassium ⬎6.5 mEq/L), or gross noncompliance were excluded. Dropout criteria were defined as follows: transfusion with more than 3 units of packed red blood cells, an acute event requiring hospitalization for longer than 3 weeks, noncompliance with medications or protocol, missed rHuEPO doses for more than 3 weeks, identification of a process leading to significant blood loss or acute inflammation, inability to tolerate new antihypertensive medications, change of modality to peritoneal dialysis, transplantation, or death. The study protocol was approved by the institutional human investigation committee and informed consent was obtained from all participating patients or their legal guardians.

Study Design A prospective crossover design was used. Patients who entered onto the study already being administered an ACE inhibitor remained on the same drug for the initial 4 months. These patients were then switched to another antihypertensive agent, usually amlodipine, and followed up for 4 more months. Patients not initially administered an ACE inhibitor were continued on their medications for 4 months before being switched to an ACE inhibitor, usually lisinopril, and were again followed up for 4 months. Therefore, patients served as their own controls. Choice and dosage of medications were determined by the primary nephrologist as required to achieve optimal blood pressure control, with a declared preference for the use of lisinopril and amlodipine when possible. Sitting, predialysis blood pressure readings were recorded and used for this study. rHuEPO was administered intravenously by a nurse at the end of each dialysis session, with the goal of maintaining weekly hematocrit values constant between 30% to 36%. Hematocrit was measured weekly by the laboratory, and rHuEPO dose for the week was chosen by the nurse by using an established sliding scale for the unit. The same sliding scale was used for patients briefly hospitalized during the study. The following blood values were measured monthly throughout the study: complete blood count, reticulocyte count, iron, iron-binding capacity, ferritin, potassium, albumin, intact parathyroid hormone, and single-pool Kt/V. Trough serum erythropoietin level, obtained predialysis 2 days after the last dose, was also measured monthly in each patient using a chemiluminescence immunoassay. Aluminum and haptoglobin levels were obtained at least once during each of the two study periods. All laboratory tests were analyzed by the Gambro Healthcare Laboratory Services (Fort Lauderdale, FL). A relational database was used for the study (4D by ACI, San Jose, CA). Classes and doses of prescribed antihypertensive medications were tracked on a monthly basis. For patients administered an intravenous iron preparation (iron dextran injection; INFeD; Schein Pharmaceuticals, Florham Park, NJ), total monthly doses were noted. Some patients were administered an oral preparation at time of enrollment (Niferex; Central Pharmaceuticals Inc, Seymour, IN), but none were started on the intravenous form after entering onto the study. Medication compliance was verified every 2 weeks by the study coordinator, who reviewed each patient’s medications at the dialysis session. For patients residing in long-term care

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facilities, medications and orders were verified by telephone with the nursing staff.

Sample Size Erythropoietin resistance was defined as a 20% increase in rHuEPO requirements during therapy with an ACE inhibitor compared with the non–ACE inhibitor treatment period. Such an increase, if present, was believed to be clinically and economically significant, amounting to approximately 2,000 U/wk/patient. A sample-size determination was based on data obtained from a retrospective study performed in the same dialysis unit.17 Based on an average rHuEPO dose in patients not administered an ACE inhibitor of 3,272 ⫾ 1,532 U/treatment (mean ⫾ SD) and after a 10% augmentation for potential dropouts, a sample size of 48 is needed to detect the predefined difference of 20% using a 95% two-tail and 80% one-tail significance for ␣ and ␤ errors, respectively.

Statistical Methods Paired Student’s t-test was used to compare all clinical and laboratory parameters between the two study periods. All values are expressed as mean ⫾ SD, with statistical significance defined as P less than 0.05. All statistical tests were performed using the Excel computer software, version 5.0, for Macintosh (Microsoft, Redmond, WA).

RESULTS

Patient Demographics Fifty-one of 136 patients met the criteria and were enrolled onto the study. Thirty-three patients completed the study. Eighteen patients dropped out for the following reasons: death (n ⫽ 4), renal transplantation (n ⫽ 2), prolonged hospitalization (n ⫽ 2), transfusion with more than 3 units of packed red blood cells (n ⫽ 2), serious infection (n ⫽ 1), and intolerance to medication switch (n ⫽ 7). Dropout rates for reasons other than intolerance were similarly distributed between the two periods. Intolerance was most commonly caused by the use of ACE inhibitors (hypotension, rash, malaise), with one patient developing impotence while receiving amlodipine. A 90% compliance rate with the scheduled biweekly medication checks ensured adherence to the intended inclusion or exclusion of an ACE inhibitor during the respective study period. The clinical characteristics of the patients completing the study are listed in Table 1. Almost half the patients developed end-stage renal disease (ESRD) from presumed diabetic nephropathy. The majority were administered monthly maintenance intravenous iron dextran therapy. As desired in a crossover study extending over 8

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ABU-ALFA ET AL Table 1. Patient Characteristics

Age (y) Women (%) Black (%) ESRD from diabetes (%) Time on hemodialysis (mon) Iron dextran (INFeD) use (%) ACE inhibitor months 1-4 (%)

53.2 ⫾ 13.3 61 64 46 38.0 ⫾ 44.5 94 54.5

months, close to half the patients (n ⫽ 18) entered the study while being administered an ACE inhibitor medication. The doses of ACE inhibitors were clinically equivalent in the two study periods. Nine of the patients entering the study while being administered an ACE inhibitor were on lisinopril therapy, with a mean daily dose of 24.2 ⫾ 8.8 mg. Most of the remaining patients were on captopril and enalapril therapy, with mean daily doses of 28.0 ⫾ 15.7 mg (n ⫽ 3) and 20.0 ⫾ 0.0 mg (n ⫽ 4), respectively. Lisinopril, at a mean daily dose of 25.0 ⫾ 10.8 mg, was chosen for 13 of the 15 patients switched to an ACE inhibitor. During the non–ACE inhibitor phase of the study, most patients were treated with amlodipine (12.7 ⫾ 7.22 mg), nifedipine (115 ⫾ 35.1 mg), or atenolol (81.3 ⫾ 57.9 mg). Hematocrit values were similar between the two study periods, averaging 32.7% ⫾ 1.9% and 33.1% ⫾ 2.1% while on and off ACE inhibitor therapy, respectively (P ⫽ 0.217). As shown in Fig 1, there was no significant increase in pertreatment rHuEPO requirements during the ACE inhibitor phase of the study, with a mean difference of 187.4 ⫾ 1,023.3 U. This was true whether the result for on versus off ACE inhibitor therapy is expressed as average dose per treatment (3,500 ⫾ 1,549 versus 3,312 ⫾ 1,492 U; P ⫽ 0.300) or average dose per week (11,345 ⫾ 4,647 versus 10,967 ⫾ 4,929 U; P ⫽ 0.514) or based on average dose per postdialysis weight per treatment (50.0 ⫾ 24.1 versus 48.0 ⫾ 26.6 U/kg; P ⫽ 0.294). These findings remained valid even when the first 2 months of data from each study period were excluded from analysis (rHuEPO average dose per treatment, 3,637 ⫾ 1,703 versus 3,359 ⫾ 1,566 U; P ⫽ 0.261). Given the potential for greater rHuEPO doses and lower hematocrit values while receiving an ACE inhibitor, the ratio of the rHuEPO dose per treatment to the corresponding weekly hemato-

crit was examined. There was no difference in the ratios between the two periods (107.7 ⫾ 49.8 versus 102.4 ⫾ 47.2; P ⫽ 0.439). Despite the greater than anticipated dropout rate, the study still retained enough statistical power to exclude an increase in rHuEPO dose as high as 20% while receiving ACE inhibitors, the threshold predefined as clinically significant (P ⬍ 0.01, one-tail). Blood pressure control, listed in Table 2, was similar between the two study periods. In addition, there were no significant differences in total intravenous iron dextran doses or transfusion requirements during the two study periods. Total days of hospitalization or infection were also similar. Other laboratory parameters that could potentially affect erythropoiesis were not significantly different on and off ACE inhibitor therapy (Table 3). Erythropoietin levels were detectable in 26 of the 33 patients (79%) on one or more of the eight monthly determinations. However, levels were detectable in only 30% and 32.5% of the overall determinations for on and off ACE inhibitor therapy, respectively. In patients with detectable levels, eythropoietin levels decreased dur-

Fig 1. Mean rHuEPO doses on and off ACE inhibitor (ACEI) therapy for individual patients.

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Table 2. Clinical Parameters

Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean blood pressure (mm Hg) Cumulative iron dextran injection dose (mg) Total PRBC transfusion (units)* Total hospitalization (d)* Total duration of infection (d)*

On ACE Inhibitors

Off ACE Inhibitors

Difference

P

154 ⫾ 13 89 ⫾ 11 110 ⫾ 10 939 ⫾ 558 5 132 292

152 ⫾ 14 87 ⫾ 12 109 ⫾ 11 984 ⫾ 775 9 121 279

2 ⫾ 13 1⫾8 1⫾9 ⫺45 ⫾ 761 ⫺0.12 ⫾ 0.86 0.67 ⫾ 8.93 0.45 ⫾ 19.8

0.450 0.475 0.426 0.743 0.423 0.671 0.896

Abbreviation: PRBC, packed red blood cell. *Values shown for hospitalizations, infections, and transfusions reflect the total for all patients in each of the study periods. Durations of individual hospitalizations were less than 3 weeks.

ing the period of ACE inhibitor therapy (9.21 ⫾ 8.04 versus 19.6 ⫾ 24.1 mU/mL on and off ACE inhibitor therapy, respectively; P ⫽ 0.037; n ⫽ 26). Haptoglobin levels were less in patients administered an ACE inhibitor but remained within the normal range (50 to 370 mg/dL). DISCUSSION

The results of this prospective, crossover study indicate that treatment with ACE inhibitors does not induce resistance to rHuEPO or increase dosage requirements in hemodialysis patients. Clinical processes known to affect erythropoiesis and cause resistance to rHuEPO, such as iron deficiency, severe hyperparathyroidism, inadequate dialysis dose, and prolonged infections, were not different between the study phases, allowing the effect of ACE inhibitor therapy on erythropoiesis to be evaluated. These findings confirm our previous observations made in a retrospective case-control analysis undertaken in

the same population of dialysis patients.17 They are also consistent with results from some,18-22 but not all,24,25,30 prior studies. Although the 35% dropout rate was greater than anticipated, our study retained enough statistical power to detect an increase in rHuEPO dose of at least 20% while receiving an ACE inhibitor. We are able to make this claim because the SD for the mean difference in rHuEPO doses was smaller than anticipated. In this circumstance, the number of patients required to reach statistical power is reduced. Because events leading to dropout would have occurred at a similar frequency in the dialysis population in general, the greater than anticipated dropout rate should not impact on the generalizability of the results. In addition, although actual pill counts were not conducted, adherence to either an ACE inhibitor– or non–ACE inhibitor–containing regimen was ensured given the high compliance rate with the biweekly medication checks.

Table 3. Laboratory Parameters

Reticulocyte count (%) Ferritin (ng/mL) Transferrin saturation (%) Intact PTH (pg/mL) Aluminum (µg/L) Potassium (mEq/L) Albumin (g/L) Kt/V (single pool) Haptoglobin (mg/dL) Serum erythropoietin (mU/mL)*

On ACE Inhibitors

Off ACE Inhibitors

Difference

P

1.0 ⫾ 0.4 708 ⫾ 441 34.2 ⫾ 10.7 215 ⫾ 156 11.7 ⫾ 10.1 4.8 ⫾ 0.6 4.0 ⫾ 0.3 1.50 ⫾ 0.26 111.6 ⫾ 68.1 7.26 ⫾ 8.07

1.1 ⫾ 0.3 693 ⫾ 478 32.0 ⫾ 11.3 232 ⫾ 167 19.1 ⫾ 38.7 4.8 ⫾ 0.5 4.0 ⫾ 0.3 1.46 ⫾ 0.27 145.6 ⫾ 80.5 15.5 ⫾ 22.6

⫺0.1 ⫾ 0.4 15 ⫾ 335 2.18 ⫾ 9.7 ⫺17 ⫾ 109 ⫺8.86 ⫾ 40.3 0.0 ⫾ 0.5 0.0 ⫾ 0.2 0.04 ⫾ 0.18 ⫺30.8 ⫾ 73.8 ⫺8.20 ⫾ 21.7

0.250 0.800 0.205 0.385 0.264 0.655 0.646 0.202 0.027 0.038

Abbreviation: PTH, parathyroid hormone. *Levels were undetectable in 68% of overall monthly determinations.

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Our study was designed with two 4-month periods of observation based on previous results examining the effect of ACE inhibitors on hematocrit. In hemodialysis patients not administered rHuEPO, captopril worsened anemia within 1 to 4 months in five of nine patients in one report3 and within 48 days in a subsequent study by the same investigators.4 Similarly, enalapril exacerbated anemia in 60 to 90 days in patients with chronic renal failure.1,2 Data for renal transplant recipients support both a similar onset of action and a rather rapid wash-out of the effect of ACE inhibitors. Anemia occurred within 3 months in renal transplant recipients started on enalapril therapy.7 When ACE inhibitors were used to treat posttransplantation erythrocytosis, the maximal decrease in hematocrit was observed within 8 to 12 weeks.8,10,16 A similar effect was observed within 8 to 12 weeks in patients with posttransplantation erythrocytosis treated with losartan, an angiotensin II–receptor blocker.31,32 When ACE inhibitors were discontinued in renal transplant recipients, an increase in hematocrit occurred within 2 to 12 weeks.33,34 Based on these data, although the duration of therapy was 7 to 18 months in some of the studies showing an adverse effect of ACE inhibitors in dialysis patients,23,26,28-30 an effect was seen in 2 to 12 weeks in the majority of studies. In addition, longer periods of therapy with ACE inhibitors failed to show an adverse effect in other studies.17,18,20 Thus, although a longer period of therapy with ACE inhibitors might have uncovered an adverse effect on rHuEPO requirements or hematocrit, it is likely that our 4-month periods of observation were long enough to detect a potential deleterious effect of ACE inhibitors based on the overall body of evidence. Furthermore, it is unlikely that inclusion of a wash-out period would have uncovered a potential carry-over effect because results were similar even after the exclusion of the first 2 months of data from each period. In the 26 patients with a detectable erythropoietin level on at least one determination, an increase in baseline erythropoietin levels was seen while off ACE inhibitor therapy. However, there was no difference in rHuEPO doses or rHuEPO dose to hematocrit ratios between the two study periods in this subgroup of patients with detectable erythropoietin levels (data not shown). As

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expected for patients with ESRD, the levels were inappropriately low given the degree of anemia; thus, the increase seen while off ACE inhibitor therapy, although statistically significant, is unlikely to be of clinical significance. Furthermore, although suppression of endogenous erythropoietin has been described in patients with chronic renal failure1 and congestive heart failure35 and healthy volunteers administered ACE inhibitors,36 this effect has not been consistently observed. For example, several studies examining the beneficial effect of ACE inhibitors or losartan in posttransplantation erythrocytosis did not show significant changes in erythropoietin levels, particularly when baseline values were normal or low.8,10-12,14,32 It is possible that the lack of an effect of ACE inhibitors on erythropoiesis in hemodialysis patients seen in our study, as well as in others,18-21 can be attributed to the use of a sufficient and liberal rHuEPO dosing regimen. In in vitro studies, angiotensin II has been shown to stimulate insulin-like growth factor-1 release and the expression of its receptor,37 which has been shown to enhance erythropoiesis.38,39 This potential effect, which may be reduced by the action of ACE inhibitors to reduce angiotensin II level, may be surmountable and possibly rendered secondary with a sufficiently high dose of exogenous rHuEPO. In previous studies in which an increase in rHuEPO requirements was observed with the concomitant use of ACE inhibitors, rHuEPO doses and achieved hematocrit levels were less than those in our study.24,26,30 In conclusion, our study shows no significant increase in rHuEPO requirements in hemodialysis patients administered an ACE inhibitor compared with other antihypertensive medications. These results suggest that ACE inhibitors do not cause rHuEPO resistance in hemodialysis patients and may be used as needed in this group of patients. REFERENCES 1. Kamper AL, Nielsen OJ: Effect of enalapril on haemoglobin and serum erythropoietin in patients with chronic nephropathy. Scand J Clin Lab Invest 50:611-618, 1990 2. Shand BI, Bailey RR, Lynn KL, Robson RA: Effect of enalapril on erythrocytosis in hypertensive patients with renal disease. Blood Press 4:238-240, 1995 3. Hirakata H, Onoyama K, Iseki K, Kumagai H, Fujimi S, Omae T: Worsening of anemia induced by long-term use

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of captopril in hemodialysis patients. Am J Nephrol 4:355360, 1984 4. Hirakata H, Onoyama K, Hori K, Fujishima M: Participation of the renin-angiotensin system in the captoprilinduced worsening of anemia in chronic hemodialysis patients. Clin Nephrol 26:27-32, 1986 5. Onoyama K, Sanai T, Motomura K, Fujishima M: Worsening of anemia by angiotensin-converting enzyme inhibitors and its prevention by antiestrogenic steroid in chronic hemodialysis patients. J Cardiovasc Pharmacol 13: S27-S30, 1989 (suppl 3) 6. Yoshida A, Morozumi K, Suganuma T, Aoki J, Sugito K, Nakamura S, Ikeda M, Oikawa T, Fujinami T, Kawahara H: Angiotensin-converting enzyme inhibitor and anemia in a patient undergoing hemodialysis. Nephron 59:334-335, 1991 7. Vlahakos DV, Canzanello VJ, Madaio MP, Madias NE: Enalapril-associated anemia in renal transplant recipients treated for hypertension. Am J Kidney Dis 17:199-205, 1991 8. Perazella M, McPhedran P, Kliger A, Lorber M, Levy E, Bia MJ: Enalapril treatment of post-transplant erythrocytosis: Efficacy independent of circulating erythropoietin levels. Am J Kidney Dis 26:495-500, 1995 9. Conlon PJ, Farrell J, Donohoe J, Carmody M, Walshe JJ: The beneficial effect of enalapril on erythrocytosis after renal transplantation. Transplantation 56:217-219, 1993 10. Danivotch GM, Jamgotchian NJ, Eggena PH, Paul W, Barrett JD, Wilkinson A, Lee DB: Angiotensin-converting enzyme inhibition in the treatment of renal transplant erythrocytosis. Clinical experience and observation of mechanism. Transplantation 60:132-137, 1995 11. Islam MS, Bourbigot B, Codet JP, Songy B, Fournier G, Cledes J: Captopril induces correction of postrenal transplant erythremia. Transpl Int 3:222-225, 1990 12. Gaston RS, Julian BA, Barker CV, Diethelm AG, Curtis JJ: Enalapril: Safe and effective therapy for posttransplant erythrocytosis. Transplant Proc 25:1029-1031, 1993 13. Rell K, Koziak K, Jarzyo I, Lao M, Gaciong Z: Correction of post-transplant erythrocytosis with enalapril. Transplantation 57:1059-1063, 1994 14. Rostaing L, Demur C, Hyun A, Durand D, Lloveras JJ, Suc JM: Erythrocytosis after renal transplant: Study of erythroid progenitors and response to enalapril. Transplant Proc 26:280-281, 1994 15. Morrone LF, Di Paolo S, Logoluso F, Schena A, Stallone G, Giorgino F, Schena FP: Interference of angiotensin-converting enzyme inhibitors on erythropoiesis in kidney transplant recipients: Role of growth factors and cytokines. Transplantation 64:913-918, 1997 16. Mazzali M, Filho GA: Use of aminophylline and enalapril in post-transplant polycythemia. Transplantation 65:1461-1464, 1998 17. Cruz DN, Perazella MA, Abu-Alfa AK, Mahnensmith RL: Angiotensin-converting enzyme inhibitor therapy in chronic hemodialysis patients: Any evidence of erythropoietin resistance? Am J Kidney Dis 28:535-540, 1996 18. Conlon PJ, Albers F, Butterly D, Schwab SJ: ACE inhibitors do not affect erythropoietin efficacy in haemodialysis patients. Nephrol Dial Transplant 8:1358, 1993 (letter) 19. Charytan C, Goldfarg-Rumyantzev A, Wang YF,

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Schwenk M, Spinowitz BS: Effect of angiotensin-converting enzyme inhibitors on response to erythropoietin therapy in chronic dialysis patients. Am J Nephrol 18:498-503, 1998 20. Sanchez JA: ACE inhibitors do not decrease rHuEPO response in patients with end-stage renal failure. Nephrol Dial Transplant 10:1476-1477, 1995 21. Kubo M, Hirakata H, Hirano T, Hidetoshi K, Okuda S, Fujishima M: Prevention of ACEI-induced worsening of anemia with a concomitant use of erythropoietin in hemodialysis patients. J Am Soc Nephrol 5:460, 1994 (abstr) 22. Yu AW, Wang AYM, Tse CTY, Lu LM, Li PKT, Lui SF: Both angiotensin II AT1 receptor antagonist and angiotensin-converting enzyme inhibitor do not worsen anemia in CAPD patients. J Am Soc Nephrol 9:292A, 1998 (abstr) 23. Truel JL, Juarez GF, Marcen R, Nogueira J, Ortuno J: Effect of angiotensin-converting enzyme inhibitors on anemia in hemodialyzed patients. Nephron 73:113, 1996 (letter) 24. Matsumara M, Nomura H, Koni I, Mabuchi H: Angiotensin-converting enzyme inhibitors are associated with the need for increased recombinant human erythropoietin maintenance doses in hemodialysed patients. Nephron 77:164168, 1997 25. Dhondt AW, Vanholder RC, Ringoir SMG: Angiotensin-converting enzyme inhibitors and higher erythropoietin requirement in chronic haemodialysis patients. Nephrol Dial Transplant 10:2107-2109, 1995 26. Walter J: Does captopril decrease the effect of human recombinant erythropoietin in haemodialysis patients? Nephrol Dial Transplant 8:1428, 1993 (letter) 27. Erturk S, Ates K, Duman N, Karatan O, Erbay B, Ertug E: Unresponsiveness to recombinant human erythropoietin in haemodialysis patients: Possible implications of angiotensin-converting enzyme inhibitors. Nephrol Dial Transplant 11:396-397, 1996 28. He␤ E, Rajtar M, Sonkodi S: Do ACE inhibitors influence the dose of human recombinant erythropoietin in dialysis patients? Nephrol Dial Transplant 11:749-751, 1996 29. Navarro JF, Macia ML, Mora-Fernandez C, Gallego E, Chahin J, Mendez ML, del Castillo N, Rivero A, Garcia J: Effects of angiotensin-converting enzyme inhibitors on anemia and erythropoietin requirements in peritoneal dialysis patients. Adv Perit Dial 13:257-259, 1997 30. Albitar S, Genin R, Fen-Chong M, Serveaux MO, Bourgeon B: High-dose enalapril impairs the response to erythropoietin treatment in haemodialysis patients. Nephrol Dial Transplant 13:1206-1210, 1998 31. Ducloux D, Sainthillier Y, Chalopin JM: Effect of losartan on haemoglobin concentration in renal transplant recipients. Nephrol Dial Transplant 12:2683-2686, 1997 32. Julian BA, Brantley RR, Barker CV, Stopka T, Gaston RS, Curtis JJ, Lee JY, Prchal JT: Losartan, an angiotensin II type 1 receptor antagonist, lowers hematocrit in post-transplant erythrocytosis. J Am Soc Nephrol 9:11041108, 1998 33. Julian BA, Gaston RS, Barker CV, Krystal G, Diethelm AG, Curtis JJ: Erythropoiesis after withdrawal of enalapril in post-transplant erythrocytosis. Kidney Int 46: 1397-1403, 1994 34. Gossmann J, Thurmann P, Bachmann T, Weller S, Kachel HG, Schoeppe W, Scheuermann EH: Mechanism of

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angiotensin-converting enzyme inhibitor-related anemia in renal transplant recipients. Kidney Int 50:973-978, 1996 35. Fyhrquist F, Karppinen K, Honkanen T, Saijonmaa O, Rosenlof K: High serum erythropoietin levels are normalized during treatment of congestive heart failure with enalapril. J Int Med 226:257-260, 1989 36. Pratt MC, Lewis-Barned NJ, Walker RJ, Bailey RR, Shand BI, Livesey J: Effect of angiotensin-converting enzyme inhibitors on erythropoietin concentrations in healthy volunteers. Br J Clin Pharmacol 34:363-365, 1992 37. Penhoat A, Leduque P, Jaillard C, Chatelain PG, Dubois PM, Saez JM: ACTH and angiotensin II regulation

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of insulin-like growth factor-1 and its binding proteins in cultured bovine adrenal cells. J Mol Endocrinol 7:223-232, 1991 38. Brox AG, Mangel J, Hanley JA, St Louis G, Mongrain S, Gagnon RF: Erythrocytosis after renal transplantation represents an abnormality of insulin-like growth factor-1 and its binding proteins. Transplantation 66:10531058, 1998 39. Brox AG, Zhang F, Guyda H, Gagnon RF: Subtherapeutic erythropoietin and insulin-like growth factor-1 correct the anemia of chronic renal failure in the mouse. Kidney Int 50:937-943, 1996