ACE inhibitors in hemodialysis patients: Does survival improve?

Abstract

Related Article, p. 1023 End-stage renal disease (ESRD) patients are characterized by a high cardiovascular morbidity and mortality.1Ma KW Greene EL Raij L Cardiovascular risk factors in chronic renal failure and hemodialysis populations.Am J Kidney Dis. 1992; 19: 505-513PubMed Scopus (251) Google Scholar, 2Foley RN Parfrey PS Sarnak MJ Clinical epidemiology of cardiovascular disease in chronic renal disease.Am J Kidney Dis. 1998; 32: S112-S119Abstract Full Text PDF PubMed Scopus (2974) Google Scholar Numerous classical and nonclassical risk factors contribute to the accelerated atherosclerosis of these patients, eg, hypertension, diabetes, hyperlipidemia and dyslipidemia, insulin resistance, oxidative stress and impaired antioxidant defense mechanisms, smoking, carbonyl stress, uremic toxins such as asymmetric dimethylarginine, hyperhomocysteinemia, hyperphosphatemia, and/or the chronic (micro)inflammatory process per se.3Zoccali C Cardiovascular risk in uremic patients: Is it fully explained by classical risk factors?.Nephrol Dial Transplant. 2000; 15: 454-456Crossref PubMed Scopus (141) Google Scholar, 4Galli F Canestrari F Bellomo G Pathophysiology of the oxidative stress and its implications in uremia and dialysis.Contrib Nephrol. 1999; 127: 1-31Crossref PubMed Scopus (59) Google Scholar, 5Shinohara K Shoji T Emoto M et al.Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease.J Am Soc Nephrol. 2002; 13: 1894-1900Crossref PubMed Scopus (316) Google Scholar, 6Longenecker JG Coresh J Powe NR et al.Traditional cardiovscular disease risk factors in dialysis patients compared with the general population: The CHOICE study.J Am Soc Nephrol. 2002; 13: 1918-1927Crossref PubMed Scopus (531) Google Scholar Many atherosclerotic cardiovascular disease risk factors are more prevalent in ESRD patients than in the general population.6Longenecker JG Coresh J Powe NR et al.Traditional cardiovscular disease risk factors in dialysis patients compared with the general population: The CHOICE study.J Am Soc Nephrol. 2002; 13: 1918-1927Crossref PubMed Scopus (531) Google Scholar In a retrospective study in this issue of the Journal, Efrati et a7Efrati S Zaidenstein R Dishy V et al.ACE inhibitors and survival of hemodialysis patients.Am J Kidney Dis. 2002; 40: 1023-1029Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar investigated the effect of angiotensin-converting enzyme (ACE) inhibitors on the mortality of ESRD patients undergoing long-term hemodialysis. Among the 126 patients studied, 60 patients received an ACE inhibitor in addition to other antihypertensive drugs, while hypertension was treated in 66 patients without an ACE inhibitor. Mortality significantly decreased in the ACE inhibitor-treated group with a risk reduction of 52%. In ACE inhibitor-treated patients aged 65 years or younger, the absolute risk reduction of mortality was 79%.7Efrati S Zaidenstein R Dishy V et al.ACE inhibitors and survival of hemodialysis patients.Am J Kidney Dis. 2002; 40: 1023-1029Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar The data are impressive and confirm findings of a recent study demonstrating a decrease in mortality associated with ramipril treatment in patients with renal insuffuciency.8Mann JR Gerstein HC Pogrue J et al.Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: The HOPE randomized trial.Ann Intern Med. 2001; 134: 629-636Crossref PubMed Scopus (1254) Google Scholar Nevertheless, as also mentioned by the authors, a prospective, randomized trial is needed to confirm the very encouraging data of this retrospective analysis. In the present study demographic, clinical and treatment characteristics of the hemodialysis patients treated or not treated with ACE inhibitors did not differ with respect to age, sex, causes of renal failure, diabetes, cardiovascular complications (except left ventricular hypertrophy), antihypertensive medication other than ACE inhibitors, serum albumin, hemoglobin or blood pressure.7Efrati S Zaidenstein R Dishy V et al.ACE inhibitors and survival of hemodialysis patients.Am J Kidney Dis. 2002; 40: 1023-1029Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar There is, however, no information on referral to a nephrologist prior to dialysis therapy or on initiation of hemodialysis treatment in both groups of patients investigated. There is also no information on body mass index, presence or absence of malnutrition, C-reactive protein (CRP) values, serum phosphorus, calcium × phosphorus ion product, or frequency of intradialytic hypotension in patients with and without ACE inhibitor therapy. All these factors may influence long-term outcome of hemodialysis patients, besides the favorable effect(s) of ACE inhibitor therapy. Oxidative stress in chronic renal failure patients is maintained by immunological and biochemical processes, metabolic acidosis, and hemodialysis therapy. Hemodialysis-induced oxidative stress may be mitigated by the use of biocompatible dialysis membranes.4Galli F Canestrari F Bellomo G Pathophysiology of the oxidative stress and its implications in uremia and dialysis.Contrib Nephrol. 1999; 127: 1-31Crossref PubMed Scopus (59) Google Scholar In the present study, all patients had been treated by cellulose triacetate hemodiayzers.7Efrati S Zaidenstein R Dishy V et al.ACE inhibitors and survival of hemodialysis patients.Am J Kidney Dis. 2002; 40: 1023-1029Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar Low plasma ascorbate levels, particularly in smoking hemodialysis patients, make these patients more susceptible to oxidative tissue damage than nonsmoking hemodialysis patients or healthy subjects.9Lim PS Wang NP Lu TC et al.Evidence for alterations in circulating low-molecular-weight antioxidants and increased lipid peroxidation in smokers in hemodialysis.Nephron. 2001; 88: 127-133Crossref PubMed Scopus (16) Google Scholar In the present study, smoking was not an exclusion criterion, and no information on smoking behaviors of the patients has been given. Treatment with ACE inhibitors increases antioxidant defenses in animal experiments10De Cavanagh EMV Fraga CG Ferder L et al.Enalapril and captopril enhance antioxidant defenses in mouse tissues.Am J Physiol. 1997; 272: R514-R518PubMed Google Scholar and in hemodialysis patients.11De Cavanagh EMV Ferder L Carrasquendeo F et al.High levels of antioxidant defenses in enalapril-treated versus non-enalapril-treated hemodialysis patients.Am J Kidney Dis. 1999; 34: 445-455Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar ACE inhibitor therapy causes greater predialytic content of red blood cell glutathione as well as higher selenium-dependent glutathione peroxidase activity and plasma β-carotene concentrations as compared to hemodialysis patients without ACE inhibitors. ACE inhibitor-induced accumulation of bradykinin may result in nitric oxide release triggering an increase in antioxidant defense levels.11De Cavanagh EMV Ferder L Carrasquendeo F et al.High levels of antioxidant defenses in enalapril-treated versus non-enalapril-treated hemodialysis patients.Am J Kidney Dis. 1999; 34: 445-455Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar CRP is a predictor of cardiovascular disease, cardiovascular mortality, and all-cause mortality in both normal people12Ridker PM Cushman M Stampfer MJ Vijt D Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men.N Engl J Med. 1997; 336: 973-979Crossref PubMed Scopus (4902) Google Scholar and hemodialysis patients.13Zimmermann J Herrlinger S Pruy A et al.Inflammation enhances cardiovascular risk and mortality in hemodialysis patients.Kidney Int. 1999; 55: 648-658Crossref PubMed Scopus (1416) Google Scholar, 14Yeun JY Levine RA Mantadilok V Kaysen GA C-reactive protein predictors all-cause and cardiovascular mortality in hemodialysis patients.Am J Kidney Dis. 2000; 35: 469-476Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar There is no information on CRP values of the patients in the study of Efrati et al.7Efrati S Zaidenstein R Dishy V et al.ACE inhibitors and survival of hemodialysis patients.Am J Kidney Dis. 2002; 40: 1023-1029Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar On the other hand, ACE inhibitor therapy may influence plasma CRP levels. Hypertension is a major risk factor for left ventricular hypertrophy (LVH) and predicts a poor prognosis in hemodialysis patients.16Tozawa M Iseki K Iseki C Takishita S Pulse pressure and risk of total mortality and cardiovascular events in patients on chronic hemodialysis.Kidney Int. 2002; 61: 717-726Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar Pulse pressure has been shown to be a more potent predictor of total mortality than systolic or diastolic blood pressure.16Tozawa M Iseki K Iseki C Takishita S Pulse pressure and risk of total mortality and cardiovascular events in patients on chronic hemodialysis.Kidney Int. 2002; 61: 717-726Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar Since ACE inhibitors caused their beneficial effects on survival of hemodialysis patients independent of blood pressure,7Efrati S Zaidenstein R Dishy V et al.ACE inhibitors and survival of hemodialysis patients.Am J Kidney Dis. 2002; 40: 1023-1029Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar it would be of interest to see how ACE inhibitor therapy reduces the pulse pressure in hemodialysis patients. ACE inhibitor therapy causes regression of LVH in dialysis patients.17Cannela G Paoletti E Delfino R et al.Prolonged therapy with ACE inhibitors induces a regression of left ventricular hypertrophy of dialyzed uremic patients independently from hypotensive effects.Am J Kidney Dis. 1997; 30: 659-664Crossref PubMed Scopus (178) Google Scholar In the study of Efrati et al,7Efrati S Zaidenstein R Dishy V et al.ACE inhibitors and survival of hemodialysis patients.Am J Kidney Dis. 2002; 40: 1023-1029Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar 82% of the patients had an echocardiography during the first 12 months from their beginning of hemodialysis treatment, but only 17% of the patients had a second echocardiography during the follow-up period. The effect of ACE inhibitors on renal anemia and the erythropoietin dosage is not really a clinically relevant issue. It is unclear whether the patients in both groups of the present study7Efrati S Zaidenstein R Dishy V et al.ACE inhibitors and survival of hemodialysis patients.Am J Kidney Dis. 2002; 40: 1023-1029Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar have been equally distributed between the morning and afternoon shifts. A recent study18Blinise DL Kutner NG Zhung R Parker KP Survival by time of day of hemodialysis in an elderly cohort.JAMA. 2001; 286: 2690-2694Abstract Full Text PDF PubMed Scopus (130) Google Scholar showed that morning-shift hemodialysis patients survived significantly longer than afternoon-shift patients. In summary, the preliminary findings of Efrati et al7Efrati S Zaidenstein R Dishy V et al.ACE inhibitors and survival of hemodialysis patients.Am J Kidney Dis. 2002; 40: 1023-1029Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar suggest that ACE inhibitors, independently of their antihypertensive effect, may markedly reduce mortality of maintenance hemodialysis patients, particularly in patients aged 65 years or younger. However, Kestenbaum et al19Kestenbaum B Gillen DL Sherrard DJ et al.Calcium channel blocker use and mortality among patients with end-stage renal disease.Kidney Int. 2002; 61: 2157-2164Crossref PubMed Scopus (40) Google Scholar did not find an association between the use of ACE inhibitors, β blockers, or aspirin and the risk of mortality among ESRD patients. In their study the use of a calcium channel blocker was associated with a 21% lower risk of total mortality and a 26% lower risk of cardiovascular specific mortality.19Kestenbaum B Gillen DL Sherrard DJ et al.Calcium channel blocker use and mortality among patients with end-stage renal disease.Kidney Int. 2002; 61: 2157-2164Crossref PubMed Scopus (40) Google Scholar Since statin therapy is also associated with a reduction of CRP levels20Ichihara A Hayashi M Ryuzaki M et al.Fluvastatin prevents development of arterial stiffness in haemodialysis patients with type 2 diabetes mellitus.Nephrol Dial Transplant. 2002; 17: 1513-1517Crossref PubMed Scopus (97) Google Scholar as well as cardiovascular death and total mortality in patients on dialysis,21Seliger SL Weiss NS Gillen DL et al.HMG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients.Kidney Int. 2002; 61: 297-304Crossref PubMed Scopus (138) Google Scholar the combination of both ACE inhibitors and statins should also be investigated in a randomized, prospective trial in this patient population.