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Vol. 24. Núm. S1.Febrero 2004
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Vol. 24. Núm. S1.Febrero 2004
Páginas 1-78
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Disfunción renal como factor de riesgo cardiovascular
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E. RITZ
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NEFROLOGÍA. Vol. XXIV. Número Extraordinario (I). 2004 Disfunción renal como factor de riesgo cardiovascular E. Ritz Universidad de Heidelberg. Alemania. Following the seminal observation of Lindner and colleagues1 on the excessive cardiovascular mortality in patients with end stage renal disease on renal replacement therapy, this observation has been repeatedly confirmed. It is currently known that in patients on renal replacement therapy the relative risk of dying from cardiac causes is higher by a factor of 10-100, depending on age2. It has only recently been recognised that even minor renal dysfunction, as reflected by an increase in urinary albumin excretion and/or a decrease in glomerular filtration rate, is an independent cardiovascular risk factor3 which should be added to the known factors contributing to the Framingham risk score. Satopinto3 recently reported on an impressively large prospective multicentre observational study covering 11,774 patients in 14 countries hospitalised for acute coronary syndromes. It is commonly agreed upon that the serum creatinine concentration is a non-reliable estimate of glomerular filtration rate. The sensitivity of the estimate can be increased with the so called Cockroft Gault formula which gives an estimate of creatinine clearance. Santopinto and collaborators found that the in-hospital mortality in patients with moderate renal dysfunction (creatinine clearance 30-60 ml/min) is higher by a factor of two (adjusted relative risk (RR) 2.01), while it was higher by a factor of almost four in patients with severe renal dysfunction (odds ratio 3.71). Confirming previous observations 4,5 they also noted that in-hospital medication (interestingly enough not medication taken before admission) was suboptimal, with less intensive use of antiplatelet agents, angiotensin converting enzyme (ACE) inhibitors, and ß blockers --presumably because of a perceived greater risk. That the risk is definitely greater is illustrated in this study by the observation of a higher rate of bleeding, presumably explained by the known platelet dysfunction in renal failure. Both Shlipak and colleagues4 and Wright and associates5 had noted that patients with renal dysfunction had received less diagnostic and therapeutic interventions, such as coronary angiography, coronary angioplasty or coronary bypass graft surgery, again because of an assumed (and real) higher risk of complications --for example, bleeding, radiocontrast renal failure, etc. The documentation of such enormous excess mortality justifies future efforts to provide a detailed and reliable quantitative risk benefit estimate --for example, for the administration of radiocontrast, for administration of antiplatelet agents, etcétera. Nevertheless it remains difficult to understand why physicians hesitate to administer ACE inhibitors or ß blockers to these patients. ADVERSE EFFECT ON SURVIVAL The highly welcome information from the present GRACE (global registry of acute coronary events) study is in perfect agreement with other observations that mild to moderate renal dysfunction has an adverse effect on survival in the general population6,7 in hypertensive individuals examined in the HOT study8, in the high cardiovascular risk population of the HOPE study9, and in patients with congestive heart failure10. While the epidemiological relationship appears now certain beyond any reasonable doubt, the underlying pathophysiological mechanisms have certainly not yet been sufficiently clarified. Nevertheless, recent studies have provided several hints pointing to an increased risk of accelerated atherosclerosis with minor renal dysfunction --for example, uninephrectomy in the apo-E knock out mouse11, increased concentrations of the nitric oxide (NO) synthase inhibitor ADMA in renal patients even when inulin clearance is still within the normal range11, early increase of blood pressure and left ventricular remodelling with evidence of impaired left ventricular diastolic function in renal patients with normal inulin clearance12, insulin resistance with minor renal dysfunction13,14, and sympathetic overactivity in renal patients even with normal glomerular filtration, as documented by microneurographic measurements of action potentials in the sural nerve by Klein and colleagues15. Atherogenesis, NO inhibition, increase in blood pressure and cardiac dysfunction, insulin resistance, and sympathetic overac71 E. RITZ tivity undoubtedly provide an unhealthy mix, but which of the factors is (are) truly culpable (and susceptible to intervention) remains to be shown. RENAL DYSFUNCTION: THE CINDERELLA OF CARDIOVASCULAR RISK There is no doubt, however, that renal dysfunction has remained the Cinderella of the cardiovascular risk profile. There are recent efforts to give renal dysfunction the status of a major cardiac risk factor, similar to diabetes mellitus, where Haffner and colleagues16 had shown that mortality in diabetics without a history of cardiac events was equal to that in nondiabetic patients surviving a myocardial infarction. As a result, in diabetic patients cardiovascular prophylaxis, including administration of ACE inhibitors (independent of blood pressure) and of statins (independent of low density lipoprotein cholesterol values) has been advocated. It will have to be seen whether renal dysfunction will be given a similar status. Nevertheless, in my opinion, because of the excessive cardiac risk, treating a patient with renal dysfunction should no longer be regarded as primary, but rather as secondary prevention. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. REFERENCES 1. Lindner A, Charra B, Sherrard DJ y cols.: Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 290: 697-701, 1974. 2. Parfrey PS, Foley RN: The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 10: 160615, 1999. 3. Santopinto JJ, Fox KAA, Goldberg RJ y cols.: Creatinine clearance and adverse hospital outcomes in patients with acute 14. 15. 16. coronary syndromes: findings from the global registry of acute coronary events (GRACE). Heart 89: 1003-8, 2003. Shlipak MG, Heidenreich PA, Noguchi H y cols.: Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients. Ann Intern Med 137: 555-62, 2002. Wright RS, Reeder GS, Herzog CA y cols.: Acute myocardial infarction and renal dysfunction: a high-risk combination. Ann Intern Med 137: 563-70, 2002. Henry RM, Kostense PJ, Bos G y cols.: Mild renal insufficiency is associated with increased cardiovascular mortality: the Hoorn study. Kidney Int 62: 1402-7, 2002. Muntner P, He J, Hamm L y cols.: Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol 13: 745-53, 2002. Ruilope LM, Salvetti A, Jamerson K y cols.: Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study. J Am Soc Nephrol 12: 218-25, 2001. Mann JF, Gerstein HC, Pogue J y cols.: Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med 134: 629-36, 2001. Hillege HL, Girbes AR, de Kam PJ y cols.: Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation 102: 203-10, 2000. Kielstein JT, Boger RH, Bode-Boger SM y cols.: Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J Am Soc Nephrol 13: 170-6, 2002. Stefanski A, Schmidt KG, Waldherr R y cols.: Early increase in blood pressure and diastolic left ventricular malfunction in patients with glomerulonephritis. Kidney Int 50: 1321-6, 1996. Fliser D, Pacini G, Engelleiter R y cols.: Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease. Kidney Int 53: 1343-7, 1998. Chen J, Muntner P, Hamm LL y cols.: Insulin resistance and risk of chronic kidney disease in nondiabetic US adults. J Am Soc Nephrol 14: 469-77, 2003. Klein IH, Ligtenberg G, Oey PL y cols.: Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension. J Am Soc Nephrol 12: 2427-33, 2001. Haffner SM, Lehto S, Ronnemaa T y cols.: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339: 229-34, 1998. 72
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