THE PROGNOSIS OF PATIENTS WITH END STAGE RENAL DISEASE AND SEVERE CONGESTIVE HEART FAILURE AFTER RENAL TRANSPLANTATION Cristina Bucşa 1, Dorina Tacu 1, Cristina Ceck², Eminee Kerezsy 1, Liliana Domnişor 1, Denise Daia 1, and Ionel Sinescu 1 1 Center of Urological Surgery, Dialysis and Renal Transplantation, Fundeni Clinical Institute, ² Prof. C.C. Iliescu Institute of Cardiovascular Diseases, Bucharest, Romania Address for correspondence: Cristina Alina Bucşa, MD 1 Center of Urological Surgery, Dialysis and Renal Transplantation, Fundeni Clinical Institute, Fundeni Str., No. 258, sector 2, code: 022328, Bucharest, Romania E-mail: cristinabucsa@yahoo.com Abstract Cardiovascular diseases are the main cause of morbidity and mortality in end stage renal disease (ESRD) patients. Over the past years the overall mortality rates have gradually decreased. One explanation for the overall decrease in mortality rates in ESRD patients has been a decrease in the incidence of deaths from cardiac causes. Heart failure (HF) affects many of these patients and the indication of kidney transplantation is controversial in certain situations like patients with high perioperative risk. 1
The aim of this study is to evaluate the impact of kidney transplantation in ESRD patients with severe congestive heart failure. Key words: end stage renal disease, severe heart failure, renal transplantation, risk of death. Introduction: Cardiovascular disease is the most important cause of death for both dialysis and transplant patients. About half of the deaths in dialysis patients are caused by cardiovascular disease. Transplant patients fare much better with expected remaining life time that are approximately two thirds as long as those found in the general population (1). Symptomatic cardiac disease results from disorders of left ventricular (LV) structure and function and from disorders of perfusion. Subjects with myocardial failure can have symptomatic heart failure (HF) or asymptomatic ventricular dysfunction. Symptoms of exercise intolerance are typically assessed by the New York Heart Association (NYHA) functional classification (2). Upon starting dialysis, 37% of patients have had a previous episode of heart failure, doubling the risk of death (3). The remaining patients will develop heart failure at a rate of about 10%/ year (4). Both systolic and/or diastolic function may be impaired. 15% of patients starting dialysis therapy have systolic dysfunction of the left ventricle (5). The prevalence of diastolic dysfunction at dialysis inception is unknown, but is likely to be high (6). Either systolic or diastolic dysfunction can lead to clinically evident congestive heart failure (CHF). Cardiomyopathy risk factors in CKD (7) patients are: 2
I. LV volume overload salt and water overload arterio-venous fistula anemia an independent risk factor for CHF (16) II. LV pressure overload hypertension arteriosclerosis aortic stenosis III. Other risk factors uremic related like hypoalbuminemia (malnutrition, catabolic status, waste thru peritoneal dialysis or urine) hyperhomocysteinemia, hyperparathyroidism (myocardial fibrosis)(21) inflammation (CRP, cytokines TNF, IL6)(15) Pathogenesis of cardiomyopathy in chronic uremia (9): 3
Hypertension Aortic stenosis Salt+ water overload AV fistula LV pressure overload LV volume overload Concentric LVH Excentric LVH Vascular remodeling Overload cardiomyopathy HPTH Malnutrition Other factors Myocyte death Myocardial fibrosis Decreased capillary density Decreased capillary perfusion LV dilation LV hypertrophy Diastolic dysfunction (Symptomatic LV failure) Systolic dysfunction (Diminished contractility) The diagnosis consists in: symptoms of heart failure 4
physical examination ECG chest X-ray echocardiogram. Echocardiography is the most important tool for the diagnosis of CHF in CKD patients. M-mode echocardiography is an useful test for the measurement of LV dilatation, hypertrophy and dysfunction. Assessment of cardiac valves and movement of walls requires 2-D echocardiography and for the assessment of diastolic dysfunction Doppler study is useful. A Canadian study followed 432 patients between 1983 to 1991 and showed a variety of abnormalities: most common was concentric LV hypertrophy found in 42% of patients, eccentric LV hypertrophy in 23%, isolated LV dilatation in 4% and systolic dysfunction in 16%. Only 16% had a normal echocardiogram (8). Similar data (about 75% patients with LVH) showed USRDS (United States Renal Data System) (1). However, LV volume fluctuates in haemodialysis patients. Therefore it is necessary to perform echocardiography at the patients dry weight the day after dialysis. In patients with anemia the increase in cardiac preload alters the pattern of Doppler signals that is used for the evaluation of diastolic function. Management of heart failure: Numerous clinical trials have shown that angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers and spironolactone have dramatically improved the survival in patients with congestive heart failure and normal 5
renal function. The available data indicate that the administration of ACE inhibitors and ARBs, both well known to nephrologists because of their effects on the progression of renal failure, is associated with a better survival in cardiac patients with mild renal failure. Because subjects with renal insufficiency have been under-represented in the above trials, there is rather limited information on the effects of the above medications in patients with advanced renal failure and/or maintenance dialysis (10). The effects of beta-blockers are not believed to be different in patients with renal failure from those in patients with normal kidney function. The effects of carvedilol, a beta-blocker reported to lead to a significant reduction in cardiac mortality in patients with mild renal failure, have not been assessed in most published studies. Recently, carvedilol has been reported to induce relaxation of renal glomerular microvasculature via an increased nitric oxide (NO) release from endothelial cells (11). This novel mechanism may be the reason for the decline in renal function occasionally observed in patients with mild to moderate renal insufficiency. In haemodialysis patients with dilated cardiomyopathy, however, a controlled study showed that carvedilol administration increased the ejection fraction and significantly reduced the cardiovascular mortality (12). Treatment of anemia has opened a new frontier in the management of heart failure. Appropriate treatment of anemia, improves ventricular function and clinical status. (13) Degree of anemia is directly related to the morbidity of cardiac disease. Correction of anemia with parenteral iron preparations and with recombinant erythropoietin, however, is associated with an improved cardiac function, a reduced need for hospitalization, a more stable renal function and an improved quality of life (14) (15). Removal of marked fluid overload is one of the most demanding and difficult to obtain challenges in the management of severe congestive heart failure, particularly in patients 6
refractory to diuretic therapy. Over the years, several centers published their experience in regarding the use of peritoneal dialysis in acute and chronic management of severe heart failure (16) (17). Peritoneal dialysis is believed by many nephrologists to be the modality of choice in the management of patients with III and IV stages of heart failure, either as palliative therapy or as a bridge to transplantation. Hemodiafiltration is an effective treatment for patients with advanced CHF (std III-IV NYHA) when cytokines have to be cleared and diuretic responsiveness needs to be restored (18). Nocturnal haemodialysis (NHD), a novel mode of renal replacement therapy, may be more effective than conventional haemodialysis in reducing intravascular volume or in removing uremic toxins with vasoconstrictor or myocardial depressant actions, and may, therefore, improve the left ventricular (LV) systolic function of patients with coexisting cardiac and renal failure.(19) Kidney transplant recipients show improvements in cardiac function, regression of LVH and reduction in hospitalizations for CHF compared with the time before transplantation (20). Subjects and methods: This is a retrospective study between January 2002 and January 2006 on 464 renal transplants. 34 of them (7.3 %) had severe heart failure NYHA III/IV and left ventricular ejection fraction (LVEF) under 40%. 3 patients received kidneys from cadaver and 31 from living donors. The mean age was 39 ±6.7 years and the mean dialysis duration was 26.1±7 months. There were 11 males, and 23 females, 21 on HD and 13 on PD. The causes of renal failure were chronic glomerulonephritis (6), polycystic kidney disease (5), nephrosclerosis (4), interstitial nephritis (4), diabetes (3), others (6) and not determined (6). 7
Immunosuppressive drug treatment consisted of cyclosporine (6 mg/kg/day) or tacrolimus (0,15 mg/kg/day), mycophenolat mofetil (2000 mg/day) and prednisone. All patients had a history of hypertension (defined as blood pressure >140/90 and/or use of antihypertensive medication). 31 patients were receiving antihypertensive medication (11 receiving longacting calcium channel blockers and 23 receiving ACE inhibitors). All patients were initially studied before transplantation, at the time of discharge, 28±6 days after surgery. The tests were repeated at 12 months after the operation. We made clinical, ECG, biological and ultrasonographic evaluation. All subjects underwent uni- and bi-dimensional echocardiography and Doppler examination. End-diastolic ventricular diameter (LVDD), end-systolic ventricular diameter (LVSD), left ventricular posterior wall thickness (LVPW) and interventricular septum (IVS) were measured. Mitral valve flow velocities were obtained. Statistics: Values are expressed as means ± standard error of the mean. The student's tests were applied to the data. A P value of <0.05 was considered significant. Results: Clinical evaluation showed a significant improvement of NYHA functional classification with reduction from an average III-IV to NYHA class I. This clinical improvement was positive correlated with correction of hypervolaemia (medium body weight loss was 5.1±1.2 kg), rising of hematocrit level (32%±5), correction of high blood pressure, and good graft function (medium serum creatinine 1.8±0.9 mg/dl). The most important arrhythmias before transplantation were sinus tachycardia (for 24 patients) and atrial fibrilation (for 6 patients). 8
Rhythm control was achieved for 33 patients, 3 of patients with atrial fibrilation underwent a spontaneously conversion to sinusal rhythm (Figure 1). Echocardiograms (Figure 2) showed a significant reduction of left posterior wall thickness from 12.2±0.2 to 11.3 mm at 12 months (P<0.05) (Figure 3a). There was also significant reduction of LV end-diastolic diameter from 68.1±0.5 to 55.3±0.2 at 12 months (P<0.001) (Figure 3b), LV end-systolic diameter from 57.2±0.5 to 39.3±0.4 at 12 months (P<0.001) (Figure 3c), pulmonary hypertension from 66±11 mmhg to 34,3±5 mmhg at 12 months (P<0.001) (Figure 3d) and medium LVEF increased from 28,5%±10 to 51%±11 at 12 months (P<0.001) (Figure 3e). One patient underwent a successful heart transplant because of ventricular function deterioration after kidney transplantation. The perioperative and 12 months mortality was zero (Figure 4). Discussions: It is already accepted that pre transplant coronary artery disease, cardiomyopathy and diabetes are associated with increased risk of cardiovascular events after the operation. Despite the benefits of kidney transplantation (20) the presence of preoperative echocardiography abnormalities including systolic dysfunction, LVH and ventricular dilatation is associated with premature death even after transplantation (21). This alteration couldn t be completely reversed after the transplantation even though our study showed important improvements in clinical manifestations and myocardial structure. The most important result of our study is the lack of the perioperative mortality and also the lack of mortality at 12 months after the transplantation even though the U. S. Renal Data System (USRD) found an increased short term risk of death after transplantation. (1) Heart 9
failure has been identified in several studies as being associated with a poorer outcome when noncardiac surgery is performed. In a study by Goldman et al (22), both the presence of a third heart sound and signs of HF were associated with a substantially increased risk during noncardiac surgery. Among patients with heart failure NYHA II, III and IV, total mortality was 7 1%, 15 0% and 28 0%, respectively (23). We also have to discuss the limitations of this study: the follow up period could be too short. The number of the patients in our study group could be too small for a statistical analysis. We didn t have a control group consist of dialysis patients. Conclusions: Kidney transplantation showed important improvements in clinical manifestations and myocardial structure even in severe congestive HF. These good results are positive correlated with correction of risk factors uremic related like anemia, fluid overload, hypoalbuminemia, hyperparathyroidism etc. References: 1. US Renal Data System. Annual Data Report. National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD:2007: 2. Braunwald E Heart Disease: A Textbook of Cardiovascular Medicine, W. B. Saunders Company, Phyladelphia, Pennsylvania, 2001. 3. Foley R, Parfrey P, Hefferton D, Kent G, Murray D, Barre P. Advance prediction of early death in patients starting maintenance dialysis. Am J Kidney Dis, 1994; 23: 836-45. 10
4. 1Churchill D, Taylor D, Cook R, LaPlante P, Barre P, Cartier P, Fay W, Goldstein M, Jindal K, Mandin H. Canadian Hemodialysis Morbidity Study. Am J Kidney Dis, 1992; 19: 214-34. 5. Foley R, Parfrey P, Harnett J, Kent G, Martin C, Murray D, Barre P. Clinical end echocardiographic disease in patients starting endstage renal disease therapy. Kidney Int, 1995; 47: 186-92. 6. Foley R. Clinical epidemiology of cardiac disease in dialysis patients: left ventricular hypertrophy, ischemic heart disease, and cardiac failure. Seminars in Dialysis, 2003; 16: 111-7. 7. Francesco Locatelli, Pietro Pozzoni, Francesca Tentori, and Lucia Del Vecchio Epidemiology of cardiovascular risk in patients with chronic kidney disease Nephrol. Dial. Transplant., Aug 2003; 18: vii2 - vii9. 8. Parfrey P, Foley R, Harnett J, Kent G, Murray D, Barre P. The outcome and risk factors for left ventricular disorders in chronic uremia. Nephrol Dial Transpl, 1996; 11: 1277-85. 9. Parfey P. S. Cardiac disease in dialysis patients: diagnostic, burden of disease, prognosis, risk factors and management. Nephrol. Dial. Transplant., Oct 2000; 15: 58-68. 10. Shlipak MG. Pharmacotherapy for heart failure in patients with renal insufficiency. Ann Intern Med 2003; 138: 917 924. 11. Kalinowski L, Dobrucki LW, Szczpanska-Konkel M et al. Third-generation betablockers stimulate nitric oxide release from endothelial cells through ATP efflux: a novel mechanism for antihypertensive action. Circulation 2003; 107: 2747 2752. 11
12. Cice G, Ferrara L, D Andrea A et al. Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy. J Am Coll Cardiol 2003; 41: 448 454. 13. Francesco Locatelli, Adrian Covic, Charles Chazot, Karel Leunissen, José Luño, and Mohammed Yaqoob Hypertension and cardiovascular risk assessment in dialysis patients Nephrol. Dial. Transplant., May 2004; 19: 1058-1068. 14. Silvergerg DS, Wexker D, Blum M, Schwartz D, Wollman Y, Iaina A. Erythropoietin should be part of congestive heart failure management. Kidney Int Suppl 2003; 87: S40 S47. 15. Basil S. Lewis, Basheer Karkabi, Ronen Jaffe, Rita Yuval, Moshe Y. Flugelman, and David A. Halon Anaemia and heart failure: statement of the problem Nephrol. Dial. Transplant., Jul 2005; 20: vii3 - vii6. 16. Nynke Cnossen, Jeroen P. Kooman, Constantijn J. Konings, Jan-Melle van Dantzig, Frank M. van der Sande, and Karel Leunissen Peritoneal dialysis in patients with congestive heart failure Nephrol. Dial. Transplant., July 2006; 21: ii63 - ii66. 17. Alexander Kagan and Jayson Rapoport The role of peritoneal dialysis in the treatment of refractory heart failure Nephrol. Dial. Transplant., Jul 2005; 20: vii28 - vii31. 18. Carmelo Libetta, Vincenzo Sepe, Manuela Zucchi, Patrizia Pisacco, Laura Cosmai, Federica Meloni, Carlo Campana, Teresa Rampino, Cristina Monti, Luigi Tavazzi, and Antonio Dal Canton. Intermittent Hemodiafiltration in refractory congestive heart failure: BNP and balance of inflammatory cytokines. Nephrol. Dial. Transplant., July 2007; 22: 2013-2019. 19. Christopher Chan, John S. Floras, Judith A. Miller, and Andreas Pierratos. Improvement in ejection fraction by nocturnal haemodialysis in end-stage renal 12
failure patients with coexisting heart failure. Nephrol. Dial. Transplant., Aug 2002; 17: 1518-1521. 20. Abbott KC, Hypolite IO, et al. The impact of renal transplantation on the incidence of congestive heart failure in patients with end stage renal disease due to diabetes. J. Nephrol 2001; 14; 369-376. 21. McGregor E, Jardine AG, Murray LS, et al. Pre-operative echocardiografic abnormalities and adverse outcome following renal transplantation. Nephrol. Dial. Transplant., 1998; 13: 1499-1505. 22. Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial index of cardiac risk in noncardiac surgical procedures N Engl J Med 1977;297:845-850. 23. J. Muntwyler, Abetel G, Gruner C, et al. One year mortality among unselected outpatients with heart failure. European Heart Journal (2002) 23, 1861 1866. Figures Figure 1. Spontaneous conversion from atrial fibrillation to sinusal rhythm after renal transplantation in a patient with severe heart failure. 13
Figure 2. Echocardiograms of a patient before renal transplant and after 12 months. Reduction of left posterior wall thickness from 12.2 to 11.3 mm at 12 months (P<0.05) 15 12,2 11,3 10 5 0 Before RT 12 mo. After RT Figure 3a. Reduction of LV end-diastolic diameter from 68.1 to 55.3 at 12 months (P<0.001) 68,1 70 55,3 50 30 10 Figure 3b. -10 Before RT 12 mo. After RT 60 50 40 30 20 10 0 LV end-systolic diameter from 57.2 to 39.3 at 12 months (P<0.001) 57,2 Before RT 39,3 12 mo. After RT 14
Figure 3c. 70 Pulmonary hypertension from 66 mmhg to 34,3 mmhg at 12 months (P<0.001) 66 50 34,3 30 10-10 Before RT 12 mo. After RT Figure 3d. Medium LVEF increased from 28,5% to 51% at 12 months (P<0.001) 60 50 40 30 20 10 0 21,5 Before RT 51 12 mo. After RT Figure 3e. Figure 4. Pulmonary radiography of a patient before renal transplant and after 12 months. 15