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• W2160455736 abstract "Renal dysfunction is a recognized complication of cardiac transplantation and can impact on the life expectancy of an already fragile population. A large proportion of these patients require transplantation because of the consequences of ischaemic heart disease (IHD) which, in turn, is often associated with ischaemic nephropathy. We studied the effect of IHD, diagnosed prior to transplantation, on the renal function of recipients who survived more than 6months after surgery. Of the 168 patients transplanted in a single centre over 15years, 132 were included in the study. Renal dysfunction was defined as a serum creatinine consistently above 200µmol/L (2.26mg/dL). Analysis confirmed that IHD was an independent risk factor for developing renal impairment. In transplant recipients with IHD, closer monitoring is warranted to detect and prevent renal dysfunction or to retard its progression. Renal dysfunction is a recognized complication of cardiac transplantation and can impact on the life expectancy of an already fragile population. A large proportion of these patients require transplantation because of the consequences of ischaemic heart disease (IHD) which, in turn, is often associated with ischaemic nephropathy. We studied the effect of IHD, diagnosed prior to transplantation, on the renal function of recipients who survived more than 6months after surgery. Of the 168 patients transplanted in a single centre over 15years, 132 were included in the study. Renal dysfunction was defined as a serum creatinine consistently above 200µmol/L (2.26mg/dL). Analysis confirmed that IHD was an independent risk factor for developing renal impairment. In transplant recipients with IHD, closer monitoring is warranted to detect and prevent renal dysfunction or to retard its progression. Renal dysfunction continues to adversely impact on the survival of cardiac transplant recipients, with van Gelder et al. showing that only 60% of cardiac transplant recipients who develop end‐stage renal disease, survive 1year after initiating dialysis (1Van Gelder T Balk AHMM Zietse R et al.Renal insufficiency after heart transplantation: a case control study.Nephrol Dial Transplant. 1998; 13: 2322-2326Crossref PubMed Scopus (99) Google Scholar). These patients remain at risk of developing renal failure for various reasons including renal hypoperfusion in the pre‐, intra‐ and post‐operative periods (2Lindelow B Bergh C‐H Herlitz H Waagstein F Predictors and Evolution of Renal Function during 9 years Following Heart Transplantation.J Am Soc Nephrol. 2000; 11: 951-957Crossref PubMed Google Scholar), and the use of nephrotoxic drugs such as cyclosporine and tacrolimus (3Bertani T Ferrazzi P Schieppati P et al.Nature and extent of glomerular injury induced by cyclosporine in heart transplant patients.Kidney Int. 1991; 40: 243-250Abstract Full Text PDF PubMed Scopus (123) Google Scholar). Identifying all of the risk factors that may contribute to renal failure in cardiac transplant recipients and where possible, modifying them, could help reduce its incidence and thereby improve patient survival. Ischaemic heart disease (IHD) may be one such predisposing factor because of its known association with renal artery stenosis (4Crowley JJ Santos RM Peter RH et al.Progression of renal artery stenosis in patients undergoing cardiac catheterization.Am Heart J. 1998; 136: 913-918Crossref PubMed Scopus (198) Google Scholar). With the background of pre‐existing renal hypoperfusion secondary to atherosclerosis, further ischaemia arising from blood loss, pump failure or drug‐induced vasospasm could result in renal failure. We therefore conducted a retrospective study to examine the effect of IHD, diagnosed prior to transplantation, on the renal function of cardiac transplant recipients and its influence on patient survival. The Irish cardiac transplant programme commenced 15years ago and is based at the Mater Misericordiae Hospital, Dublin. From September 1985 to January 2000, 169 transplants have been performed. Data on these patients from the time of pre‐transplant evaluation to April 2000 were collected by chart review. All patients received cyclosporine, azathioprine and prednisolone as their initial immunosuppression. Cyclosporine was administered at 5 mg/kg/12 hourly and then adjusted to maintain 12‐h trough levels at 200–250µg/L [measured by high‐performance liquid chromatography (HPLC)] for the first 3months after transplantation. Between 3months and 1year, dosage was adjusted to maintain levels below 200, but above 150µg/L, and after 1year at levels between 100 and 150µg/L. In the immediate post‐transplant period, azathioprine was administered at 2mg/kg/day and intravenous (i.v.) methyl prednisolone 125mg q8h, the latter being replaced with 0.1mg/kg/day of oral prednisolone, 48h after surgery. Azathioprine dosage was adjusted according to white cell counts. Inadequate immunosuppression, rejection or drug toxicity were the only reasons for variations from this protocol. All patients with a serum creatinine consistently above 200µmol/L (2.26mg/dL) for 2months or more were classified as having renal dysfunction. IHD was diagnosed prior to transplantation by reduction in lumen diameter of 50% or more in at least one major epicardial coronary artery at angiography (5Franch RH Douglas Jr, JS King III, SB Cardiac catheterization and coronary arteriography.in: Alexander RW Schlant RC Fuster V Hurst's the Heart. 9th edn. McGraw‐Hill, New York, NY1998: 537-574Google Scholar) and/or ECG proven myocardial infarction. Baseline and follow‐up data of the following variables were recorded (Table 1): presence of diabetes mellitus, hypertension, hypercholesterolemia, use of HMG CoA reductase inhibitors and antihypertensive medication, cyclosporine levels and dosage, age, sex, and baseline serum creatinine at entry onto the transplant waiting list were also recorded. Age at transplant was evaluated as a continuous variable. Hypertension was defined as persistent BP > 140/90mmHg or patients on antihypertensive medication; the last category was included to allow for those who previously had hypertension but were normotensive during the study period because of antihypertensive medication or worsening cardiac function. Hypercholesterolemia was diagnosed at serum levels > 5.2mmol/L. A cyclosporine dose of more than 7mg/kg/day and blood levels greater than 200µg/L at 1year after transplant surgery were considered high.Table 1Data of patients included in study (baseline and follow up)VariableMedianRangeRatioAge at transplantation (years)50.7511–66Sex ratio male/female114/18Cholesterol mmol/LaMean readings for blood pressure and highest for cholesterol for each patient throughout the study period were included to calculate medians of the whole study population.5.052.5–8.9Systolic BP mmHgaMean readings for blood pressure and highest for cholesterol for each patient throughout the study period were included to calculate medians of the whole study population.110.585–150Diastolic BP mmHgaMean readings for blood pressure and highest for cholesterol for each patient throughout the study period were included to calculate medians of the whole study population.7050–95Pre‐transplant weight kg7636–150Pre‐transplant creatinine µmol/L9956–442Cyclosporine dose mg/kg/daybCyclosporine dose and level were studied at 1‐year post‐transplantation.4.32.4–13.75Cyclosporine level µg/LbCyclosporine dose and level were studied at 1‐year post‐transplantation.16080–375Diabetes yes/no13/119a Mean readings for blood pressure and highest for cholesterol for each patient throughout the study period were included to calculate medians of the whole study population.b Cyclosporine dose and level were studied at 1‐year post‐transplantation. Open table in a new tab Kaplan–Meier survival functions were used to construct the graphs. The survivor functions for IHD on renal outcome were adjusted for age. Cox proportional hazards models were used to compare the effects of baseline and follow‐up variables on the development of renal failure and patient survival. The statistical software used were JMP 4 (SAS Institute Inc., Cary, NC, USA) and Stata 6.0 (Stata Corporation, College Station, TX, USA). A p‐value of 0.05 or less was considered significant. In the study period, 169 hearts were transplanted into 168 patients of whom 33 (19.6%) died within 6months of surgery. Three patients had been transplanted less than half a year at the time of analysis and 1‐year survival in the remaining 132 was 92.4%. Median survival was 13.6years with 1, 5 and 10‐year survival in those who lived for more than 6months after transplantation being 94%, 86% and 70%, respectively. In the 132 (114 male, 18 female) patients studied, median age at time of transplantation was 50.8years (range 11–66) and median duration of follow up was 5years (range 6months − 14years). Renal dysfunction developed in 25% of patients by 3 and in 50% by 8years after transplantation and was found to increase patient mortality substantially, as depicted in Figure 1. Ten‐year survival with and without renal impairment was predicted at 59% and 85%, respectively, and survival at 12years was 52% and 85%, respectively (p = 0.044). Pre‐existing IHD was present in 49% of our patients, dilated cardiomyopathy in 44% and valvular heart disease, congenital heart disease and other cardiomyopathies in the remaining. There was no significant difference in patient survival between those individuals who had IHD and those who did not (p = 0.371, Figure 2). A further analysis was performed to compare mortality in IHD patients without renal failure and nonIHD recipients, regardless of their renal status. No significant difference in survival was noted (p = 0.284). Univariate analysis demonstrated the following variables to be associated with the development of renal impairment and are presented in Table 2. Ischaemic heart disease was found to be a significant risk factor at the 5% level. In addition, hypertension was found to adversely affect renal function and developed in 88% of patients with renal failure and in only 47% of those without. A separate analysis was performed to study only those patients who had blood pressures above 140/90 mmHg (whether they were on antihypertensive medication or not) and these levels did not increase the risk of renal dysfunction (p = 0.845). Further analysis was performed to evaluate the effect of mean arterial pressures averaged over time as a continuous variable. The association with renal dysfunction was significant only at the 10% level (p = 0.097). Increasing age was associated with renal failure (p = 0.004).Table 2Univariate tests on predictor variablesVariableHazard ratioStandard errorp‐value95% CIIHD2.9141.0230.0021.464–5.799Hypertension4.8013.4790.0301.160–19.867Age at transplant1.0410.0150.0031.013–1.070Pre‐transplant creatinine0.9990.0030.7680.993–1.004Cyclosporine Level0.4190.2550.1530.128–1.379Cyclosporine dose0.3980.4060.3660.054–2.931Weight1.0140.1310.3170.987–1.041Gender1.1910.5190.6890.506–2.801Hypercholesterolemia1.4500.5940.3630.650–3.240Lipid lowering agents1.5490.8310.4140.541–4.435ACE inhibitors1.7600.5470.0690.956–3.237Diabetes1.4050.6270.4470.585–3.370CI: confidence interval. Open table in a new tab CI: confidence interval. The three factors, age, hypertension and IHD were included in the multivariate analysis, the results of which are summarized in Table 3.Table 3Multivariate analysis of risk factors for the development of renal dysfunctionVariableHazard ratioStandard errorp‐value95% CIHypertension1.2090.3930.5600.639–2.287Age1.0250.0170.1390.992–1.060IHD2.3110.9060.0331.072–4.985CI: confidence interval. Open table in a new tab CI: confidence interval. The adverse effect of IHD on renal function is depicted in Figure 3. As patients with IHD were significantly older (p < 0.001), the graph in Figure 3 was adjusted for age. Cardiac transplantation is a life‐saving procedure that entails some degree of risk and requires substantial inputs from all of the health professionals involved. Transplantable hearts are a scarce and precious resource, which makes their optimum utilization mandatory. An important part of this process involves maximizing the duration and quality of life of transplant recipients. As the techniques and immediate results improve, more attention has been focussed on long‐term outcomes. The factors affecting mortality in this vulnerable population are numerous, all of which require identification and modification, if survival is to be optimized. Renal failure is known to adversely influence the outcome of cardiac transplant recipients (1Van Gelder T Balk AHMM Zietse R et al.Renal insufficiency after heart transplantation: a case control study.Nephrol Dial Transplant. 1998; 13: 2322-2326Crossref PubMed Scopus (99) Google Scholar). Our results confirm this observation and demonstrate that there is a substantial reduction in the 10‐year survival of those recipients with renal dysfunction. Prevention of renal failure therefore should reduce mortality and factors that could predispose to it were examined to identify those with the greatest impact. Age at transplantation has been shown previously to be a risk factor for developing renal failure (2Lindelow B Bergh C‐H Herlitz H Waagstein F Predictors and Evolution of Renal Function during 9 years Following Heart Transplantation.J Am Soc Nephrol. 2000; 11: 951-957Crossref PubMed Google Scholar), and this observation was confirmed in our study. This finding could reflect an acceleration of the age‐related decline in renal function due to the influence of numerous processes including cyclosporine‐induced vasospasm (6Textor SC Burnett JC Carlos Romero J et al.Urinary endothelin and renal vasoconstriction with cyclosporine or FK506 after liver transplantation.Kidney Int. 1995; 47: 1426-1433Abstract Full Text PDF PubMed Scopus (71) Google Scholar) followed by arteriosclerosis and interstitial fibrosis (3Bertani T Ferrazzi P Schieppati P et al.Nature and extent of glomerular injury induced by cyclosporine in heart transplant patients.Kidney Int. 1991; 40: 243-250Abstract Full Text PDF PubMed Scopus (123) Google Scholar), persistent cardiac failure with the resultant renal hypoperfusion, and the progression of atherosclerosis. Interestingly, age lost its significance in our study when analysed in conjunction with hypertension and IHD, suggesting that the effects of age on renal function may be mediated by cardiovascular abnormalities. A similar observation was made by Lindelow et al. who concluded that age was a significant predictor of renal function but found that it lost its significance after correction for IHD (2Lindelow B Bergh C‐H Herlitz H Waagstein F Predictors and Evolution of Renal Function during 9 years Following Heart Transplantation.J Am Soc Nephrol. 2000; 11: 951-957Crossref PubMed Google Scholar). Also, in the case–control study performed by Van Gelder et al. there was no significant difference in age between transplant recipients who developed renal failure and those who did not (1Van Gelder T Balk AHMM Zietse R et al.Renal insufficiency after heart transplantation: a case control study.Nephrol Dial Transplant. 1998; 13: 2322-2326Crossref PubMed Scopus (99) Google Scholar). These findings suggest that in this population, other factors outweigh the influence of age on renal function. Hypertension was also significantly associated with renal failure. However, it is difficult to differentiate between cause and effect. Whatever its origin, hypertension is known to predispose individuals to renal failure (7Laragh JH Pickering TG Essential hypertension.in: Brenner BM The Kidney. 4th edn. W.B. Saunders Co, Philadelphia1991: 1909-1939Google Scholar) and accelerate the progression of renal failure (8Pisoni R Remuzzi G How much must blood pressure be reduced in order to obtain the remission of chronic renal disease?.J Nephrol. 2000; 13: 228-231Google Scholar) in the general population. It should therefore be tightly controlled in all cardiac transplant recipients. When the mean arterial pressures averaged over time or blood pressure readings of more than 140/90mmHg were studied regardless of the use of antihypertensive medication, the association with renal dysfunction became weaker. This probably reflects the effect of confounding factors in our patient population including low perfusion pressures resulting from poor cardiac function and the residual effects of hypertension on the vasculature despite subsequent control. When studied in conjunction with age at transplant and IHD, hypertension lost its significance as a risk factor for renal failure in our patients. This lack of correlation between hypertension and renal dysfunction in cardiac transplant recipients has been noted before (9Herlitz H Lindelow B Renal failure following cardiac transplantation.Nephrol Dial Transplant. 2000; 15: 311-314Crossref PubMed Scopus (32) Google Scholar). However, blood pressure control remains an integral part of our practice. Of the variables studied, IHD diagnosed before transplantation was found to remain a significant independent risk factor for developing renal failure in any age group. To our knowledge, this is the first time that this association (and its persistence after correction for age) has been demonstrated. Our findings vary from those of Lindelow et al. (2Lindelow B Bergh C‐H Herlitz H Waagstein F Predictors and Evolution of Renal Function during 9 years Following Heart Transplantation.J Am Soc Nephrol. 2000; 11: 951-957Crossref PubMed Google Scholar) in whose patients, IHD was not a predictor for renal impairment once age at transplant was factored into the analysis. As there is a known association between IHD and athersclerotic renal artery stenosis (4Crowley JJ Santos RM Peter RH et al.Progression of renal artery stenosis in patients undergoing cardiac catheterization.Am Heart J. 1998; 136: 913-918Crossref PubMed Scopus (198) Google Scholar), which in turn is associated with ischaemic nephropathy (10Tuttle KR Toward more rational management of ischaemic nephropathy: the need for clinical evidence.Am J Kidney Dis. 2000; 36: 863-865Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar), the risk imposed by IHD or more accurately, the vascular pathology that gives rise to IHD on the development of renal insufficiency is not surprising. In addition, renal impairment itself is known to accelerate atherosclerosis (11Jungers P Massy ZA Nguyen Khoa T et al.Incidence and risk factors of atherosclerotic cardiovascular accidents in predialysis chronic renal failure patients: a prospective study.Nephrol Dial Transplant. 1997; 12: 2597-2602Crossref PubMed Scopus (288) Google Scholar) and arterial calcification (12Nakayama Y Sakata R Ura M Miyamoto TA Coronary artery bypass grafting in dialysis patients.Ann Thorac Surg. 1999; 68: 1257-1261Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar), making the interplay between these factors complex and probably self‐perpetuating. Among other things, the well‐documented effects of calcineurin inhibitors on renal perfusion, blood pressure, lipid profiles and glucose tolerance are likely to complicate matters further. However, high cholesterol levels and the use of statins to reduce serum lipid levels did not influence the incidence of renal failure, suggesting that atherosclerosis and ischaemic nephropathy are not the only pathogenic processes involved. The increased mortality seen in our patients with renal failure could have resulted from diseases of different vascular beds, as is suggested by the observation that cardiovascular pathology is now the leading cause of mortality in dialysis patients (13Locatelli F Marcelli D Conte F et al.Cardiovascular disease in chronic renal failure: the challenge continues.Nephrol Dial Transplant. 2000; 15: 69-80Crossref PubMed Scopus (117) Google Scholar). However, in our study, IHD did not shorten patient survival, thereby suggesting that the influence of renal dysfunction on mortality is not solely due to IHD. Higher pre‐transplant serum creatinines were not associated with a greater incidence of renal failure in our patients, an observation that parallels the findings of others. Pre‐existing renal dysfunction is therefore not a contraindication for heart transplantation. The guidelines may be made more specific, however, using inotropes to improve cardiac function prior to transplantation and assessing the reversibility of renal failure after removing the ‘pre‐renal’ element (2Lindelow B Bergh C‐H Herlitz H Waagstein F Predictors and Evolution of Renal Function during 9 years Following Heart Transplantation.J Am Soc Nephrol. 2000; 11: 951-957Crossref PubMed Google Scholar). To summarize, renal failure is a common occurrence in cardiac transplant recipients with increased incidence over time and a substantial adverse impact on patient mortality. Age at transplant, hypertension and IHD are significantly associated with the development of renal impairment, making strict control of hypertension and increased renal surveillance in older patients mandatory. However, these three factors are likely to be related and this relationship could explain why IHD alone remained significant when the three variables were analysed together. This is the first time that IHD has been shown to negatively impact on the renal function of cardiac transplant recipients. Therefore, greater precautions to prevent renal insults including the avoidance of nephrotoxic drugs, where possible, should be undertaken in patients who have had IHD diagnosed prior to cardiac transplantation. Regular, life‐long monitoring of renal function should be more intense in these individuals than in those without IHD, to detect and delay progression of renal insufficiency, in order to maximize their survival." @default.
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• W2160455736 title "The Effect of Pre-existing Ischaemic Heart Disease on Renal Dysfunction in Cardiac Transplant Recipients" @default.
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