ISSN 1401-7431 print/ISSN 1651-2006 online © 2010 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)DOI: 10.3109/14017430903337369

Scandinavian Cardiovascular Journal, 2009; 44: 168–176

Correspondence: Mahender Macha, Suite 301 1100 E. Michigan Avenue, Jackson, MI 49201, USA. Tel: +1 517 817 7605. Fax: +1 517 817 7606. E-mail: mmacha@med.umich.edu

(Received 14 February 2009; accepted 4 September 2009)

ORIGINAL ARTICLE

Outcomes after heart transplantation in patients with and without pretransplant renal dysfunction

EZEQUIEL J. MOLINA1, MATTHEW F. SANDUSKY1, DIPIN GUPTA1, JOHN P. GAUGHAN2, JAMES B. MCCLURKEN1, SATOSHI FURUKAWA1 & MAHENDER MACHA3

1Department of Cardiac and Thoracic Surgery, Temple University School of Medicine, Philadelphia, PA, USA, 2Biostatistics Consulting Center, Temple University School of Medicine, Philadelphia, PA, USA and 3Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI, USA.

AbstractObjective. To compare long-term survival and incidence of ESRD between patients with and without preoperative renal dys-function following heart transplantation. Design. Fifty consecutive patients with preoperative estimated GFR � than 50 ml/min were compared with 50 age-matched patients with estimated GFR � than 80 ml/min who underwent heart trans-plantation between 1994 and 1998. We investigated two primary outcomes: death and development of ESRD. We also analyzed risk factors. Results. Eight patients (16%) developed ESRD and 19 (38%) died in the control group whereas 10 patients (20%) developed ESRD and 26 (52%) died in the renal failure group during a mean follow-up period of 6.74 � 3.31 years. Survival and time to ESRD were not signifi cantly different. In univariate and multivariate analysis, waiting time was the only risk factor found to predict mortality but not ESRD. High cyclosporine levels were only found to be associated with lower estimated GFR (p � 0.009). Among the control group, mortality was signifi cantly higher in the subgroup of patients that developed � 50% reduction of estimated GFR at the end of the fi rst post transplant year (p � 0.05). Conclusions. This study suggests that low pre-transplant estimated GFR may not accurately predict long-term development of ESRD.

Key words: Heart failure, heart transplantation, renal failure, dialysis, cyclosporine

End stage renal disease following heart transplanta-tion represents a common complication and is asso-ciated with signifi cant morbidity, mortality and fi nancial cost (1,2). The incidence of mild to moder-ate renal dysfunction refl ected by an elevation of serum creatinine has been reported to be as high as 45% at fi ve years post transplantation (3). Moreover, numerous studies have reported an incidence of end stage renal disease (ESRD) between 3 and 20% among transplanted patients over time (4–10). Typi-cally, more recent studies with longer follow-up peri-ods have shown higher cumulative risk for ESRD as a late complication of heart transplantation (4,8).

A signifi cant proportion of patients undergoing evaluation for heart transplantation have some degree of pre-existing renal dysfunction. Patients who pres-ent with an initial glomerular fi ltration rate of less than 50 ml/min at the time of evaluation and listing are sometimes considered candidates for both heart and kidney transplantation. This may be supported

by results of the ISHLT registry which demonstrates that worse pre-op renal function at the time of listing is a risk factor for poorer post-operative survival (11). Also, some studies have suggested a relationship between low pre-transplant estimated glomerular fi l-tration rates and post transplant renal insuffi ciency requiring dialysis (12–14). Many patients are listed with higher initial glomerular fi ltration rates at the time of evaluation. However, prolonged waiting times and worsening of cardiac performance over time fre-quently leads to further deterioration of the renal function. As a result, at the time of transplantation many of these patients demonstrate much lower esti-mated glomerular fi ltration rates than at the time of listing. The outcome of these particular patients in terms of survival and incidence of end stage renal disease has not been well characterized. The primary objective of this study was to compare survival and the incidence of end stage renal disease up to12 years after heart transplantation between

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ESRD after heart transplantation 169

cholesterol levels; the use of any of the following pre-transplant hemodynamic support measures: intravenous inotropes, intra-aortic balloon pump and ventricular assist device; pre-transplant cardiac index; creatinine levels; listing status according to the UNOS classifi cation; waiting time; heart ischemic time; the use of anti-thymocyte globulin (ATG) induction ther-apy; cyclosporine levels and development of end stage renal disease requiring onset of dialysis therapy.

Creatinine levels were collected before transplan-tation (the most recent preoperative value) and then the closest level to one month, one, two, fi ve, seven and 10 years post-transplantation. Estimated glom-erular fi ltration rates were calculated at these differ-ent time points using the Cockroft-Gault formula as previously explained (GFR � [140 − age] x weight /72 × plasma creatinine). Although creatinine clear-ance testing was available for many patients pre-operatively, these data were not used in order to allow for consistent comparisons with post-operative esti-mates of renal function.

Conventional immunosuppression at our institu-tion included cyclosporine, methylprednisolone (replaced by prednisone after postoperative day 3) and azathioprine. Towards the end of the transplanta-tion period of interest in this study (1993–1998), mycophenolate mofetil replaced azathioprine in many of the cases. Preoperative dosing of cyclosporine followed these guidelines: for a creatinine clearance >75 ml/min an oral dose of 2 mg/kg was given; for a creatinine clearance �75 ml/min the dose was 1 mg/kg. Postoperative dosing of cyclosporine included 1 mg/kg/day IV for the fi rst postoperative day; 1 mg/kg PO BID or 2 mg/kg/day IV for postoperative day 2; 3 mg/kg PO BID for postoperative day 3; and 3 mg/kg PO BID for postoperative day 4 and onwards. At our institution, targets for cyclosporine levels are 300–400 ng/ml within the fi rst month post-transplantation; 300–350 ng/ml between one and four months; 250–300 ng/dl between four and nine months; 250 ng/ml between nine and 12 months; 150–200 ng/ml between 12 months and two years; and 100–200 ng/ml beyond two years. For the pur-pose of this study, cyclosporine levels were collected at one month, one, two, fi ve, seven and 10 years post-transplantation. These trough morning levels repre-sent the closest level to the time points studied.

The clinical outcomes of interest analyzed in this study included the development of post-transplant end stage renal disease and death. End stage renal disease was defi ned as an estimated GFR below 15 ml/min or those requiring chronic dialysis irre-spective of GFR. After patients developed ESRD and were started on dialysis, creatinine and cyclosporine levels were no longer included in this analysis. Com-plete follow-up data was available for all the patients

patients with pre transplant renal dysfunction not requiring dialysis and patients with normal pre trans-plant renal function. We analyzed risk factors that place heart transplant patients at risk for development of these two outcomes, including cyclosporine levels. We also sought to assess the incidence of end stage renal disease and survival in the subgroup of patients whose estimated glomerular fi ltration rate declined more than 50% at one year post-transplantation.

Material and methods

Study design and subjects

Four hundred and forty patients underwent orthoto-pic heart transplantation at Temple University Hos-pital between January 1993 and December 1998. We calculated estimated glomerular fi ltration rates (GFR) according to the Cockroft-Gault formula in patients who survived more than one month postop-eratively. The Cockroft-Gault formula estimates the glomerular fi ltration rate based on the patient’s serum creatinine, age, sex, and actual weight without con-sidering height and body surface area (15). As sug-gested by Cockroft and Gault and also observed by Gupta (16), the actual body weight overestimates the creatinine clearance in obese patients and patients with fl uid overload (such as patients with heart fail-ure). In an effort to eliminate this error, the ideal body weight was used for each patient in the formula. Ideal body weights were calculated from nomograms using each patient’s height and weight.

Fifty consecutive patients with an estimated glomerular fi ltration rate less than or equal to 50 ml/min (renal failure group) were randomly age matched with 50 patients with an estimated glom-erular fi ltration rate equal to or higher than 80 ml/min (control group). Patients who underwent com-bined transplants (heart-lung, heart-kidney), patients who had received a prior heart transplant, and patients who died within the fi rst month post trans-plantation were excluded from this retrospective analysis. The follow-up period extended until May 2005. Data was available for all the patients included in the study. IRB approval was obtained for the study from the Temple University School of Medicine.

Data collection

Data was collected from medical records and the heart transplant electronic database including: demo-graphic parameters such as age, gender and race; ideal body weight; etiology of heart failure; the pres-ence of any of the following comorbidities: history of smoking, diabetes, hypertension, peripheral vascular disease and previous sternotomy; pre-transplant

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170 E. Molina et al.

of survival and ESRD were analyzed using univariate and multivariate Cox proportional hazard models. Creatinine, GFR and cyclosporine were analyzed as time-dependent covariates. Signifi cance was based on p � 0.05.

Results

Characteristics of the control group and renal failure group are shown in Table I. Patients in the renal fail-ure group tended to be older and had a slightly higher incidence of diabetes, smoking history, previ-ous sternotomy and ischemic heart disease. More commonly these patients were listed as status I. However, there were no statistically signifi cant differences.

In the control group, mean pre-transplant creatinine levels and mean estimated glomerular fi ltration rates were 0.80 � 0.17 mg/dl and 93.7 � 15.93 ml/min, respectively. In the renal failure group, the means for the same parameters were 1.83 � 0.54 mg/dl and 40.5 � 7.56 ml/min (p � 0.001 for comparison between groups). In the control group, mean creatinine levels increased signifi cantly at one month (1.16 � 0.54 mg/dl; p � 0.001 compared to baseline) and again at one

included in this study from the date of transplanta-tion to May 2005.

Statistical analysis

Results are expressed as mean � standard deviation. Between-group comparisons of qualitative variables (gender, race, etiology of heart failure, history of smoking, diabetes, HTN, peripheral vascular disease, history of previous sternotomy, inotropic support, use of intra aortic balloon pump and ventricular assist device and use of anti-thymocyte globulin ther-apy) were carried out using the Fisher’s exact test. Between-group comparisons of quantitative variables (age, ideal body weight, cholesterol level, pre-transplant cardiac index and ischemic time), were performed with the student’s t-test. Time-varying measures of creatinine, GFR and cyclosporine levels were compared between groups using a mixed model analysis of variance for repeated measures with a Bonferroni adjustment for multiple comparisons. Differences in survival and development of ESRD between the GFR groups and between the subgroups of patients with and without �50% fall of estimated GFR were studied using Kaplan Meier analysis fol-lowed by log-rank tests. Potential predictor variables

Table I. Preoperative risk factors for control and renal failure groups.

Characteristic Control N�50 (%) Renal Failure N�50 (%) p-value

Age (years) 56.52 � 6.22 57.56 � 8.00 0.47Gender Male 32 (64%) 31 (62%) 1.00Race White Black Other

38 (76%)10 (20%)2 (4%)

39 (78%)9 (18%)2 (4%) 1.00

Ideal Body Weight (kg) 67.68 � 7.48 65.84 � 7.14 0.21Etiology Coronary Artery Disease Idiopathic Dilated Cardiomyopathy Other

26 (52%)19 (38%)5 (10%)

30 (60%)17 (34%)3 (6%) 0.55

Smoking History 18 (36%) 21 (42%) 0.68Diabetes 9 (18%) 12 (24%) 0.62Hypertension 21 (42%) 20 (40%) 1.00Peripheral Vascular Disease 4 (8%) 4 (8%) 1.00Cholesterol (mg/dl) 186.84 � 56.52 189.08 � 52.89 0.84Previous sternotomy 18 (36%) 21 (42%) 0.68Pre Transplant Inotropic Support 42 (84%) 46 (92%) 0.36Ventricular Assist Device Support 3 (6%) 3 (6%) 1.00Intra Aortic Balloon Pump 3 (6%) 3 (6%) 1.00Pre Transplant Cardiac Index (L/min/m²) 2.17 � 0.56 2.13 � 0.67 0.72Pretransplantation Creatinine (mg/dl) 0.80 � 0.17 1.83 � 0.54 �0.0001Pretransplantation Estimated GFR (ml/min) 93.78 � 15.93 40.52 � 7.76 �0.0001Listing Status Status I 44 (88%) 46 (92%) 0.74Waiting time (days) 93.60 � 101.98 97.46 � 143.89 0.87Heart Ischemic Time (minutes) 235.98 � 54.88 240.56 � 57.47 0.68Induction with Anti-Thymocyte Globulin 0 (0%) 2 (4%) 0.49Cyclosporine level at 1 month (ng/ml) 374.94 � 117.99 357.25 � 94.68 0.41

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ESRD after heart transplantation 171

fi ltration rates fell below pre-transplant levels (35.73 � 12.74 ml/min; p � 0.03 compared to baseline) and progressively decreased thereafter (31.00 � 10.30 ml/min at 10 years; p � 0.11 compared to baseline). There remained a signifi cant difference in GFR at two years between the two groups (p � 0.03).

Cyclosporine levels were not statistically different between groups at any given follow-up time. Levels were highest at one month post-transplantation for both groups (control group: 374 � 118 ng/ml; renal

year post transplantation (1.86 � 0.84 mg/dl; p � 0.001 compared to baseline). Mean creatinine levels remained relatively stable thereafter, below 2 mg/dl. In the renal failure group, mean creatinine levels remarkably improved at one month post-transplantation (1.56 � 0.56 mg/dl; p � 0.01 compared to baseline). However, levels signifi cantly exceeded pre-transplant values at one year (2.15 � 0.75 mg/dl; p � 0.02 compared to baseline) and remained relatively stable above 2 mg/dl afterwards. Beyond one month there was no signifi cant differ-ence in mean creatinine levels between the two groups. The changes described for mean creatinine levels were inverse to the changes in mean glomerular fi ltration rates, as expected (Figure 1). In the control group, estimated mean glomerular fi ltration rates decreased dramatically at one month and again at one year post transplantation (73.06 � 23.36 ml/min and 47.13 � 20.52 ml/min respec-tively; p � 0.001 compared to baseline for both time intervals). Estimated mean glomerular fi ltration rates slightly decreased thereafter in this group to reach the lowest levels at 10 years (37.77 � 14.82 ml/min; p � 0.001 compared to baseline). In the renal failure group estimated mean glomeru-lar fi ltration rates signifi cantly increased at one month post-transplantation (50.66 � 18.64 ml/min; p � 0.001 compared to baseline). However, as creatinine levels climbed signifi cantly at one year post transplantation, estimated mean glomerular

Figure 2. Kaplan Meier plot demonstrating freedom from ESRD for both groups. The log rank comparison of the actuarial curves showed no statistical difference (p � 0.60).

Figure 1. Mean estimated glomerular fi ltration rates before transplantation and at one month, one, two, fi ve, seven and 10 years after transplant. Number of patients with data at each time interval is indicated. P-values for comparison between groups at each time interval are also shown.

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172 E. Molina et al.

Because we noted an earlier decline in renal func-tion in the control group, subgroup analysis was per-formed for those patients in whom there was �50% decline in estimated GFR by one year. This revealed that 23 of 45 control patients at one year after trans-plantation (51%) had demonstrated a 50% decline of the estimated glomerular fi ltration rate. Although mortality and development of end stage renal disease were worse in this subgroup, only mortality was found to be signifi cantly different by actuarial analy-sis (p � 0.05) (Figure 4). In the renal failure group, only two patients of 45 patients (4.44%) had a 50% fall of the estimated GFR at one year. Given this small number, no subgroup analysis was performed for this group.

No preoperative factors were associated with increased risk of development of ESRD (Table II). Waiting time was the only analyzed preoperative risk factor associated with decreased survival. In multi-variate analysis, waiting time again predicted increased mortality (HR: 1.003 for every waiting day; 95% con-fi dence limits: 1.001–1.005; p � 0.01). None of the other preoperative risk factors were found to be a signifi cant predictor of development of ESRD or decreased survival in multivariate analysis.

Although no relationship was found between cyclosporine levels and survival or development of end stage renal disease in univariate and multivariate analysis, higher cyclosporine levels were found to be related to slightly lower glomerular fi ltration rates (p � 0.009, Figure 5). Although signifi cant, the slope of the curve suggests a modest clinical impact.

failure group: 357 � 94.68 ng/ml; p � 0.80). Mean cyclosporine levels progressively decreased through-out the follow-up period in both groups as expected: 280 � 81 ng/ml, 269 � 94 ng/ml, 237 � 105 ng/ml, 180 � 45 ng/ml and 179 � 37 ng/ml for the control group, and 299 � 125 ng/ml, 262 � 118 ng/ml, 227 � 83 ng/ml, 195 � 49 ng/ml and 162 � 62 ng/ml for the renal failure group at one, two, fi ve, seven and 10 years post transplantation. These levels were within or slightly above the target levels for any given follow-up time.

The mean follow-up time for all patients was 6.74 � 3.32 years (range 0.09 to 12.11 years). Mean follow-up time was similar for both groups (6.87 � 3.34 years for the control group versus 6.61 � 3.31 years for the renal failure group, p � 0.69). As of May 2005, eight patients (16%) in the control group and 10 patients (20%) in the renal failure group developed end stage renal disease requiring chronic dialysis (Figure 2). The mean time to development of end stage renal disease was 5.67 � 2.12 years (range 2.39 to 9.92 years). Mean time to ESRD was longer for the renal failure group but the difference was not statistically different (4.98 � 1.88 years for the control group versus 6.21 � 2.23 years for the renal failure group, p � 0.22). The median time to ESRD was 5.36 years (5.12 years for patients in the control group and 5.96 years for patients in the renal failure group). In terms of survival, 31 patients (62%) in the con-trol group and 24 patients (48%) in the renal fail-ure group were alive at the time of follow-up (Figure 3).

Table II. Univariate analysis (HR: hazard ratio; CL: confi dence limits).

Outcome ESRD Outcome survival

Variable HR 95% CL p-value HR 95% CL p-value

Group (renal failure, control) 1.281 0.505 – 3.251 0.60 1.396 0.773 – 2.524 0.27Age (years) 1.012 0.949 – 1.080 0.71 0.992 0.953 – 1.033 0.70Gender 1.507 0.537 – 4.229 0.43 0.609 0.339 – 1.094 0.09Race 0.812 0.235 – 2.806 0.74 1.225 0.619 – 2.423 0.56Ideal body weight (kg) 1.040 0.975 – 1.109 0.23 0.996 0.954 – 1.041 0.87Etiology 2.340 0.832 – 6.581 0.10 1.113 0.616 – 2.013 0.72Smoking history 1.394 0.544 – 3.574 0.49 1.066 0.587 – 1.938 0.83Diabetes mellitus 0.858 0.247 – 2.986 0.81 1.822 0.951 – 3.488 0.07Hypertension 1.342 0.526 – 3.426 0.54 1.305 0.726 – 2.345 0.37PVD 0.791 0.104 – 5.991 0.82 2.085 0.811 – 5.355 0.13Cholesterol (mg/dl) 0.995 0.986 – 1.004 0.31 0.994 0.988 – 1.000 0.06Previous sternotomy 2.303 0.902 – 5.875 0.08 1.558 0.863 – 2.813 0.14Inotropic support 1.189 0.273 – 5.181 0.82 0.838 0.355 – 1.981 0.69IABP 0.000 0.000 – 0.000 0.99 0.652 0.158 – 2.694 0.55VAD 0.714 0.094 – 5.415 0.74 0.611 0.148 – 2.528 0.50Cardiac index (L/min/m²) 1.268 0.618 – 2.602 0.51 0.950 0.564 – 1.600 0.85Listing status 0.439 0.058 – 3.306 0.42 0.840 0.301 – 2.345 0.74Waiting time (days) 1.001 0.998 – 1.004 0.35 1.002 1.000 – 1.004 0.01Ischemic time (min) 0.998 0.990 – 1.007 0.70 1.005 1.000 – 1.010 0.07ATG induction 0.000 0.000 – 0.000 0.99 2.297 0.314 – 16.81 0.41Cyclosporine (ng/ml) 1.000 0.995 – 1.005 0.93 0.998 0.993 – 1.002 0.26

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ESRD after heart transplantation 173

higher mortality than the group of patients with �50% decline of estimated GFR. This fi nding sug-gests that the degree of deterioration of renal func-tion that occurs during the fi rst post-transplant year has a signifi cant impact upon the outcome of these patients.

Both groups of patients showed a progressive decline of estimated GFR throughout the follow-up period. As it has been described before (18), we found a biphasic response with a rapid decline during the fi rst year post-transplantation and a slower but progressive deterioration thereafter. The estimated GFR in the normal renal function group fell by 22% at one month, 50% at one year, and 60% at 10 years compared with pre-transplant estimated rates. In the renal failure group, estimated GFR initially improved by 20% at one month. A rapid decline was however seen at one year (12% below pre transplant levels) and a slow but progressive deterioration occurred thereafter falling by 24% at 10 years. The greater magnitude of rapid deterioration of estimated GFR found at one year post transplantation in the control group is remarkable. This fi nding may explain in part why no long-term signifi cant differences were found between the groups with respect to mortality and development of ESRD. Prior studies have indicated that patients at risk of developing end stage renal disease are those with a more rapid decline of renal function early on during the fi rst few months post transplantation (4,7,17). Several factors may con-tribute to this rapid deterioration of GFR including

Conclusions

In our retrospective review, the global incidence of ESRD was 18% (20% in the renal failure group and 16% in the control group). This fi nding correlates with other recent studies (4,8,14). The mean time to development of ESRD in our study was greater than fi ve years, an interval period also comparable to recent reports among studies with similar follow-up intervals (4,6,8,10). The characteristics of the patients in this study may not be similar to those in prior studies, however. Given the design of this retrospec-tive review (renal failure group versus aged matched control group), the patients analyzed were older than the general heart transplant population and this fac-tor may affect the fi ndings. Also, the percentage of African American patients in this study (19%) is higher than in most prior studies. The higher inci-dence of chronic renal disease among these patients may have increased the incidence of end stage renal disease as well.

The two primary outcomes analyzed in this study, survival and development of end stage renal disease, were not statistically different between the normal renal function group and the renal failure group. There was, however, a tendency towards increased mortality and increased incidence of renal dysfunc-tion requiring dialysis in the latter group. Among patients with normal renal function, the subgroup of patients with �50% decline of estimated GFR at one year post transplantation demonstrated a signifi cantly

Figure 3. Kaplan Meier plot demonstrating survival for both groups. Actuarial curves were statistically not signifi cant (p � 0.26).

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174 E. Molina et al.

perioperative hemodynamic insult to the kidney, nephrotoxic effects of cyclosporine and other drugs, dyslipidemia, post-transplant hypertension, and dia-betes mellitus. As preoperative GFR may not accu-rately predict postoperative renal failure (18,19), all transplanted patients should be carefully monitored for early development of postoperative renal dysfunc-tion after heart transplantation. Early hemodialysis or hemofi ltration may be required for the manage-ment of volume overload in these patients. Discon-tinuation or minimization of calcineurin inhibitors

Figure 5. Cyclosporine trough levels plotted against estimated GFR. Higher trough levels were found to be associated with lower rates of glomerular fi ltration. P-value and the coeffi cient of determination (r2) are indicated.

Figure 4. Kaplan Meier plot for control patients demonstrating �50% decline in GFR and �50% decline in GFR at one year for survival.

and utilization of alternative immunosupressors may also be necessary.

Upon univariate and multivariate analysis, none of the pre-existing risk factors that we studied other than waiting time signifi cantly increased the risk of death or development of ESRD, including group assignment (GFR > 80 ml/min vs. GFR � 50 ml/min). These fi ndings also suggest that low preopera-tive estimated GFR may not accurately predict devel-opment of ESRD and long-term survival in this group of patients. Waiting time was found to be asso-ciated with decreased survival in univariate and mul-tivariate analysis, but there was no association with increased risk of development of ESRD.

Cyclosporine induced nephrotoxicity has been a subject of particular interest in several studies (17,20–23). In contrast to acute cyclosporine neph-rotoxicity which is usually reversible, chronic cyclosporine nephrotoxicity is accompanied by pro-nounced anatomic changes, such as interstitial fi bro-sis, tubular atrophy and arteriolar hyalinosis, and is often irreversible (20,21). Although some studies have found an association between high early cyclosporine trough levels and ESRD (2,22), others have failed to do so (7,17,18,23). While it has been suggested that cyclosporine nephrotoxicity leading to advanced renal failure may not be related to high serum levels, Rubel et al. have recently described an association between high mean cyclosporine trough levels during the fi rst six months post-transplantation and the development of ESRD (4). In this study,

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ESRD after heart transplantation 175

cyclosporine formulations, better understanding of the pharmacodynamics of this drug, and new immu-nosuppressive regimens may have led to reduced nephrotoxicity over time (25–27). The potential impact of these factors is also eluded in this study.

Finally, we conclude that low preoperative esti-mated GFR assessed at the time of transplantation may not accurately predict long-term development of ESRD. The remarkable decline of estimated GFR among patients with normal preoperative renal func-tion observed at one year post-transplantation may partially explain these long-term fi ndings. Further studies in larger groups of patients are necessary in order to conclusively identify the factors that lead to such impressive deterioration of renal function among patients with normal preoperative renal func-tion. Only after the identifi cation of these factors, can strategies be implemented in order to preserve nor-mal preoperative glomerular fi ltration rates and avoid the devastating consequences of end stage renal disease.

Acknowledgements

The authors gratefully acknowledge the review of the manuscript by Dr Joyce Wald (Medical Director, Heart Transplantation Program, Temple University Hospital, Philadelphia, PA) and Dr Patricio Silva (Medical Director, Kidney Transplantation Program, Temple University Hospital, Philadelphia, PA).

Declaration of interest: The authors report no confl icts of interest. The authors alone are respon-sible for the content and writing of the paper.

References

Frimat L, Villemot JP, Cormier L, Cao-Huu T, Renoult E, Hes-1. tin D, et al. Treatment of end-stage renal failure after hart trans-plantation. Nephrol Dial Transplant 1998;13:2905–2908.Hornberger J, Best J, Geppert J, McClellan M. Risks and 2. costs of end-stage renal disease after heart transplantation. Transplantation 1998;66:1763-1770.Garrido IP, Crespo-Leiro MG, Paniagua MJ, Muñiz J, 3. Rodríguez JA, Regueiro M, et al. Renal dysfunction after orthotopic heart transplantation: Incidence, natural history, and risk factors.Transplant Proc 2003;35:2014-2016.Rubel JR, Milford EL, McKay DB, Jarcho JA. Renal 4. insuffi ciency and end stage renal disease in the heart transplant population. J Heart Lung Transplant 2004;23:289-300.Vossler MR, Ni H, Toy W, Hershberger RE. Pre-operative 5. renal function predicts development of chronic renal insuf-fi ciency after orthotopic heart transplantation. J Heart Lung Transplant 2002;21:874-881.Satchithananda DK, Parameshwar J, Sharples L, Taylor GJ, 6. McNeil K, Wallwork J, et al. The incidence of end-stage renal

higher cyclosporine levels were found to be associ-ated with slightly lower estimated GFR. However, the clinical impact of this association does not seem to be signifi cant as suggested by the slope of the curve shown in Figure 5. No relationship between cyclosporine levels and survival or ESRD was dem-onstrated by univariate or multivariate analysis. As previously suggested (6,7,24), it is possible that indi-viduals may have different degrees of susceptibility to the nephrotoxic effects of cyclosporine indepen-dent of actual cyclosporine levels.

This study has several important limitations. 1) The sample size is small, includes very few ESRD outcomes and arises from a single institution. The results of this study may be subject to a type II error. The analysis was probably underpowered to show statistically signifi cant differences between the two groups in the intended outcomes. Although there were no statistically signifi cant differences between ESRD and mortality between the two groups, there was certainly a clear trend towards these two out-comes in the group with the worse preoperative renal function. The analysis of the ISHLT Registry (� 70 000 heart transplants performed worldwide) has consistently shown that poor preoperative renal function represents a risk factor for decreased post-operative survival (11). However, the Registry uses preoperative creatinine at the time of listing as an index of preoperative renal function and we actually estimated GFR using the Cockroft-Gault formula as near to the time of transplant as possible. We believe our estimation of pre-operative renal function may be more accurate. 2) The estimated glomerular fi ltra-tion rates do not accurately represent inulin clear-ance, the gold standard method to measure GFR. We believe that the use of ideal body weight instead of actual weight for the calculation of GFR using the Cockroft-Gault formula may partially reduce this inaccuracy. 3) Creatinine and cyclosporine trough levels collected represent the closest levels to the time points we arbitrarily chose in our study design. These levels may not accurately refl ect changes in renal function or represent the total cyclosporine area under the curve respectively, and this may also have affected our fi ndings. 4) Pharmacological therapy has not been included in our analysis and this could have a profound effect on the outcomes analyzed. The use of ACE inhibitors, angiotensin II receptor blockers, beta blockers, and diuretics may have a sig-nifi cant impact on pre and postoperative renal function and should be analyzed in prospective studies. 5) Although this study has a follow-up inter-val of up to 12 years, the mean follow-up is only 6.73 years. Larger multicenter prospective studies with longer follow-up may better evaluate ESRD as a complication of heart transplantation. 6) Changes in

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Sehgal V, Radhakrishnan J, Appel GB, Valeri A, Cohen DJ. 17. Progressive renal insuffi ciency following cardiac transplanta-tion: Cyclosporine, lipids, and hypertension. Am J Kidney Dis 1995;26:193-201.Lindelöw B, Bergh CH, Herlitz H, Waagstein F. Predictors 18. and evolution of renal function during 9 years following heart transplantation. J Am Soc Nephrol 2000;11:951-957.Hamour IM, Omar F, Lyster HS, Palmer A, Banner NR. 19. Chronic kidney disease after heart transplantation. Nephrol Dial Transplant 2009;24:1655-1662.Mihatsch MJ, Antonovych T, Bohman SO, Habib R, 20. Helmchen U, Noel LH, et al. Cyclosporine A nephropathy: Standardization of the evaluation of kidney biopsies. Clin Nephrol 1994;41:23-32.Myers BD, Sibley R, Newton L, Tomlanovich SJ, Boshkos 21. C, Stinson E, et al. The long-term course of cyclosporine-associated chronic nephropathy. Kidney Int 1988;33:590-600.Cantarovich M, Giannetti N, Cecere R. Correlation 22. between serum creatinine, creatinine clearance, the calcu-lated creatinine clearance and the glomerular fi ltration rate in heart transplant patients. J Heart Lung Transplant 2002;21:815-817.El Kossi MM, Ibrahim A, Lock TJ, El Nahas AM. Impact of 23. cardiac transplantation on kidney function: A single-center experience. Transplant Proc 2003;35:1527-1531.Woolfson RG, Neild GH. Cyclosporine nephrotoxicity fol 24. lowing cardiac transplantation. Nephrol Dial Transplant 1997;12:2054-2056.Eisen H, Ross H. Optimizing the immunosuppressive regi 25. men in heart transplantation. J Heart Lung Transplant 2004;23:S207-213.Valantine H. Neoral use in the cardiac transplant recipient. 26. Transplant Proc 2000;32:27S-44S. Keogh A. Calcineurin inhibitors in heart transplantation. J 27. Heart Lung Transplant 2004;23:S202-206.

failure in 17 years of heart transplantation: A single center experience. J Heart Lung Transplant 2002;2:651-657.van Gelder T, Balk AH, Zietse R, Hesse C, Mochtar B, 7. Weimar W. Renal insuffi ciency after heart transplantation: A case-control study. Nephrol Dial Transplant 1998;13:2322-2326.Veillon S, Caillard S, Epailly E, Eisenmann B, Hannedouche 8. T, Moulin B. Chronic renal failure after cardiac transplanta-tion: Predictive factors and infl uence on mortality-results of a monocenter study in 141 patients. Transplant Proc 2002;34:2819-2820.Herlitz H, Lindelow B. Renal failure following cardiac trans 9. plantation. Nephrol Dial Transplant 2000;15:311-314.Goldstein DJ, Zuech N, Sehgal V, Weinberg AD, Drusin R, 10. Cohen D. Cyclosporine-associated end-stage nephropathy after cardiac transplantation: Incidence and progression. Transplantation 1997;63:664-668.Taylor DO, Edwards LB, Boucek MM, Trulock EP, Deng MC, 11. Keck BM, et al. Registry of the International Society for Heart and Lung Transplantation: Twenty-second offi cial adult heart transplant report -- 2005. J Heart Lung Trans-plant 2005;24:945-955. Adajar FL, Lawless CE, Malinowska K. Outcome of heart 12. transplant in patients with renal insuffi ciency. J Heart Lung Transplant 2001;20:248. (Abstract).Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, 13. Young EW, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349:931-940.Al Aly Z, Abbas S, Moore E, Diallo O, Hauptman PJ, Bastani B. 14. The natural history of renal function following orthotopic heart transplant. Clin Transplant 2005;19:683-689.Cockcroft DW, Gault MH. Prediction of creatinine clearance 15. from serum creatinine.Nephron 1976;16:31-41.Gupta R, Birnbaum Y, Uretsky BF. Calculation of creatinine 16. clearance based on unadjusted body weight leads to errors in renal and heart failure patients. Circulation 2004;110:e70.

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