PEDIATRICS Vol. 107 No. 6 June 2001, pp. 1346-1350

Renal Function After Pediatric Cardiac Transplantation: The Effect of Early Cyclosporin Dosage

Tim S. Hornung, MRCP^*, Christian G.E.L. de Goede, MRCP^*, Chris O'Brien, MRCP, Nadeem E. Moghal, MRCP^§, John H. Dark, FRCS, and John J. O'Sullivan, MRCP^*

From the ^* Department of Paediatric Cardiology, Freeman Hospital,  Department of Paediatrics, Royal Victoria Infirmary, ^§ Department of Paediatric Nephrology, Royal Victoria Infirmary, and  Department of Cardiothoracic Surgery, Freeman Hospital, Newcastle upon Tyne, United Kingdom.

	ABSTRACT

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Background.  There is little data on renal function in pediatric heart transplant recipients. Early rejection is a major concern and most units run high cyclosporin A (CyA) levels during the 2 to 3 months after transplantation. We sought to document long-term renal function after transplantation and to assess influence of early CyA levels.

Methods.  We reviewed all of our pediatric transplants between June 1985 and August 1998 who survived longer than 6 months (n = 54). Glomerular filtration rate (GFR) was estimated at 1, 2, 4, and 8 years posttransplantation using the Schwartz formula:
GFR (mL/min/1.73m²) = [Ht(cm)/creatinine(µmol/L)] × X We also analyzed whether change in renal function correlated with trough CyA levels.

Results.  Median age at transplant was 4 years and median follow-up was 5 years. Survival rates were 87% at 1 year and 80% at 5 years. Mean GFR pretransplant was 79 ± 19 mL/min/1.73 m², reflecting prerenal impairment. One year later, mean GFR was 72 mL/min/1.73 m²; after 2 years it was 65 mL/min/1.73 m², after 4 years (n = 35) it was 60 mL/min/1.73 m², and after 8 years (n = 14) it was 57 mL/min/1.73 m². CyA levels during the first 2 months correlated with the change in GFR during the first year (r² = 0.21).

Conclusions.  This study demonstrates for the first time that decline in renal function after heart transplantation correlates with early CyA exposure; this dysfunction persists even when CyA doses are subsequently reduced.  Key words:  heart transplant, kidney function, cyclosporin A.

Despite widespread recognition of the nephrotoxic effects of cyclosporin therapy,^1-4 there is little data available regarding long-term renal function in pediatric cardiac transplant recipients. Because of concerns about early cardiac rejection, most units run high cyclosporin levels during the first months after transplantation, and these levels are often considerably higher than the levels used after renal transplantation. The glomerular filtration rate (GFR) is often reduced before transplantation in this population because of low cardiac output and poor renal perfusion. Restoration of renal perfusion after transplantation should improve GFR; however, in many patients this is not the case. The purpose of this study was to document the progression of renal dysfunction in survivors of pediatric heart transplantation and to assess the influence of cyclosporin exposure.

	PATIENTS AND METHODS

We retrospectively reviewed all patients who underwent cardiac transplantation at <16 years of age at our center between June 1985 and August 1998 who had structurally normal kidneys by ultrasound and who survived for >6 months after transplantation. Height and plasma creatinine was documented before transplantation and at 1 month, 1 year, 2 years, 4 years, and 8 years posttransplantation. Height was measured using a Harpenden wall-mounted stadiometer, and creatinine was measured from whole blood using a homogeneous enzyme immunoassay technique (Emit 2000, Syva.Company, Cupertino, CA). GFR was estimated using the modified Schwartz formula^5,6:

Immunosuppression Regime

Patients initially receive combination immunotherapy with cyclosporin, azathioprine (2 mg/kg/d), and prednisolone (0.2 mg/kg/d). Children <5 years old do not receive steroids after the first 24 hours. Cyclosporin dosage is adjusted aiming to achieve 12-hour trough levels between 300 to 400 ng/mL during the first 6 weeks after transplantation and 100 to 200 ng/mL thereafter. Antithymocyte globulin is also routinely given during the first week after transplantation, with the dosage being adjusted to keep the T-cell count below 50 000/mL. Prednisolone is routinely stopped 6 weeks after transplantation to minimize effects on growth⁷; very few patients required maintenance steroids. Thereafter, patients are maintained on cyclosporin ± azathioprine (depending on the white cell count). The cyclosporin preparation used was changed from Sandimmun to Neoral for all of our patients in July 1995, therefore, 17 patients received only Neoral. Neoral is a preconcentrate formulation of cyclosporin that undergoes a microemulsification process in the presence of gastrointestinal fluid and has less patient-to-patient pharmacokinetic variability. Patients who were previously taking Sandimmun were prescribed an initial Neoral dose 20% lower than their Sandimmun dose, and this was retitrated according to 12-hour trough levels.

Cyclosporin exposure was assessed in terms of mean serum cyclosporin trough levels and was divided into 3 periods: 1) the first 2 months after transplantation; 2) the next 10 months, ie, the remainder of the 1st year; and 3) the period from the end of the 1st year onward. The calculation of mean cyclosporin A (CyA) trough level was performed using all available cyclosporin levels to determine the average trough level during a particular period, as follows:

We assessed whether there was a correlation between cyclosporin exposure and decline in renal function, and also between decline in renal function and the use of other drugs. Blood pressure measurements were compared with age-matched population figures to determine whether uncontrolled hypertension (defined as blood pressure >95th percentile for age and height) correlated with decline in renal function.

Statistical Analysis

Estimated GFR values are expressed as group mean ± standard deviation. Group mean values were analyzed using analysis of variance and by comparing 95% confidence limits of group means. Correlation was assessed using linear regression analysis.

	RESULTS

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During the study period, 62 patients underwent cardiac transplantation, of whom 54 (27 boys) survived beyond 6 months after transplantation and were included in the study. Median age at transplantation of study patients was 4 years (range: 0.3-15 years), median length of follow-up was 5.2 (range: 0.8-11 years). Overall survival rates were 87% at 1 year and 80% at 5 years. Cardiac function was good in all cases except 2, both of whom developed left ventricular dysfunction at a late stage secondary to hypertension associated with severe renal impairment.

Height range for the whole group was reduced slightly compared with the normal population (Fig 1); however, the 12 patients who have reached 16 years of age show a normal range of heights. Although numbers are small, this suggests a normal spread of final heights and raises the possibility that the lower percentiles seen in the population as a whole represent growth delay rather than reduced growth potential.

View larger version (35K): [in this window] [in a new window]   Fig. 1.   Group heights compared with population standard deviation values. Ninety-five percent confidence limits of the transplant population height at various stages after transplantation. Shaded area is ± 2 standard deviations for the normal population.

Renal Function

Mean GFR before transplantation was 79 ± 19 mL/min/1.73 m², the low value partly reflecting the subgroup with low cardiac output and reduced renal perfusion. At 1 month after transplantation, the mean GFR had fallen slightly to 76 ± 19 mL/min/1.73 m².

Figure 2 shows that 1 year after transplantation, there was a fall in mean GFR to 72 ± 20 mL/min/1.73 m² (P = .05 of 0 years vs 1 years) and after 2 years an additional fall to a mean of 65 ± 15 mL/min/1.73 m² (P = .03 of 2 years vs 1 years); there was no correlation between pretransplant GFR and posttransplant GFR. After this, the decline in renal function then seemed to slow down somewhat, such that after 4 years (35 patients), the mean GFR is 60 ± 14 mL/min/1.73 m^2, and after 8 years (14 patients) the mean GFR is 57 ± 14 mL/min/1.73 m². Figure 3 shows this data in terms of the number of patients with varying degrees of renal impairment at each time point. At the most recent follow-up, 1 patient with severe renal failure had died having declined dialysis; another is expected to start dialysis imminently, and 2 more have severely impaired renal function (GFR<30 mL/min/1.73 m²).

View larger version (11K): [in this window] [in a new window]   Fig. 2.   Mean GFR of the transplant population. Shows mean values and 95% confidence limits of the mean.

View larger version (56K): [in this window] [in a new window]   Fig. 3.   Change in GFR with time, expressed as group values.

Cyclosporin Levels

Mean trough cyclosporin levels were 345 ± 52 ng/mL (range: 232-454 ng/mL) during the first 2 months after transplantation. For the remainder of the first year, the mean levels were 215 ± 64 ng/mL (137-497 ng/mL), and after the first year 159 ± 27 ng/mL (113-254 ng/mL). Cyclosporin levels during the first 2 months showed a significant correlation with change in GFR during the first year after transplantation (P = .0007, r² = 0.21; Fig 4). There is an additional correlation between cyclosporin levels during the remainder of the first year and reduction in GFR during the second year after transplantation (P = .03, r² = 0.13). The additional decline in GFR after the second year was not significantly correlated with cyclosporin levels, although numbers were small and there was less variation in cyclosporin levels between patients.

View larger version (40K): [in this window] [in a new window]   Fig. 4.   Mean CyA level during first 2 months versus change in GFR during the first year.

The rate of decline of renal function did not differ significantly between the group initially treated with Sandimmun (n = 37, mean CyA trough level in first 2 months = 349 ng/mL, mean change in GFR during the first year = 7 mL/min/1.73 m²) and the group initially treated with Neoral (n = 17, mean CyA trough level in first 2 months = 345 ng/mL, mean change in GFR during first year = 9 mL/min/1.73 m²), although median length of follow-up was only 2.4 years in the neoral group. We found no correlation between deterioration in renal function and use of other drugs, age at transplantation, or sex. Detailed blood pressure data were available for 49 of 52 patients and showed that hypertension was frequent in this population, 82% of patients having been hypertensive at some stage. The mean number of hypertensive days during the first year was 50 ± 81 days; there was no correlation between decline in renal function and number of hypertensive days (P = .91). Hypertension after the first year was rare, although the 2 patients with the most severe renal dysfunction developed significant late hypertension requiring treatment with >1 antihypertensive agent.

	DISCUSSION

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Although cyclosporin is known to adversely effect renal function,^1-4 there is very little data regarding its effects after heart transplantation in children. We now present data from our complete population of pediatric transplant survivors which shows that moderate renal dysfunction is a near universal problem in this population, and that in a minority, the degree of renal impairment is severe. We also demonstrate a correlation between early cyclosporin levels and rate of decline of renal function, allowing us to suggest safe cyclosporin trough levels for this population.

Prevalence of Renal Impairment

Our pediatric transplant population is maintained on a combination of cyclosporin ± azathioprine, without the use of steroids. It has been our expectation that this regimen would maximize growth potential, while allowing adequate immunosuppression.^7-9 The dosage of cyclosporin required to avoid rejection is, however, higher with such a regimen. Although overall survival figures are very good (80% 5-year survival), 2 of our 54 transplant survivors have developed end-stage renal disease, and an additional 2 have severe impairment of renal function with expected progress to end-stage renal disease; this represents 7% of our population with severe renal impairment. This data differs from the most recent report of pediatric heart transplant results from the International Society for Heart and Lung Transplantation,¹⁰ which shows 5-year survival of 65% but no patients with severe renal impairment (defined as a creatinine >2.5 mg/mL). Although it is possible that this discrepancy is attributable to underreporting to a voluntary registry or to differing definitions of severe renal impairment, it is also possible that, particularly earlier on in our experience, we have been running cyclosporin levels higher than many other centers. When compared with International Society for Heart and Lung Treatment registry figures, the results of our protocol seem to be better overall survival, but higher rates of renal impairment. Studies of adult heart transplant recipients are comparable to our experience, with a prevalence of end-stage renal disease of 3% to 10%.^11-17

Influence of Cyclosporin Level

This study demonstrates a correlation between cyclosporin exposure during the first year and decline in GFR. This suggests that the maintenance of high early cyclosporin levels is an important factor in the renal damage seen in this group and that lower levels may result in less renal damage. Previous studies in adult populations have found no such correlation, but have often studied isolated trough levels taken at, for example, 3 or 12 months. In our study, we have used all available cyclosporin levels to determine the average trough level during a particular period; we believe this has enabled us to give a more accurate estimation of the total cyclosporin exposure. Despite this, our results provide only a relatively weak correlation (r² = 0.21), which is likely to be attributable to the remaining inaccuracies associated with the use of 12-hour trough cyclosporin levels. It is recognized that cyclosporin trough levels are an imperfect way of controlling dosage and, likewise, estimation of total cyclosporin load. It is possible that a more detailed cyclosporin profile would allow more accurate delineation of the renal effects of cyclosporin; however, in a retrospective study such as this, the only consistent measure available to us, as in most transplant centers, is the trough cyclosporin level. Furthermore, a detailed cyclosporin profile would require more blood samples to be taken and more time to be spent in hospital, raising ethical dilemmas particularly in the pediatric population.

Although it is likely that genetic influences have some influence on renal prognosis in this group,¹¹ we believe that cyclosporin load is important and that maintenance of the lowest possible cyclosporin levels will be beneficial in terms of long-term renal function. These data suggest that an early mean cyclosporin trough level of 300 ng/mL is not associated with development of renal impairment; in fact most patients with mean levels <300 ng/mL showed an improvement in renal function as would be expected with restoration of normal cardiac output and renal perfusion. Trough cyclosporin levels >300 ng/mL are associated with progressively greater risk of renal impairment in this population. We, therefore, suggest that the target trough cyclosporin level during the aggressive period of early immunosuppression should be 300 ng/mL or less.

Progression of Renal Impairment

Our data would suggest that although our immunosuppression regime results in excellent survival figures, there is a price to pay in terms of progressive impairment of renal function. The data demonstrate an early and rapid decline in renal function in the first 2 years after transplantation, with an additional, slower decline in subsequent years, despite lower maintenance cyclosporin levels. This differs from the pattern reported by several other groups in adult transplant recipients, in whom there is an early decline in renal function, but a subsequent plateau.^13,18,19

It is too early to predict with confidence the number of children in this group that will eventually develop severe renal impairment. The observed continuing decline in renal function suggests that the early cyclosporin toxicity has caused a significant renal insult, such that progressive ongoing damage may develop as a result of hyperfiltration injury.²⁰

Study Limitations

This study is a retrospective study that uses an indirect estimate of renal function and relies on 12-hour trough cyclosporin levels for estimation of total cyclosporin load. The accuracy of the study and the statistical power could potentially be improved by the direct measurement of glomerular filtration rate and by more detailed cyclosporin profiles. This sort of monitoring would, however, be both expensive and time-consuming and would result in an ever greater amount of time spent in hospital for a group of children who are already frequent visitors to the outpatient department.

	CONCLUSION

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This study is important because it demonstrates for the first time that decline in renal function after heart transplantation is correlated with early cyclosporin exposure.

These long-term data have had a significant impact on our overall immunosuppressive strategy in the pediatric age group, with individualization of immunosuppressive regimes to achieve the lowest cyclosporin level that will prevent rejection for each patient. We have also established a joint cardiac-renal clinic to improve the renal monitoring and outcome of this population. The use of alternative immunosuppressive agents may, in the future, result in an improved renal outlook for this patient group.

	ACKNOWLEDGMENT

We thank Dr Malcolm Coulthard for his assistance with reviewing the manuscript.

	FOOTNOTES

Received for publication Jan 6, 2000; accepted Oct 12, 2000.

Reprint requests to (T.S.H.) Adult Congenital Cardiac Centre, Toronto General Hospital, Elizabeth St, Toronto, Canada, M5A 2C4. E-mail: tim.hornung{at}uhn.on.ca

	ABBREVIATIONS

GFR, glomerular filtration rate; CyA, cyclosporin A.

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