Department of Medicine, Division of Nephrology, University Hospital Leuven, Leuven, Belgium
Correspondence and offprint requests to: P. Evenepoel, MD, PhD, Dienst nefrologie, Universitair Ziekenhuis Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Email: Pieter.Evenepoel{at}uz.kuleuven.ac.be
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Abstract |
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Methods. Charts of 1165 allograft kidney recipients transplanted between 1989 and 2000 were reviewed. Patients with an intact parathyroid hormone (iPTH) level available at the time of transplantation were identified. The charts of the latter patients were checked for a variety of demographic and clinical data, and all determinations of the iPTH concentration available since transplantation were recorded. Serum levels of calcium, phosphorus, alkaline phosphatases and creatinine, concurrently determined, were also registered.
Results. After an initial fall, iPTH levels showed a slow but steady decline towards the upper normal limit. The prevalence of persistent HPT, defined as an iPTH level 2.5 times the upper normal limit or the need for parathyroidectomy following transplantation, remained stable at
17% up to 4 years after transplantation. Patients with persistent HPT had significantly elevated serum levels of iPTH, calcium and phosphorus at the time of RT, and had spent a longer time on dialysis. Post-transplant iPTH levels correlated significantly with transplant kidney function.
Conclusion. Kidney transplant recipients with a high iPTH and calcium x phosphate product at the time of transplantation are at risk for persistent HPT especially when renal function is suboptimal. Therapy for persistent HPT, if considered, should be initiated 3 months post-transplantation since further spontaneous improvement of parathyroid function thereafter is limited.
Keywords: calcium metabolism; hyperparathyroidism; intact parathyroid hormone; renal transplantation
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Introduction |
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Only few data are available in the literature on the long-term natural history of HPT after successful renal transplantation. This can be explained by the lack of a reliable and precise iPTH assay until the late 1980s. Before this time, radioimmunoassays for iPTH measured different fragments of PTH and thereby provided imprecise, inconsistent and non-uniform estimates of biologically active PTH. The introduction of an immunoradiometric assay (IRMA) to measure intact PTH in the late 1980s resulted in an important improvement in the study of HPT in both non-uraemic and uraemic individuals [4].
The aim of the present study was to evaluate the natural history of HPT after successful renal transplantation and to identify risk factors for persistent HPT present at the time of transplantation. Knowledge of the natural history might help in determining the time at which specific treatment should be initiated in order to minimize any detrimental effect of persistent HPT on bone and the cardiovascular system. The presence of risk factors in kidney transplant recipients may warrant a closer follow-up.
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Subjects and methods |
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Patients with data on parathyroid function available at the time of transplantation were identified (study population). Their charts were reviewed in detail. Information abstracted included demographic and laboratory data, modality and duration of dialysis treatment, and details concerning the immunosuppressive regimen.
To evaluate the natural history of the parathyroid function after transplantation in patients with a functional graft, all determinations of the iPTH level available from the time of transplantation up to January 1, 2001 were recorded. Serum levels of calcium, phosphorus, alkaline phosphatases and creatinine, concurrently determined, were also registered. Data obtained after graft failure or PTX were censored from the analysis. The patients did not routinely receive oral calcium or vitamin D supplements following transplantation.
To identify risk factors for persistent HPT present at the time of transplantation, demographic, clinical and baseline laboratory data obtained in patients with persistent HPT were compared with those obtained in a control population. Persistent HPT was defined as (i) a history of a PTX because of HPT during the first year after transplantation or (ii) a mean iPTH level registered during the second year after transplantation of 100 ng/l. The control group consisted of patients belonging to the study population with (i) no history of post-transplant PTX and (ii) a mean iPTH level registered during the second year after transplantation of <100 ng/l.
To evaluate the impact of graft function on the natural history of secondary HPT, iPTH levels obtained in patients with optimal graft function, defined as a creatinine clearance >60 ml/min, were compared with those obtained in patients with a creatinine clearance 60 ml/min. Since the pre-transplant parathyroid function emerged as an important risk factor for persistent HPT, the natural history of iPTH levels in patients with moderate to severe HPT at the time of transplantation was also evaluated.
Determinations
Total serum calcium [normal range: 8.9 10.5 mg/dl (2.222.62 mmol/l)], phosphorus [normal range: 2.34.7 mg/dl (0.741.52 mmol/l)], alkaline phosphatases (normal range: 90260 U/l) and creatinine [normal range: 0.71.3 mg/dl (62115 µmol/l)] were measured using a computerized autoanalyser. Creatinine clearance was calculated from a 24 h urinary specimen. Serum concentrations of iPTH were determined by the IRMA described above.
Statistical analysis
For descriptive purposes, laboratory data were grouped by time of analysis (relative to the time of transplantation): months 03, months 36, months 612, months 012, months 1224, months 2436, months 3648 and months 4860. If a biochemical analysis had been performed more than once in a certain period, the values obtained were averaged.
Parameters with Gaussian distribution are expressed as mean±SD, whereas parameters with skewed distribution are expressed as median and interquartile range (IQR). Univariate and multivariate logistic regression were used to investigate the association between risk of persistent HPT and explanatory variables. Spearman correlation coefficients were used to express associations between continuous parameters. Statistical significance was considered with a P-value of <0.05.
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Results |
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Incidence of secondary HPT
Serum iPTH levels at the time of transplantation showed a leftward skewed distribution with a median of 64.8 ng/l (IQR 23.7151.5) (Figure 1). The incidence of secondary HPT, defined as an iPTH level above the upper normal limit, was 63.3%. Mild, moderate and severe HPT were present in 26.1, 33.0 and 4.2% of the transplant recipients, respectively. Neither the incidence nor the severity of HPT were influenced by the era of transplantation.
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Table 3 shows the post-transplant natural history of the parathyroid function and calcium metabolism in a subgroup of patients with moderate to severe HPT at the time of transplantation. Obviously, the major decline of iPTH levels occurs during the first 3 months following transplantation. The prevalence of persistent HPT (Figure 3), post-transplant hypercalcaemia and hypophosphataemia (Table 3) was at all time points higher in the subgroup of patients with moderate to severe HPT at the time of transplantation as compared with the whole study population.
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Risk factors for persistent HPT at 1 year
As compared with controls, patients with persistent HPT at 1 year were characterized by significantly higher serum levels of iPTH (P<0.001), calcium (P<0.001) and phosphorus (P<0.01) at the time of transplantation. These patients had also been dialysed for a significantly longer time (P<0.001). No significant difference was present between the two groups in distribution of gender, renal diagnosis, mode of dialysis and maintenance immunosuppressive drugs (Table 1). Multivariate analysis revealed similar results, indicating that serum levels of iPTH, calcium and phosphorus, and dialysis vintage were independent predictors of persistent HPT.
Correlations
Table 4 shows correlations between serum iPTH levels and other biochemical variables at different time points. A significant positive correlation was observed between the actual serum iPTH levels and the corresponding pre-transplant serum iPTH levels up to the fourth year post-transplantation. Significant positive correlations were also noted between the serum iPTH levels on the one hand and the serum calcium and creatinine levels on the other hand.
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Discussion |
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As evidenced by the natural history of parathyroid function in patients with moderate to severe HPT at the time of transplantation, the decline of iPTH levels is most pronounced during the first 3 months after transplantation. This rapid improvement of parathyroid function is most probably related to post-transplant changes in calcaemia and phosphataemia. Like others, we observed high prevalences of hypercalcaemia and hypophosphataemia in the early post-transplant period, especially in the subgroup of patients with moderate to severe HPT at the time of transplantation. Post-transplant hypercalcaemia may be due to resorption of extra-skeletal calcifications, to phosphate depletion or to the progressive recovery of the normal calcaemic activity of PTH following transplantation [6,7]. Hypophosphataemia after transplantation mainly results from a decreased tubular reabsorption of phosphate. The fact that PTH is now able to exert its phosphaturic effect in the transplanted kidney [3], the occurrence of an intrinsic tubular defect [8,9] and the persistence of a phosphatonin-like substance [10] have all been implicated in the pathogenesis of hypophosphataemia and exaggerated phosphaturia following transplantation. Finally, renal phosphate wasting may also be induced by therapy with steroids and/or diuretics [7,11].
In summary, our data on post-transplant parathyroid function extend those reported in other series [13,12] and confirm that renal transplantation is not necessarily the ideal treatment which solves the problem of HPT.
In agreement with previous studies [2,3], we found that patients with a high serum level of iPTH, calcium, phosphorus and/or alkaline phosphatases at the time of transplantation are at risk for persistent HPT. Patients with persistent HPT, moreover, had been treated with dialysis for a longer time. These findings together with the significantly positive correlation noticed between actual and baseline iPTH levels indicate that the severity of post-transplant HPT largely depends on the parathyroid gland volume reached during uraemia.
The correlation analyses, furthermore, indicate that besides pre-transplant parathyroid function, renal graft function is an important determinant of post-transplant iPTH serum levels, especially after the first year (Table 4). However, when evaluating the natural history of parathyroid function in patients with optimal graft function as compared with patients with suboptimal graft function, significant differences were not observed, most probably as a result of a large interindividual variability of serum iPTH levels and/or the arbitrary definition of optimal graft function.
Apart from persistence of parathyroid hyperplasia and suboptimal graft function, some immunosuppressive drugs are thought to contribute to persistent HPT [11,12]. In the present study, however, none of the maintenance immunosuppressive drugs were found to be associated with persistent HPT. Finally, deficient 25(OH)vitamin D3 [3] and calcitriol levels [12,13], and diminished expression of vitamin D and calcium sensing receptor [14] have been implicated in the pathogenesis of persistent HPT after renal transplantation. Unfortunately, vitamin D levels were not routinely determined in our transplant population.
The detrimental consequences of persistent HPT are well known. Persistent HPT is considered an independent and important risk factor for post-transplant bone disease [11,15]. Furthermore, elevated iPTH levels appear to play a role in soft tissue and organ calcification (e.g. atherosclerosis, calcifications of cardiac valves), metabolic abnormalities of carbohydrate and lipid metabolism, hypertension and cardiomyopathy [1618].
These complications emphasize the importance of early reversal of HPT. The target iPTH in renal transplant recipients should be individualized and mainly correlated with renal transplant function.
In conclusion, kidney transplant recipients with a high serum level of iPTH, calcium, phosphorus and/or alkaline phosphatases at the time of transplantation are at risk for persistent HPT especially when renal function is suboptimal. Therapy for persistent HPT, if considered, should be initiated 3 months post-transplantation since further spontaneous improvement of the parathyroid function thereafter is limited.
Conflict of interest statement. None declared.
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References |
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