|Year : 2015 | Volume
| Issue : 4 | Page : 671-677
|Sequential changes in bone biochemical parameters and bone mineral density after renal transplant
Manish Rathi1, Deepak Kumar1, Sanjay Kumar Bhadada2, Niranjan Khandelwal3, Harbir S Kohli1, Vivekanand Jha1, Vinay Sakhuja1
1 Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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|Date of Web Publication||8-Jul-2015|
| Abstract|| |
To evaluate sequential changes in biochemical bone parameters, parathyroid hormone (iPTH), vitamin D levels and bone mineral density (BMD) over a period of 24 weeks after renal transplantation, we studied 75 patients (58 males, with a mean age of 35.4 years) who underwent their first renal transplantation without a past history of parathyroid surgery or fractures. Serum calcium, phosphorus and albumin were measured before transplant, then weekly for four weeks and monthly for the following 20 weeks. Serum iPTH and vitamin D levels and BMD were measured at baseline and 24 weeks after transplantation. After transplantation, there was a significant fall in serum calcium in the first week, followed by a gradual rise. At 12 and 24 weeks, respectively, 17.5% and 8% patients had hypercalcemia. Serum phosphorus decreased after transplant and at 24 weeks; 25% patients had hypophosphatemia. The iPTH levels declined significantly from 251 ± 218.2 pg/mL before transplant to 97 ± 142.8 pg/mL at the end of the study period. At 12 and 24 weeks, 42.7% and 51.3% patients, respectively, had persistent hyperparathyroidism (HPT). Elevated baseline iPTH levels and graft dysfunction were the risk factors for HPT at 12 weeks, while low vitamin D levels were the risk factor at 24 weeks. The BMD showed a significant decline of 2.7% after transplant, and it negatively correlated with the pre-transplant iPTH levels; the patients who received tacrolimus immunosuppression had a lower decline in BMD than the rest of the patients. No fractures were reported during the study period. We conclude that, after renal transplantation, hypercalcemia and hypophosphatemia are common, while a significant proportion of patients have persistent HPT and decline in bone mineral density.
|How to cite this article:|
Rathi M, Kumar D, Bhadada SK, Khandelwal N, Kohli HS, Jha V, Sakhuja V. Sequential changes in bone biochemical parameters and bone mineral density after renal transplant. Saudi J Kidney Dis Transpl 2015;26:671-7
|How to cite this URL:|
Rathi M, Kumar D, Bhadada SK, Khandelwal N, Kohli HS, Jha V, Sakhuja V. Sequential changes in bone biochemical parameters and bone mineral density after renal transplant. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2019 Jul 23];26:671-7. Available from: http://www.sjkdt.org/text.asp?2015/26/4/671/160127
| Introduction|| |
Disorders of bone and mineral metabolism are common in patients with chronic kidney disease (CKD-MBD). Renal transplantation corrects many of these disturbances, but they may persist or worsen after transplantation. In addition to the pre-existing bone disease, the immunosuppressive medications and impaired graft function also have a great impact on these disorders after renal transplantation. ,,
Some previous studies have reported the incidence of post-transplant hypercalcemia and hypophosphatemia in up to 90% of the transplant patients; however, there is no clarity on the time of onset and the course of these abnormalities. ,,, Moreover, the majority of these studies were carried out in the era when we did not have modern medicines to manage pretransplant hyperparathyroidism (HPT).
The parathyroid hormone (iPTH) levels have been reported to decline rapidly (>50%) during the first three to six months after renal transplantation, followed by a more gradual decline that is probably attributable to the slow and incomplete involution of the parathyroid gland, and the incidence of post-transplant HPT has been reported to be in the range of 25-75%. ,,,
The bone mineral density (BMD) also demonstrates a fall after renal transplantation. Prospective studies have demonstrated a rapid rate of bone loss during the first six months, from 2-7% at the lumbar spine to 3-9% at the femoral neck after renal transplant, mainly affecting the trabecular bone compartment with an increased rate of fractures. ,,
The aim of the present study was to assess the sequential changes in the biochemical bone parameters, the incidence of secondary HPT and the changes in BMD during the first 24 weeks after renal transplant.
| Materials and Methods|| |
We prospectively studied consecutive endstage renal disease patients who underwent their first renal transplantation over a period of one year after obtaining their informed consent. Those with a past history of parathyroid surgery, spine fracture or deceased kidney transplants were excluded. The study was approved by our Institute Ethics Committee.
All the patients received calcineurin inhibitor (CNI)-based immunosuppression along with mycophenolate mofetil (MMF) and prednisolone. Serum calcium, serum phosphorus, alkaline phosphatase, creatinine and albumin were measured using the standard auto-analyzer technique at baseline before transplant and then weekly for four weeks and monthly for the next 20 weeks after transplantation. Serum iPTH and 25-hydroxyvitamin D levels were measured by the electro-chemiluminescence assay at baseline, 12 weeks and 24 weeks after transplantation. The BMD was assessed at baseline and 24 weeks after transplantation by the dualenergy X-ray absorptiometry method (DEXA) using a Norland scanner (model XR46; Norland a Cooper Surgical Company, Fort Atkinson, WI USA) and the T and Z scores were calculated.
Hypercalcemia was defined as corrected serum calcium levels >10.3 mg/dL, while levels <8.4 mg/dL were defined as hypocalcemia. Similarly, hyperphosphatemia and hypophosphatemia were defined as serum phosphorus levels >4.5 mg/dL and levels <2.8 mg/dL, respectively. Values of iPTH levels >65 pg/mL were considered compatible with HPT, while levels <15 pg/mL were considered compatible with hypoparathyroidism. We considered 25 hydroxyvitamin D levels <25 ng/mL as vitamin D deficiency and levels between 25 and 30 ng/mL as vitamin D insufficiency. Osteopenia and osteoporosis were defined if T scores were between -1.0 and -2.5 and <-2.5 (World Health Organization classification).
| Statistical Analysis|| |
The SPSS (Statistical Package for Social Sciences version 17.0; International Business Machines Corporation, IBM, Armonk, New York, USA) was used for statistical analysis. Data were expressed as mean ± standard deviation. For comparison of means, two-paired t-test or independent sample t-test was used. The analysis of variance (ANOVA) test was used for measurable variables. The Wilcoxon signed-rank test was used to evaluate the association between variables compared with the paired t-test, while the Mann-Whitney test was used for variables compared with the unpaired t-test. The Pearson correlation coefficient was used to assess the correlation between the different variables. P-values <0.05 were considered as significant.
| Results|| |
There were 75 patients (58 male and 17 female, with a mean age of 35.4 years) eligible for the study. The most common cause of renal failure was chronic glomerulonephritis (CGN) in 42 patients, followed by chronic interstitial nephritis (CIN) in 10 patients and diabetic nephropathy (DN) in nine patients. Seventy-one (94%) patients were on maintenance hemodialysis prior to transplantation, and all patients were on oral phosphate binders; of them, 53 (70%) patients received non-calcium-based phosphate binder (lanthanum carbonate in 31 and sevelamer carbonate in 22). Seven (9%) patients received active vitamin D (calcitriol), while none of them was on cinacalcet. The baseline demographic characteristics and laboratory values of the patients are summarized in [Table 1].
All the patients were started on a combination of CNI (Tacrolimus-69, Cyclosporine-6), MMF and prednisolone. Twenty-three patients received induction (17-basiliximab, 6-antithymocyte globulin). The mean cumulative doses (in grams) at 24 weeks after transplantation was 1.95 ± 0.91 for tacrolimus, 38.16 ± 10.39 for cyclosporine, 1.7 ± 0.71 for prednisolone and 279 ± 54.12 for MMF. Fourteen (18.6%) patients developed biopsy-proven acute rejection (nine acute cellular rejection, five acute humoral rejection, one combined acute cellular and humoral rejection).
Serum calcium declined significantly during the 1 st week after transplant, followed by a rise from three to 12 weeks [Figure 1]. At 12 and 24 weeks, about 17.5% and 8% of patients, respectively, were hypercalcemic. We divided patients into three categories depending on their baseline iPTH, i.e., iPTH <150, 150-300 and >300 pg/mL. The biphasic pattern of serum calcium levels was observed in all the three groups of patients in a similar manner. Serum phosphorus levels also decreased significantly. immediately post-transplant. At the 2 nd and 3 rd weeks, about 48% and 49% of patients, respectively, developed hypophosphatemia, with gradual normalization over the 24-week period. However, at the end of the study period, about 25% of the patients still had low serum phosphorus levels [Figure 1]. The fall in serum phosphorus was similar in the three categories of patients according to the baseline iPTH levels.
The mean of the iPTH levels at the time of transplantation was 251.8 ± 218.2 pg/mL (11-951 pg/mL). There was a significant decline in the iPTH levels at 12 and 24 weeks after transplantation [Figure 1]. Thirty-two (42.7%) patients at 12 weeks and 38 (51.3%) patients at 24 weeks had persistent HPT. The factors associated with persistent HPT are shown in [Table 2]. At 12 weeks, the persistent HPT was associated with higher pre-transplant iPTH and higher post-transplant serum creatinine, while at 24 weeks it was associated with low levels of vitamin D. Hypovitaminosis D was observed in 56%, 49.3% and 52% of the patients at pretransplant, 12 weeks and 24 weeks, respectively. Among patients with persistent HPT, about 50% of the patients at 12 weeks and 62.5% patients at 24 weeks had low vitamin D3 levels. The sequential changes of important biochemical parameters during the study period are summarized in [Figure 1].
The DEXA scan was performed in 58 (77%) patients. The mean BMD at the L2-4D vertebrae before transplant was 0.95 ± 0.19 g/cm 2 (T = -1.07 + 1.27, Z = -0.78 ± 1.22). The baseline BMD was inversely correlated with the baseline iPTH (r = -0.281, P = 0.032). At the end of 24 weeks post-transplantation, there was a significant decline in the BMD at the L2-4D vertebrae by 2.7% to 0.92 ± 0.14 g/cm 2 (P = 0.054). The BMD at the individual lumbar vertebrae also showed a significant decline. However, no significant difference was noted in the prevalence of osteopenia and osteoporosis (43.1% versus 44.8% and 12.1% versus 10.3% at baseline and 24 weeks after transplantation, respectively). None of the patients developed a bone fracture during the study period.
The decline in BMD negatively correlated with the pre-transplant iPTH levels (r = -0.286, P = 0.028), while persistent HPT and low vitamin D3 did not affect BMD decline significantly. Diabetic patients experienced greater BMD loss, while female subjects experienced gain in BMD. There was no correlation between the decline in BMD at L2-4 D and BMD, cumulative dose of steroid, MMF and CNI, or serum creatinine, after transplantation. However, patients who received cyclosporine suffered a significant BMD decline at the L2D compared with those who received tacrolimus (P = 0.001); however, there was no significant decline at L2-4 D. Patients with acute rejection experienced similar BMD loss compared with patients without any rejection episodes [Table 3].
| Discussion|| |
We observed in our study that the serum calcium had a biphasic pattern, with a decline in the first week followed by a rise in the early period after kidney transplant. This pattern of calcium with hypocalcemia immediately after transplantation and subsequent hypercalcemia was similar to previously reported trials. , Christensen et al  observed a peak in serum calcium levels in 16.7% of patients more than two months after kidney transplantation, which is similar to the pattern observed in our study. The hypercalcemia generally develops some weeks after transplantation, possibly related to the removal of the suppressing effect of high doses of corticosteroids used in the immediate post-operative period on bone turnover. Persistent HPT, correction of uremia and normalization of serum phosphorus levels are additional factors contributing to hypercalcemia. 
We also observed in our study that the serum phosphorus levels declined rapidly after transplantation and, at the 2 nd and 3 rd weeks of transplant, about 48% and 49% of all patients respectively had hypophosphatemia, with gradual normalization over 24 weeks. Earlier studies have reported that up to 93% of transplanted patients can develop moderate hypophosphatemia within the first six months post-transplant, with peak around the third month.  Thus, the incidence of hypophosphatemia was lower in our study. The factors responsible for the hypophosphatemia in the immediate post-transplant period are decreased phosphate reabsorption due to tubular defect and the phosphaturic effect of the persistent HPT. In our study, about 42.7% patients at 12 weeks and 52% patients at 24 weeks had persistent HPT, while in the literature, the prevalence was reported to be highly variable, ranging from 27-75%. ,,,, The course and severity of post-transplant HPT correlates positively with the duration and severity of pre-transplant HPT. Additional factors that may contribute to high iPTH concentration are the number of years on dialysis, incomplete normalization of renal function, suboptimal levels of calcitriol and decreased intestinal calcium absorption induced by corticosteroids. , Therefore, a better management of HPT in the pre-transplant period may result in a decreased incidence of hypophosphatemia and persistent HPT as observed in our study.
In the BMD analysis, we observed that 43% of patients had osteopenia and 12% had osteoporosis at the time of transplantation. This may be because most of our patients were dialysis dependent and had HPT at the time of transplantation and about 50% were had low vitamin D3. We found that pre-transplant iPTH was negatively associated with the pre-transplant BMD, which is in agreement with several prior studies. ,, Our study also demonstrated a significant fall in the lumbar vertebra BMD in the first 24 weeks after transplantation. The average decline in BMD was 2.7% during this period. In a similar study carried out by Mikuls et al,  a mean BMD decline of 2.4% at the lumbar spine was observed. These observations corroborate with previous studies showing significant BMD reductions early after transplantation. ,, However, only a few of these studies were prospective in nature. Although glucocorticoids have been incriminated as the most important contributor to bone loss after transplantation, many studies, including ours, have failed to show any association between BMD loss and the cumulative doses of steroids. ,, In transplant recipients, the effect of glucocorticoids may be modified by other factors such as persistent HPT and tacrolimus therapy. In the present study, we noted that patients who received CSA had accelerated bone loss compared with patients who received tacrolimus, which was statistically significant at the L2D vertebrae. There are few studies that show that tacrolimus has a favorable bone protective profile than cyclosporine, most probably related to the steroid-sparing effect. ,,
Both severe HPT at the time of transplantation and persistent HPT after transplantation have been shown to be risk factors for post-transplant osteopenia. , However, in the study by Casez et al,  low baseline iPTH was associated with continued bone loss, in contrast to high baseline iPTH. They observed that the baseline iPTH was a major determinant of BMD changes at the cortical bone, in contrast to steroids, which causes mainly trabecular bone loss. Although the protective effect of iPTH was more pronounced on the appendicular skeleton, it was also noticed at the axial skeleton. Furthermore, the DEXA scan could not differentiate between the trabecular and the cortical bone. We also found that the iPTH levels at 24 weeks posttransplantation were not associated with increased loss of bone density.
Limitations of our study include the small sample size, which does not allow us to generalize the results. Further studies with a larger sample size would allow inference with greater confidence. Our study was also limited by the methodology used to measure the BMD, as the DEXA scan cannot differentiate between the cortical and the trabecular bone.
To summarize, despite the improvement in the knowledge of the CKD-MBD and the enhanced armamentarium to manage these disorders in the pre-transplant period, persistent HPT and consequent hypercalcemia and hypophosphatemia remain significant problems in the short term in post-kidney transplant patients.
Conflict of interest: None
| Acknowledgment|| |
The authors thank Dr. Pramod K. Gupta, Assistant Professor, Department of Biostatistics, Post Graduate Institute of Medical Education and Research, Chandigarh, who helped in the statistical analysis.
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Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012
[Table 1], [Table 2], [Table 3]
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