|Year : 2021 | Volume
| Issue : 3 | Page : 199-204
Changes in bone mineral density in patients undergoing kidney transplantation
Manjunath P Ramakrishna1, Chankramath S Arun1, Sandeep Sreedharan2, Praveen V Pavithran1, Nisha Bhavani1, Renjitha Bhaskaran3, Harish Kumar1
1 Department of Endocrinology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
2 Department of Nephrology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
3 Department of Biostatistics, Amrita School of Medicine, Kochi, Kerala, India
|Date of Submission||06-Mar-2021|
|Date of Decision||05-May-2021|
|Date of Acceptance||03-Jun-2021|
|Date of Web Publication||30-Sep-2021|
Dr. Sandeep Sreedharan
Department of Nephrology, Amrita Institute of Medical Sciences, Kochi - 682 041, Kerala
Source of Support: None, Conflict of Interest: None
Background and Aims: Bone health in chronic kidney disease (CKD) and its changes after kidney transplantation has been a subject of considerable interest. Kidney transplantation could potentially impact this process positively by reversing hyperparathyroidism, but immunosuppression including steroids could be deleterious to bone health. We studied the baseline and posttransplant bone mineral density (BMD) and factors affecting the changes in BMD after transplantation. Methods: Patients who were included in the study underwent biochemical tests and dual-energy absorptiometry for BMD. These tests were performed at baseline and 8 months after transplantation. Results: The mean BMD in lumbar spine was 1.09 ± 0.15 g/cm2 at baseline and 1.06 ± 0.15 g/cm2 posttransplantation (P = 0.002). The mean BMD at left forearm was 0.88 ± 0.10 g/cm2 at baseline and 0.89 ± 0.10 g/cm2 after transplantation (P = 0.013). The mean BMD at femur was 0.91 ± 0.16 g/cm2 and 0.89 ± 0.10 g/cm2 (P = 0.77) after transplantation. At baseline, intact parathyroid hormone (iPTH) had a significant negative correlation with femoral BMD (r = 0.44, P = 0.02) and 25-hydroxy Vitamin D (25(OH) Vit-D) had a positive correlation with forearm BMD (r = 0.50, P = 0.004). Eight months after transplantation, 25(OH) Vit-D levels showed a positive correlation with lumbar spine BMD (r = 0.36, P = 0.04). Cumulative steroid dose negatively correlated with spine BMD (r = −0.43, P = 0.01) posttransplantation. Conclusions: In this study, the baseline BMD was well preserved. Higher iPTH was associated with lower femoral BMD. Low 25(OH) Vit-D was associated with reduced forearm BMD. There was worsening of spinal BMD and improvement in forearm BMD 8 months after transplantation. No significant change in femoral BMD was noted. Cumulative steroid dose had a significant negative impact on BMD at spine. There were no fractures noted during the study, but two patients had avascular necrosis of the femur.
Keywords: Bone Mineral Density, chronic kidney disease–mineral and bone disorder, kidney transplantation, osteoporosis, renal osteodystrophy
|How to cite this article:|
Ramakrishna MP, Arun CS, Sreedharan S, Pavithran PV, Bhavani N, Bhaskaran R, Kumar H. Changes in bone mineral density in patients undergoing kidney transplantation. Indian J Transplant 2021;15:199-204
|How to cite this URL:|
Ramakrishna MP, Arun CS, Sreedharan S, Pavithran PV, Bhavani N, Bhaskaran R, Kumar H. Changes in bone mineral density in patients undergoing kidney transplantation. Indian J Transplant [serial online] 2021 [cited 2022 Nov 29];15:199-204. Available from: https://www.ijtonline.in/text.asp?2021/15/3/199/327391
| Introduction|| |
Renal osteodystrophy comprises alterations in bone morphology associated with chronic kidney disease (CKD) and includes changes in bone turnover, mineralization, and volume. Skeletal abnormalities such as high- or low-turnover bone disease, mixed renal osteodystrophy, and osteomalacia occur in such patients resulting in reduced quality and quantity of bone. When such patients undergo kidney transplantation, complex bone remodeling process occurs which depends upon both preexisting and posttransplantation factors. Multiple factors such as recovery of kidney function, parathyroid function, use of immunosuppressive drugs, and Vitamin D status influence these changes.
There are a number of studies on bone mineral density (BMD) changes in patients undergoing kidney transplantation.,,, However, only a few have investigated the relationship between BMD estimated by dual-energy absorptiometry (DXA) scan, factors affecting those changes, and fracture risk. Moreover, studies from India on changes in BMD after kidney transplantation using DXA are sparse, and to our knowledge, only one study has looked at changes in BMD at three sites in relation to kidney transplantation.
This study was conducted to evaluate the changes in BMD in patients undergoing renal transplantation and to examine the factors that might affect the changes in BMD in such patients.
| Methods|| |
This prospective study was conducted from July 2018 to August 2019 in patients undergoing kidney transplantation at this center. All patients over the age of 18 years who underwent kidney transplantation during the study period were included. Exclusion criteria were primary hyperparathyroidism, hematological malignancies, history of low fragility fractures, those treated with anti-osteoporotic medications, and patients with active diseases that influence bone metabolisms such as rheumatoid arthritis and coeliac disease.
Informed consent was obtained from all patients. Based on the results of mean changes and standard deviation in lumbar spine and femoral neck BMD after transplantation observed in an earlier study, the minimum sample was estimated to be 20 with a 95% confidence interval and 80% power.
All patients underwent biochemical investigations such as serum calcium, phosphorus, alkaline phosphatase, serum creatinine, intact parathyroid hormone (iPTH) levels, and 25-hydroxy Vitamin D (25(OH) Vit-D) levels at baseline and again 8 months after transplantation. DXA scanning was done using GE Lunar Prodigy Advance DXA scanning was done using GE Lunar Prodigy Advance, GE Healthcare, Madison, WI, enCORE ver. 14.10 prior to transplantation and 8 months after transplantation. BMD assessment at three sites, i.e. lumbar spine, total femur, and forearm, was performed. Results of the BMD were expressed as g/cm2, and T scores and Z scores were estimated both at baseline and posttransplantation. All analysis in this study has been made based on the actual BMD in g/cm2 instead of the T and Z scores, as we had a mixed population with age group both less than and more than 50 years. Information on demographics and medications at baseline and at 8 months including steroid dose were collated.
Antithymocyte globulin was used as an induction agent at a total dose of 3 mg/kg. A triple immunosuppressant regimen was followed in our hospital, with initial dose of tacrolimus (0.1 mg/kg/day), mycophenolate mofetil (35 mg/kg/day), and prednisolone (0.5 mg/kg/day). Tacrolimus dose was optimized based on therapeutic drug monitoring. The dose of prednisolone was continued at 0.5 mg/kg/day for a month after transplantation and was tapered by 2.5 mg/week to reach 7.5 mg/day at 16 weeks. The dose was reduced to 5 mg/day at the end of 6 months.
Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 20.0. (Armonk, NY: USA; IBM Corp.). Categorical variables are expressed using frequency and percentage. Continuous variables are presented by mean and SD. To find the correlation between various factors with BMD, Spearman rank correlation was used and its significance was tested by linear regression t-test. Multiple linear regression analysis was used to predict BMD with independent factors.
The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.
The study was approved by the Dissertation Protocol Committee, Amrita Institute of Medical Sciences, Kochi (No: DM/2017/02, dated April 13, 2018). The procedure was carried out in accordance with the Declaration of Helsinki and International Council for Harmonization-Good Clinical Practice (ICH-GCP).
| Results|| |
A total of 30 consecutive patients who underwent kidney transplantation were recruited into the study. There were 25 males and 5 females. The mean age was 37 ± 10 years and the mean CKD duration was 46.5 ± 35.8 months and the mean duration of dialysis prior to transplant was 9.43 ± 7.5 months [Table 1]. The mean BMI was 20.64 ± 2.82 kg/m2 at baseline. The mean serum calcium, phosphorus, alkaline phosphatase, and iPTH levels were 8.77 ± 0.89 mg/dl, 5.19 ± 1.25 mg/dl, 77.5 ± 40.7 IU/L, and 237.74 ± 283.12 pg/ml, respectively. The mean 25(OH) Vit-D level was 24.37 ± 7.82 ng/ml. Eight patients had normal 25(OH) Vit-D levels (26.7%), 13 (43.3%) had insufficiency, and 9 (30%) had Vitamin D deficiency. None of our patients gave a history of significant alcohol intake/chronic smoking.
|Table 1: Baseline characteristics of 30 subjects who underwent kidney transplantation|
Click here to view
[Table 1] also shows the distribution of native kidney disease. In 15 patients (50%), the native kidney disease could not be determined as they presented with severe renal failure and were too late/unfit for renal biopsy. Five patients had biopsy-proven immunoglobulin A nephropathy, out of which two patients have received long-term steroids. Diabetic nephropathy was seen in five and focal segmental glomerulosclerosis was seen in three patients, out of which one patient had received long-term steroids prior to transplantation. Two patients had cystic kidney disease. All of them were on oral Vitamin D, calcium supplementations, and calcium acetate as phosphate-lowering agents.
All of them underwent live-related renal transplantation and received antithymocyte globulin induction and triple immunosuppression regimen as described earlier. None of our patients had delayed graft function or any major surgical complications requiring re-exploration. Three patients had episodes of rejection, out of which two had acute cellular rejection and one had acute antibody-mediated rejection. Acute cellular rejection was treated with pulse methylprednisolone injections and acute antibody-mediated rejection was treated with pulse methylprednisolone followed by plasmapheresis (3 sessions) and intravenous immunoglobulin. All patients with rejection had full recovery. Three patients had urinary tract infection, which was treated with culture-specific antibiotics. All patients were continued on oral calcium supplements after procedure, but none of them received bisphosphonate injections.
The changes in biochemical parameters 8 months after transplantation compared to the pretransplant values are given in [Table 2]. The mean serum creatinine was 9.53 ± 3.10 mg/dl before transplantation and 1.34 ± 0.28 mg/dl at the end of 8 months (P < 0.001). The serum calcium level 8 months after kidney transplantation was 9.56 ± 0.46 mg/dl compared to pretransplant value of 8.77 ± 0.89 mg/dl (P < 0.001). The mean phosphorus level was 3.06 ± 0.68 mg/dl at 8 months compared to 5.19 ± 1.25 mg/dl (P < 0.001). The mean iPTH was 67.83 ± 48.86 pg/ml (P < 0.001) at 8 months compared to 237.74. ±283.12 pg/ml before transplantation. Other parameters such as alkaline phosphatase and 25(OH) Vit-D were similar before and 8 months after transplantation.
|Table 2: Comparison of biochemical parameters at baseline and 8 months after kidney transplantation|
Click here to view
At spine and total femur, 26 patients had normal BMD before transplantation and only 4 had abnormal BMD. After transplantation, 22 had normal BMD and 8 had abnormal BMD, but the difference was not statistically significant. At left forearm level, 23 out of 30 had normal BMD before transplantation, and 22 of them continued to have normal BMD on follow-up.
The baseline mean BMD (g/cm2) in the lumbar spine was 1.09 ± 0.15 and 8 months after transplantation was 1.06 ± 0.15 (P = 0.002). The baseline mean BMD in the left forearm was 0.88 ± 0.10 and 8 months after transplantation was 0.89 ± 0.10 (P = 0.013) [Table 3]. The mean BMD in the femur did not show a significant change after transplantation. The mean percentage change in BMD at lumbar spine was 2.95%, at femur was 0.36%, and at left forearm was 1.6%.
|Table 3: Changes in bone mineral density at various sites 8 months after kidney transplantation|
Click here to view
At baseline, iPTH had a significant negative correlation with femoral BMD (r = 0.44, P = 0.02) and 25(OH) Vit-D had a positive correlation with forearm BMD (r = 0.50, P = 0.004). None of the other parameters studied had any significant correlation with BMD at any site. At 8 months after transplantation, only 25(OH) Vit-D levels showed a positive correlation with lumbar spine BMD (r = 0.36, P = 0.04). None of the other parameters studied had any significant correlation with BMD at any site [Table 4].
|Table 4: Correlation between clinical and biochemical factors with bone mineral density 8 months after transplantation|
Click here to view
The mean cumulative dose of steroid used in our study was 3.88 ± 3.64 g, the mean cumulative dose of tacrolimus was 1.48 ± 0.68 g, and the mean cumulative dose of mycophenolate mofetil was 688 ± 74 g. [Table 5] shows the correlation between cumulative doses of drugs with BMD 8 months after transplantation. Cumulative steroid (prednisolone) dose (r = −0.428, P = 0.018) showed a negative correlation with BMD at lumbar spine [Figure 1]. There was no correlation of cumulative steroid dose with other sites. A cumulative dose of tacrolimus and mycophenolate mofetil did not show any association with BMD. None of the patients developed fractures in 8 months of follow-up, but two patients developed avascular necrosis of the hip.
|Table 5: Correlation between cumulative doses of immunosuppressive agents with bone mineral density|
Click here to view
|Figure 1: Scatter plot showing correlation between cumulative steroid dose and BMD at spine 8 months after transplantation|
Click here to view
| Discussion|| |
Patients had relatively well preserved BMD in our series. This is likely due to young age of patients and shorter duration of CKD. Similar findings were reported from India in a study where spinal BMD using quantitative computed tomography was estimated. However, a large study had found that a significant proportion of CKD patients had osteopenia, which remained almost same after transplantation. Fractures were also reported in the same study, with hip being the most common site.
The improvement in left forearm BMD as early as 8 months posttransplantation was one of the most significant finding in our study. The increase in BMD in the radius within 6 months was shown in another study despite worsening of vertebral BMD. A cross-sectional study on kidney transplant recipients that had estimated forearm BMD a few years after transplantation noticed that only 23% had normal values. However, neither baseline BMD data nor any information on iPTH or vitamin D levels were available in that study.
A study from India in 2013 showed osteopenia in 37% of the CKD patients and osteoporosis in 12%, whereas 75% of the patients in our cohort had normal BMD in all three sites at baseline. The same study had also shown that 80% of the patients had Vitamin D deficiency compared to only 30% in our study. This suggests that patients who are being planned for kidney transplant have better bone health compared to other CKD patients which could potentially have a positive impact after transplantation. Despite the satisfactory baseline vitamin D status, there was a drop in spine BMD, suggesting that other factors are operational in such situations. Bone loss after transplantation predominantly occurs in trabecular bone, namely spine, as it has the maximum metabolic activity.
Since the introduction of early steroid withdrawal regimens, several studies have shown an improvement in posttransplant BMD in the spine and femur but not necessarily a decrease in fracture incidence. A study in 2014 had shown a paradoxical response, with preservation of bone strength in central skeleton and a decline in peripheral skeleton. Our results appear to be in contrast with the abovementioned study with an increase of BMD in forearm. The reason for this finding is unclear but could be related to longer duration of CKD, older age, and more severe hyperparathyroidism at baseline in the reference study.
We found a decline in lumbar spine BMD posttransplantation, but femoral BMD was maintained. Mikuls et al. also documented a similar decline in lumbar spine BMD at 6 months after transplantation without any change in total femoral BMD.
Cumulative steroid dose had a significant negative impact on spinal BMD in our study, whereas tacrolimus did not. Several studies have shown that cumulative steroid dose after kidney transplantation has been associated with BMD loss. The association of tacrolimus with bone loss after transplantation has been inconsistent.,,, It is possible that other factors such as Vitamin D levels and hyperparathyroidism might also influence these changes. Whether increased immunosuppression as a part of antirejection therapy had any effect on BMD could not be assessed due to the low sample size.
Hyperparathyroidism also showed significant improvement 8 months after transplantation in the current study. Similar findings have been reported in a previous study, and the persistence of hyperparathyroidism was postulated as a reason for reduction in spinal BMD secondary to trabecular bone loss. Earlier studies have also noted bone loss which could be secondary to persisting parathyroid hyperplasia.,
It is still unclear whether all patients undergoing kidney transplant require routine screening of BMD. The 2017 KDIGO guidelines recommend BMD testing in CKD G1T–G5T patients with risk factors, as recent studies have shown that DXA BMD can predict hip fracture occurrences. It is suggested that low BMD on DXA might help consider bone biopsy in such patients and individualize treatment based on the nature of osteodystrophy.
Our study is unique for Indian population as information on BMD in all three sites and all metabolic parameters (pre- and 8 months posttransplant) were available for all patients. The prospective nature of the study enhances the validity of the results, and the time point of 8 months was considered for assessment as the first 6 months are considered to be a period of intense immunosuppression. Measuring the BMD in all three sites gave us insight into changes in both cortical and trabecular bones. A small sample size might have restricted us from studying the BMD changes in each site in more detail. A longer follow-up would have helped us understand the changes in BMD better over time.
Small sample size and short follow up are the limitations of the study.
In summary, bone health in patients undergoing kidney transplantation was satisfactory at baseline. There was a reduction in spinal BMD and an improvement in forearm BMD on follow-up. A higher cumulative steroid dose was associated with reduction of spine BMD. The cohort was largely Vitamin D sufficient at baseline. There were no incidences of fractures during the study, and two patients had avascular necrosis of femur.
| Conclusion|| |
In a relatively young Indian cohort, parameters of BMD showed significant changes after kidney transplantation, and was associated with alterations in the metabolic parameters and the cumulative steroid dose.
We would like to thank the senior faculty of the Department of Nephrology, Dr. Rajesh R Nair, Dr. George Kurian, Dr. Anil Mathew, and Dr. Zachariah Paul, for their help and guidance for this study. This study would not have been possible without their support.
We also thank the Department of Medical Administration, Urology, Vascular Surgery, and Anaesthesia at Amrita Institute of Medical Sciences, Kochi.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Moe S, Drüeke T, Cunningham J, Goodman W, Martin K, Olgaard K, et al.
Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006;69:1945-53.
Carlini RG, Rojas E, Weisinger JR, Lopez M, Martinis R, Arminio A, et al.
Bone disease in patients with long-term renal transplantation and normal renal function. Am J Kidney Dis 2000;36:160-6.
Govindarajan S, Khandelwal N, Sakhuja V, Jha V. Bone mineral density in patients with end-stage renal disease and its evolution after kidney transplantation. Indian J Nephrol 2011;21:85-9.
] [Full text]
Julian BA, Laskow DA, Dubovsky J, Dubovsky EV, Curtis JJ, Quarles LD. Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 1991;325:544-50.
Sudhagar K, Chandrasekar S, Rao SM, Ravichandran R. Bone densitometry in post renal transplant patients. Indian J Nephrol 2001;11:58-60. [Full text]
Nikkel LE, Hollenbeak CS, Fox EJ, Uemura T, Ghahramani N. Risk of fractures after renal transplantation in the United States. Transplantation 2009;87:1846-51.
Priyanka G, Abraham G, Balaji P, Milly M, Saravanan S, Varun S, et al
. Bone mineral disease in renal transplantation – An Indian experience. JNRT 2009:2;63-70.
Casez JP, Lippuner K, Horber FF, Montandon A, Jaeger P. Changes in bone mineral density over 18 months following kidney transplantation: The respective roles of prednisone and parathyroid hormone. Nephrol Dial Transplant 2002;17:1318-26.
Jabbar Z, Aggarwal PK, Chandel N, Khandelwal N, Kohli HS, Sakhuja V, et al.
Noninvasive assessment of bone health in Indian patients with chronic kidney disease. Indian J Nephrol 2013;23:161-7.
] [Full text]
Iyer SP, Nikkel LE, Nickolas TL, Nishiyama KK, Dworakowski E, Cremers S, et al.
Kidney transplantation with early corticosteroid withdrawal: Paradoxical effects at the central and peripheral skeleton. J Am Soc Nephrol 2014;25:1331-41.
Mikuls TR, Julian BA, Bartolucci A, Saag KG. Bone mineral density changes within six months of renal transplantation. Transplantation 2003;75:49-54.
Almond MK, Kwan JT, Evans K, Cunningham J. Loss of regional bone mineral density in the first 12 months following renal transplantation. Nephron 1994;66:52-7.
Julian BA, Quarles LD, Niemann KM. Musculoskeletal complications after renal transplantation: Pathogenesis and treatment. Am J Kidney Dis 1992;19:99-120.
Aroldi A, Tarantino A, Montagnino G, Cesana B, Cocucci C, Ponticelli C. Effects of three immunosuppressive regimens on vertebral bone density in renal transplant recipients: A prospective study. Transplantation 1997;63:380-6.
McIntyre HD, Menzies B, Rigby R, Perry-Keene DA, Hawley CM, Hardie IR. Long-term bone loss after renal transplantation: Comparison of immunosuppressive regimens. Clin Transplant 1995;9:20-4.
Rathi M, Kumar D, Bhadada SK, Khandelwal N, Kohli HS, Jha V, et al.
Sequential changes in bone biochemical parameters and bone mineral density after renal transplant. Saudi J Kidney Dis Transpl 2015;26:671-7.
] [Full text]
Briner VA, Thiel G, Monier-Faugere MC, Bognar B, Landmann J, Kamber V, et al.
Prevention of cancellous bone loss but persistence of renal bone disease despite normal 1,25 vitamin D levels two years after kidney transplantation. Transplantation 1995;59:1393-400.
Parker CR, Freemont AJ, Blackwell PJ, Grainge MJ, Hosking DJ. Cross-sectional analysis of renal transplantation osteoporosis. J Bone Miner Res 1999;14:1943-51.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl (2011) 2017;7:1-59.
Akaberi S, Simonsen O, Lindergård B, Nyberg G. Can DXA predict fractures in renal transplant patients? Am J Transplant 2008;8:2647-51.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]