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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 15  |  Issue : 1  |  Page : 34-38

Prevalence and risk factors for postrenal transplant hyperparathyroidism: A cross-sectional study


1 Meenakshi Mission Hospital and Research Centre, Madurai, Tamil Nadu, India
2 Department of Nephrology, Meenakshi Mission Hospital and Research Centre, Madurai, Tamil Nadu, India
3 Department of Nephrology, Meenakshi Mission Hospital, Madurai, Tamil Nadu, India

Date of Submission25-Jul-2020
Date of Acceptance12-Dec-2020
Date of Web Publication31-Mar-2021

Correspondence Address:
Dr. Krishnaswamy Sampathkumar
Meenakshi Mission Hospital and Research Centre, Madurai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_83_20

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  Abstract 


Introduction: Chronic kidney disease (CKD) commonly results in secondary hyperparathyroidism. Even after a successful renal transplant, residual parathyroid overactivity persists. We studied its prevalence and risk factors in Indian patients. Patients and Methods: Patients who underwent renal transplantation in our unit from 2013 to 2019 and completed 3 months of the posttransplant period were included. We excluded patients with advanced allograft dysfunction and those on medications with the potential impact of divalent cations. A detailed history, physical examination, and laboratory parameters were obtained. Results: There were 110 subjects, of whom 78% were male. The mean age group was 38 ± 12 years. Chronic glomerulonephritis was the most common etiology of CKD (54%). Posttransplant vintage was 48 ± 44 months. The mean serum parathyroid hormone (PTH) level was 135 ± 176 pg/ml. Sixty-seven percent of them had raised serum PTH levels above 70 pg/ml. The patients were asymptomatic. Hypercalcemia and hypophosphatemia were rare. The mean 25 OH Vitamin D levels were low (23 ± 8 ng/ml) with 41% of the subjects showing either deficiency or insufficiency. Higher serum PTH levels were significantly associated with female sex, lower estimated glomerular filtration rate, and lower serum 25 OH Vitamin D levels. Serum parathormone levels were significantly negatively correlated with serum calcium (r2 = −0.39. P = 0.0003) and Vitamin D levels (r2 = −0.50. P = 0.002). Conclusions: Posttransplant hyperparathyroidism (PTHP) persists even after many years of normal allograft function. Hypercalcemia and hypophosphatemia are insensitive tests to identify the condition. Vitamin D deficiency has a strong correlation with PTHP.

Keywords: Calcium, phosphorus, parathyroid hormone, renal transplantation, Vitamin D


How to cite this article:
Sampathkumar K, Rajiv A, Kumar S, Selvan K. Prevalence and risk factors for postrenal transplant hyperparathyroidism: A cross-sectional study. Indian J Transplant 2021;15:34-8

How to cite this URL:
Sampathkumar K, Rajiv A, Kumar S, Selvan K. Prevalence and risk factors for postrenal transplant hyperparathyroidism: A cross-sectional study. Indian J Transplant [serial online] 2021 [cited 2021 Apr 15];15:34-8. Available from: https://www.ijtonline.in/text.asp?2021/15/1/34/312761


  Introduction Top


Chronic kidney disease (CKD) results in a wide gamut of biochemical and hormonal imbalances. A pentad of factors, namely serum calcium, phosphorus, parathormone parathyroid hormone (PTH), Vitamin D, and fibroblast growth factor-23 regulate bone mineral and vascular axis. What begins as an adaptive phenomenon by these factors in response to failing renal function soon morphs into a maladaptive pathological state producing off-target bone and cardiovascular adverse effects. These are grouped under the wide arching terminology of CKD-mineral bone abnormalities (MBD). Thankfully, renal transplantation results in improvement and normalization of many components of the uremic milieu such as anemia, inflammation, and malnutrition. However, abnormalities in CKD-MBD may not be fully ameliorated. A recent US study showed that after 1 year of renal transplantation, as many as 86% of patients still had significant elevations of serum PTH levels.[1] Excess PTH predisposes toward bone fractures and cardiovascular diffuse hyperplasia of parathyroid glands develops during the progression of CKD. These regress after a successful allograft function. However, progression to nodular hyperplasia of the gland is marked by a reduction in calcium-sensing receptor and Vitamin D receptor density at the cellular level. In the latter, autonomous PTH secretion continues even after many years of adequate graft function.[2] There are a few recent publications of posttransplant hyperparathyroidism (PTHP) from the Indian subcontinent.[3],[4] Indian transplant patients cannot be equated with western counterparts since they are significantly younger, have shorter dialysis vintage, and with different etiological spectrum contributed mainly by chronic glomerulonephritis rather than diabetic nephropathy for end-stage renal disease.[3],[5] It follows that the magnitude of alterations in the mineral metabolism will also be different in Indian transplant patients. Vitamin D regulates nearly 3% of the human genome which implicates it in a wide array of fields such as cardiovascular, renal, and cancer biology.[6] Vitamin D deficiency is widely prevalent in both general and CKD populations, especially in India.[7] Vitamin D and PTH interact in myriad ways which are still a subject of ongoing research. In contrast to standardized protocols for the management of renal allograft dysfunction, there are many gray areas in the evaluation and treatment of PTHP. There is no consensus on a PTH level that clearly defines the presence of persistent PTHP. The objective of our study was to track the prevalence of postrenal transplant hyperparathyroidism with its attendant the risk factors.


  Patients and Methods Top


Inclusion criteria

This cross-sectional study was conducted on patients who underwent renal transplantation in a tertiary care center. The study was approved by the institutional ethics committee and informed consent was obtained from patients who underwent kidney transplantation (live donor and deceased donor) from January 2013 to January 2019.

Exclusion criteria

Patients who had renal allograft dysfunction with Stage 4 CKD, on treatment with calcium supplements, Vitamin D agents, and cinacalcet were excluded. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI formula. A complete medical history followed by anthropometry and physical examination was carried out. Renal function tests with special reference to the bone mineral axis were undertaken. Specifically, 25 hydroxy Vitamin D levels and intact PTH levels were measured in serum by chemiluminescent immunoassay.

Statistical methods

Descriptive statistics were done for quantitative data. The student's t-test was used to identify the significance of quantitative data, whereas the Chi-square test was used to address the significance of the qualitative data. Pearson correlation and multiple regression analysis were carried out to analyze the association between PTH as dependent factor and multiple independent factors. P < 0.05 was considered as statistically significant. Statistical analysis was carried out using data analysis of MS Excel 2016 software.

Patient consent

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names, initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

Institutional Ethics Committee, Meenakshi Mission Hospital and Research Centre, Madurai. All protocols were followed as per Declaration of Helsinki.


  Results Top


There were 110 subjects, of whom 78% were male. The mean age group was 38 ± 12 years. As shown in [Table 1], chronic glomerulonephritis was the most common etiology of CKD (54%). The mean serum PTH level was 135 ± 176 pg/ml. A diagnosis of PTHP was made when plasma PTH levels were >70 pg/ml. Overall, 62% of patients showed elevated PTH levels. Ten percent of patients had more than five-fold elevations of PTH levels as shown in [Figure 1]. The condition was largely asymptomatic barring a single patient with recurrent pancreatitis. The posttransplant period ranged between 4 months and 7 years. When they were analyzed according to the transplantation vintage, 47%, 55%, and 69% of patients in the periods of 1, 2, and 3 years, respectively, still showed elevated PTH levels. Overall, the subjects were in a state of Vitamin D insufficiency with a mean level of 23 + 8 ng/ml.
Table 1: Demographics and laboratory data of patients

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Figure 1: Histogram of serum parathyroid hormone levels in pg/ml

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As shown in [Table 2], female gender, hemoglobin level, and Vitamin D levels were significantly different between the group showing normal and elevated PTH levels respectively.

There was a moderate negative correlation with serum calcium and PTH levels (r2 = −0.0.39. P = 0.003) and no correlation with serum phosphorus (r2 = 0.03). 36% of the study group was Vitamin D deficient (Vitamin D level <20 ng/ml) and 31% were showing insufficiency (Vitamin D level 20–29 ng/ml).
Table 2: Comparison of normal with high parathormone groups

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There was a highly significant negative correlation between Vitamin D levels and PTH (r2 = −0.50) as shown in [Figure 2].
Figure 2: Parathyroid hormone levels negatively correlated with Vitamin D levels. (r2 =- 0.50. P = 0.002)

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A step-wise linear regression analysis was performed with serum PTH as the dependent variable and multiple clinical and laboratory parameters as independent variables. Four factors stood out as significant predictors which were eGFR, serum calcium, hemoglobin, and Vitamin D as shown in [Table 3].
Table 3: Multiple linear regression of factors affecting parathormone levels

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  Discussion Top


Our results show that a high percentage of patients in the posttransplant period have raised PTH levels which remain elevated even up to 3 years. There are several characteristics which are at variance with global experience in our study. Patients are at least one to two decades younger and nondiabetic renal diseases such as chronic glomerulonephritis and chronic interstitial nephritis together constituted 80% of the cohort.

In another recent study from India, elevated intact PTH levels at 3 and 6 months after transplant were seen in 66.7% and 30.8% of patients, respectively.[4] A revealing finding from our study is that both hypercalcemia and hypophosphatemia are uncommon and hence are not useful indicators of PTHP. Only 2 out of the 76 cases of PTHP patients had raised serum calcium above 10.5 mg/dl with a poor sensitivity of 2.63% and with 98% specificity. Serum phosphorus of <2.5 mg/dl was encountered in only 14 out of 76 cases of hyperparathyroidism with a low sensitivity of 18% and specificity of 88%.

Another interesting finding was that 36% of the study group was Vitamin D deficient (Vitamin D level <20 ng/ml) and 31% were showing insufficiency (Vitamin D level 20–29 ng/ml). Vitamin D levels of the hyperparathyroid group were significantly lower than the group with normal PTH levels (30 ± 5 vs. 23 ± 8 ng/ml, respectively, P = 0003). A highly significant negative correlation was shown between levels of 25 (OH) D3 and PTH (r2 = 0.50. P = 0.002). What could be the driving factors for these? Multiple studies show that up to 70%–90% of the adult Indian general population have Vitamin D deficiency.[8] The reasons are not clear, but dietary deficiency and lack of exposure to sunshine (urban areas) are possible explanations. A study from Brazil looking at the association between Vitamin D deficiency and PTH in the general population showed a similar negative correlation.[9] In a recent Indian study, Vitamin D deficiency was seen in 25.0% of recipients before transplant which increased to 48.1% at 6 months posttransplant.[3] This finding is counterintuitive given the improved appetite and overall better mobility of the patient.

A dietary calcium defect which is aggravated by corticosteroid therapy could be operative in renal transplantation. Rats which are deprived of calcium have reduced levels of 25 (OH) D3. This is brought about by increased clearance and inactivation of 25 (OH) D3 due to a state of secondary hyperparathyroidism. The renal production of calcitriol is increased in such a state which through the feedback loop inhibits the 25 (OH) D3. In our study, we did not test 1, 25 (OH) D3 levels. Another possibility is the urinary loss of 25 (OH) D3 due to loss of Vitamin D binding globulins in the urine. In our patients, the low levels of proteinuria and serum albumin levels were not pointing toward this possibility. Pretransplant cinacalcet use was associated with reduced levels of PTH in the posttransplant period according to a study.[10] However, none of our patients were on cinacalcet.

Vitamin D deficiency stimulates the parathyroid gland by multiple pathways which include reduced repression of PTH gene transcription, reduced density of Vitamin D, and calcium-sensing receptors which ultimately leads to the increased set point for calcium-regulated PTH secretion.[11] Since it has been shown that low Vitamin D levels lead to persistence of secondary hyperparathyroidism in the postrenal transplant setting, we wanted to see if serum calcium has a negative correlation with PTH levels in contrast to primary hyperparathyroidism. There was indeed a moderate negative correlation with serum calcium levels. Higher pretransplantation serum PTH levels are associated with higher odds of PTHP.[1] However, we did not have the data about the pretransplant PTH levels in our patients.

In a similar study by Lobo et al., 1,25 Vitamin D levels correlated negatively with intact PTH in 82 postrenal transplant patients. These patients were also normocalcemic with normal phosphorus levels akin to our cohort. Of the 42 patients studied after 2 years posttransplant, 23 patients had elevated PTH levels. After treatment with pharmacological doses of 1, 25 Vitamin D, PTH levels decreased in most of the patients.[12] Cinacalcet and surgical parathyroidectomy are other measures to manage PTHP as shown by many studies.[13],[14],[15]

Limitations of the study

The drawbacks of our study include the cross-sectional study design, smaller sample size, and lack of pretransplant data on mineral metabolism.


  Conclusions Top


In this cross-sectional study conducted in Indian kidney transplant recipients, secondary hyperparathyroidism was common and it persists even after many years of normal allograft function. Hypercalcemia and hypophosphatemia are very insensitive measures to identify PTHP. There is a strong negative correlation with Vitamin D deficiency. Our study opens up the question as to whether Vitamin D supplementation will benefit PTHP which can only be answered by future work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Wolf M, Weir MR, Kopyt N, Mannon RB, Von Visger VJ, Deng H, et al. A prospective cohort study of mineral metabolism after kidney transplantation. Transplantation 2016;100:184-93.  Back to cited text no. 1
    
2.
Santos DR, Rossi A, Coyne D, Maw TT. Management of post-transplant hyperparathyroidism and bone disease. Drugs 2019;79:501-13.  Back to cited text no. 2
    
3.
Prasad N, Jaiswal A, Agarwal V, Kumar S, Chaturvedi S, Yadav S, et al. FGF23 is associated with early post-transplant hypophosphataemia and normalizes faster than iPTH in living donor renal transplant recipients: A longitudinal follow-up study. Clin Kidney J 2016;9:669-76.  Back to cited text no. 3
    
4.
Mehrotra S, Sharma R, Patel M. Vitamin D 1,25-Dihydroxyvitamin D, FGF23, and graft function after renal transplantation. Indian J Nephrol 2019;29:242-7.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
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 Nephro 2011;21:85-9.  Back to cited text no. 5
    
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Jean G, Souberbielle J, Chazot C. Vitamin D in chronic kidney disease and dialysis patients. Nutrients 2017;9:328.  Back to cited text no. 6
    
7.
Melamed ML, Chonchol M, Gutiérrez OM, Kalantar-Zadeh K, Kendrick J, Norris K, et al. The role of vitamin D in CKD stages 3 to 4: Report of a scientific workshop sponsored by the national kidney foundation. Am J Kidney Dis 2018;72:834-45.  Back to cited text no. 7
    
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Johari A, Mehta B, Priyanka J. Vitamin D deficiency in India. Ann Biol 2015;31;157-60.  Back to cited text no. 8
    
9.
Martins JS, Palhares MO, Teixeira OC, Ramos GM. Vitamin D status and its association with parathyroid hormone concentration in Brazilians. J Nutr Metab 2017;2017:9056470.  Back to cited text no. 9
    
10.
Al-Moasseb Z, Aitken E. Natural history of serum calcium and parathyroid hormone following renal transplantation. Transplant Proc 2016;48:3285-91.  Back to cited text no. 10
    
11.
Comprehensive Clinical Nephrology-9780323479097 | US Elsevier Health Bookshop. Available from: https://www.us.elsevierhealth.com/comprehensive-clinical-nephrology-9780323479097.html. [Last accessed on 2020 May 02].  Back to cited text no. 11
    
12.
Lobo PI, Cortez MS, Stevenson W, Pruett TL. Normocalcemic hyperparathyroidism associated with relatively low 1:25 vitamin D levels post-renal transplant can be successfully treated with oral calcitriol. Clin Transplant 1995;9:277-81.  Back to cited text no. 12
    
13.
Cohen JB, Gordon CE, Balk EM, Francis JM. Cinacalcet for the treatment of hyperparathyroidism in kidney transplant recipients: A systematic review and meta-analysis. Transplantation 2012;94:1041-8.  Back to cited text no. 13
    
14.
Zavvos V, Fyssa L, Papasotiriou M, Papachristou E, Ntrinias T, Savvidaki E, et al. Long-term use of cinacalcet in kidney transplant recipients with hypercalcemic secondary hyperparathyroidism: A single-center prospective study. Exp Clin Transplant 2018;16:287-93.  Back to cited text no. 14
    
15.
Jabłońska WE, Gałązka Z, Durlik M. Treatment of persistent hypercalcemia and hyperparathyroidism with cinacalcet after successful kidney transplantation. Transplant Proc 2016;48:1623-5.  Back to cited text no. 15
    


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  [Table 1], [Table 2], [Table 3]



 

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