FEBRUARY 2012 • VOL. 60                           SPECIAL ISSUE: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

Original Article

Are we Overconcerned about Secondary Hyperparathyroidism and Underestimating the More Common Secondary Hypoparathyroidism in Our Dialysis Patients?

Tarun Jeloka*, Manish Mali**, Anjali Jhamnani***, Santosh Konde†, Vikas Jadhav†

*Sr. Consultant and Head of Dept of Nephrology, **Associate Consultant, Dept of Nephrology, ***Sr. Registrar, Dept of Nephrology, †Sr. Consultant, Dept of Radiology, Aditya Birla Memorial Hospital, Pune.
Received : 09.06.2010; Revised : 13.10.2010; Accepted : 08.11.2010

Abstract

Objectives : The aim of the study was to determine the prevalence of hyper and hypo-parathyroid state in prevalent dialysis patients. The second part of the study was to look for the prevalence of vascular calcification (abdominal aortic) and factors predicting calcification in these patients.

Methods : All adult patients, who were more than 1 month on dialysis, were included in the study. A total of 68 patients, of which 75% were on hemodialysis and 25% on peritoneal dialysis, were finally studied. Patients’ parathyroid status was defined as per target recommendation of KDOQI – hypoparathyroid with iPTH < 150 pg/ml and hyperparathyroid with iPTH > 300 pg/ml. Vascular calcification was determined by X ray of lateral lumbar spine to look for abdominal aortic calcification (AAC). The AAC was scored as validated. The prevalence of hyper- and hypoparathyroidism in dialysis patients was determined as percentage of total dialysis patients. The prevalence of AAC and factors predicting it was analyzed by ‘univariate’ and ‘multiple logistic regression analyses.

Results : The mean age of patients was 50.04 ± 14.15 years, 58.82% were males and 42.64% were diabetics. Mean duration of dialysis was 22.36 ± 19.17 months. Hyperparathyroidism was seen in only 27.94 % of all dialysis patients, while hypoparathyroidism was in 45.58%. Abdominal aortic calcification was seen in 79.41% of overall patients and 13.23% had significant calcification (score 7-24). On univariate analysis, age (0.000) and iPTH (0.03) were the only variables predicting AAC and on logistic regression analysis, age was the only independent predictor of abdominal aortic calcification (p=0.002, OR 1.11, CI 1.038-1.186).

Conclusion : Hypoparathyroidism is more common (46%) in our dialysis patients as compared to hyperparathyroidism (28%). There is high prevalence of vascular (abdominal aortic) calcification (80%) in our dialysis patients.

Introduction

Chronic kidney disease (CKD) is associated with variety of bone disorders and abnormality of calcium and phosphate metabolism. Chronic kidney disease associated mineral bone disorder (CKD-MBD) is an area of ongoing discussion because of its role in morbidity and mortality in dialysis patients. Out of all, secondary hyperparathyroidism (HPTH) has gained the most importance as it has been shown to be common and independently associated with mortality in CKD patients.1 However, besides HPTH, hypoparathyroid state (low iPTH) is also associated with increased risk of pelvic and vertebral fractures in CKD patients2,3 and studies have shown increased risk of death among dialysis patients with low serum iPTH.4,5 The risk of vascular calcification is also increased in CKD and is a surrogate marker of cardiac disease.6 Hence, this study was undertaken to look at the prevalence of hyper- and hypoparathyroidism and also the prevalence of vascular calcification in our dialysis patients.

Materials and Methods

All prevalent adult patients (> 18 years age) who were on dialysis (hemodialysis or peritoneal dialysis) at our center were eligible for the study. Patients with HIV positive serology, active systemic infection, surgery or intervention in last 4 weeks were excluded. New patients less than 1 month on dialysis were also excluded. Patients’ parathyroid status was defined as per target recommendation of KDOQI – hypoparathyroid, iPTH < 150 pg/ml as group A and hyperparathyroid, iPTH > 300 pg/ml as group B.7 We also planned to look for the prevalence of abdominal aortic calcification (details mentioned below) and factors correlating it, in all these patients.

Blood chemistry

Monthly pre-dialysis blood chemistries included hemoglobin, urea nitrogen, creatinine, urea reduction ratio (hemodialysis), Kt/V (peritoneal dialysis), sodium, potassium, glucose, albumin, calcium, phosphate, and total cholesterol. Hemoglobin was done by ‘Pentra 60 C+, Horiba ABX’, France and other biochemistries were done by Roche Hitachi 902 Autoanalyzer, Japan. Parathyroid hormone level (iPTH) was done every 3-6 monthly by chemiluminescence assay method. We follow the K/DOQI guidelines for the target calcium, phosphorus and iPTH levels. The use of phosphate binders (calcium based or non calcium based) and calcitriol depends upon the monthly blood tests and are intended to achieve the target. Routine blood chemistries were averaged for last 3 months (2 months for recent start of dialysis) for the analysis. Highly sensitive C reactive protein (hs CRP) was also done as part of the study.

Abdominal aortic calcification

Calcification of aorta was semi-quantitatively estimated as validated in earlier study by Kaupilla et al.8 In brief, patient underwent lateral X ray of their lumbar spine. Calcification of anterior and posterior wall of the aorta at the level of L1 to L4 vertebra was scored from 0-3. Scoring was 0 for no calcification, 1 for <1/3rd length, 2 for 1/3rd to 2/3rd length, and 3 for > 2/3rd length of the aortic wall showing calcification. Hence, the total score could be between 0-24. X rays were read by our radiologist on picture archive and communication system (PACS). X rays were reported independently by two radiologist and Pearson’s correlation coefficient calculated (0.84, p=0.0001).

Statistical Analysis

Mean with standard deviation was calculated for continuous variables and percentage for categorical variables. Continuous variables were compared between groups (low and high iPTH) by ‘independent sample t-test’ and categorical variables by ‘chi-square’ test. Factors correlating AAC was determined by ‘general linear model univariate analysis’ and independent predictors by ‘multiple logistic regression analysis’ for presence of calcification (AAC score > 1). Statistical analysis was done with SPSS 17 (SPSS Inc., Chicago, IL, USA).

Results

78 patients were undergoing dialysis (58 hemodialysis and 20 peritoneal dialysis), of which 4 patients were less than one month on dialysis, 2 had pneumonia in last 4 weeks, 1 PD patient had HIV, 1 had hernia repair in last 4 weeks, and 2 had missing data and were excluded. After exclusion, 68 patients were finally included in the analysis. 75% were on hemodialysis and 25% on peritoneal dialysis. Table 1 shows the baseline and biochemical characteristics of patients included in the study. Mean age of these patients was 50.04 ± 14.15 years. 58.82 % were males and 42.64 % were diabetics. Mean duration on dialysis was 22.36 ± 19.17 months.

Thirty-one out of 68 (45.58%) patients had hypoparathyroidism (below target recommended by KDOQI) as compared to 19 out of 68 (27.94%) having hyperparathyroidism. Group A patients having hypoparathyroidism were older (51.77 ± 13.4 vs. 43 ± 16.9 years, p=0.04) and had higher corrected calcium (8.9 ± 0.8 vs. 8.4 ± 0.8 mg/dl, p=0.03) than group B having hyperparathyroidism. There was no difference in percentage of diabetics (54.83 vs. 47.36%), serum phosphate (5.1 ± 1.6 vs. 5.3 ± 1.3 mg/dl, p=0.6), or calcium-phosphate product (45 ± 14.6 vs. 44.5 ± 12.1, p=0.8) between the two groups. The percentage of patients on calcium based phosphate binders were 51.28% in group A and 73.68% in group B (p=0.156) and mean elemental calcium intake in the two groups were 179.8 ± 207.6 and 351.5 ± 241.9 mg per day (p=0.007). The percentage of patients on active vitamin D3 were 5.1% in group A and 36.8% in group B (p=0.004).

Abdominal aortic calcification (Figure 1) was seen in 79.41% of overall patients and 13.23% had significant calcification (score 7-24). The prevalence of AAC was significantly higher in group A as compared to group B (87.17% vs. 57.89%, p=0.01). The mean calcification score, representing severity of calcification, was also higher (4.1 ± 4.4 vs. 1.8 ± 2.3, p= 0.04) in group A as compared to group B. Factors correlating abdominal aortic calcification were age (p=0.000) and iPTH (p=0.031) in univariate analysis while factors not correlating were corrected calcium (p=0.56), phosphate (p=0.22), corrected calcium phosphate product (p=0.15), duration of dialysis (p=0.54) and hs CRP (p=0.251). On logistic regression analysis, age was the only factor independently predicting the presence of AAC (p=0.002, OR 1.11, CI 1.038-1.186, Table 2).

Discussion

Mineral bone disorder secondary to chronic kidney disease is ongoing concern and important cause of morbidity and mortality in dialysis patients. Hyperparathyroidism is more common and reported in 47 – 78% of dialysis patients in the west.9-11 Dialysis outcomes and practice patterns study (DOPPS) has data from 11 different countries12 and has reported the overall prevalence of hyperparathyroidism, based on KDOQI guidelines, to be 34.3%, with US, UK and Japan having 47.6%, 33.1%, and 19.9% respectively. The prevalence of hyperparathyroidism in our study was only 28%.

Similarly, hypoparathyroidism is also reported differently from different countries. DOPPS reports the prevalence of hypoparathyroidism in 36.2% of overall dialysis patients with US, UK, and Japan having 20.5%, 46.6%, and 49.7% respectively. We found high prevalence of hypoparathyroidism in our dialysis population (45%).

There could be many causes of higher prevalence of hypoparathyroidism in our dialysis population. Studies have shown old age and diabetics are at higher risk of hypoparathyroidism.13 Our hypoparathyroid patients were also older as compared to the hyperparathyroid group but were similar in diabetic status. Asian dialysis patients could be at higher risk of hypoparathyroidism due to their ethnicity, as it is a common observation from countries like Japan and Taiwan.13,14 However, this has not been verified in any study. Another factor leading to higher incidence of hypoparathyroidism in dialysis patients is inadvertent use of active vitamin D3. This happens at two levels: first, blind prescription of active vitamin D3 without monitoring iPTH levels in early stages of CKD patients by physicians and at later stages even by nephrologists, which is not uncommonly seen in clinical practice in India. Secondly, use of combination pills (calcium carbonate and active vitamin D3) as phosphate binders, carry with it excess dose of active vitamin D3 thereby over-suppressing the PTH.

Vascular calcification in dialysis patients is common and is the result of abnormal bone mineral metabolism. The modality of assessment of vascular calcification varies from electron beam computed tomography (EBCT) to simple radiological X - ray. Simple X ray has been accepted as an easy and inexpensive alternative for routine evaluation of abdominal aortic calcification by KDIGO.15

Our study showed high prevalence of aortic calcification in our dialysis patients (79.41%), similar to Okuno et al16 reporting 56.5% and Honaken et al 81%.17 On overall analysis in our study, the factor predicting aortic calcification was age only. However, other studies have reported age and duration of dialysis as correlating factors.17,18 Honaken study also reported history of cardiovascular disease and Guerin18 reported smoking habits, lower plasma albumin, increases of CRP and fibrinogen to be associated with higher calcification scores. Our study did not show correlation of calcification score with albumin and hs CRP and did not look into the variables of presence of cardiovascular disease, smoking habits, and fibrinogen. Other relevant factors like blood pressure, pulse pressure and cholesterol were also not correlated with calcification (not shown).

This is the first study looking at the prevalence of parathyroid status and vascular calcification in Indian dialysis patients but there were a few limitations in this study. It is a single center study. It includes both hemodialysis as well as peritoneal dialysis patients. However, there was no difference in results when they were separated by the modality of dialysis. We looked at the point prevalence of hyper- and hypoparathyroidism, which in fact is a changing variable with treatment. However, it still gives an outlook of the problem and justifies monitoring and improvement in their management.

Conclusion

Hypoparathyroidism is more common than hyperparathyroidism in our dialysis patients. Vascular calcification is common in dialysis population. Almost 80% patients on dialysis have evidence of abdominal aortic calcification as determined by X ray. Age is the only independent predictor of aortic calcification in our study, which unfortunately is non-modifiable. Judicious use of active vitamin D3, calcium based phosphate binders and iPTH monitoring is recommended to prevent hypoparathyroidism in CKD patients.

References

1. Carlstedt F, Lind L, Wide L, Lindahl B, Hanni A, Rastad J, Ljunghall S. Serum levels of parathyroid hormone are related to the mortality and severity of illness in patients in the emergency department. Eur J Clin Invest 1997;27:977-981.
2. Atsumi K, Kushida K, Yamazaki K, Shimizu S, Ohmura A, Inoue T. Risk factors for vertebral fractures in renal osteodystrophy. Am J Kidney Dis 1999;33:287-293.
3. Coco M, Rush H. Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone. Am J Kidney Dis 2000;36:1115-1121.
4. Block GA, Port FK. Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: recommendations for a change in management. Am J Kidney Dis 2000;35:1226-1237.
5. Avram MM, Fein PA, Bonomini L, Mittman N, Loutoby R, Avram DK, Chattopadhyay J. Predictors of survival in continuous ambulatory peritoneal dialysis patients: A five year prospective study. Perit Dial Int 1996;16:S190-S194.
6. Wislon PWF, Kaupilla LI, O’Donnell CJ, Kiel DP, Hannan M, Polak JM, Cupples LA. Abdominal aortic calcific deposits are an important predictor of vascular morbidity and mortality. Circulation 2001;103:1529-1534.
7. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003;42:S12.
8. Kauppila LI, Polak JF, Cupples LA, Hannan MT, Kiel DP, Wilson PWF. New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: a 25 year follow-up study. Atherosclerosis 1997;132:245-250.
9. Billa V, Zhong A, Bargman J, Vas S, Wong PY, Oreopoulos DG. High prevalence of hyperparathyroidism among peritoneal dialysis patients: A review of 176 patients. Perit Dial Int 2000;20:315-321.
10. Salem MM. Hyperparathyroidism in the hemodialysis population: a survey of 612 patients. Am J Kidney Dis 1997;29:862-865.
11. Owda A, Elhwairis H, Narra S, Towery H, Osama S. Secondary hyperparathyroidism in chronic hemodialysis patients: prevalence and race. Ren fail 2003;25:595-602.
12. The DOPPS Annual Report. Dialysis Outcomes and Practice Patterns Study. 2007;www.dopps.org.
13. Akizawa T, Kinugasa E, Akiba T, Tsukamoto Y, Kurokawa K. Incidence and clinical characteristics of hypoparathyroidism in dialysis patients. Kidny Int suupl 1997;62:S72-S74.
14. Guh JY, Chen HC, Chuang HY, Huang SC, Chien LC, Lai YH. Risk factors and risk of mortality of mild hypoparathyroidism in hemodialysis patients. Am J Kidney Dis 2002;39:1245-1254.
15. KDIGO guideline for chronic kidney disease – mineral and bone disorder. Kidney Int 2009;76:S6.
16. Okuno S, Ishimura E, Kitatani K, Fujino Y, Kohno K, Maeno Y, Maekawa K, Yamakawa T, Imanishi Y, Inaba M, Nishizawa Y. Presence of abdominal aortic calcification is significantly associated with all-cause and cardiovascular mortality in maintenance hemodialysis patients. Am J Kidney Dis 2007;49:417-425.
17. Honkanen E, Kauppila L, Wikstrom B, Rensma PL, Krzesinski J, Aasarod K, Verbeke F, Jensen PB, Mattelaer P, Volck B. Abdominal aortic calcification in dialysis patients: results of the CORD study. Nephrol Dial Transplant 2008;23:4009-4015.
18. Guerin AP, London GM, Marchais SJ, Metivier F. Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 2000;15:1014-1021.