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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2009  |  Volume : 20  |  Issue : 4  |  Page : 623-627
Risk factors of hyperparathyroidism in advanced stages of chronic kidney disease

Sheffield Kidney Institute, Northern General Hospital (Sorby Wing), Sheffield, United Kingdom

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Date of Web Publication8-Jul-2009


The pathogenesis of renal osteodystrophy is not clearly defined. We evaluate in this study the potential effect of demographic and biochemical markers on parathormone (PTH) level in patients with chronic kidney disease (CKD) stages 4 and 5. We retrospectively studied 138 patients with CKD stages 4 and 5 selected from the database of the Sheffield Kidney Institute in the interval from 1996 to 2005. All patients had baseline as well as follow-up levels of PTH, adjusted serum calcium, phosphate, calcium phosphorus product, albumin, bicarbonate and estimated glomerular filtration rate (eGFR). At baseline, serum albumin, eGFR and adjusted serum calcium levels signi­ficantly negatively correlated with PTH serum levels. Adjusted serum calcium levels at last follow­up remained a significant negative predictor of PTH levels; however, baseline PTH levels demons­trated a significant positive correlation with final serum PTH levels. This study high lights the significance of serum PTH levels at presentation on the long-term effect of parathyroid gland function. This reinforces the need for early intervention to achieve optimal control of hyperpara­thyroidism in CKD patients.

How to cite this article:
El Kossi M, Rana A, El Nahas M. Risk factors of hyperparathyroidism in advanced stages of chronic kidney disease. Saudi J Kidney Dis Transpl 2009;20:623-7

How to cite this URL:
El Kossi M, Rana A, El Nahas M. Risk factors of hyperparathyroidism in advanced stages of chronic kidney disease. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2021 Jan 16];20:623-7. Available from: https://www.sjkdt.org/text.asp?2009/20/4/623/53252

   Introduction Top

Secondary hyperparathyroidism (SHPT) is a frequent complication of chronic kidney disease (CKD). [1] It is characterized by parathyroid hy­perplasia and deranged calcium and phosphorus homeostasis. [1]

Decreased levels of active vitamin D and ionized calcium in CKD are the main drivers of in­creased secretion of parathyroid hormone (PTH). Furthermore, phosphorus induces hyperplasia of the parathyroid glands independently of cal­cium and calcitriol, and increases PTH synthe­sis and secretion by a post-transcriptional me­chanism. [2] ,[3] Some other factors have a variabley contributed to the development of hyperpara­thyroidism in uremic patients such as alumi­num, estrogens, and catecholamines. [3]

Parathormone hormone is considered to be one of the major uremic toxins. [4] Renal osteodys­trophy, soft tissue calcification particularly blood vessels, [5] immune dysfunction, and anemia, [6] ,[7] are among the long term consequences of SHPT. Although SHPT is a universal complication of CKD, not all patients experience the same de­gree of severity.

In addition to the well recognized variables affecting PTH levels, many cross-sectional stu­dies revealed conflicting results about the in­fluence of other biochemical parameters in dia­lysis patients such as metabolic acidosis, gender, serum albumin, age, race, degree of renal impair­ ment. [8],[9],[10],[11],[12]

We aim in this study to evaluate the potential effect of demographic and biochemical markers on PTH levels in patients with CKD stages 4 and 5.

   Patients and Methods Top

We retrospectively studied a group of 138 CKD patients (stages 4 and 5) with elevated PTH levels selected from the database of Sheffield Kidney Institute, UK, from 1996 to 2005. All patients had baseline PTH serum levels, adjusted serum calcium (Ca), phosphate (PO4), albumin, calcium phosphate product, bicarbonate, serum creati­nine, and eGFR based on the MDRD formula. Patients with parathyroidectomy and kidney trans­plant recipients were excluded from the ana­lysis. SHPT patients were treated with vitamin D (alfacalcidol) and/or phosphate binders either in the form of calcium carbonate or acetate, or combination of these drugs. PTH was analyzed on the Advia Centaur automated immunoassay analyzer (Siemens Medical solutions Diagnos­tics). All other assays (serum Ca, Pi, bicarbonate, and albumin) were performed on the Synchron LX 20 automated chemistry analyzer (Beckman Coulter). The Centaur iPTH assay is a two site sandwich immunoassay using direct chemilu­minescent technology. Sensitivity and assay range: 2.5-1900 pg/mL (0.265-201 pmol/L).

   Statistical Analysis Top

Analysis was performed using the Statistical Package for Social Science (SPSS) version 14. Results are presented as mean and standard error of the mean (mean ± SEM). We used the stepwise linear regression analysis to examine the association between changes in PTH levels as the dependant variable. Other variables were independent including patients' age, race, sex, and biochemical variables. For comparison bet­ween pre and post follow-up parameters, paired t-test for normally distributed variables and Mann-Whitney test for non-parametric variables were applied. A P value < 0.05 was considered statistically significant.

   Results Top

Baseline and follow-up characteristics

The baseline characteristics of the 138 patients are summarized in [Table 1]. The patients were predominantly males and whites (62.3% and 93.4%, respectively). Patients with CKD 4 and 5 were 58% and 42%, respectively, on study entry. At the end of the observation period (Median 525, rang 3633, minimum 21 and maximum 3654 days), 25, 50 and 75 percentiles were 287, 525, and 955 days respectively and around 9 patients were followed up for less than 3-month obser­vation period. Changes in the proportion of CKD stages were 46 and 54% for CKD 4 and 5, respectively. There was a significant increase of PTH levels without any significant change in adjusted serum Ca, PO4, or Ca x PO4 levels. There was a significant reduction in eGFR du­ring the follow-up period reflecting the natural progression of CKD [Table 1].

Predictors of PTH levels:

Adjusted serum Ca, albumin, and eGFR at ba­seline showed a significantly negative correla­tion with baseline PTH serum levels as shown in [Table 2]. Other parameters including age, sex, race, serum PO4, Ca x PO4 product, serum bi­carbonate, and the cause of CKD did not cor­relate with serum PTH levels.

The significant positive predictors of elevated PTH levels at the end of the observation period included white race and serum PTH levels at baseline, [Table 3]. Adjusted serum calcium at the last follow-up as well last eGFR negatively cor­related with elevated PTH serum levels at the end of the observation period. Last serum PO4 level, a traditional positive predictor of PTH did not correlate with the final serum PTH levels. Gender, age, serum bicarbonate, Ca x PO4 pro­duct, rate of progression of CKD, different forms of treatment of hyperparathyroidism did not predict serum PTH levels neither at the onset nor at the end of the observation period.

   Discussion Top

We found that eGFR, serum albumin, and ad­justed serum Ca negatively correlated with PTH levels at presentation of the CKD 4and 5 pa­tients at our center. The effect of serum albumin on PTH level is controversial since some re­ports showed a positive correlation between se­rum albumin and PTH levels in dialysis pa­tients, [13] ,[14] while another study did not show any correlation with PTH levels. [15] This contradic­tion could be due to the fact that these studies involved dialysis patients in whom changes in serum albumin levels often reflect patients' nutritional status, which may in turn impact on PTH levels and the underlying nature of the renal osteodystrophy. Moreover, the nature of renal osteodystrophy may differ between the early and late stages of CKD with less response at the later stages to external influences. Para­thyroid cell proliferation is initially polyclonal, but later on it may be complicated by mono­clonal or multiclonal proliferation, which is characteristic of severe and autonomous forms of hyperparathyroidism. [3] The majority of para­thyroid glands removed surgically from uremic patients with severe forms of secondary hyper­parathyroidism are nodular, with a reduction in vitamin D receptor and calcium receptor ex­pression, indicating a reduced capacity to res­pond to therapy. [16] Another potential explana­tory hypothesis would be that serum albumin could affect PTH levels indirectly via its effects on serum calcium; low serum albumin could be associated with low serum ionized calcium le­vels and vice versa [17] and the total calcium pool available for parathyroid cells' stimulation may be reduced as well.

Interestingly, after parathyroidectomy there is a significant increase in serum albumin levels in patients with end-stage renal disease. [7] A simi­lar association was found in a cohort of CKD patients not yet started on dialysis, where serum albumin levels positively correlated with serum 25(OH)D, and this correlation was lost when patients started hemodialysis. [18] Importantly, hy­perphosphatemia and hypocalcemia typically occur only in advanced CKD, whereas calcitriol deficiency is an earlier phenomenon, [19] leading some authors to suggest that calcitriol defi­ciency may be the primary initiating mechanism of SHPT. [20] Such observations might suggest that albumin effect on PTH is exerted via changes in circulating vitamin D.

The impact of low GFR and serum calcium le­vels on inducing secondary hyperparathyroi­dism is in agreement with the previously pub­lished studies. [21],[22],[23]

Because of the limited number of the non­Caucasians we did not rely much on the out­come of race analysis, even if it was statistically significant.

We noted that baseline PTH level was a posi­tive predictor of the severity of hyperparathy­roidism at the end of the study. This was ob­served in hemodialysis patients where initial PTH levels were a significant predictor of PTH le­vels after a follow-up period of 4 weeks. [15] The same was observed in patients with primary hy­perparathyroidism, where elevated PTH and low 25 OHD were shown by multivariate analysis to be significant predictors of re-elevation of PTH after parathyroidectomy and this was explained principally by increased renal resistance to PTH in patients with high PTH levels. [24]

We failed to demonstrate any significant effect of the cause of CKD on serum PTH levels as demonstrated by others. [12] This is most probably related to the great heterogeneity of our popu­lation as well as the lack of definitive diagnosis in a significant portion of our patients.

We realize the limitations of this study inclu­ding the lack of estimation of serum vitamin D levels, which is one of the key regulators of pa­rathyroid gland function. Another short coming is the retrospective design and the lack of ho­mogeneity of some variables such as race and absence of the definitive etiology of many CKD patients.

In conclusion, this study demonstrates the sig­nificance of serum PTH levels at presentation on the long-term effect of parathyroid gland func­tion in CKD patients. This reinforces the need for early intervention to achieve optimal control of hyperparathyroidism. Further prospective in­ terventional studies are required to show the impact of modifying such risk factors in early CKD on hyperparathyroidism.

   References Top

1.Slatopolsky E, Brown A, Dusso A. Pathoge­nesis of secondary hyperparathyroidism. Kidney Int Suppl 1999;73:S14-9.  Back to cited text no. 1  [PUBMED]  
2.Slatopolsky E, Dusso A, Brown AJ. The role of phosphorus in the development of secondary hyperparathyroidism and parathyroid cell proli­feration in chronic renal failure. Am J Med Sci 1999;317:370-6.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Drueke TB. The pathogenesis of parathyroid gland hyperplasia in chronic renal failure. Kidney Int 1995;48:259-72.  Back to cited text no. 3    
4.Horl WH. The clinical consequences of secon­dary hyperparathyroidism: focus on clinical outcomes. Nephrol Dial Transplant 2004;19 Suppl 5:V2-8.  Back to cited text no. 4    
5.Slinin Y, Foley RN, Collins AJ. Calcium, phos­phorus, parathyroid hormone, and cardiovas­cular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. J Am Soc Nephrol 2005;16:1788-93.  Back to cited text no. 5    
6.Kcomt J, Sotelo C, Raja R. Influence of adyna­mic bone disease on responsiveness to recombi­nant human erythropoietin in peritoneal dialysis patients. Adv Perit Dial 2000;16:294-6.  Back to cited text no. 6  [PUBMED]  
7.Yasunaga C, Nakamoto M, Matsuo K, et al. Effects of a parathyroidectomy on the immune system and nutritional condition in chronic dia­lysis patients with secondary hyperparathyroi­dism. Am J Surg 1999;178:332-6.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Fournier AE, Arnaud CD, Johnson WJ, et al. Etiology of hyperparathyroidism and bone disease during chronic hemodialysis. II. Factors affecting serum immunoreactive parathyroid hormone. J Clin Invest 1971;50:599-605.  Back to cited text no. 8    
9.Fuss M, De Backer M, Brauman J, et al. Para­thyroid hormone plasma level in untreated chro­nic renal failure and in hemodialyzed patients. Nephron 1976;17:144-54.  Back to cited text no. 9  [PUBMED]  
10.Pitts TO, Piraino BH, Mitro R, et al. Hyperpara­thyroidism and 1,25dihydroxyvitamin D defi­ciency in mild, moderate, and severe renal failure. J Clin Endocrinol Metab 1988;67:876­81.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Salem MM. Hyperparathyroidism in the hemo­dialysis population: a survey of 612 patients. Am J Kidney Dis 1997;29:862-5.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Gupta A, Kallenbach LR, Zasuwa G, et al. Race is a major determinant of secondary hyperpara­thyroidism in uremic patients. J Am Soc Nephrol 2000;11:330-4.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Heaf JG, Lokkegard H. Parathyroid hormone during maintenance dialysis: influence of low calcium dialysate, plasma albumin and age. J Nephrol 1998;11:203-10.  Back to cited text no. 13    
14.Avram MM, Sreedhara R, Avram DK, et al. Enrollment parathyroid hormone level is a new marker of survival in hemodialysis and perito­neal dialysis therapy for uremia. Am J Kidney Dis 1996;28:924-30.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Indridason OS, Pieper CF, Quarles LD. Predic­tors of short-term changes in serum intact parathyroid hormone levels in hemodialysis patients: role of phosphorus, calcium, and gen­der. J Clin Endocrinol Metab 1998;83:3860-6.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Locatelli F, Cannata-Andia JB, Drueke TB, et al. Management of disturbances of calcium and phosphate metabolism in chronic renal insu­fficiency, with emphasis on the control of hyperphosphataemia. Nephrol Dial Transplant 2002;17:723-31.  Back to cited text no. 16    
17.Butler SJ, Payne RB, Gunn IR, et al. Correlation between serum ionized calcium and serum albumin concentrations in two hospital popu­lations. Br Med J (Clin Res Ed) 1984;289:948­50.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Gonzalez EA, Sachdeva A, Oliver DA, et al. Vitamin D insufficiency and deficiency in chronic kidney disease. A single center observa­tional study. Am J Nephrol 2004;24:503-10.  Back to cited text no. 18    
19.Gutierrez O, Isakova T, Rhee E, et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005;16: 2205-15.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]
20.Llach F, Massry SG. On the mechanism of secondary hyperparathyroidism in moderate renal insufficiency. J Clin Endocrinol Metab 1985;61: 601-6.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Miller PD. Treatment of metabolic bone disease in patients with chronic renal disease: a pers­pective for rheumatologists. Curr Rheumatol Rep 2005;7:53-60.  Back to cited text no. 21  [PUBMED]  
22.Yamamoto M, Igarashi T, Muramatsu M, et al. Hypocalcemia increases and hypercalcemia decreases the steady-state level of parathyroid hormone messenger RNA in the rat. J Clin Invest 1989;83:1053-6.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.De Boer IH, Gorodetskaya I, Young B, et al. The severity of secondary hyperparathyroidism in chronic renal insufficiency is GFR-depen­dent, race-dependent, and associated with car­diovascular disease. J Am Soc Nephrol 2002; 13:2762-9.  Back to cited text no. 23  [PUBMED]  [FULLTEXT]
24.Yamashita H, Noguchi S, Moriyama T, et al. Reelevation of parathyroid hormone level after parathyroidectomy in patients with primary hyperparathyroidism: importance of decreased renal parathyroid hormone sensitivity. Surgery 2005;137:419-25.  Back to cited text no. 24  [PUBMED]  [FULLTEXT]

Correspondence Address:
M El Kossi
Doncaster Royal Infirmary, Armthorpe Road, Doncaster & Bassetlaw Hospitals NHS Foundation Trust Doncaster, DN2 5LT
United Kingdom
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PMID: 19587504

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