| Abstract|| |
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 2019 Jul 16];20:623-7. Available from: http://www.sjkdt.org/text.asp?2009/20/4/623/53252
| Introduction|| |
Secondary hyperparathyroidism (SHPT) is a frequent complication of chronic kidney disease (CKD).  It is characterized by parathyroid hyperplasia and deranged calcium and phosphorus homeostasis. 
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.  , Some other factors have a variabley contributed to the development of hyperparathyroidism in uremic patients such as aluminum, estrogens, and catecholamines. 
Parathormone hormone is considered to be one of the major uremic toxins.  Renal osteodystrophy, soft tissue calcification particularly blood vessels,  immune dysfunction, and anemia,  , 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. ,,,,
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|| |
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|| |
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|| |
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|| |
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,  , while another study did not show any correlation with PTH levels.  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.  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.  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  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.  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.  Importantly, hyperphosphatemia and hypocalcemia typically occur only in advanced CKD, whereas calcitriol deficiency is an earlier phenomenon,  leading some authors to suggest that calcitriol deficiency may be the primary initiating mechanism of SHPT.  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. ,,
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.  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. 
We failed to demonstrate any significant effect of the cause of CKD on serum PTH levels as demonstrated by others.  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|| |
|1.||Slatopolsky E, Brown A, Dusso A. Pathogenesis of secondary hyperparathyroidism. Kidney Int Suppl 1999;73:S14-9. [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. [PUBMED] [FULLTEXT]|
|3.||Drueke TB. The pathogenesis of parathyroid gland hyperplasia in chronic renal failure. Kidney Int 1995;48:259-72. |
|4.||Horl WH. The clinical consequences of secondary hyperparathyroidism: focus on clinical outcomes. Nephrol Dial Transplant 2004;19 Suppl 5:V2-8. |
|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. |
|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. [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. [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. |
|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. [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. [PUBMED] [FULLTEXT]|
|11.||Salem MM. Hyperparathyroidism in the hemodialysis population: a survey of 612 patients. Am J Kidney Dis 1997;29:862-5. [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. [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. |
|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. [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. [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. |
|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. [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. |
|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. [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. [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. [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. [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. [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. [PUBMED] [FULLTEXT]|
M El Kossi
Doncaster Royal Infirmary, Armthorpe Road, Doncaster & Bassetlaw Hospitals NHS Foundation Trust Doncaster, DN2 5LT
[Table 1], [Table 2], [Table 3]