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Journal of Journal of Parathyroid Disease 2014,2(1),33–37 Mini-Review

Parathyroid gland function in dialysis patients Effat Afaghi1, Ali Tayyebi1*, Behzad Einollahi1

Abstract Parathyroid disorder, is a common consequence of end-stage kidney disease (ESRD) and maintenance dialysis patient. This article, aims to investigate parathyroid disorders consisting symptoms, signs, laboratory findings, prevention and its treatment in dialysis patients. Directory of Open Access Journals (DOAJ), Google Scholar, PubMed, and Web of Science has been searched. Secondary is one of disorders in minerals metabolism in ESRD patients, resulted from calcium reduction in blood due to a decrease in synthesis of active vitamin D, acidosis, and an increase in blood phosphorus, and also 1-alpha-hydroxylase deficiency that can cause bone demineralization as well as renal osteodystrophy with symptoms such as bone pain and fractures, and even vessels and soft-tissue calcification which can affect duration of hospitalization, hospital costs and length and quality of life. The findings show that with accurate measurement of serum level of laboratory values of alkaline phosphatase, calcium, and phosphorous monthly, and parathormone every six months, training the dialysis patients, recommending a diet with low phosphorous and appropriated use of phosphate binding agents will improve the outcome of hemodialysis patients. Keywords: Parathormone, Hyperparathyroidism, Dialysis, Renal osteodystrophy Please cite this paper as: Afaghi E, Tayyebi A, Einollahi B. function in dialysis patients. J Parathyr Dis 2014; 2(1): 33-37. Copyright © 2014 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction (due to chronic hypocalcemia, reduction of vitamin D Parathyroid glands are four glands located along the as a result of other diseases) or third (due to long-term posterior of thyroid lobes. The function of these glands secondary hyperparathyroidism) (4). This article aims is distinct from parathyroid. These glands produce to investigate parathyroid disorders, signs, laboratory (PTH) that controls calcium level findings, prevention, and treatment of dialysis patients. of body with vitamin D and calcitonin hormone which We searched Directory of Open Access Journals (DOAJ), is secreted by thyroid (1). Calcium is involved in various electronic databases, including Google Scholar, PubMed, actions such as normal work of nerves and muscles, bone and Web of Science with keywords relevant to parathyroid metabolism, blood clotting and natural permeability of hormone, hyperparathyroidism, PTH and dialysis for cell membrane, while its abnormal decrease or increase studies between December 1990 and December 2014. has several effects (2). PTH causes the bones to release calcium into blood and increases the activity of osteoclasts Parathyroid disorders in dialysis patients cells. It also prevents calcium excretion from kidneys In the early 1960, dialysis was used for the first time and increases calcium absorption in the intestine with for patients of end-stage renal disease (ESRD) due to activating vitamin D. The typical interaction ion for advantages such as patients’ longevity (5). Now, in the US calcium is phosphate. PTH increases renal phosphate about 400 thousand people suffer ESRD and the number is clearance and prevents the genesis of supersaturate increasing (6). In Iran, the prevalence has risen from 238 concentration of calcium and phosphate in plasma (3). per million in 2000 to 357 per million in 2006 which show is caused by low PTH levels that an increase of 28% during six years. Total incidence of leads to reduction of ionized calcium in serum and ESRD is about 260 per million (7). Mortality rate in ESRD increase in phosphate level. Overproduction of PTH is has alarmingly risen despite science advancement in this called hyperparathyroidism that leads to an increase in field, and in the US 20% of these patients die annually (8). blood calcium. Hyperparathyroidism may be primary Secondary hyperparathyroidism (SHPT) is one of the (due to gland cell hyperplasia with unknown reason, small first disorders in minerals metabolism in ESRD patients benign tumors or ) or secondary and over 50% of dialysis patients influenced this disorder

Received: 12 January 2014, Accepted: 21 February 2014, ePublished: 1 March 2014 1Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran. *Corresponding author: Ali Tayyebi, Email: [email protected] Afaghi E et al.

cause symptoms such as bone pain, joint problems, Implication for health policy/practice/research/ fracture, itch, or even soft-tissue calcification (lung, medical education blood vessels, joints, and skin) that all affect duration Accurate measurement of serum level of laboratory of hospitalization, treatment costs as well as length and values of alkaline phosphatase, calcium, and quality of life (11). Studies have shown that patients with phosphorous monthly, and parathormone every six high levels of parathyroid hormone experience high risk month, training the dialysis patients, recommending of cardiovascular diseases (due to calcium-phosphate a diet with low phosphorous and appropriated use of deposition in the artery wall) and death (23,24). phosphate binding agents with improve the outcome of hemodialysis patients. Laboratory findings of hyperparathyroidism in dialysis patients Alkaline phosphatase (9,10). In ESRD patients, increase of parathormone is The serum level of bone alkaline phosphatase increases caused by acidosis, resistance to calcitriol, increase of and reaches as much as 10 times the maximum normal blood phosphorous, decrease of blood calcium due to range. Alkaline phosphatase comes from other sources in reduction of 1,25(OH)2D3 synthesis (active form of addition to the bone the most important ones including vitamin D) and 1-alpha hydroxylase deficiency (11). liver, intestine, and kidney. In 1920, vitamin D was introduced as an essential vitamin for calcium hemostasis (12). On the way to Calcium convert vitamin D into its biological active form, first, Total and ionized calcium concentration is normal vitamin D3 binds vitamin D binding protein or albumin or slightly low. Hypercalcemia may emerge during in blood circulation and is transported to the liver to be overzealous treatment with calcium or vitamin D converted into 25(OH)D3 by cytochrome P-450 enzyme analogues. (13). Then 25(OH)D3 is converted into the active form of 1,25(OH)2D3 by CYP27B1 (a mitochondrial Phosphorous cytochrome P-450 enzyme) (14). Kidney is the main place It increases to about 6-7 mg/dl or more before dialysis. of 1,25(OH)2D3 production; that is released from kidney into blood and transported to target sites throughout Parathyroid hormone the body (15). 1,25(OH)2D3 inhibits PTH synthesis and Measurement of normal (intact) hormone shows that prevents cell proliferation of parathyroid gland (16). In serum PTH level increases completely. The amount of contrast, PTH in different physiological conditions such 150-300 ρg/ml is in the normal range and levels higher as low level of blood calcium, stimulates renal conversion than 300 show color Doppler sonography, the gland of 25(OH)2D3 to 1,25(OH)2D3. Dialysis patients are not volume changes are detected (25). capable to produce 1,25(OH)2D3; as a result, PTH level in blood circulation is high in these patients. Reduction of Clinical guidelines of national kidney foundation kidney kidney glomerular filtration leads to phosphate retention disease outcomes quality initiative (NKF-K/DOQI) that also leads to an increase in PTH secretion and in calcium, phosphorus, and parathyroid hormone fibroblast growth factor 23. Fibroblast growth factor 23 metabolism in different stages of inhibits the activity of renal 1alpha-hydroxylase (17,18). are presented in Table 1 (25,26). In a study, Carlson et al. (19), explained that chronic renal failure patients suffer numerous hormonal disorders which Prevention and treatment certainly include increasing parathormone concentration To prevent problems created by SHPT, there is a need and decreasing testosterone hormone; however, prolactin to examine and analyze the methods used to reduce and growth hormones increase. The study conducted parathyroid hormone: by Young et al. (20), showed that the prevalence of The first and most important step in maintaining serum hyperphosphatemia was high in dialysis patients and phosphorus in normal range by diet and use of phosphate in 52% of patients serum phosphate levels were higher binders such as calcium carbonate, calcium acetate and than 5.5 mg/dl. Owda et al. (21), examined the race and renagel (27). hyperparathyroidism prevalence in 122 dialysis patients The second step is controlling PTH in the normal in Michigan for a year and concluded that 78% of patients range that is done with the help of active vitamin D faced the increase of parathyroid hormone with average of compounds: calcitriol, zemplar, calcimimetic cinacalcet 481 ρg/ml. Moreover, parathyroid hormone average was HCL (Sensipar/Mimpara) (that affects calcium-sensing more in black patients compared to white patients. receptors and increases its sensitivity to calcium and leads to the reduction of parathyroid hormone secretion Hyperparathyroidism symptoms in dialysis patients consequently) (Table 2) (28,29). Increase of parathyroid hormone levels in dialysis patients Moe et al. (30), introduced long-term treatment (100 is considered as a toxin of uremia that can stimulate weeks) with cinacalcet HCL as a reason for reduction rapid bone absorption and reabsorption causing bone of parathyroid hormone without increasing calcium demineralization and renal osteodystrophy (22). It can

34 Journal of Parathyroid Disease, Volume 2, Number 1, March 2014 Parathyroid in dialysis

Table 1. Calcium, phosphorus and parathyroid hormone metabolism in different stages of chronic kidney disease. GFR Phosphorous Calcium Calcium × Phosphorus Intact PTH CKD Stage (ml/min/1.73m2) (mg/dl) (mg/dl) (mg2/dl2) (ρg/ml) 3 30-59 2.7-4.6 8.4-10.2 35-70 4 15-29 2.7-4.6 8.4-10.2 Less than 55 70-110 5 Less than 15 or dialysis 3.5-5.5 8.4-9.5 150-300 CKD= Chronic kidney disease

Table 2. Drugs control parathormone secretion Drug name Indications Side effects Contraindication • Helps to regulate calcium and • Seizure (convulsions) phosphorus with increasing the • Swelling sensitivity of parathyroid gland to • Allergy to any ingredient in Sensipar • Rapid weight gain calcium cinacalcet (cinacalcet) • • Treating secondary • Low blood calcium levels Tab 30,60 mg • Diarrhea hyperparathyroidism • Vomiting (mild to • Treating hypercalcemia in patients with moderate) • Similar to vitamin D • Allergy to any ingredient in • Dizziness • Helps to lower high levels of paricalcitol Zemplar (paricalcitol) • Allergic reaction parathyroid hormone • High levels of vitamin d or calcium Cap 1,4 mcg • Arthritis • Preventing and treating secondary in the blood • Rash hyperparathyroidism • A form of vitamin D • Diarrhea • Allergy to any ingredient in • Managing certain conditions caused by Rocaltrol • Allergic reaction rocaltrol high or low parathyroid hormone levels (calcitriol) • Bizarre behavior • High levels of vitamin d or calcium • Managing low blood calcium levels Cap 0.25,0.5 mcg • Fever in the blood in patients who suffer chronic kidney • Dizziness dialysis • Allergy to any ingredient in Hectorol • A synthetic form of vitamin D • Tendency toward high calcium • Lowering elevated parathyroid • Abscess levels or evidence of vitamin D Hectorol hormone levels in patients undergoing • Difficulty sleeping overdose(eg, weakness, nausea, (doxercalciferol) kidney dialysis • Joint pain headache, drowsiness, vomiting, Cap 0.5 µg • Promoting the proper absorption and • Upset stomach dry mouth, constipation, muscle use of calcium and phosphate by the • Weight gain pain, bone pain, loss of appetite) body • High levels of calcium, phosphate, or vitamin D in the blood • Fever • Allergy to any ingredient in Calcijex Calcijex • A form of vitamin D • Allergic reaction solution (calcitriol) • Treating low calcium levels in dialysis • Bone pain • High levels of vitamin D or calcium Injection, solution patients' blood • Bizarre behavior in the blood 1µg/ml • Constipation and phosphorus. Block et al. (31), performed a study to Sanadgol et al. (34), showed that the average of PTH serum determine the effects of cinacalcet HCL in dialysis patients level reduced at the end of two months intervention with with PHT>3000 ρg/dl and concluded that daily use vitamin C (200 mg, three times a week) compared to base according to the need and prescription leads to reduction time. However, this effect gradually decreased in the third of parathyroid hormone, calcium, phosphorus, and Ca×P month which may be due to the reduction of calcium- product. sensing receptors’ sensitivity to parathyroid cells over Another method mentioned in studies is the use of time. vitamin C. The study conducted by Richter et al. (32), Partial or total parathyroidectomy with implantation of showed that there was a relationship between high levels a part of parathyroid in arm is the last method used in of plasma vitamin C with low level of PTH. Vitamin C patients who have iPTH>800 ρg/dl with hypercalcemia affects post-receptor events in calcium-sensing receptors and hyperphosphatemia and dose not respond to medical on parathyroid cells which explain reverse interactions treatment (35). between vitamin C and PTH. However, Biniyaz et al. (33), in a double-blind, placebo-controlled study found Conclusion that vitamin C has no beneficial effect on secondary Since parathyroid hormone serum level is high in dialysis hyperparathyroidism. patients and on the other hand, excessive suppression

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