Total Parathyroidectomy with Forearm Autotransplantation as the Treatment of Choice for Secondary Hyperparathyroidism

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1 The Journal of International Medical Research 2011; 39: Total Parathyroidectomy with Forearm Autotransplantation as the Treatment of Choice for Secondary Hyperparathyroidism J NARANDA 1,2, R EKART 1,3 AND B PEČOVNIK-BALON 1,2 1 Faculty of Medicine, University of Maribor, Maribor, Slovenia; 2 Nephrology Department, and 3 Dialysis Department, University Clinical Centre Maribor, Maribor, Slovenia Chronic kidney disease mineral and bone disease (CKD MBD) is associated with uraemic bone disease, vascular calcification, reduced quality of life and reduced survival. This study evaluated the efficacy of parathyroidectomy (PTX) with autotransplantation in improving shortterm and long-term outcomes. Dialysis patients who underwent PTX showed significantly more favourable biochemical parameters after PTX. These changes were accompanied by a lower coronary artery calcification score, reduced thickness of the intimae media and comparable bone mineral density measures compared with control dialysis patients who did not undergo PTX. Despite the risk of a substantially lower intact parathyroid hormone level postoperatively that might lead to adynamic bone disease, none of the patients reported clinical signs of this disease, such as bone pain or fractures. In conclusion, PTX with autotransplantation led to improvement of CKD MBD so may be considered in patients with secondary hyperparathyroidism that is resistant to treatment with vitamin D analogues and calcimimetics. KEY WORDS: CHRONIC KIDNEY DISEASE; HYPERPARATHYROIDISM; MINERAL AND BONE DISEASE; CALCIFICATION; PARATHYROIDECTOMY; MINERAL METABOLISM; BONE MINERAL DENSITY Introduction Secondary hyperparathyroidism (SHPT) is a common complication among patients with chronic kidney disease (CKD) and represents part of a broad spectrum of mineral metabolism disorders that occur in this clinical setting. 1 3 Alterations in the control mechanisms for calcium and phosphorus homeostasis, which occur early in the course of CKD and progress as kidney function decreases, along with diminished value of active vitamin D, lead to an increase of serum intact parathyroid hormone (ipth) and results in SHPT. 4 The term CKD mineral and bone disease (CKD MBD) is now used to describe the systemic manifestations of CKD that include abnormalities in calcium, phosphorus, ipth and vitamin D metabolism, abnormalities in bone turnover (mineralization, volume, growth), and vascular calcifications and deposits of calcium in soft tissues

2 Bone abnormalities due to CKD include the effects of high levels of ipth on bone, which results in the high-turnover bone disease, osteitis fibrosa. 1 In contrast, adynamic bone, characterized by extremely low bone turnover, may also occur in the setting of CKD or after parathyroidectomy (PTX). 8 This wide spectrum of skeletal abnormality can give rise to a variety of mixed patterns. High-turnover bone disease is the result of SHPT development. It has been shown that hyperplasia of the parathyroid glands and high levels of ipth occur early in the course of CKD and lead to over-activity of the parathyroid gland. 9 The factors that influence parathyroid gland hyperplasia include the retention of phosphorus, decreased levels of calcitriol, intrinsic alterations within the parathyroid glands, skeletal resistance to ipth and hypocalcaemia. 10 Research indicates that 5 25% of patients with CKD develop severe forms of SHPT while, in another 75%, nodular dysplasia of the parathyroid gland can be found histologically. 11 The majority of patients can, however, be successfully treated conservatively by controlling the serum level of phosphorus with dietary intake restrictions and phosphorus binders to reduce gastrointestinal tract absorption. 12 Additionally, the level of calcium can be controlled by monitoring calcium levels in the daily diet relative to calcium levels in serum, by adjusting the level of calcium in dialysis fluid, and with the use of vitamin D analogues In spite of advances in medical therapy, some patients with CKD become resistant to drug treatment and, therefore, still have marked elevations in serum ipth. This disorder is called tertiary hyperparathyroidism (THPT). It characteristically presents with hyper - calcaemia and refractory hyperpara - thyroidism due to hyperfunctional parathyroid tissue that does not respond appropriately to physiological regulation or to medical therapy. 19 The most probable causes of THPT are thought to be delayed and/or inadequate therapy, persistent hyperphosphataemia leading to irreversible parathyroid gland hyperplasia and autonomous behaviour of the parathyroid gland. 20 These patients have a greater risk of developing CKD MBD and require aggressive operative treatment, i.e. PTX, in order to prevent long-term complications The parathyroid gland can be removed partially (subtotal PTX) or totally (total PTX) with or without autotransplantation (AT). 24 In most cases, PTX results in a dramatic reduction in the serum ipth level, an improvement of SHPT and a decrease in the risk of cardiovascular diseases and bone fractures. 11,25 Substantially low ipth levels that are usually reported postoperatively may predispose a patient to adynamic bone disease (ABD) and can also lower the patient s quality of life due to the clinical symptoms of fractures, bone pain and vascular calcifications. 26 The aim of the present study was to evaluate the efficacy of PTX with AT, which is one of the surgical treatment options for patients that develop severe forms of SHPT due to CKD and who do not respond to the recommended drug therapy. Patients and methods STUDY POPULATION AND DESIGN This study was carried out at the University Clinical Centre, Maribor, Slovenia, between 2003 and All dialysis patients who underwent total PTX with AT of one parathyroid gland in the forearm due to SHPT because of CKD were enrolled into the study. Indications for PTX were very high levels of ipth (> 900 pg/ml) that could not be normalized with the drug treatment available at the time. Dialysis patients who 979

3 did not undergo PTX with AT, matched for age, gender, duration of dialysis treatment and mean ipth value, were selected to form a control group. This study was a retrospective observational study so ethical approval was not required. All patients enrolled into the study were informed about the aim of the study and their verbal consent was obtained. STUDY TREATMENT AND MONITORING Dialysis patients who underwent PTX with AT were treated three times per week for 4 6 h on a Gambro AK 200 dialysis apparatus (Rhein Medical Solutions, Duesseldorf, Germany). The level of calcium in dialysis fluid was kept at mmol/l based on the calcium and phosphorus electrolyte levels in serum. Serum calcium, phosphorus, and alkaline phosphatase levels were monitored once a month for 6 months preoperatively and ipth was measured once every 4 months. After PTX, all biochemical parameters were monitored once a month and ipth once per 4 months. Measurement taken immediately after PTX was a single measurement and was recorded as the measurement at 1 month. Other measurements were recorded as the mean values for 12, 24 and 36 months; for example, the measurement recorded for 12 months was the mean value of all measurement taken in the first year after PTX, the measurement recorded for 24 months was the mean value of all measurement taken in the second year after PTX, and so on. Levels of ipth were measured with the Elecsys immunoassay kit (Roche Diagnostics, Mannheim, Germany) and the other biochemical parameters were measured using standard biochemical methods. Patients were treated with phosphorus binders (calcium carbonate, sevelamer) and calcitriol. POSTOPERATIVE EVALUATIONS From the dialysis patients who underwent PTX with AT, a subgroup with full data availability was selected as a test group to be compared with a control group of comparable age, gender and duration of dialysis. The coronary artery calcification score (CACS), thickness of the intima media (TIM) and bone mineral density (BMD) were measured in both the test and control groups of dialysis patients. CACS was estimated using the scale of Agatson et al. 27 following multislice spiral computed tomography (CT) with a Toshiba Aquilion 64 scanner (Toshiba Medical Systems Corp., Otawara, Japan). TIM was obtained by ultrasound using a Philips ATL HDI 3000 ultrasound machine (Philips Healthcare, Best, The Netherlands). BMD (absolute value [g/m 2 ], percentage value and T-score) was measured using a Hologic QDR 2000 Plus densitometer (Braintec, Ljubljana, Slovenia). Patients in both groups were also evaluated for clinical signs of bone fractures, bone pain and pruritus. STATISTICAL ANALYSES The mean ± SD of the data were calculated and statistical analyses were carried out using the SPSS statistical package, version 12.0 (SPSS Inc., Chicago, IL, USA) for Windows. Data were compared by t-test for paired and independent samples. A P-value < 0.05 was considered to be statistically significant. Results Of the 26 dialysis patients who developed SHPT because of CKD and underwent PTX with AT, only 17 (12 females, five males) could be followed postoperatively: three from the time of the operation until death and the remaining 14 for a mean ± SD of 2.5 ± 1.0 years postoperatively. Nine patients were excluded: five of them underwent kidney 980

4 transplantation, three died soon after the operation and one changed health institutions. The 17 patients included in the analysis had the following diagnoses: four had autosomal dominant polycystic kidney disease, three had chronic glomerulonephritis, two had diabetic nephropathy, two had chronic pyelonephritis, one had cysplatin nephropathy, one had Balkan nephropathy, one had analgesic nephropathy, one had reflux nephropathy and two had unknown diagnoses. The characteristics of the 26 dialysis patients who underwent PTX with AT and the group of 17 patients that were followed postoperatively are shown in Table 1. Among the 17 patients who underwent PTX with AT, only the nine patients who had full data availability (CACS, TIM and BMD) were chosen as the test group; the remaining eight patients refused to undergo diagnostic procedures. The test group was compared with nine dialysis patients who had not undergone PTX with AT (control group), matched to the test group for age, gender distribution, and duration of dialysis treatment in order to generate two comparable groups (Table 2). Table 3 presents the mean preoperative (6 months) and postoperative levels for the biochemical parameters for the 17 patients who underwent PTX with AT. Before the operation, none of the patients was hypercalcaemic, two (12%) had hyperphosphataemia and seven (41%) had overly high values for the calcium phosphorus product (> 4.4 mmol 2 /l 2 ). Postoperatively, only two (12%) patients achieved a mean level of serum ipth that was within the normal range; all patients had normal values for the calcium phosphorus product. Table 4 presents the mean postoperative levels of calcium, phosphorus, ipth and alkaline phosphatase at different time- TABLE 1: Baseline characteristics of dialysis patients who underwent parathyroidectomy (PTX) with autotransplantation (AT) and the group of patients followed postoperatively Gender Treatment Dialysis duration Duration after Group Age (years) (males/females; n) (n) (months) PTX (months) Total treated with PTX with AT (n = 26) 51.1 ± /17 HD = 22 PD = ± 58.9 Patients treated with PTX with AT and followed 55.3 ± /12 HD = 14 postoperatively (n = 17) PD = ± ± 12.0 Data presented as mean ± SD or number of patients (n). HD, haemodialysis; PD, peritoneal dialysis. 981

5 TABLE 2: Baseline characteristics of selected dialysis patients who underwent parathyroidectomy (PTX) with autotransplantation (AT) compared with the matched control dialysis patients (control) who did not undergo PTX with AT PTX with AT Control group Statistical Characteristics/parameters (n = 9) (n = 9) significance a Age, years 57 ± ± 13 NS Gender, males/females 3/6 4/5 Dialysis duration, months Overall 126 ± ± 64 NS Before PTX 82 ± 56 After PTX 43 ± 15 Data presented as mean ± SD or number of patients (n). a Independent-samples t-test; NS, not statistically significant (P > 0.05). TABLE 3: Biochemical analyses in the dialysis patients before and after parathyroidectomy with autotransplantation (n = 17) Biochemical parameter Preoperative Postoperative Normal range Intact parathyroid hormone, pg/ml 1467 ± ± 50* Calcium, mmol/l 2.37 ± ± 0.17* Phosphorus, mmol/l 1.80 ± ± 0.34* Alkaline phosphatase, µkat/l 2.52 ± ± 0.58* Calcium phosphorus product, mmol 2 /l ± ± 0.7* < 4.4 Data presented as mean ± SD of all preoperative (6 months) and postoperative measurements (mean ± SD time period of postoperative measurements was 2.5 ± 1.0 years). *P < 0.05 versus preoperative value (paired-samples t-test). TABLE 4: Biochemical analyses in the dialysis patients at 1, 12, 24 and 36 months after parathyroidectomy with autotransplantation 1 month 12 months 24 months 36 months Normal Biochemical parameter (n = 17) (n = 14) (n = 14) (n = 9) range Intact parathyroid 44 ± 62* 51 ± 60* 51 ± 49* 63 ± 50* hormone, pg/ml Calcium, mmol/l 2.22 ± ± ± 0.19* 2.08 ± Phosphorus, mmol/l 1.09 ± 0.49* 1.53 ± ± 0.38* 1.46 ± Calcium phosphorus 2.3 ± 0.8* 3.5 ± ± 0.9* 3.1 ± 1.2 < 4.4 product, mmol 2 /l 2 Alkaline phosphatase, µkat/l 1.51 ± ± 0.65* 1.31 ± 0.55* 1.57 ± Data presented as mean ± SD. All parameters were monitored once a month, except intact parathyroid hormone which was monitored once every 4 months. The measurement at 1 month is a single measurement taken immediately after parathyroidectomy. The 12 months measurement is the mean of all measurements taken in the first year after parathyroidectomy, the 24 months measurement is the mean of all second year measurements, and so on. *P < 0.05 versus preoperative value (paired-samples t-test). 982

6 TABLE 5: Biochemical analyses in the selected dialysis patients who underwent parathyroidectomy (PTX) with autotransplantation (AT) compared with the matched control dialysis patients (control) who did not undergo PTX with AT Biochemical parameter PTX with AT (n = 9) Control group (n = 9) Intact parathyroid hormone, pg/ml a Overall b 1147 ± 182* 892 ± 323 Before PTX 1484 ± 231 After PTX 42 ± 49 CACS a 1056 ± ± 2350 Intima media thickness, mm a 0.81 ± ± 0.78 Bone mineral density a Absolute value, g/m ± ± 0.55 Percentage, % c 96.4 ± ± 3.8 T-score d 1.41 ± ± 0.36 Clinical data, n Fractures 0 1 Pain 0 5 Pruritis 0 3 Data presented as mean ± SD or number of patients (n). a Overall intact parathyroid hormone, CACS, intima media thickness and bone mineral density measurements represent the mean ± SD of values taken for the following periods: PTX with AT group, 126 ± 65 months after the beginning of dialysis (or 82 ± 56 months after PTX); control group 103 ± 64 months after the beginning of dialysis. b Mean of before and after PTX. c Calculated as a percentage of the bone mineral density of young healthy adults. d Deviation from the bone mineral density of young healthy adults, recalculated as a standard deviation. *P < 0.05 versus control group (paired samples t-test). CACS, coronary artery calcification score. points after PTX. There was a gradual increase in ipth over time. Table 5 presents the ipth, CACS, TIM, BMD, bone fracture, bone pain and pruritus data for the test and matched control groups. None of the patients who underwent PTX with AT showed any clinical signs of fractures, bone pain or pruritus, whereas in patients who had not undergone PTX with AT, there was one fracture, five had bone pain and three had pruritis at follow-up. Discussion In the majority of CKD patients CKD MBD is present and is associated with disturbance of calcium and phosphorus homeostasis and altered vitamin D metabolism. 5 Excess levels of ipth, phosphorus and calcium are linked to parathyroid gland hyperplasia, renal bone disease, vascular calcifications, a lower quality of life and higher mortality Treatment of CKD MBD is stepwise, multidimensional, and must be initiated at an early stage in order to avoid complications and reduce the likelihood of the case becoming difficult to treat. Restriction of dietary phosphorus intake is introduced but phosphorus binders and vitamin D are also usually subsequently required. 20 Vitamin D analogues 31 and calcimimetics 32 have demonstrated efficacy in the prevention of CKD MBD. Unfortunately, during the study period ( ), neither vitamin D analogues nor calcimimetics were available at the University Clinical Centre Maribor. As a 983

7 result, many patients developed substantially high levels (> 300 pg/ml) of ipth and required PTX. 9 Paricalcitol (vitamin D analogue) and/or cinacalcet (calcimimetic) have been used at the University Clinical Centre Maribor since 2007 in patients developing high ipth levels despite dietary phosphorus restriction and treatment with phosphorus binders. In some patients, the effort to correct hyperphosphataemia with calcium-based phosphorus binders results in hypercalcaemia, especially when calcitriol is coadministered to suppress ipth secretion. 33 In the course of SHPT, nodular hyperplasia of the parathyroid gland develops with decreased calciumsensing receptors to regulate ipth secretion. 34 Altered receptor numbers make the parathyroid gland less responsive to medical treatment, cause skeletal resistance to ipth and renal bone disease. 20 The medical treatment of patients in the present study had been previously unsuccessful; all 17 patients had developed resistant SHPT (ipth > 900 pg/ml) with high levels of calcium and phosphorus. Seven patients (41%) had a calcium phosphorus value > 4.4 mmol 2 /l 2. It is known that hypercalcaemia and higher values of calcium phosphorus lead to vascular calcification and an increased risk for cardiovascular disease. 35 Thus, treatment with calcium and vitamin D had to be discontinued and PTX with AT was performed. The main finding of the present study was the correction of SHPT; all of the patients demonstrated significantly lower serum levels of ipth, calcium, phosphorus and alkaline phosphatase after treatment with PTX. The postoperative results were comparable with the literature reporting satisfactory biochemical and clinical results after PTX therapy which, in some cases, was achieved in > 95% of patients. 39 In spite of good short-term clinical results, there appears to be an increased risk of reaching overly low ipth values after PTX, which predisposes the patient to ABD, increases the risk of fractures and lowers the patient s quality of life. 40 Although only two (13%) patients in the present study reached the recommended Kidney Disease Improving Global Outcomes (KDIGO) ipth serum value ( pg/ml) postoperatively, 5 no clinical signs of fractures, bone pain or pruritus before or after PTX were observed. In contrast, these clinical signs were observed in the control group (one patient with fracture, five with bone pain and three with pruritus). Postoperative data showed transitory favourable bone metabolism, since the alkaline phosphatase level was significantly lower at 12 and 24 months after PTX. Furthermore, postoperative BMD parameters indicated satisfactory bone structure in patients who underwent PTX. 41,42 To evaluate the success of PTX with AT in lowering the long-term risk for cardiovascular disease and death, CACS and TIM were measured in the test and control groups. Lower mean values of CACS and TIM in patients who underwent PTX indicated that PTX was successful, despite the differences between the two groups only being numerical and not statistically significant. Other studies have also shown improved survival and fewer complications among patients who underwent PTX. 37,38 Despite a previous report of excellent shortterm clinical results and long-term normalization of ipth in 40% of patients after PTX, 39 overly low values of ipth are more usually reported. 40 Only two patients in the present study had ipth levels within the normal range; this occurred at a mean ± SD of 2.5 ± 1.0 years after PTX. Similarly, at 5 years after PTX, the main clinical finding reported in the literature is 984

8 hypoparathyroidism. 38 These patients have a long-term risk of developing ABD. By measuring the biochemical parameters at different time-points after PTX, it was demonstrated that the ipth level gradually increased but did not reach the minimal desired level. Although levels of calcium, phosphorus and alkaline phosphatase were improved after PTX, patients were still required to take calcium and vitamin D supplements. In conclusion, the present study demonstrated that PTX with AT is an efficient short-term treatment option for severe SHPT. Nevertheless, PTX with AT does not seem to be the optimum therapeutic option for patients with severe SHPT because it does not target the recommended National Kidney Federation Kidney Disease Outcomes Quality Initiative nor the KDIGO values for ipth. 5,40,43 The potential risk of an overly low ipth, which can lead to ABD, appears to be counter-balanced by the favourable effect of PTX on vascular calcification and improved long-term survival. New treatments for SHPT include vitamin D analogues and calcimimetics. Modulating the calcium-sensing receptor on the parathyroid gland, thereby lowering ipth secretion, improves bone remodelling and prevents parathyroid hyperplasia. 35 Since beginning use of these agents at the University Clinical Centre Maribor, there has been no need for PTX with AT. In patients who still require PTX because of severe SHPT that is resistant to drug treatment, histological assessment of the removed parathyroid gland should be performed and only the required amount of the active gland should be re-implanted. Some authors have already described satisfactory results with this technique. 35,44,45 Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 17 January 2011 Accepted subject to revision 3 February 2011 Revised accepted 22 April 2011 Copyright 2011 Field House Publishing LLP References 1 Moe S, Drüeke T, Cunningham J, et al: Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006; 69: Felsenfeld AJ, Llach F: Parathyroid gland function in chronic renal failure. Kidney Int 1993; 43: Hernández A, Concepción MT, Rodríguez M, et al: High phosphorus diet increases prepropth mrna independent of calcium and calcitriol in normal rats. Kidney Int 1996; 50: Nichols P, Owen JP, Ellis HA, et al: Parathyroidectomy in chronic renal failure: a nine-year follow-up study. Q J Med 1990; 77: Kidney Disease: Improving Global Outcomes (KDIGO) CKD MBD Work Group: KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease Mineral and Bone Disorder (CKD MBD). Kid Int 2009; 76(suppl 113): S1 S Guérin AP, London GM, Marchais SJ, et al: Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 2001; 15: Safar ME, Blacher J, Pannier B, et al: Central pulse pressure and mortality in end-stage renal disease. Hypertension 2002; 39: Andress DL: Adynamic bone in patients with chronic kidney disease. Kidney Int 2008; 73: Slatopolsky E, Delmez JA: Pathogenesis of secondary hyperparathyroidism. Nephrol Dial Transplant 1996; 11(suppl 3): Martin KJ, González EA: Metabolic bone disease and chronic kidney disease. J Am Soc Nephrol 2007; 18: Neyer U, Hoerandner H, Haid A, et al: Total parathyroidectomy with autotransplantation in renal hyperparathyroidism: low recurrence after intra-operative tissue selection. Nephrol Dial Transplant 2002; 17: Coladonato JA: Control of hyperphosphatemia 985

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10 42 Qi Q, Monier-Faugere MC, Geng Z, et al: Predictive value of serum parathyroid hormone levels for bone turnover in patients on chronic maintenance dialysis. Am J Kidney Dis 1995; 26: National Kidney Foundation: K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003; 42(4 suppl 3): S1 S Coen G, Calabria S, Bellinghieri G, et al: Parathyroidectomy in chronic renal failure: short- and long-term results on parathyroid function, blood pressure and anemia. Nephron 2001; 88: Sato S, Ohta M, Kawaguchi Y, et al: Effects of parathyroidectomy on left ventricular mass in patients with hyperparathyroidism. Miner Electrolyte Metab 1995; 21: Author s address for correspondence Dr Jakob Naranda Faculty of Medicine, University of Maribor, Slomškov trg 15, SI-2000 Maribor, Slovenia. mf@uni-mb.si 987