Parathyroidectomy for tertiary hyperparathyroidism after second kidney transplantation: a case report

Abstract

Successful kidney transplantation usually resolves secondary hyperparathyroidism (SHPT). However, some patients fail to normalize, and their condition is often referred to as tertiary hyperparathyroidism (THPT). Surgical consensus on the timing of post-transplant parathyroidectomy (PTX) for THPT has not been reached. Herein, we report a case of a 58-year-old post-transplant woman, considering the concrete timing of PTX for both SHPT and THPT. She initiated hemodialysis with end-stage renal disease at the age of 24, and underwent first kidney transplantation at the age of 28. When peritoneal dialysis (PD) was induced due to the worsening kidney function at the age of 50, the serum intact parathyroid hormone (iPTH) level remarkably increased (2332 pg/mL). Although cinacalcet was administered, the patient’s iPTH levels were not sufficiently suppressed for seven years. Diagnostic images including ultrasound, computed tomography, and ^99mTc-methoxyisobutylisonitrile scintigraphy indicated THPT as the reason for prolonged post-transplant hypercalcemia. Therefore, PTX was performed 14 months after the second transplantation. Histology showed nodular hyperplasia of all parathyroid glands, indicating autonomous secretion of parathyroid hormone. In general, patients with more severe THPT are recognized with more severe SHPT prior to transplantation during the dialysis period. We should consider a referral for surgery based on the individual risk factors. We recommend to perform parathyroidectomy earlier, before the kidney transplantation in the clinical suspicion of severe SHPT.

Introduction

Secondary hyperparathyroidism (SHPT) commonly occurs in patients with end-stage renal disease. The mechanism remains unclear but is involved in calcium, phosphorus, and vitamin D metabolism [1]. Successful kidney transplantation leads to the resolution of SHPT. However, more than 25% of patients fail to normalize intact parathyroid hormone (iPTH) levels one year after the kidney transplantation [2]. This condition is often referred to as tertiary hyperparathyroidism (THPT) [3]. Patients with more severe THPT are usually recognized with more severe SHPT prior to transplantation and the use of calcimimetics during the dialysis period [4].

Calcimimetics and parathyroidectomy (PTX) are the treatment options for THPT [4]. However, no evidence-based guidelines for the treatment of THPT have been established. Calcimimetics have not been approved for the treatment of THPT in Japan. The frequency of cases requiring PTX for THPT is approximately 0.5–5.0% [5]. Surgical consensus on the timing has not been reached yet. Here, we report a rare case of a patient with THPT after two kidney transplantations who underwent total PTX with autotransplantation. This case is important and suggestive when considering the timing of PTX for both SHPT and THPT.

Case report

The patient was a 58-year-old woman who underwent a second kidney transplantation at the age of 56, complaining of persistent post-transplant hypercalcemia with levels over 12 mg/dL. She was initiated on hemodialysis with an end-stage renal disease due to acute glomerulonephritis at the age of 24 and had undergone first kidney transplantation at the age of 28. She had a history of hypertension, hyperlipidemia, and chronic hepatitis C. Her kidney function gradually worsened with chronic antibody-mediated rejection. She was initiated on maintenance peritoneal dialysis (PD) at the age of 50 years. The patient’s clinical course before and after the PD induction is presented in Fig. 1. During the PD induction, the serum iPTH level remarkably increased (2332 pg/mL; normal, < 65 pg/mL). We did not measure the iPTH levels before the PD induction. After the administration of cinacalcet as a daily dose of 25 mg at the PD induction, the level of one of the calcimimetics, iPTH decreased to 323 pg/mL in three years. However, iPTH levels gradually increased to 805 pg/mL within five years, despite the increase in the daily dose of cinacalcet up to 50 mg. Thus, iPTH levels were not sufficiently suppressed during the seven years of the entire PD period (Fig. 1). Although she had no symptoms of mineral or bone disorder, she had reduced lumbar spine and total body bone mineral density (BMD) (Fig. 2).

Fig. 1.

Time course before second kidney transplantation. iPTH intact parathyroid hormone, ALP alkaline phosphatase, cCa corrected calcium, P phosphorus, sCr serum creatinine, PD peritoneal dialysis

Fig. 2.

Time course of T-score data of lumbar spine and total body scans. BMD bone mineral density, PD peritoneal dialysis

Hypercalcemia and elevated alkaline phosphatase (ALP) levels were observed soon after the second kidney transplantation up to 12.4 mg/dL and 929 IU/L, respectively, at seven months (Fig. 3). Severe hypercalcemia persisted for 14 months after the second transplantation. On the other hand, ALP levels gradually declined to 349 IU/L at 12 months and then increased up to 424 IU/L at 14 months. Antinuclear antibody, antimitochondrial antibodies, and hepatitis B virus antibody were negative. Hepatitis C virus (HCV) antibody was positive, but HCV RNA was negative. Abdominal ultrasound, computed tomography (CT), and magnetic resonance cholangiopancreaticography revealed no remarkable changes, including biliary obstruction and liver parenchymal lesion. Parathyroid ultrasound showed four hyperplastic parathyroid glands: 9.6 mm × 4.7 mm × 6.8 mm (Fig. 4a), 3.2 mm × 3.0 mm × 2.7 mm (Fig. 4b), 5.6 mm × 3.6 mm × 3.8 mm (Fig. 4c), and 6.2 mm × 4.2 mm × 4.3 mm (Fig. 4d). CT scan revealed four enlarged parathyroid glands (Fig. 4e, f). Dual-phase ^99mTc-methoxyisobutylisonitrile (MIBI) scintigraphy demonstrated uptake in the right mediastinum in the initial phase (15 min) (Fig. 4g) and in the four glands in the late phase (120 min) (Fig. 4h). Based on these results, she was diagnosed with THPT and underwent total PTX with autotransplantation to the forearm (Fig. 5a). The largest parathyroid gland weighed 300 mg. Histology showed nodular hyperplasia of all parathyroid glands (Fig. 5b). The iPTH level was 245 pg/mL before the PTX and 52 pg/mL postoperatively. After the early post-PTX period, vitamin D was administered to avoid hypocalcemia. Serum levels of calcium and ALP were maintained within the normal range after discharge, with a normal iPTH level (92 pg/mL, eight months after PTX). PTX did not affect the serum creatinine level.

Fig. 3.

Time course after second kidney transplantation. iPTH intact parathyroid hormone, ALP alkaline phosphatase, cCa corrected calcium, P phosphorus, sCr serum creatinine, PD peritoneal dialysis, PTX parathyroidectomy

Fig. 4.

Parathyroid imaging. Ultrasound revealing four hyperplastic parathyroid nodules. a The upper right parathyroid gland (green arrow), b lower right parathyroid gland (orange arrow), c upper left parathyroid gland (blue arrow), and d lower left parathyroid gland (purple arrow). e, f Computed tomography scan showing four enlarged parathyroid glands. ^99mTc-MIBI scintigraphy demonstrating uptake g in the right mediastinum in the initial phase (15 min) and h in the four glands in the late phase (120 min)

Fig. 5.

Parathyroid pathological studies a Intraoperative view of total parathyroidectomy, b Histology showing single nodular hyperplasia of the parathyroid gland

Discussion

The present case provides an important clinical suggestion. To the best of our knowledge, this is the first case report highlighting the importance of treating SHPT with PTX before kidney transplantation in patients on dialysis patients without sufficiently suppressed iPTH levels.

THPT is involved in multifunctional mechanisms, including phosphate retention and loss of renal 1-hydroxylase activity with low 1,25-(OH)₂ vitamin D₃ levels [6]. In contrast to SHPT, THPT represents persistent hypercalcemia, moderately increased iPTH levels, and increased ALP levels [7]. The level of iPTH one year after the transplantation (> 130 pg/mL) indicates THPT [4], which was applicable to our case. THPT is mostly asymptomatic, but is a risk factor for bone disease, soft tissue and organ calcification, renal graft loss, and mortality [8–11]. Some reports suggested that surgery should not be postponed longer than three–six months in the post-transplant period [1, 2], whereas others suggested that a conservative approach is recommended for post-transplant hypercalcemia and surgery should be reserved for patients with symptomatic or asymptomatic persistent hypercalcemia more than one year after the transplantation [12, 13]; we performed a PTX at 14 months after the second transplantation based on the latter conservative approach. PTX is the only treatment for THPT unresponsive to medication. Thus, the timing of surgery is important but remains controversial. The prevalence of post-transplant hypercalcemia is approximately 30% [5]. The long duration of dialysis before the transplantation and post-transplant hypercalcemia are independent risk factors for THPT [14], which was applicable to this case as well. However, because she was asymptomatic with chronic post-transplant hypercalcemia (mild or moderate), we stopped falecalcitriol and did not treat hypercalcemia with medications. From this case, we also recognized that we should identify the cause of post-transplant hypercalcemia earlier using parathyroid imaging studies. Due to the persistent post-transplant hypercalcemia and increased ALP, we performed a total PTX with autotransplantation. In contrast, a similar report showed that subtotal PTX was performed for THPT [7]. We found no evidence regarding which procedure is more efficacious [2].

The two most useful imaging modalities for the diagnosis of SHPT and THPT are neck ultrasound and MIBI scintigraphy [2]. In this case, parathyroid imaging studies were not performed until the second kidney transplantation. We should have investigated parathyroid glands earlier, which might have been enlarged quite a long time before. We also did not measure the iPTH levels before the PD induction. Considering the extremely high level of iPTH at PD induction, THPT might have been existing for a long time since the first kidney transplantation. Moreover, during the PD period, the iPTH levels could not be sufficiently suppressed, indicating severe SHPT. The Japanese Society for Dialysis Therapy clinical practice guidelines recommend an operation for severe SHPT in patients refractory to medical treatment with high iPTH levels (iPTH > 500 pg/mL). They are also recommended PTX before kidney transplantation [15]. In addition, considering a decrease in BMD and her risk of fractures, PTX should have been performed earlier after the clinical suspicion of severe SHPT. As a result of prolonged hypocalcemia in chronic kidney disease, hyperplasia of the parathyroid glands occurs. Parathyroid cells initially grow in a diffuse pattern, then in a monoclonal and proliferative pattern, forming nodules. Patients with nodular hyperplasia are known to be refractory to medical treatment against hyperparathyroidism [16, 17]. Parathyroid histopathology in this case revealed nodular hyperplasia, which might have induced resistance to medical treatment.

Serum ALP levels significantly increase for a period up to the sixth month after transplantation and decrease thereafter [18, 19]. However, its precise mechanism remains unclear. Because γ-glutamyl transpeptidase (γGTP) level also increased in addition to ALP in this case (data not shown), we further investigated possible causes for this increase. However, no obvious organic etiologies were found. The reason for ALP level increase just after kidney transplantation and its return to normal level before PTX was uncertain. Considering the re-elevation of ALP level before PTX and its reduction after PTX, THPT was also thought to be involved in this elevation.

In summary, this is a concrete and suggestive case in which PTX should have been performed earlier, before the kidney transplantation, after the clinical suspicion of severe SHPT. Although the timing of the surgery for THPT remains controversial, a referral for surgery should be considered based on individual risk factors.

Compliance with ethical standards

Conflict of interest

The authors have declared that no Conflict of interest exists.

Human and animal rights

This article contains no studies involving humans or animals.

Informed consent

Informed consent was obtained from the individual participant included in the study.