Successful Deceased Donor Parathyroid Allotransplantation: A Novel Approach in a Patient with Severe Refractory Hypoparathyroidism After Thyroidectomy for Thyroid Cancer

Abstract

Research Problem

Permanent hypoparathyroidism after surgical treatment of thyroid disease is a challenging iatrogenic injury, which can produce severe symptoms including paresthesia and many others, resulting in reduced quality of life and increased mortality.¹ Existing treatment consists of life-long high dose calcium and active vitamin D analogue therapy. Recombinant parathyroid hormone (PTH) has been used in refractory cases with limited success in decreasing pill burden or improving quality of life and has unknown long-term safety.²

While Halstead experimented with canine parathyroid transplantation, the first human parathyroid allotransplant was reported in 1911.³ In a recent systematic review on parathyroid allotransplantation, the authors surmise that graft survival would likely be optimized with consideration of avoidance of human leukocyte antigen (HLA) antibodies and individualized immunosupression.⁴

Methods

A 46-year-old mother of four self-identified a nodule in the thyroid isthmus in 2009 (9 years prior to referral to our center) and was investigated with ultrasound and fine needle aspiration biopsy, which showed benign thyroid tissue. A right thyroid lobectomy and isthmusectomy were performed at the outside center with pathology revealing two foci of papillary thyroid carcinoma, follicular variant (PTC-FV), measuring 0.8 and 0.3 cm, whereas the isthmus nodule was benign. A formal central neck dissection was not performed, however, four central lymph nodes were negative for malignancy and one normal parathyroid gland was present. She subsequently underwent completion left thyroid lobectomy. Additional information on operative decision making was not available. Pathology revealed an additional focus of 0.2 cm PTC-FV and three central lymph nodes were negative for malignancy (pT1aN0Mx). Two normal parathyroid glands were identified. Postoperatively, the patient required readmission with hypocalcemia for 1 week. She was discharged on high-dose calcium and calcitriol and subsequently readmitted for a month with severe refractory hypocalcemia requiring intravenous (IV) calcium. She had no known inflammatory bowel disease or gut absorption issues. She was given teriparatide subcutaneously twice daily in addition to her existing supplementation. She had frequent visits to the emergency department with hypocalcemia requiring hospitalization and suffered complications including a PICC line infection leading to sepsis, porta-catheter complications, pulmonary emboli, and seizures. The patient started off-label administration of continuous teriparatide via continuous ambulatory delivery device on which she remained for over 2 years. This was discontinued owing to long-term safety concerns. At presentation to our center, she was taking elemental calcium (16 g daily), magnesium (12 g daily), calcitriol (8 μg daily), and hydrochlorothiazide (50 mg daily), and required biweekly intravenous calcium for symptoms and calcium levels of 1.6 mmol/L and PTH 1.1 mmol/L (Table 1). Her quality of life was poor, with new mental health issues, limited ability to travel, and lack of employment.

Table 1.

Pre-Parathyroid Transplant Laboratory Values

Date	CaN 2.2−2.6	Ion CaN 1.15–1.35	PTHN 1.4–7.6	PO4N 0.8–1.45	MgN 0.70–1.05	AlbN 35–50	25OHDN 76–250	TSHN 0.35–5	TGN 0–40	TG AB	CrN 5–50
10/2017	1.19	1.02			0.71	47
08/2018	1.83	0.93	1.1		0.66	39			0.30
09/2018	2.13^a				0.88	41	118	0.65	0.56		85
09/2021	1.84	0.88	1.2		0.59
10/2021	1.79	1.05			0.66	39	50		0.30	<10	114
11/2021	2.09^a	1.05		1.56	0.61	39	59				124
03/2022	1.98					41	89	0.60

Blood drawn immediately post IV calcium and magnesium infusion.

Ca, calcium (mmol/L); Ion Ca, ionized calcium (mmol/L); PTH, parathyroid hormone (pmol/L); P04, phosphate (mmol/L); Mg, magnesium (mmol/L); Alb, albumin (g/L); 25OHD, 25 hydroxy vitamin D (nmol/L); TSH, thyrotropin (mIU/L); TG, thyroglobulin (pmol/L); TGAb, thyroglobulin antibody (pmol/L); Cr, creatinine (μmol/L).

A protocol for deceased donor parathyroid transplantation was developed with the University Health Network Ajmera Transplant Centre in Toronto, relevant stakeholders, and presented to the innovation committee for approval. Health Canada approval was obtained under the scope of existing cell tissue and organ regulations within the provincial organ procurement agency owing to minimal processing of the tissues. We received a waiver from the University Health Network Research Ethics Board, with review of the patient consent form.

Donor criteria excluded patients with thyroid cancer, prior thyroid or parathyroid surgery, hypercalcemia, and chronic kidney disease. To minimize infectious risk, we did not consider exceptional distribution/increased risk donors. To minimize immunological risk, we determined prior to patient listing that we would strictly avoid any current class I HLA donor-specific antibodies (DSAs) to reduce the risk of hyperacute/accelerated rejection, and we would prefer avoidance of class II current DSAs, but would consider crossing if required to increase access to suitable donors. Crossing class I and class II historical DSAs (in light of risk of memory responses) would also be considered on a case-by-case basis.

The recipient had multiple pregnancies as sensitizing events and her initial calculated panel-reactive antibody (cPRA) was 95% (Supplementary Table S1). From an allocation perspective, we would anticipate only 1/20 otherwise eligible donors to have a negative virtual crossmatch (no DSA to either class I or II HLA antigens) with the recipient.

The first attempt at parathyroid transplant was performed and showed no evidence of function at 3 months post-transplant. This underwent multidisciplinary review and the patient was relisted for transplant. In the intervening period, a new HLA antibody to DQ2 was identified, corresponding to the initial donor DQ2 antigen. The updated cPRA considering this new antibody was now 98%, reducing the likelihood of finding an acceptably mismatched donor for both class I and class II HLA antigens to 1/50 otherwise suitable donors. Given this restriction, we decided to consider a donor with class II DSAs to optimize access.

In May 2023, a second medically suitable, neurologically deceased donor was identified and accepted. The recipient did have DQ2 donor-specific antibody to this donor (Supplementary Table S2).

Four healthy parathyroids were retrieved by endocrine surgeons and transported to our institution in Wisconsin solution. The tissue was minced and placed into pockets in the recipient’s right brachioradialis muscle, under local anesthesia with sedation. No immediate complications occurred. Total tissue ischemic time was 2.5 hours. The patient was induced with basiliximab and discharged from hospital 1 day later. She continues to receive tacrolimus, mycophenolate, and low-dose prednisone as maintenance immunotherapy consistent with kidney transplant protocols at our institution for patients with known DSAs and potential for HLA memory responses. As the patient was CMV IgG positive and basiliximab induction was used, no CMV prophylaxis was indicated as per our center’s protocol. Anti-infective prophylaxis consists of TMP-SMX thrice weekly.

Results

Evidence of biochemical parathyroid function was present post-transplant day 9 with a PTH of 1.7 mmol/L. At postoperative day 14, when the patient would normally have required IV calcium infusion, she continued to be asymptomatic. She weaned off all calcium homeostatic medications by day 35. At the time of writing, over 22 months post-transplant, she remains asymptomatic and has not required any oral or IV calcium therapy. Serum PTH is 0.8–2.1 pmol/L and calcium is 2.00–2.37 mmol/L (Table 2).

Table 2.

Post-Parathyroid Transplant

Date	CaN 2.2−2.6	Ion CaN 1.15–1.35	PTHN 1.4–7.6	PO4N 0.8–1.45	MgN 0.70-1.05	AlbN 35–50	25OHDN 76–250	TSHN 0.35–5	TGN 0–40	TG AB	CrN 5–50
06/2022	2.26	1.17	2.1	1.53	0.59	44	113
10/2022	2.07	1.13	0.8				120	0.03			92
01/2023	2.23	1.15	0.6	1.76	0.60	45	110	0.08	0.30	<10	98
04/2023	2.00	1.01	0.8	1.76	0.58	46	114	0.01			107
06/2023	1.98	1.02	0.9	1.30	0.63	44	113	0.19			96
09/2023	2.22	1.09	1.0			48		2.49
02/2024	1.97	1.05	1.1	1.4			126

No post-transplant DSAs have been identified. In addition to the above immunotherapy, she takes hydrochlorothiazide 12.5 mg daily, calcitriol 0.5 μg three times per week, and levothyroxine 125 μg daily. The patient’s quality of life significantly improved, enabling full reintegration into the workforce and participation in daily activities such as travel and long-distance running. Her HLA antibody profile remains mostly unchanged post second transplant with a cPRA of 98% and notably, persistence of the DQ2 donor-specific antibody at higher levels than pre-transplant. There is no biochemical (Table 2) or neck ultrasound evidence of thyroid cancer recurrence. Ongoing graft function is monitored with calcium and PTH levels as well as patient-reported symptoms requiring calcium supplementation.

Discussion

While we were not privy to the original rationale and informed consent discussion, this case demonstrated that overtreatment of thyroid nodules and microcarcinomas can have severe consequences and, thus, requires judicious decision making and careful surgery.

Parathyroid transplantation has included differences in tissue harvesting and processing for example, cryopreservation and attempts to encapsulate parathyroids. Donor parathyroid tissue (normal and hyperplastic) has been retrieved from both living and deceased donors and implanted into various anatomical locations. Using deceased donor tissue has the advantage of obtaining fresh tissue without harms to living donors. Furthermore, there have been different approaches to immunosuppression. A recent systematic review concluded that graft survival would be optimal using fresh parathyroid tissue and immunosupression.⁴ Agha et al. reported a successful living-donor fresh tissue transplant for postsurgical hypoparathyroidism in a nontransplant recipient.⁵ Only one prior report described the use of fresh tissue from a deceased donor without immunosuppression.⁶

To our knowledge, we are reporting the first successful case of a deceased donor fresh tissue parathyroid allotransplant with immunosuppression in a transplant-naïve recipient. For many years, our patient suffered from low calcium levels and chronic severe symptoms of hypocalcemia despite high dosage of oral supplements. While her first attempt at transplant failed, after the second transplant, she was able to come off all supplements. Her calcium levels remain in the low-normal range, but intravenous infusion of calcium has not been required. While her PTH is not significantly higher than pre-transplant, this stable finding is her new range to physiological normocalcemia. Increase in vitamin D3 level and reduction in TSH levels was seen post-transplant, illustrating improvement in absorption in the gastrointestinal tract. We believe that her low-dose calcitriol does not impact engraftment. There has been complete resolution of all symptoms of hypocalcemia, including notable improvement in muscle endurance and mental health.

Despite minimal surgical risks, there are potential long-term risks of immunosuppression that must be considered and discussed with patients. A 2018 patient survey, of whom 93% reported an emergency admission to hospital within the last 6 month for hypocalcemia, found that despite immunosuppression risks, 31% of patients would consider parathyroid allotransplantation.⁷ All risks were thoroughly discussed in shared decision making prior to listing and again at the time of each transplant. The recipient felt very strongly that the benefit to her quality of life outweighed the risks associated with closely monitored immunosuppression.

Conclusion

While our patient had her original surgery prior to the 2015 American Thyroid Association Guidelines⁸ for the management of thyroid nodules and differentiated thyroid cancer, this case demonstrates the potential perils of overtreatment. We also discover the transformative potential of deceased donor fresh tissue parathyroid allotransplant in restoring physiological function, alleviating symptoms, and improving quality of life for a patient with this debilitating complication. Future research should focus on refining transplant protocols, optimizing immunosuppressive regimens, and expanding donor pool accessibility. We are currently recruiting additional patients, with severe intractable postsurgical hypoparathyroidism, to demonstrate that this is a safe and viable approach, for the first time offering the chance of physiological cure in this population.

Footnotes

Acknowledgments

The authors would like to acknowledge significant contributions from the UHN Ajmera Transplant Centre, the UHN Histocompatibility and Immunogenetics Laboratory, the UHN Sprott Department of Surgery, and the Trillium Gift of Life Network.

Author’s Contributions

K.D.: Conceptualization, methodology, investigation, resources, writing—original draft, writing—review and editing. A.H.: Conceptualization, methodology, resources, writing—review and editing. A.M.: Methodology, investigation, writing—review and editing. J.D.P.: Conceptualization, methodology, investigation, writing—review and editing. B.S.-B.: Methodology, investigation, writing—original draft, writing—review and editing. K.T.: Conceptualization, methodology, investigation, writing—original draft, writing—review and editing. A.Z.: Conceptualization, methodology, investigation, writing—original draft, writing—review and editing.

Author Disclosure Statement

All authors declare no conflict of interest.

Funding Information

No funding was received for this study.

Supplementary Material

Supplementary Table S1

Supplementary Table S2

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