Medical and surgical management of Secondary hyperparathyroidism in hemodialysis patient :
A 50 year old Aboriginal lady from Central Australia with end stage renal disease secondary to presumed diabetic nephropathy commenced haemodialysis on August 2012 and was being worked up for renal transplant. She developed severe secondary hyperparathyroidism with poor response to calcitriol associated with hypercalcemia. Her parathyroid hormone (PTH) level was 132 pmol/L (reference range 1.6-7.2) in November 2015, Serum corrected calcium 2.51 mmol/L (2.10-2.60), Phosphate 1.54 mmol/L (0.75-1.50) and serum alkaline phosphatase was 487 U/L (30-110) while on Calcitriol 1 mcg three times a week. Calcium carbonate was substituted with sevelamer hydrochloride and subsequently calcitriol was ceased as she developed hypercalcemia. She was started on cinacalcet on February 2017 however after starting cinacalcet her PTH initially declined to 54 p.mol/L but incrementally rose to 345 pmol/L in spite of incrementally increasing the dose of cinaclacet. Serum protein electrophoresis and serum immunofixation was normal and other radiological surveys for malignancy were negative. Bone mineral density scan showed bone mineral density loss particularly in the femoral neck with T score of -1.6 whereas lumbar spine T score was -0.8. In December 2018 she developed severe right lower limb weakness .Plain x-rays and MRI showed a large lytic lesion of the right proximal femur involving the medullary space and medial cortex of the right sub trochanteric femur, 70 mm in width and also a mid –medial cortical lesion of her left femur secondary to severe hyperparathyroidism (figure 1,3). An ultrasound scan of the neck showed enlarged parathyroid glands along with the multinodular changes in the thyroid gland. She had fine needle aspiration cytology of the thyroid isthmus which was suspicious of a follicular neoplasm. She underwent simultaneous left hemithyroidectomy subtotal parathyroidectomy (PTX) and prophylactic intramedullary nailing of the femur (Figure 4) on 2/1/2019. Histology of the lesion of the right femur showed osteoclast like giant cells and new woven bone formation consistent with Brown tumour associated with Hyperparathyroidism (Figure 5, 6). Her PTH levels declined immediately after parathyroidectomy. However PTH levels started to rise again six weeks after parathyroidectomy. She was restarted on cinacalcet and referred back to surgeon for removal of the remaining parathyroid gland
Discussion:
Secondary Hyperparathyroidism (SHPT) is a common complication of CKD. This patient has high bone turnover disease in view of raised alkaline phosphatase and PTH, associated with significant skeletal changes of SHPT (secondary hyperparathyroidism) radiologically manifesting as Rugger jersey spine (Figure 2) and a Brown tumour (Figure 3). Histologically the bone biopsy of these patients would show osteitis fibrosa cystica.(figure 5)
Initial is medical management with calcium carbonate calcitriol and non calcium binders . Despite initial therapy, this patient developed hypercalcaemia because of which cinacalcet was started. The efficacy of calcimimetics such as Cinacalcet remain controversial and its use has been limited in Australia after its removal from subsidisation by the Pharmaceutical Benefits Scheme in 2015. A 1 year retrospective cohort Japanese study on 25 haemodialysis patients demonstrated an improvement in bone mineral density with cinacalcet compared to placebo, especially seen in those with elevated serum ALP (5). A pre-specified analysis of the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial reported reduction of fracture rates by 16-29% compared to placebo after adjusting for baseline differences (6). This however, was not supported in a Cochrane systematic review, which revealed a reduction in need for parathyroidectomy for dialysis patients on cinacelcet, albeit no significant effect on all-cause or cardiovascular mortality (10). In view of her rural location and delayed access to parathyroidectomy, cinacalcet was approved using the compassionate access scheme.
Parathyroidectomy (PTX) was indicated for our patient as she was not responding to maximal medical therapy and had severe biochemical and skeletal complications (1). Unfortunately the subtotal PTX initially resulted in significant decline in PTH levels she again developed severe secondary hyperparathyroidism six weeks after the subtotal parathyroidectomy, necessitating recommencement of cinacalcet and calcitriol. Subtotal PTX is preferred after kidney transplantation, for which the incidence of recurrent secondary hyperparathyroidism is low (2) and total parathyroidectomy with autotransplantation is preferred for patients with compelling reasons to avoid reoperative neck surgery such as
Finally the role of anti-resorptive agents in high/ normal bone turnover disease patients including our index patient. There have been limited studies for CKD-MBD in dialysis patients. To our knowledge, the available oral bisphosphonate options in Australia, risedronate and alendronate, have not been studied in dialysis patients. Denosumab is approved for use in all stages of kidney disease. A single dose of denosumab (DN) improved femoral neck and lumbar spine BMD over 6 months in dialysis patients, in a separate study, reduced bone specific ALP over 2 years (7). Hypocalcaemia remains a significant side effect and requires close monitoring and management with high calcium dialysate baths, calcium and vitamin D analogues. There were no studies to date demonstrating fracture risk reduction with anti-resorptive therapy in dialysis patients. Bone biopsy remains the most accurate tool CKD stage G3a to G5D, provided results again will prompt a change in treatment. However based on major osteoporosis trials, withholding treatment with antiresorptives in the absence of a bone biopsy is no longer supported by the 2017 KDIGO clinical guidelines. Currently, there is no consensus on the management of osteoporosis in severe CKD/dialysis, which is largely opinion based.
This case demonstrates