A roadmap to parathyroidectomy for kidney transplant candidates

Abstract

Chronic kidney disease mineral and bone disorder may persist after successful kidney transplantation. Persistent hyperparathyroidism has been identified in up to 80% of patients throughout the first year after kidney transplantation. International guidelines lack strict recommendations about the management of persistent hyperparathyroidism. However, it is associated with adverse graft and patient outcomes, including higher fracture risk and an increased risk of all-cause mortality and allograft loss. Secondary hyperparathyroidism may be treated medically (vitamin D, phosphate binders and calcimimetics) or surgically (parathyroidectomy). Guideline recommendations suggest medical therapy first but do not clarify optimal parathyroid hormone targets or indications and timing of parathyroidectomy. There are no clear guidelines or long-term studies about the impact of hyperparathyroidism therapy. Parathyroidectomy is more effective than medical treatment, although it is associated with increased short-term risks. Ideally parathyroidectomy should be performed before kidney transplantation to prevent persistent hyperparathyroidism and improve graft outcomes. We now propose a roadmap for the management of secondary hyperparathyroidism in patients eligible for kidney transplantation that includes the indications and timing (pre- or post-kidney transplantation) of parathyroidectomy, the evaluation of parathyroid gland size and the integration of parathyroid gland size in the decision-making process by a multidisciplinary team of nephrologists, radiologists and surgeons.

Keywords: kidney transplant; parathyroidectomy; secondary hyperparathyroidism.

Graphical Abstract

FIGURE 1:

Post-KT CKD-MBD. In KTRs, the progression of bone disease results from the evolution of pre-existing CKD-MBD with several risk factors already present in the pretransplantation period. The successive evolution of post-KT bone disease is conditioned by several posttransplant factors, including the use of immunosuppressive drugs, the degree of graft dysfunction and disturbances in mineral metabolism, including an increased level of FGF23, ongoing SHPT and vitamin D deficiency. The two factors that mainly impact bone health in the posttransplant phase are steroid therapy and persistent hyperparahtyroidism (PHPT). While PHPT involves mainly cortical bone, in the early posttransplant period, bone loss affects the trabecular side following decreased bone formation as a result of steroid therapy.

FIGURE 2:

FGF23 and PTH interaction. FGF23 and PTH mutually regulate each other in a negative feedback loop, where PTH stimulates FGF23 production and FGF23 suppresses PTH synthesis. PTH increases FGF23 expression by the nuclear orphan receptor Nurr1. In the parathyroid glands, FGF23 either binds to an FGFR1 and membrane-bound Klotho, to elicit activation of the MAPK pathway, or acts via a calcineurin-dependent signaling pathway. CNI that blocks calcineurin signaling may worsen PHPT in patients with reduced Klotho levels such as in CKD. In the kidney, PTH and FGF23 share the same effect on phosphorus and calcium handling. PTH raises urinary phosphorus excretion, downregulating NPT2a and NPT2c in the kidney. PTH also enhances calcium absorption through the direct effect on bones and kidneys, indirectly upregulating 1,25(OH)₂D synthesis by increasing 1α-hydroxylase. FGF-23 inhibits renal phosphorus reabsorption through FGFR1–Klotho signaling on NaPi-2a and 2c at the proximal tubule. FGF-23 suppresses in both a Klotho-dependent pathway (FGFR1) and through FGFR3 and FGFR4 in a Klotho-independent manner 1,25(OH)₂D production by decreasing 1α-hydroxylase expression and increases in a Klotho-dependent pathway the expression at distal tubulus of glycosylated TRPV5, leading to increased calcium reabsorption (see text for details). NaPi-2, type II sodium–phosphate cotransporters; TRPV5, transient receptor potential vannilloid-5.

FIGURE 3:

PTH resistance. The target organs’ responses to the action of PTH are progressively impaired in CKD, a condition commonly referred to as PTH resistance. Multiple factors are involved, including phosphate loading, calcitriol deficiency, oxidative stress, PTH1R downregulation and dysfunction, accumulation of PTH fragments, antagonists of the Wnt/β-catenin pathway and uremic toxins and accumulation of PTH fragments and uremic toxins.

FIGURE 4:

Pathophysiology of secondary hyperparathyroidism in CKD. Initially in SHPT, the parathyroid glands grow diffusely with polyclonal parathyroid cell proliferation (diffuse hyperplasia). At this stage, VDRAs activators and calcimimetics are effective in lowering PTH concentrations. Afterward, cells in the nodules are transformed monoclonally and proliferate. In parallel are four patterns of parathyroid hyperplasia: diffuse hyperplasia, early nodularity in diffuse hyperplasia, nodular hyperplasia and single nodular glands. In the advanced stages of SHPT, downregulation of calcium sensing receptor (CaSR), VDR and Klotho-FGFR 1 makes parathyroid cells resistant to the inhibitory effect of calcimimetics, calcitriol and FGF-23.

FIGURE 5:

Four-dimensional parathyroid CT scan of a patient with SHPT before parathyroidectomy. The image in the coronal planes shows three hyperplastic parathyroid glands (black arrows).

FIGURE 6:

(A) Ultrasound of the neck showing inferior parathyroid adenomas (roughly 1.16 × 0.69 cm) located behind the thyroid. The parathyroid adenoma appears as a well-circumscribed, oval mass, hypoechoic in comparison to the adjacent thyroid gland. Longitudinal (left) and transvers (right) scans. (B) An inferior parathyroid adenoma located behind the thyroid with color Doppler imaging (longitudinal scan). (C) Longitudinal scan demonstrating an inferior parathyroid adenoma located near the inferior pole of the thyroid lobe (left). The CEUS examination is characterized by a strong early contrast enhancement in the arterial phase beginning 15 s after the bolus injection (right). (D) CEUS time–intensity curves: the wash-in (arterial phase in the figure, 0–30 s after application of contrast agent) and wash out (venous phase, 30–120 s) of the adenomas (a), represented in the graph by the red line, compared with the thyroid gland (b), represented by the yellow line.

FIGURE 7:

Roadmap to parathyroidectomy for kidney failure patients with SHPT candidates to KT. The first step to reduce the risk of persistent HPT in KT candidates is the correction of modifiable factors: hypocalcemia, hyperphosphatemia, hyperparathyroidism (PTH target values 2–9 times the upper limit of normal in dialysis patients). If PTH levels are >800 pg/mL with or without hypercalcemia and/or hyperphosphatemia and symptoms or complications coexist related to SPHT, referral for parathyroidectomy should be considered. Imaging is necessary for preoperative parathyroidectomy planning, aimed to localize and define the size of parathyroid glands. Enlarged parathyroid glands (volume >500 mm³ and/or diameter >10 mm) represent a further parameter, in addition to high PTH levels, in the decision-making regarding parathyroidectomy. In our centers, a multidisciplinary team (nephrologists, otolaryngologists, radiologists) decides on the indication of parathyroidectomy based on preoperative findings. In all cases, CEUS is performed a few days before surgery by an expert and dedicated sonographer in the presence of the nephrologist and surgeon to verify helpful landmarks (skin, vascular axis, trachea, esophagus, upper and lower thyroid poles) for surgery. EPO, erythropoietin; 4D-CT, 4-dimensional computed tomography.