INTRODUCTION — Kidney transplant recipients are vulnerable to persistent hyperparathyroidism and other disorders of mineral and bone metabolism associated with chronic kidney disease (CKD).
This topic reviews recommendations regarding monitoring and treatment of hyperparathyroidism, hypercalcemia, and hypophosphatemia among kidney transplant candidates and recipients.
Other bone disorders that affect kidney transplant recipients, including osteoporosis and osteonecrosis, are discussed elsewhere. (See "Kidney transplantation in adults: Bone disease after kidney transplantation".)
The pathogenesis of metabolic bone disease and the treatment of hyperparathyroidism in nontransplant CKD patients are discussed elsewhere:
PATHOPHYSIOLOGY — Most patients with chronic kidney disease (CKD) develop some degree of secondary hyperparathyroidism by the time they initiate kidney replacement therapy (KRT). Secondary hyperparathyroidism occurs in response to multiple abnormalities that initially stem from decreased glomerular filtration rate (GFR) . The pathophysiology of secondary hyperparathyroidism in CKD patients is discussed at length elsewhere. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Overview'.)
In patients with mild disease, secondary hyperparathyroidism resolves after kidney transplantation as a more normal GFR is restored [2-7]. However, persistent hyperparathyroidism is reported to occur in approximately 15 to 50 percent of patients following transplantation [4,8-14]. This is because of the persistence of structural changes in the parathyroid glands, such as hyperplasia and adenoma formation, despite removal of the initial stimuli for hyperparathyroidism [4,15-18].
The clinical manifestations of persistent hyperparathyroidism in the transplant recipient differ from those associated with hyperparathyroidism in nontransplant CKD patients. In the transplant recipient, the clinical manifestations resemble primary hyperparathyroidism and are characterized by hypercalcemia and hypophosphatemia  (see 'Clinical manifestations' below). By contrast, nontransplant CKD patients with hyperparathyroidism typically have hyperphosphatemia and hypocalcemia. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Disorders of calcium balance'.)
Factors additional to hyperparathyroidism contribute to hypercalcemia and hypophosphatemia in transplant recipients . Increased calcitriol production and resorption of soft-tissue calcium phosphate deposition can cause hypercalcemia [4,10,19]. Some patients have an increase in total plasma calcium because of an increase in the plasma albumin concentration (which is often due to better nutrition after transplantation). However, the increase in total calcium due to an increase in albumin is generally mild and of no clinical significance. Increased serum albumin raises the total plasma calcium concentration by increasing the albumin-bound fraction but has no effect on the physiologically important free or ionized calcium concentration. High-dose glucocorticoids may mask hypercalcemia due to effects to limit gastrointestinal calcium absorption, with hypercalcemia variably manifested during tapering of the glucocorticoid dose. (See "Relation between total and ionized serum calcium concentrations".)
Hypophosphatemia after transplantation is caused by both persistent hyperparathyroidism and excess FGF-23 production [11,20-23]. FGF-23 is secreted by bone osteocytes and osteoblasts in response to calcitriol, increased dietary phosphate load, and parathyroid hormone (PTH) [24-27]. Patients with CKD have increased FGF-23 concentrations due to decreased phosphate clearance [28-30]. Markedly elevated FGF-23 levels before kidney transplantation may persist after transplant , but more commonly FGF-23 concentrations decline rapidly following transplantation .
The relative contribution of excess PTH and FGF-23 to phosphate wasting after transplantation depends on the timing of onset after transplantation. Both hyperparathyroidism and hyperphosphatonism (ie, increased FGF-23 secretion) may contribute to phosphate wasting during the early posttransplant period [20-23]. Persistent hyperparathyroidism, but not increased FGF-23, likely causes phosphate wasting that persists beyond one year .
Mammalian (mechanistic) target of rapamycin (mTOR) inhibitors may contribute to hypophosphatemia , though not all studies have shown this . Higher doses of glucocorticoids have been associated with higher levels of FGF-23 .
CLINICAL MANIFESTATIONS — The primary manifestations of persistent hyperparathyroidism after transplantation include hypercalcemia and hypophosphatemia [7-9,14]. However, some patients may have only an elevated parathyroid hormone (PTH) concentration, without other laboratory abnormalities.
Symptoms that are commonly observed in nontransplant chronic kidney disease (CKD) patients with severe hyperparathyroidism, including bone pain, pruritus, nephrolithiasis, and myopathy, are not generally observed among transplant recipients, since hyperparathyroidism is much less severe among transplant recipients. However, these symptoms may be manifested and associated with adverse outcomes if the hyperparathyroidism is severe and persistent.
Hypercalcemia — Hypercalcemia is common following kidney transplantation [6,14,34,35]. In one study of 1165 transplant recipients, the prevalence of hypercalcemia from any cause (defined as total serum calcium >10.5 mg/dL [2.6 mmol/L]) was 31 percent during the first year after transplantation and 12 percent at five years posttransplantation .
Symptomatic hypercalcemia most commonly occurs in the early posttransplant period, usually within the first three months [34-36].
Hypercalcemia causes direct vasoconstriction of the allograft and natriuresis-induced volume contraction. Severe hypercalcemia (plasma calcium concentration >12.5 mg/dL [3.1 mmol/L]) can cause acute kidney injury and, rarely, calciphylaxis, in which vascular calcification leads to local ischemic necrosis [4,37,38]. (See "Calciphylaxis (calcific uremic arteriolopathy)".)
Hypophosphatemia — Hypophosphatemia has been reported in 40 to 90 percent of patients in the early period following transplantation [6,14,39]. Hypophosphatemia usually decreases over time after transplantation, although it may persist in some patients [6,14,39]. In one study of 1165 recipients, the prevalence of hypophosphatemia (defined as serum phosphate concentration <2.3 mg/dL [0.74 mmol/L]) was 40 percent in the first year and 11 percent during years 4 and 5 .
Severe hypophosphatemia (plasma phosphate levels <1 to 1.5 mg/dL [0.32 to 0.48 mmol/L]) can cause muscle weakness, and longstanding hypophosphatemia can lead to osteomalacia (although the latter has not been a consistent finding). (See "Hypophosphatemia: Clinical manifestations of phosphate depletion".)
Mortality — Persistent hyperparathyroidism has been associated with increased mortality [40-42]. In a multivariate analysis of 1614 transplant recipients identified from the Assessment of Lescol in Renal Transplantation (ALERT) trial, parathyroid hormone (PTH) values >65 pg/mL were associated with an increase in all-cause mortality (hazard ratio [HR] 1.46, 95% CI 1.12-1.92) .
The mechanism underlying increased PTH-associated mortality is not known. High PTH levels and hypercalcemia promote vascular calcifications, which are associated with an increased posttransplant morbidity and mortality in kidney transplant patients .
Allograft loss — Increased PTH is associated with increased graft loss [40,42]. In an analysis of data from the ALERT trial, PTH >65 pg/mL (6.9 pmol/L) was associated with an 85 percent increase in death-censored graft loss (HR 1.85, 95% CI 1.41-2.42) .
The mechanism by which hyperparathyroidism contributes to graft loss is not known.
Bone disease and fractures — Uncontrolled hyperparathyroidism and hypercalcemia are risk factors for posttransplant bone disease, and hyperparathyroidism is associated with an increased risk of fractures . In a study of 143 kidney transplant recipients, a PTH level >130 pg/mL (13.8 pmol/L) at three months after transplantation was associated with a 7.5-fold increased risk of fracture over five years (HR 7.5, 95% CI 2.18-25.50) . (See "Kidney transplantation in adults: Bone disease after kidney transplantation".)
PREVENTION — The optimal treatment of hyperparathyroidism prior to transplantation may prevent persistent hyperparathyroidism after transplantation. The management of secondary hyperparathyroidism in patients with advanced chronic kidney disease (CKD), including those with end-stage kidney disease (ESKD) on dialysis, is discussed in more detail elsewhere:
The approach to transplant candidates who have refractory hyperparathyroidism prior to transplantation varies among transplant centers. Almost all experts suggest parathyroidectomy for transplant candidates who have refractory hyperparathyroidism and moderate to severe symptoms (eg, bone pain, fractures, muscle pain, weakness), particularly if transplantation is not imminent. This approach is the same as the approach for nontransplant ESKD patients. (See "Refractory hyperparathyroidism and indications for parathyroidectomy in adult dialysis patients".)
Transplant nephrologists have differing recommendations for transplant candidates who have only mild or no symptoms. Prior to transplantation, independent of the absence or presence of symptoms, we generally refer for subtotal parathyroidectomy all transplant candidates who have an intact parathyroid hormone (PTH) ≥800 pg/mL (84.8 pmol/L) despite medical therapy. PTH concentrations >800 pg/mL (84.8 pmol/L) have been associated with a >80 percent risk of graft failure . Intact PTH values above this threshold are unlikely to respond to vitamin D or active vitamin D derivatives [45-48]. In addition, as noted above, severe hyperparathyroidism is associated with delayed graft function, hypercalcemia/hypercalciuria, nephrolithiasis, hypophosphatemia, and decreased patient and allograft survival after transplantation. (See 'Clinical manifestations' above and 'Outcomes' above.)
However, some transplant nephrologists do not perform parathyroidectomy prior to transplantation in asymptomatic patients, since, as noted above, hyperparathyroidism resolves in many, though not all, patients after transplantation [6,49,50]. (See 'Pathophysiology' above.)
Parathyroidectomy may be safer if performed prior to transplantation. Parathyroidectomy performed after transplantation has been associated with abrupt deterioration of kidney allograft function [51,52]. However, some data have shown that glomerular filtration rate (GFR) recovers in the long term , and allograft survival has not been shown to be lower in patients who have undergone parathyroidectomy after kidney transplant . (See 'Treatment' below.)
For potential recipients of deceased-donor kidneys, but not living-donor kidneys, the decision regarding parathyroidectomy may depend on the anticipated time on the waiting list, which will vary based upon the geographic region. The indications for parathyroidectomy for patients who are expected to have a prolonged wait on the deceased-donor waiting list are the same as for patients who are not awaiting transplantation. (See "Refractory hyperparathyroidism and indications for parathyroidectomy in adult dialysis patients", section on 'Potential indications for parathyroidectomy'.)
Cinacalcet and etelcalcetide are commonly used among nontransplant-candidate ESKD patients who have refractory hyperparathyroidism. However, we generally do not use cinacalcet, the only calcimimetic available in oral formulation, in transplant candidates, unless parathyroidectomy is contraindicated. The use of cinacalcet prior to kidney transplantation has been associated with rebound hypercalcemia and hypophosphatemia when cinacalcet is discontinued at the time of transplantation [55-57].
Patients who are being treated with cinacalcet or etelcalcetide should have the calcimimetic stopped prior to transplantation, at least temporarily, in order to assess the severity of hyperparathyroidism off treatment. This approach may identify patients who might benefit from pretransplant parathyroidectomy and minimize the number of cinacalcet-treated patients who have rebound hypercalcemia posttransplantation. (See 'Patients with hypercalcemia' below.)
MONITORING AFTER TRANSPLANT — Among all kidney transplant recipients, we routinely monitor serum calcium, phosphorus, and parathyroid hormone (PTH) levels. Initially, serum calcium and phosphorus should be measured at each visit during the first year and PTH measured quarterly or more frequently in the presence of hypercalcemia or hypophosphatemia. Patients with a PTH concentration that is two to three times the upper limit of normal are considered to have persistent hyperparathyroidism. 25-hydroxyvitamin D should be measured posttransplant, with repeated testing determined by baseline values and therapeutic interventions.
TREATMENT — Our approach to the management of persistent hyperparathyroidism (ie, parathyroid hormone [PTH] concentration that is two to three times the upper limit of normal) after transplantation depends upon the patient’s clinical presentation. As noted above, patients may present with hypercalcemia or hypophosphatemia. Some patients have an increased PTH concentration without either hypercalcemia or hypophosphatemia.
Patients with hypercalcemia — The approach to transplant recipients with hypercalcemia due to persistent hyperparathyroidism varies among centers. The severity of the hypercalcemia and PTH elevations determines the approach:
●Mild to moderate hypercalcemia – In patients with hyperparathyroidism and mild to moderate hypercalcemia (ie, serum calcium levels >0.5 to 1 mg/dL [0.12 to 0.25 mmol/L] than the upper limit of normal) posttransplant, we typically treat with cinacalcet (30 mg daily) initially to prevent complications of increased calcium and PTH excess. We monitor serum calcium levels every two weeks and make dose adjustments at monthly intervals as needed. If the patient does not respond to cinacalcet by 6 to 12 months, we typically refer the patient for subtotal parathyroidectomy.
Data from several observational studies and two small, randomized trials have shown that cinacalcet reduces PTH levels and lowers serum calcium levels without any short-term adverse effects on allograft function [58-66]. However, one retrospective, single-center analysis of 133 patients with hyperparathyroidism after kidney transplantation found that parathyroidectomy was associated with a lower rate of allograft failure compared with cinacalcet (9 versus 33 percent, respectively) .
Cinacalcet may reduce blood tacrolimus concentrations. In a study of 14 kidney transplant patients that evaluated the interaction between cinacalcet and immunosuppressive therapy, one week of cinacalcet therapy induced a moderate but significant decrease in systemic exposure of tacrolimus, while cyclosporine and mycophenolate pharmacokinetics were unaffected .
●Severe hypercalcemia – Parathyroidectomy is the preferred treatment for patients with persistent hyperparathyroidism and severe hypercalcemia (ie, serum calcium values >12 mg/dL [3.0 mmol/L] or symptomatic hypercalcemia regardless of the level). In a multicenter, open-label, randomized trial of 30 patients with a serum calcium concentration >10.5 mg/dL (2.6 mmol/L), subtotal parathyroidectomy was more likely to result in normocalcemia at 12 months compared with medical management with cinacalcet (100 versus 67 percent) .
In the setting of hyperparathyroidism, the calcium concentration that provides an indication for treatment is variable. Initially (ie, within six months of transplantation), most clinicians rely on the presence of symptoms rather than the absolute calcium concentration to determine the approach. As noted, the predominant symptom/sign is polyuria with prerenal acute kidney injury, although, less commonly, calciphylaxis may occur. Even in the absence of symptoms, many clinicians refer for parathyroidectomy all patients with marked hypercalcemia (serum calcium values >11 mg/dL [2.7 mmol/L]) that is present for >6 months from time of transplantation. (See "Calciphylaxis (calcific uremic arteriolopathy)", section on 'Hyperparathyroidism and vitamin D'.)
Hypercalcemia that occurs in the absence of hyperparathyroidism may be treated the same as in nontransplant recipients. In particular, patients should ensure adequate fluid intake and avoid drugs that can cause hypercalcemia. (See "Treatment of hypercalcemia", section on 'Preferred approach'.)
Patients with hypophosphatemia — The treatment of hypophosphatemia depends on the severity of hypophosphatemia, the PTH concentration, and the presence or absence of hypercalcemia .
Our approach is as follows:
●Mild to moderate hypophosphatemia (1.0 to 2.3 mg/dL [0.32 to 0.74 mmol/L]) – The treatment of mild or moderate hypophosphatemia depends on the PTH level. Among patients who have an increased PTH concentration (ie, approximately two to three times the upper limit of normal), we first treat the hyperparathyroidism. (See 'Patients with increased PTH without hypercalcemia' below.)
If hypophosphatemia persists following successful treatment of high PTH, we increase the intake of phosphate-rich foods (table 1A-B).
●Severe hypophosphatemia (<1 mg/dL [<0.32 mmol/L]) – Most clinicians give oral phosphate supplements regardless of the PTH or calcium concentration (see "Hypophosphatemia: Evaluation and treatment", section on 'Treatment'). Vitamin D derivatives can also be used to raise phosphorus in this setting if patients are not hypercalcemic.
Patients with severe hypophosphatemia and hyperparathyroidism are also referred for parathyroidectomy. (See 'Patients with increased PTH without hypercalcemia' below.)
Patients with increased PTH without hypercalcemia — The treatment of patients with persistent hyperparathyroidism (ie, two to three times the upper limit of normal) without hypercalcemia depends upon the 25-hydroxyvitamin D concentration:
●If the 25-hydroxyvitamin D concentration is normal or if parathyroid hormone (PTH) is persistently elevated despite normalization of 25-hydroxyvitamin D levels with vitamin D3 therapy, which may occur if there is a significant degree of CKD, we treat with an activated vitamin D derivative, such as calcitriol. We start with a low dose (0.25 micrograms daily) and titrate up to a maximum of 0.5 micrograms per day. Serum calcium should be checked frequently (ie, every month) while titrating up the active vitamin D3 derivative dose. This approach is effective in most patients. Patients who develop hypercalcemia are treated as described above. (See 'Hypercalcemia' above.)
Treatment options for persistent hyperparathyroidism without hypercalcemia should lead to consideration of confounding factors, such as concurrent nutritional vitamin D deficiency, high-dose glucocorticoid treatment, low calcium intake, primary renal calcium wasting (loop diuretics), active bone uptake due to healing of renal osteodystrophy, or treatment with cinacalcet that may lower calcium but not suppress PTH. A subtotal parathyroidectomy or addition of cinacalcet is not indicated to treat elevated PTH in the absence of hypercalcemia.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)
SUMMARY AND RECOMMENDATIONS
●General principles – Persistent hyperparathyroidism may occur in up to 50 percent of kidney transplant recipients. It has been associated with fractures, increased mortality, and decreased allograft survival. (See 'Introduction' above and 'Pathophysiology' above and 'Outcomes' above.)
●Clinical manifestations – The primary manifestations of persistent hyperparathyroidism include hypercalcemia and hypophosphatemia. Symptoms observed in nontransplant chronic kidney disease (CKD) patients such as bone pain, pruritus, and myopathy are rare. (See 'Clinical manifestations' above.)
●Prevention – The optimal treatment of hyperparathyroidism prior to transplantation is generally the safest approach to prevention of persistent hyperparathyroidism after transplantation. (See 'Prevention' above.)
●Monitoring – In all transplant recipients, we monitor serum calcium and phosphorus at each visit during the first year. We measure parathyroid hormone (PTH) quarterly or more frequently in the presence of hypercalcemia or hypophosphatemia. Patients with a PTH concentration that is two to three times the upper limit of normal are considered to have persistent hyperparathyroidism. 25-hydroxyvitamin D should be measured posttransplant, with repeated testing determined by baseline values and therapeutic interventions. (See 'Monitoring after transplant' above.)
•Patients with hypercalcemia – The approach to transplant recipients with hypercalcemia due to persistent hyperparathyroidism varies among centers. Our approach is determined by the severity of the hypercalcemia and PTH elevations:
-In patients with mild to moderate hypercalcemia (ie, serum calcium levels >0.5 to 1 mg/dL [0.12 to 0.25 mmol/L] above the upper limit of normal) and hyperparathyroidism, we suggest initial treatment with cinacalcet. If the patient does not respond to cinacalcet by 6 to 12 months, we typically refer the patient for subtotal parathyroidectomy.
-In patients with severe hypercalcemia (ie, serum calcium values >12 mg/dL [3.0 mmol/L] or symptomatic hypercalcemia regardless of the level) caused by elevated PTH, we suggest referral for subtotal parathyroidectomy. (See 'Patients with hypercalcemia' above.)
•Patients with hypophosphatemia – The treatment of hypophosphatemia due to persistent hyperparathyroidism depends upon the severity of hypophosphatemia, the PTH concentration, and the presence or absence of hypercalcemia. Our approach is as follows:
-In patients with mild to moderate hypophosphatemia (1.0 to 2.3 mg/dL [0.32 to 0.74 mmol/L]), treatment depends upon the PTH level. Among patients who have an increased PTH concentration, we first treat the hyperparathyroidism. If hypophosphatemia persists following successful treatment of high PTH, we increase the intake of phosphate-rich foods (table 1A-B).
-In patients with severe hypophosphatemia (<1 mg/dL [<0.32 mmol/L]), we give oral phosphate supplements regardless of the PTH or calcium concentration. Vitamin D derivatives can also be used to raise phosphorus in this setting if patients are not hypercalcemic. Patients with severe hypophosphatemia and hyperparathyroidism are also referred for parathyroidectomy. (See 'Patients with hypophosphatemia' above.)
•Patients with persistent hyperparathyroidism without hypercalcemia – The treatment of patients with persistent hyperparathyroidism without hypercalcemia depends upon the 25-hydroxyvitamin D concentration. A subtotal parathyroidectomy or addition of cinacalcet is not indicated to treat elevated PTH in the absence of hypercalcemia:
-If the 25-hydroxyvitamin D concentration is normal or if PTH is persistently elevated despite normalization of 25-hydroxyvitamin D levels with vitamin D3 therapy, which may occur if there is a significant degree of CKD, we treat with an activated vitamin D derivative, such as calcitriol. (See 'Patients with increased PTH without hypercalcemia' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David W Butterly, MD, who contributed to an earlier version of this topic review.