Mineral and Bone Disorders After Kidney Transplantation
Elizabeth A. Kendrick
Mineral and bone disorders frequently complicate management of kidney transplant recipients. Varying severity of abnormalities are likely to exist at the time of transplant related to end-stage kidney disease (ESKD) management; improved renal function after transplantation and management of recipients including immunosuppression drug management significantly impacts these disorders. Although the natural history of bone and mineral disorders after kidney transplantation is reasonably well-defined, optimal management of these abnormalities is less clear based on available evidence.
CALCIUM
Serum calcium levels may follow a biphasic pattern with significant decline in the first 1 to 2 weeks posttransplant followed by a significant increase during the first 3 to 6 months after transplantation.1
Hypercalcemia
Hypercalcemia occurs in 15% to 60% of patients in the early posttransplant period. Total calcium may underestimate diagnosis of hypercalcemia compared to ionized calcium due to concurrent metabolic acidosis; documented prevalence can vary based on total calcium value used to diagnose hypercalcemia or whether ionized calcium is used. Higher prevalence of hypercalcemia is associated with the use of ionized calcium measurements to diagnose hypercalcemia.1,2,3
Posttransplant hypercalcemia is associated with persistence of hyperparathyroidism and most likely caused by parathyroid hormone (PTH)-mediated skeletal calcium release. Increased renal tubular reabsorption due to elevated PTH and increased intestinal calcium absorption due to calcitriol may also contribute. However, decreased urinary fractional excretion of calcium associated with persistent hyperparathyroidism has not consistently been noted; calcitriol levels have not always been shown to differ when compared to transplant recipients without hypercalcemia.
Hypercalcemia is generally moderate in the range of total calcium 10.5 to 11.5 mg/dL; severe hypercalcemia (total calcium level >12 mg/dL) is uncommon.
Hypercalcemia prevalence decreases over time. However, hypercalcemia can persist in as much as 15% of patients at 1 year after transplantation but generally is reported to be in the 0.5% to 5.6% range.
Management of hypercalcemia: Severe hypercalcemia requiring urgent treatment is uncommon in the transplant setting but, if present, can be treated as in the non-chronic kidney disease (CKD) population. Management of hypercalcemia associated with hyperparathyroidism not requiring urgent management is further discussed in the following text.
PHOSPHORUS
Phosphorus metabolism
Fibroblast growth factor 23 (FGF-23) is a main regulator of phosphate levels in plasma, along with complex interactions with PTH and activated vitamin D.6
Filtered phosphorous is nearly completely reabsorbed in the proximal tubule via type IIa and IIc sodium-phosphate cotransporters.
PTH regulates these cotransporters by stimulating internalization and reducing their availability on the brush border membrane.
FGF-23 reduces expression of the transporters.
Hypophosphatemia
Hypophosphatemia can be seen in 40% to 90% of patients after transplant; majority of cases are mild to moderate (serum phosphorous between 1.5 and 2.3 mg/dL).
Hypophosphatemia is most pronounced within the first 3 months posttransplant, generally recovering to normal levels by 1 year.
Etiologies of hypophosphatemia posttransplant: High serum levels of the bonederived phosphaturic hormone FGF-23 and hyperparathyroidism contribute to renal phosphate wasting causing hypophosphatemia.
FGF-23 levels gradually decrease in the first few months after transplant in response to low phosphorous levels resulting in decreased phosphaturia and improvement in serum phosphate.7
Elevated PTH levels can persist beyond improved serum phosphorus, making it appear that FGF-23 may be the more important factor in causing hypophosphatemia; elevated FGF-23 levels more strongly correlate with hypophosphatemia than do PTH.6
FGF-23 inhibits 1-alpha-hydroxylase, reducing conversion of 25-hydroxy vitamin D3 to 1,25-dihydroxy vitamin D3 resulting in reduced intestinal phosphate absorption.
Other contributors to hypophosphatemia can include
Metabolic acidosis stimulates phosphaturia as phosphate serves as a titratable acid.
Glucocorticoids inhibit intestinal sodium-phosphate transporter activity.
Mammalian target of rapamycin (mTOR) inhibitors (rapamycin, everolimus) inhibit renal tubular phosphate reabsorption probably through inhibition of Klotho, the cofactor of the FGF-23 receptor on the tubular epithelial cell.
Treatment
Mild to moderate hypophosphatemia is not likely to be associated with significant adverse symptoms and does not need to be treated.
More pronounced hypophosphatemia may be associated with symptoms of muscle weakness.
Serum phosphate level of 1.5 mg/dL (approximately 0.5 mmol/L) has been suggested as the lower limit to consider initiation of oral phosphate replacement, as symptoms can develop below this level. Patients with symptoms of muscle weakness and phosphate levels between 1.5 and 3.0 mg/dL (0.5 and 1.0 mmol/L) can have treatment initiated to evaluate symptom response (opinion based). Because of potential for adverse effects related to phosphorus supplementation, strict minimum dosing should be used.4,5
Potential adverse effects of phosphorous supplementation
Gastrointestinal intolerance
Worsening existing hyperparathyroidism and elevated FGF-23 levels
Vascular and kidney allograft calcifications
Hyperphosphatemia
Hyperphosphatemia can complicate early or late/long-term renal transplant dysfunction and should be managed similar to CKD patients.
Hyperphosphatemia seen early after transplant often improves without specific treatment as renal function improves.
Oral phosphate binders can potentially interfere with the absorption of immunosuppression drugs as in the case of sevelamer and mycophenolate mofetil.
PARATHYROID HORMONE
Secondary hyperparathyroidism improves after kidney transplantation with good allograft function with progressive decrease PTH levels in the first 3 to 6 months. Involution of parathyroid hyperplasia occurs very slowly and is associated with persistent hyperparathyroidism.5
Fifty percent of recipients continue to have elevated PTH levels at 1-year posttransplant; longer term follow-up has shown that only approximately 25% of recipients have normal PTH levels, and 25% continue to have elevated PTH levels >2 times normal at 5 years after transplantation.3,5
Transplant recipients with history time on dialysis >6 years, calcium-phosphate product >55 (mg/dL), and cinacalcet use prior to transplant had higher risk of persistent hyperparathyroidism posttransplant.
Higher pretransplant PTH levels, larger gland size and presence of multinodular hyperplasia, and persistent elevation of alkaline phosphatase are other factors found to be associated with persistent hyperparathyroidism after transplantation.
Adverse effects associated with persistent hyperparathyroidism after transplant include
Hypercalcemia.
Development or exacerbation of osteopenia/osteoporosis.
Fractures.
Allograft dysfunction.
Renal calcinosis.
Vascular calcifications.
Increased risk of cardiovascular event.
Treatment
Clinically significant hypercalcemia due to persistent (tertiary) hyperparathyroidism after transplantation may be managed medically (calcium-sensing receptor agonist) or surgically (parathyroidectomy).
The use of calcium-sensing receptor agonist
The use of cinacalcet for the treatment of hypercalcemia after transplant is offlabel as has not been approved for this indication by the U.S. Food and Drug Administration (FDA).
A metanalysis of nonrandomized studies using cinacalcet to treat hypercalcemia in renal transplant recipients8 demonstrated
Control of hypercalcemia with cinacalcet doses of 30 to 60 mg in most patients.
Decrease in PTH levels of approximately 20% to 50%; a more pronounced effect on PTH decrease is seen with higher PTH levels.
PTH levels remain more than 2 times normal value in the majority of patients and above Kidney Disease Outcomes Quality Initiative (KDOQI) PTH goals for CKD patients in a significant proportion.
Improvement in hypophosphatemia associated with a modest decrease in phosphaturia.
Inconsistent changes in calciuria.
No overall effect on renal function (there are anecdotal reports of renal impairment due to nephrocalcinosis or development of kidney stones associated with use of cinacalcet).
Inconsistent effect on bone density in the few studies assessing this outcome.
Hypocalcemia is not common and easily managed.
Gastrointestinal intolerance in <10% of patients, generally managed without treatment cessation.
A more recent larger randomized controlled study in 114 patients using cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism9 showed similar changes in hypercalcemia, hypophosphatemia, and PTH levels as the smaller studies earlier. No effect was seen on renal function; urinary calcium excretion decreased slightly in the cinacalcet group. Markers of bone density (alkaline phosphatase, osteocalcin, urine N-telopeptide) did not differ from placebo group and no significant difference in measured bone mineral density (BMD) at 1 year. Fractures were not assessed.
Parathyroidectomy
Observational studies of parathyroidectomy in renal transplant recipients for persistent (tertiary) hyperparathyroidism10 show high success rates in resolving hyperparathyroidism with subtotal parathyroidectomy or total parathyroidectomy with autotransplantation. Limited glandular resection (of only 1 or 2 macroscopically enlarged glands) is associated with significant risk of recurrence of hyperparathyroidism.
A review of retrospective and prospective cohort studies, case series, and one randomized study comparing treatment of hypercalcemia due to tertiary hyperparathyroidism with parathyroidectomy versus cinacalcet8,9,10,11,12 revealedRelated posts:
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