Missed Opportunities to Diagnose and Treat Tertiary Hyperparathyroidism After Transplant.

INTRODUCTION: Tertiary hyperparathyroidism (3HPT) is common after renal transplant. However, guidelines for diagnosis are not clear and few patients are treated surgically. This study aims to determine rates of diagnosis and treatment of 3HPT in renal transplant patients with hypercalcemia. MATERIALS AND METHODS: This retrospective chart review identified all renal transplant recipients at a single tertiary care institution between 2011 and 2021. Patients with post-transplant hypercalcemia (> 10.2 mg/dL) were identified. The time in months of index hypercalcemia was noted. Measurement of parathyroid hormone (PTH) levels after index hypercalcemia was determined and noted as elevated if > 64 pg/mL at least 6 mo after transplant. Documentation of symptoms of hyperparathyroidism, a diagnosis of hyperparathyroidism in the electronic medical record, and medical or surgical management of patients with classic 3HPT (elevated calcium and PTH) were determined. RESULTS: Of 383 renal transplant recipients, hypercalcemia was identified in 132 patients. The majority of hypercalcemic patients had PTH levels measured (127, 96.2%). PTH was elevated in 109 (82.6%). Among the 109 patients with classic 3HPT, 54 (49.5%) had a documented diagnosis of hyperparathyroidism in the electronic medical record (P = 0.01). Kidney stones or abnormal DEXA scan were present in 16 (14.7%) and 18 (16.5%), respectively. Most patients were managed non-surgically (101, 92.6%); calcimimetics were prescribed for 42 (38.5%, P = 0.01). Eight (7.3%) patients with classic 3HPT were referred to a surgeon (P = 0.35); all were initially prescribed calcimimetics (P = 0.001). CONCLUSIONS: 3HPT is underdiagnosed in patients with elevated calcium and PTH levels post-transplant. A significant percentage of these patients go without surgical referral and curative treatment.

Osteoporosis and Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD): Back to Basics.

Osteoporosis is defined as a skeletal disorder of compromised bone strength predisposing those affected to an elevated risk of fracture. However, based on bone histology, osteoporosis is only part of a spectrum of skeletal complications that includes osteomalacia and the various forms of renal osteodystrophy of chronic kidney disease-mineral and bone disorder (CKD-MBD). In addition, the label "kidney-induced osteoporosis" has been proposed, even though the changes caused by CKD do not qualify as osteoporosis by the histological diagnosis. It is clear, therefore, that such terminology may not be helpful diagnostically or in making treatment decisions. A new label, "CKD-MBD/osteoporosis" could be a more appropriate term because it brings osteoporosis under the official label of CKD-MBD. Neither laboratory nor noninvasive diagnostic investigations can discriminate osteoporosis from the several forms of renal osteodystrophy. Transiliac crest bone biopsy can make the diagnosis of osteoporosis by exclusion of other kidney-associated bone diseases, but its availability is limited. Recently, a classification of metabolic bone diseases based on bone turnover, from low to high, together with mineralization and bone volume, has been proposed. Therapeutically, no antifracture treatments have been approved by the US Food and Drug Administration for patients with kidney-associated bone disease. Agents that suppress parathyroid hormone (vitamin D analogues and calcimimetics) are used to treat hyperparathyroid bone disease. Antiresorptive and osteoanabolic agents approved for osteoporosis are being used off-label to treat CKD stages 3b-5 in high-risk patients. It has now been suggested that intermittent administration of parathyroid hormone as early as CKD stage 2 could be an effective management strategy. If confirmed in clinical trials, it could mitigate the retention of phosphorus and subsequently the rise in fibroblast growth factor 23 and may be beneficial for coexisting osteoporosis.

A Combination of Hemodialysis with Hemoperfusion Helped to Reduce the Cardiovascular-Related Mortality Rate after a 3-Year Follow-Up: A Pilot Study in Vietnam.

AIMS: Moderate to severe hyperparathyroidism (parathyroid hormone [PTH] concentrations ≥600 pg/mL) may increase the risk of cardiovascular problems and bone disease. We assume that a combination of hemodialysis with hemoperfusion may reduce the cardiovascular-related mortality rate in maintenance hemodialysis. SUBJECTS AND METHODS: From 625 maintenance hemodialysis patients, 93 people met with our inclusion criteria. Based on the level of serum PTH, the patients were divided into 2 groups: 46 patients who underwent a combination of hemodialysis and hemoperfusion (HD + HP group) for consecutive 3 years and 47 patients who used hemodialysis only (HD group). RESULTS: During 3 years of follow-up, the ratio of mortality was 4.3% in the HD + HP group which was significantly lower than in the HD group (17%), p = 0.049. Based on Kaplan-Meier analysis of cardiovascular-related mortality, patients in the HD group (red line) exhibited a significantly higher death rate compared to the HD + HP group (violet line) (log-rank test, p = 0.049). CONCLUSION: We demonstrated that a combination of hemodialysis and hemoperfusion for 3 years helped to reduce the cardiovascular-related mortality rate.

Parathyroidectomy versus cinacalcet for tertiary hyperparathyroidism; a retrospective analysis.

INTRODUCTION: Tertiary hyperparathyroidism (tHPT), i.e., persistent HPT after kidney transplantation, affects 17-50% of transplant recipients. Treatment of tHPT is mandatory since persistently elevated PTH concentrations after KTx increase the risk of renal allograft dysfunction and osteoporosis. The introduction of cinacalcet in 2004 seemed to offer a medical treatment alternative to parathyroidectomy (PTx). However, the optimal management of tHPT remains unclear. METHODS: A retrospective analysis was performed on patients receiving a kidney transplantation (KT) in two academic centers in the Netherlands. Thirty patients undergoing PTx within 3 years of transplantation and 64 patients treated with cinacalcet 1 year after transplantation for tHPT were included. Primary outcomes were serum calcium and PTH concentrations 1 year after KT and after PTx. RESULTS: Serum calcium normalized in both the cinacalcet and the PTx patients. PTH concentrations remained above the upper limit of normal (median 22.0 pmol/L) 1 year after KT, but returned to within the normal range in the PTx group (median 3.7 pmol/L). Side effects of cinacalcet were difficult to assess; minor complications occurred in three patients. Re-exploration due to persistent tHPT was performed in three (10%) patients. CONCLUSION: In patients with tHPT, cinacalcet normalizes serum calcium, but does not lead to a normalization of serum PTH concentrations. In contrast, PTx leads to a normalization of both serum calcium and PTH concentrations. These findings suggest that PTx is the treatment of choice for tHPT.

Endocrine Emergencies in Obstetrics.

Endocrine emergencies in pregnancy can be life threatening and are associated with increased morbidity for both the mother and fetus. Thyroid storm, diabetic ketoacidosis, and hypercalcemic crisis require a high clinical suspicion, rapid treatment, and multidisciplinary care to ensure best outcomes. Critical care consultation and intensive care unit admission are often warranted. Fetal testing may initially be concerning; however often improves with correction of the underlying metabolic derangement(s) and delivery is generally avoided until maternal status improves.

Parathyroid Diseases.

Although uncommon in pregnancy, parathyroid dysfunction may produce significant perinatal and maternal morbidity and mortality. The prevalence of hyperparathyroidism is 0.5%. The most common cause of primary hyperparathyroidism in pregnancy is a single parathyroid adenoma, which is present in nearly 80% of cases. Surgery is the only definitive treatment for primary hyperparathyroidism, with a cure rate that is excellent. The most common etiology of hypoparathyroidism is damage to the parathyroid glands after surgery, with an incidence of 0.2%. Treatment of hypoparathyroidism is usually a high-calcium diet with vitamin D supplementation. Vitamin D deficiency is common, associated with perinatal morbidity and easily corrected.

Mineral disorders in pediatric pre-emptive kidney transplantation.

BACKGROUND: Pre-emptive kidney transplantation (PEKT) is beneficial for patients, improves graft survival and minimizes the complications associated with chronic kidney disease. Reports on pediatric PEKT, however, are limited, and little is known about the parathyroid hormone (PTH) abnormalities and calcium-phosphorus disorders (CPD) in this condition. This study was the first to report on mineral disorders in pediatric PEKT patients during a 1 year period. METHODS: We conducted a comparative examination of the abnormalities in calcium, phosphorus, calcium-phosphorus products and PTH before and 1 year after living donor kidney transplantation in PEKT and non-PEKT patients. RESULTS: Thirty-one patients were included. The patients were divided into two groups: PEKT (n = 11; 5 months in CKD stage 4-5) and non-PEKT (n = 20; 31.5 months in dialysis). Mean age at transplantation was 9.4 ± 5.0 years. Hypercalcemia and hyperphosphatemia were observed before and after transplantation in the PEKT and non-PEKT groups, and >15% of patients in each group had bone disorder and ectopic calcification associated with mineral disorder. Mineral disorder was present for approximately 3 months after transplantation in both treatment groups. CONCLUSIONS: No significant differences in PTH or CPD were noted between PEKT and non-PEKT groups; moreover, normalization of abnormal values did not differ between the PEKT and non-PEKT groups. Compared with non-PEKT, PEKT did not improve the course of mineral metabolism disorders. Mineral and bone disorder treatment was likely insufficiently provided to pediatric PEKT patients. To obtain the maximum advantage of PEKT, calcium and phosphorus levels should be strictly controlled before kidney transplantation.

Effect of Cinacalcet Combined with Calcitriol on the Clinical Outcome and Bone Metabolism in Patients on Hemodialysis with Severe Secondary Hyperparathyroidism.

OBJECTIVE: To observe the clinical outcome and the effect of bone metabolism of cinacalcet combined with calcitriol in maintenance hemodialysis (MHD) patients with severe secondary hyperparathyroidism (SHPT). METHODS: Thirty MHD patients with SHPT were enrolled into the study. All patients were given cinacalcet 25-75 mg and 0.5 µg calcitriol daily. Serum Ca, P, intact parathyroid hormone (iPTH), and bone metabolic markers were measured. The clinical symptoms and their changes were investigated. RESULTS: The baseline levels of iPTH, Ca, and P were 1,787.3 ± 1,321 pg/mL, 2.54 ± 0.19 mmol/L, and 2.06 ± 0.15 mmol/L respectively. After 3 months treatment, iPTH decreased by 70%. Serum Ca and P fell to 2.39 ± 0.17 and 1.56 ± 0.50 mmol/L (p < 0.05), respectively. After 6 months, the bone-specific alkaline phosphatase, osteocalcin, and ß-cross levels were decreased by 50, 37, and 49% respectively compared with corresponding values before treatment. A decline in the bone density patients was inhibited. CONCLUSION: Cinacalcet combined with low dose calcitriol can improve high calcium, high phosphorus, and high iPTH in MHD patients with severe SHPT and also improve bone metabolism. It can be used as a favorable choice for SHPT treatment.

PDGFB-based stem cell gene therapy increases bone strength in the mouse.

Substantial advances have been made in the past two decades in the management of osteoporosis. However, none of the current medications can eliminate the risk of fracture and rejuvenate the skeleton. To this end, we recently reported that transplantation of hematopoietic stem/progenitor cells (HSCs) or Sca1(+) cells engineered to overexpress FGF2 results in a significant increase in lamellar bone matrix formation at the endosteum; but this increase was attended by the development of secondary hyperparathyroidism and severe osteomalacia. Here we switch the therapeutic gene to PDGFB, another potent mitogen for mesenchymal stem cells (MSCs) but potentially safer than FGF2. We found that modest overexpression of PDGFB using a relatively weak phosphoglycerate kinase (PGK) promoter completely avoided osteomalacia and secondary hyperparathyroidism, and simultaneously increased trabecular bone formation and trabecular connectivity, and decreased cortical porosity. These effects led to a 45% increase in the bone strength. Transplantation of PGK-PDGFB-transduced Sca1(+) cells increased MSC proliferation, raising the possibility that PDGF-BB enhances expansion of MSC in the vicinity of the hematopoietic niche where the osteogenic milieu propels the differentiation of MSCs toward an osteogenic destination. Our therapy should have potential clinical applications for patients undergoing HSC transplantation, who are at high risk for osteoporosis and bone fractures after total body irradiation preconditioning. It could eventually have wider application once the therapy can be applied without the preconditioning.

Normocalcemic hyperparathyroidism is associated with complications similar to those of hypercalcemic hyperparathyroidism.

Normocalcemic primary hyperparathyroidism (NC-PHPT) is a variant of hyperparathyroidism, characterized by normal serum calcium levels, high parathyroid hormone (PTH) and normal 25-OH vitamin D status. The present study aimed to compare complications related to hyperparathyroidism in patients with NC-PHPT and hypercalcemic PHPT (HC-PHPT). We retrospectively evaluated the records of 307 PHPT patients between January 2010 and March 2013. We excluded patients with impaired renal function and liver failure. All patients underwent a biochemical and hormonal examination including serum glucose, albumin, total calcium, phosphorus, creatinine, lipoproteins, PTH and 25-OH vitamin D. Nephrolithiasis and bone mineral density were documented based on a review of the medical records. The study population consisted of 36 (12 %) males and 271 (88 %) females with a mean age of 53.3 ± 9.5 years (29-70 years). Twenty-three of the patients were diagnosed with NC-PHPT (group 1) and 284 were diagnosed with HC-PHPT (group 2). There were no significant differences in terms of age, gender, prevalence of hypertension, low bone mineral density and kidney stones between the groups. The mean thyroid-stimulating hormone (TSH) and low-density lipoprotein (LDL) levels were significantly higher in group 1 than in group 2. Our study found that patients with NC-PHPT have similar several complications as patients with HC-PHPT. NC-PHPT patients have higher TSH levels despite being within the normal range, and higher LDL-C levels than patients with HC-PHPT. However, this relationship needs to be clarified in future studies with larger cohorts.

The evaluation and treatment of endocrine forms of hypertension.

Endocrine hypertension is an important secondary form of hypertension, identified in between 5% and 10% of general hypertensive population. Primary aldosteronism is the most common cause of endocrine hypertension, accounting for 1%-10% in uncomplicated hypertension and 7%-20% in resistant hypertension. Other less common causes of endocrine hypertension include Cushing syndrome, pheochromocytoma, thyroid disorders, and hyperparathyroidism. Diagnosis requires a high index of suspicion and the use of appropriate screening tests based on clinical presentation. Failure to make proper diagnosis may lead to catastrophic complications or irreversible hypertensive target organ damage. Accordingly, patients who are suspected to have endocrine hypertension should be referred to endocrinologists or hypertension specialists who are familiar with management of the specific endocrine disorders.

Oral alendronate can suppress bone turnover but not fracture in kidney transplantation recipients with hyperparathyroidism and chronic kidney disease.

Post-transplantation bone diseases negatively affect the quality of life of solid organ recipients. Secondary or tertiary hyperparathyroidism is a frequent complication in kidney transplantation (KTx) recipients. Treatment with immunosuppressive agents including glucocorticoids can lead to deterioration in bone metabolism in these patients. In the present study, we explored the effects of a three-year treatment period with oral alendronate (ALN) in long-term KTx recipients. Post-KTx recipients were recruited (n = 24, M/F = 12/12, mean age 52.0 ± 7.8 years) into this study. All patients were prescribed methylprednisolone (4.07 ± 0.86 mg/day) with various immunosuppressive agents. Before treatment with oral ALN (35 mg/week), the mean concentrations of intact parathyroid hormone (iPTH) and 25-hydroxyvitamin D were 139.2 ± 71.4 pg/mL and 20.8 ± 4.1 ng/mL, respectively. After 36 months of ALN treatment, mean iPTH levels increased slightly (+20.9 %). Treatment with ALN reduced bone-specific alkaline phosphatase (-35.4 %), serum type I collagen N-terminal telopeptide (-31.2 %) and osteocalcin (-55.6 %) levels. ALN did not increase bone mass after 24 months. Four patients with the highest baseline iPTH levels suffered a clinical osteoporotic fracture during the 36-month ALN treatment period. Higher iPTH levels with chronic kidney disease (CKD) at baseline were associated with the incidence of new clinical fractures during ALN treatment. In conclusion, anti-resorptive therapy with ALN can suppress bone turnover even when iPTH concentration is elevated in long-term KTx recipients. However, hyperparathyroidism with CKD seems to be associated with new clinical fractures during ALN treatment.

A case of multiple brown tumors with primary hyperparathyroidism.

We report a case of large multiple brown tumors in a patient with primary hyperparathyroidism. A 52-year-old woman suffered from pain in the ribs and developed left facial swelling and deformity. CT showed a large destructive osteolytic lesion in the left maxillary sinus. Biopsy showed a lesion with newly formed bone tissue, diffuse giant cells and deposits of hemosiderin. In addition, similar lesions were also observed in the ribs, iliac bones and pelvis. The laboratory data showed hypercalcemia and hyperparathyroidism. Cervical echo and (201)Tl-(99m)TcO(4-) scintigraphy demonstrated a right lower swollen parathyroid adenoma. The diagnosis was multiple brown tumors with primary hyperparathyroidism and parathyroidectomy was performed. Follow-up CT showed marked decreases in the size of osteolytic lesions with calcification in the brown tumors compared to pre-treatment findings. These changes were associated with marked improvement in pain and facial deformity. We described a rare case of multiple brown tumors appeared in the maxilla associated with primary hyperparathyroidism.

Secondary and tertiary hyperparathyroidism.

We reviewed the etiology and management of secondary and tertiary hyperparathyroidism. Secondary hyperparathyroidism is characterized by an increase in parathyroid hormone (PTH) that is appropriate and in response to a stimulus, most commonly low serum calcium. In secondary hyperparathyroidism, the serum calcium is normal and the PTH level is elevated. Tertiary hyperparathyroidism is characterized by excessive secretion of PTH after longstanding secondary hyperparathyroidism, in which hypercalcemia has ensued. Tertiary hyperparathyroidism typically occurs in men and women with chronic kidney disease usually after kidney transplant. The etiology and treatment of secondary hyperparathyroidism is relatively straightforward whereas data on the management of tertiary hyperparathyroidism is limited to a few small trials with short follow-up.

Parathyromatosis following spontaneous rupture of a parathyroid adenoma: natural history and the challenge of management.

Parathyromatosis, the presence of small nodules of hyper-functioning parathyroid tissue scattered throughout the soft tissues of the neck and superior mediastinum, is a rare cause of persistent primary hyperparathyroidism. We report the first case of parathyromatosis secondary to spontaneous rupture of a parathyroid adenoma. Despite running an indolent course, this case highlights the potential challenges of management of parathyromatosis and the value of calcimimetic therapy as an adjunct to surgery for disease control.

Endocrine disease in pregnancy.

Endocrine disease is common in pregnancy. Most pre-existing endocrine conditions, if well controlled, have little impact on maternal or fetal morbidity. Uncontrolled endocrine conditions in pregnancy, whether poorly controlled pre-conception or newly diagnosed, are associated with a variety of adverse fetal outcomes and maternal morbidity. Also, transplacental transfer of maternal antibodies can have adverse fetal or neonatal consequences. The initial diagnosis of many conditions is hindered by the overlap of symptoms that occur in normal pregnancy and those that suggest specific endocrine pathologies, and also by the changes in reference ranges for common biochemical measurements that occur as a result of physiological changes in pregnancy. This article summarises the common endocrine disorders in pregnancy and describes how pregnancy can alter their investigation, treatment and ongoing management, as well as the potential effects on the fetus.