Use of Calcitonin for Hypercalcemia in a Premature Neonate With Congenital Mesoblastic Nephroma

Abstract

We report on a premature neonate (31 4/7 weeks' gestation) who presented with hypercalcemia secondary to congenital mesoblastic nephroma (CMN), the most common type of renal tumor in neonates. Typical presentation includes a palpable abdominal mass or swelling and may include abdominal pain, hematuria, fever, or hypertension. A less common complication of CMN is hypercalcemia of malignancy. Although the primary management strategy for hypercalcemia of malignancy is to treat the underlying disease, there are several agents that can be used as well for acute hypercalcemia including fluids, loop diuretics, corticosteroids, bisphosphonates, and calcitonin. However, there is minimal evidence to guide efficacious and safe treatment selection and dosing as hypercalcemia is a rare complication of this tumor type. This case adds to the current body of literature as only the second case of parathyroid hormone-related peptide-mediated hypercalcemia in a preterm neonate treated with calcitonin and is the first to specify a successful dose escalation strategy of calcitonin for this indication.

Introduction

Congenital mesoblastic nephroma (CMN) is a mesenchymal renal tumor diagnosed in utero and is associated with polyhydramnios, prematurity, and neonatal hypertension. Renal tumors comprise approximately 7% of all neonatal tumors, with CMN being the most prevalent type of renal tumor in newborns and Wilms tumor in older children.¹ The 5-year event-free survival rate and overall survival are promising at 80% and 86%, respectively.² Surgical resection with nephrectomy alone is commonly sufficient for complete remission in most cases and is standard of care for localized disease.³ Adjuvant chemotherapy may also be used in some cases. In rare cases, CMN can present with hypercalcemia and hypertension. It is theorized that prostaglandins may be the primary mediator for hypercalcemia because both blood and urinary prostaglandins demonstrate a return to baseline after removal of the tumor.⁴ Additionally, secretion of parathyroid hormone (PTH) or parathyroid hormone-related peptide (PTH-rp) from the tumor have been observed.⁵

Agents that may be used in pediatric patients for hypercalcemia of malignancy include hyperhydration, loop diuretics, bisphosphonates, corticosteroids, and calcitonin. Calcitonin is a peptide similar to endogenous calcitonin, which functionally antagonizes the effects of PTH. It directly inhibits osteoclastic bone resorption and also promotes the renal excretion of calcium, phosphate, sodium, magnesium, and potassium through a reduction in tubular resorption. The evidence for dosing of calcitonin in term and preterm neonates with CMN is limited for this indication, making treatment challenging with unclear safety and efficacy parameters.⁶ Our report is only the second published case describing the use of calcitonin for likely PTH-rp-mediated severe hypercalcemia in a premature neonate with CMN. Additionally, ours is the first case to specifically outline a successful dose escalation strategy of calcitonin in any neonate for this indication.

Case

A 31 4/7 weeks' gestation Black male was born via cesarean section due to preterm labor with a prenatally diagnosed left-sided large renal mass (8.3 cm × 7 cm) thought to be CMN with associated polyhydramnios. The birth weight was 2.01 kg. The patient was born to a 25-year-old G3P1001 mother with no pertinent past medical history and a therapeutic amnioreduction at 29 weeks' gestation. The patient was intubated just after delivery due to no spontaneous respiratory effort. Laboratory values immediately after birth were significant for a serum calcium concentration of 13.5 mg/dL (normal range, 9–11 mg/dL), magnesium of 2.9 mg/dL, and phosphorous of 4.7 mg/dL. Urine output (UOP) in the first 12 hours of life was elevated from expected at 8.6 mL/kg/hr. Due to the observed increased UOP and serum calcium concentration, fluids were started at 1.5 times maintenance rate (150 mL/kg/day). On day of life (DOL) 1, the patient's serum calcium ranged from 15.0 to 15.9 mg/dL. The patient's total fluid goal was increased to 170 mL/kg/day, and the patient was initiated on intravenous (IV) furosemide 1 mg/kg every 12 hours as well as subcutaneous (SQ) calcitonin 4 units/kg every 6 hours.

On DOL 2, calcitonin was increased to 6 units/kg SQ every 6 hours as the serum calcium concentration had rebounded to 18 mg/dL, and total fluids were also increased to 175 mL/kg/day. Baseline PTH on DOL 2 was 6 pg/mL, suggesting that the hypercalcemia was not a PTH-mediated hypercalcemia. The urine calcium/serum creatinine ratio was 0.5, demonstrating hypercalciuria. A chest, abdominal, and pelvis computed tomography scan was performed on DOL 2 confirming the left renal mass (7.9 × 6.6 × 7.6 cm), which was displacing bowel and blood vessels into the right abdomen. An electrocardiogram was performed with no notable findings.

On DOL 3, calcitonin was increased to 8 units/kg SQ every 6 hours due to persistently high serum calcium concentrations, ranging from 12.8 to 15.9 mg/dL. The patient continued to have polyuria with a documented UOP of 8.9 mL/kg/hr. A plasma PTH-rp was determined and was 7.5 pmol/L, which is above the reference range of ≤ 4.2 pmol/L. Another electrocardiogram was performed demonstrating right ventricular hypertrophy with secondary ST-T abnormality or strain pattern, T-wave inversions in the inferior leads, and a borderline prolonged QTc of 457 ms (previously 363 ms).

On DOL 4, furosemide was increased to 1 mg/kg IV every 8 hours due to a serum calcium concentration of 14.4 mg/dL. On DOL 6, the patient was started on neoadjuvant chemotherapy consisting of dactinomycin (0.0225 mg/kg) and vincristine (0.025 mg/kg), with a goal to decrease tumor burden while awaiting surgical resection. The serum calcium immediately prior was 12.6 mg/dL. On DOL 7 at 7 hours post–chemotherapy initiation, the patient's serum calcium had decreased to 10.3 mg/dL. Furosemide and calcitonin therapy were then discontinued as there was the potential that the initiation of chemotherapy could resolve the hypercalcemia and actually lead to hypocalcemia with continued use of these agents. The patient's UOP returned to normal (4.7 mL/kg/day) by DOL 8. The patient had 1 documented episode of hypocalcemia with a serum calcium of 7.8 mg/dL on DOL 8. No acute intervention was given other than adding maintenance calcium 150 mg/kg/day to the parenteral nutrition, which was increased to 300 mg/kg/day the following day. The patient's calcium trend and timing of interventions are presented in the Figure. The peak serum calcium value was reported on DOL 2 at 18.0 mg/dL.

Figure.

Calcium trends over the first 7 days of life with interventions.

During his admission, the patient underwent 2 cycles of vincristine and dactinomycin per Pediatric Oncology Group 9444/Childrens Cancer Study group 4942: National Wilms Tumor Study-5 – Regimen EE-4A. This regimen consists of vincristine every week for 6 weeks from weeks 0 to 5 and dactinomycin once every 3 weeks for 2 doses on weeks 0 and 3. Pathology results confirmed the diagnosis of CMN, with findings supporting subclassification as the cellular variant. On DOL 30, the patient underwent a laparotomy exploratory with left radical nephrectomy and left diaphragm repair with no complications. The patient's calcium concentration dropped from 10.5 to 8.1 mg/dL after surgery, presumably secondary to the removal of the PTH-rp source as the assumed pathophysiology of the patient's hypercalcemia. The serum calcium concentration normalized with additional calcium gluconate 100 mg/kg/day in the patient's total parenteral nutrition. At follow-up at 8 months of age, the patient has remained stable with no local reoccurrence, distal metastasis, or readmissions since birth.

Discussion

Hypercalcemia of malignancy is defined as an increase in serum calcium above the patient's upper limit of normal due to a malignancy, and occurs in patients with both solid tumors and hematologic malignancies.⁷ To avoid complications such as acute renal failure, altered mental status, and arrhythmias, medications are used to treat hypercalcemia until the underlying disease is treated.⁷ This disease process is mediated by one of several different mechanisms: tumor production of PTH-rp, osteolytic metastases and excessive calcium release from bone, and ectopic activity of 1-alpha-hydroxylase and formation of 1,23-dihydroxycholecalciferol.⁷ The major mechanism of hypercalcemia in patients with CMN is thought to be PTH-rp-mediated hypercalcemia since PTH-rp acts on osteoblasts enhancing synthesis of receptor activator of NF-κB ligand facilitating bone remodeling and subsequent calcium release.⁷ Although hypercalcemia may not be a common consequence of CMN, it has been described as one of the potential presenting features. Management of hypercalcemia of malignancy includes hyperhydration, loop diuretics, bisphosphonates, corticosteroids, and calcitonin. Specifically, calcitonin is a polypeptide hormone secreted by the thyroid that suppresses resorption of the bone by osteoclast activity and inhibits tubular reabsorption of calcium and phosphorus.⁸ The majority of pharmacokinetic data for exogenously administered calcitonin is limited to adults, which demonstrates an onset of action within 2 hours, duration of 6 to 8 hours, and metabolism in the kidneys, blood, and peripheral tissue. Common adverse events reported include gastrointestinal side effects such as nausea, reduced appetite, diarrhea, abdominal pain, and discomfort. It may also lead to flushing after administration, including the face, hands, and feet. Local inflammatory reactions have been reported at the site of injection as well.

In our patient case, the mechanism of hypercalcemia was consistent with being mediated by PTH-rp as the plasma was high (7.5 pmol/L) with a normal plasma PTH. Due to the persistent nature of continued secretion of PTH-rp without immediate plan for tumor removal due to the patient's size, our patient needed continued management strategies such as calcitonin to avoid consequences of hypercalcemia.

An early case report of an infant with CMN with hypercalcemia was managed with fluids and calcitonin (unknown dose) prior to nephrectomy, and the serum calcium concentrations returned to normal post-surgery.⁹ A second case reported a patient born at 33 weeks' gestation with a peak serum calcium of 16.8 mg/dL that was managed with furosemide and fluids with a resultant UOP of 3 to 5 mL/kg/hr.⁵ The patient's PTH was normal on the first DOL, and increased by 3-fold after calcium correction. The pathogenesis of the patient's hypercalcemia was favored to be PTH-rp or prostaglandin as the primary mechanism.

Another patient case of hypercalcemia and CMN described a term neonate that received pamidronate for hypercalcemia.¹⁰ Pamidronate is a bisphosphonate that disrupts osteoclast activity and in adults has an onset of action around 48 hours and duration of 7 to 14 days. The patients' initial serum calcium was 17 mg/dL, and the patient failed management with normal saline and furosemide. The patient received 2 IV doses of pamidronate 1.5 mg/kg daily for 2 days with serum calcium concentrations normalizing within 18 hours prior to surgical intervention. There was no documented serum or plasma PTH. There were no complications including hypocalcemia with the use of pamidronate in this patient. The last 2 cases published describe calcitonin use in a 1-month-old term patient with a serum calcium concentration of 16.7 mg/dL and calcitonin use in a 29 weeks' gestational age patient with a serum calcium concentration of 12.8 mg/dL, which is the only other published use of calcitonin in a premature neonate prior to this case report.¹¹ These patients were treated with saline hydration, furosemide, calcitonin (dose unknown for both patients), and eventually the second patient received pamidronate 0.25 mg/kg/dose for 2 doses on days 4 and 5 of admission. Both patients had resolution of hypercalcemia prior to surgical or chemotherapy intervention, and both patients underwent surgical resection on day 16 and day 8 of admission, respectively. There was no information regarding the calcitonin dose or proximity to pamidronate dosing. However, after surgical intervention, these 2 cases had low to normal serum calcium and phosphorous concentrations with an elevated serum PTH and a normalized serum PTH-rp concentration. The patients also had undetectable or low urinary excretion of calcium and phosphorous leading to the concern of a “hungry-bone-like” state requiring continued calcitriol, calcium, and phosphorus supplementation for 8 and 12 weeks, respectively.¹¹ In our patient the multidisciplinary team was concerned about using a bisphosphonate due the potential for prolonged hypocalcemia or a “hungry-bone-like” state with the potential for tumor lysis syndrome after chemotherapy administration due to the long half-life of pamidronate. This was a major reason for consideration of calcitonin over pamidronate for our patient. Another consideration for the avoidance of this agent was that it was not readily available for administration at our institution.

In order to prevent the potential for hypocalcemia and a “hungry-bone-like” state as described in some of the above previous cases,¹¹ after chemotherapy administration and subsequent decrease in the serum calcium concentration in our patient, calcitonin and furosemide were quickly discontinued with no further need for supplementation besides a small proactive increase in routine calcium supplementation in total parenteral nutrition. It should also be noted that hypercalcemia in CMN is frequently resolved by chemotherapy or surgery, which was consistent in our case in which our patient's hypercalcemia was resolved by 7 hours after chemotherapy administration.

There are limited data for the successful use of calcitonin for treatment of hypercalcemia of malignancy in neonates with CMN, as outlined above with only 3 cases reported (only 1 of which was in a premature neonate) with no dosing provided in any of the publications.^8,10 There are additional case reports available describing the use and dosing of calcitonin in neonates with subcutaneous fat necrosis. In 2 cases describing full term infants, calcitonin 4 units/kg twice and calcitonin 2 units/kg twice were used without adverse events in combination with pamidronate as the mainstay therapy.¹² Our dosing of calcitonin (between 4 and 8 units/kg/dose SQ every 6 hours) was more aggressive compared with these 2 cases. We did not observe any side effects from calcitonin or tachyphylaxis. There are additional case reports describing the unsuccessful use of calcitonin for hypercalcemia of malignancy from causes other than CMN,^13,14 1 of which reported a dosing of 4 units/kg/dose SQ every 6 hours without dose escalation.¹⁴

Management of our patient was challenging due to the complexity of this disease state and the concern for side effects in light of the minimal literature available. Although there is no definitive literature to guide the decision between bisphosphonates and calcitonin for neonates with hypercalcemia due to CMN, our report demonstrates that calcitonin remains a reasonable option for these patients if hyperhydration and loop diuretics are inadequate. This is especially true for patients with acutely high serum calcium concentrations when rapid reduction of the serum calcium is needed, since pamidronate has a much longer onset of action of up to 48 hours compared with 2 hours with calcitonin. The calcitonin dose escalation strategy used in our case was an initiation of 4 units/kg SQ every 6 hours, which was titrated up to 6 units/kg then 8 units/kg SQ every 6 hours using the serum calcium concentration to assess response daily. This is the first case report to describe the dosing of calcitonin in a premature neonate using a dose escalation strategy to successfully lower calcium in a patient with CMN.

ABBREVIATIONS

CMN

congenital mesoblastic nephroma

DOL

day of life

IV

intravenous

PTH

parathyroid hormone

PTH-rp

parathyroid hormone-related peptide

SQ

subcutaneous

UOP

urine output

Funding Statement

Disclosures. The authors declare no financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all patient information in this report and take responsibility for the integrity and accuracy of the report.