Evaluation of Nephrolithiasis in a 14-Year-Old Girl: Leave No Stone Unturned!

A 14-year-old girl presents to the nephrology clinic for routine follow-up of nephrolithiasis with complaints of right lower quadrant pain. She denies fevers, chills, flank pain, hematuria, dysuria, or any passing of stone in urine. She reports constipation, but no other symptoms. She reports good fluid intake (3–4 bottles [16 oz each] of water per day). On physical examination, vital signs show mildly elevated systolic blood pressure of 125/60 mm Hg, with a heart rate of 88 beats/min. She is afebrile. Her height is 63 inches (160 cm) (51st percentile) and weight is 155 lb (70.3 kg) (94th percentile), with a BMI of 27 (95th percentile). Cardiovascular examination shows a normal rate and regular rhythm with no murmurs present. Respirations are clear. Bowel sounds are normoactive, and abdomen is soft and nontender, with no organomegaly. There is no costovertebral angle tenderness. There is no family history of nephrolithiasis and no report of prescribed or herbal medication use.Her medical history is significant for nephrolithiasis diagnosed by urology 2 years earlier after presenting with left flank pain. Per reports, she was managed conservatively with hydration. She established care in a nephrology clinic 1 year ago after relocating to the region and underwent a renal stone evaluation after her first visit. Renal ultrasonography showed a 1-cm nonobstructive left renal stone (Figure 1). A routine urinalysis and random urine calcium/creatinine ratio (151 mg/g; reference range, 10–240 mg/g) were normal. A 24-hour urine stone risk analysis, also called a supersaturation profile, includes measurement of urine pH, volume over a 24-hour period, and urine metabolites such as calcium, oxalate, citrate, uric acid, sodium, potassium, chloride, magnesium, phosphorus, ammonia, and creatinine. The result helps identify metabolic risk factors, and serial profiling helps guide therapy as well. The results of the 24-hour urine stone risk analysis for this patient were normal except for low urine volume. The patient was recommended to make dietary changes of increased fluids, low salt, and low animal protein. At follow-up 6 months later she was clinically doing well, without any concerning symptoms.A repeated 24-hour urine stone risk analysis is performed to evaluate her new onset of right lower quadrant pain. The study reveals elevated calcium excretion of 5.9 mg/kg (reference range, 4 mg/kg) and a calcium/creatinine ratio of 404 mg/g (reference range, 51–262 mg/g). Comprehensive metabolic panel, magnesium, phosphorus, 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, and parathyroid hormone (PTH) levels are tested and show elevated calcium, phosphorous, and 1,25 dihydroxyvitamin D levels and low 25-hydroxyvitamin D levels (Table 1).A genetic panel looking for 40 genes associated with nephrolithiasis was sent to the laboratory but did not show any pathogenic mutation or variant of unknown significance.This patient’s presentation is significant for nephrolithiasis with hypercalciuria and hypercalcemia. Laboratory evaluation for kidney function and electrolytes, vitamin D and PTH levels, and spot and timed urine collection for stone risk profile are warranted in the initial evaluation for kidney stones in children. Imaging modalities such as renal ultrasonography and computed tomography are performed to localize the stone.The differential diagnosis of hypercalciuria in the pediatric population can be divided based on normal or elevated serum calcium levels (Figure 2). First, we discuss causes of hypercalciuria with hypercalcemia. Hypervitaminosis D can occur with excessive use of over-the-counter supplements containing 25-hydroxyvitamin D or fortified milk. Although hypervitaminosis D can cause kidney stones, our patient lacked other common symptoms of the condition, such as nausea, dizziness, or excessive thirst, and she did not report use of over-the-counter vitamin supplements. Elevated levels of 1,25 dihydroxyvitamin D can occur with ingestion of calcitriol when used as treatment for hypoparathyroidism, which our patient had not been previously diagnosed as having. Primary hyperparathyroidism is a rare condition in children but can be caused by a single parathyroid adenoma or multiple adenomas, as can be seen in familial hyperparathyroidism or multiple endocrine neoplasia.1 Without imaging, it was unknown whether the current patient had an adenoma. Endogenous overproduction of 1,25 dihydroxyvitamin D can occur in granulomatous conditions such as sarcoidosis, a multisystem disease affecting lung, skin, kidney, or eye. Our patient had no constitutional symptoms that typically manifest in sarcoidosis. Williams-Beuren syndrome is an autosomal dominant disorder and may involve endocrine abnormalities, such as hypercalcemia and hypercalciuria.2 It typically presents within the first few years after birth and with significant developmental delays, unlike the current patient.The elevated PTH level is another diagnostic clue when discussing the differential diagnosis. Williams-Beuren syndrome and sarcoidosis typically do not present with elevated PTH levels, but rare exceptions have been found for both conditions.3,4 In addition, medications that can cause elevated serum calcium levels include thiazide diuretics and lithium.5 As such, a medication history should be taken in all patients; it did not reveal use of these drugs in our patient.Patients with hypercalciuria and normal calcium levels can be further differentiated based on presence of metabolic alkalosis and hypokalemia as seen in Bartter syndrome and loop diuretic use, presence of low-molecular-weight proteinuria as in Dent disease, neurologic involvement as in Lowe syndrome, and acidosis as seen in distal renal tubular acidosis.In the context of elevated urinary calcium excretion, elevated PTH and 1,25 dihydroxyvitamin D levels, recurrent nephrolithiasis in a pediatric patient is most suggestive of a parathyroid adenoma. A sestamibi parathyroid scan was conducted on the patient. The scan showed persistent asymmetrical radiotracer accumulation in nodularity inferior to the left thyroid lobe. This finding and her laboratory values were most consistent with a parathyroid adenoma, causing primary hyperparathyroidism.More than 90% of cases of childhood primary hyperparathyroidism are caused by single parathyroid adenomas.1 Patients may also be asymptomatic or show nonspecific signs of nausea, vomiting, fatigue, constipation, or headache due to hypercalcemia.6 Owing to these nonlocalized symptoms, diagnosis and treatment may be delayed.7 More severe signs and symptoms may include arrhythmias, cardiac arrest, severe cognitive impairment, or altered consciousness.7,8 End-organ damage may present as kidney stones, bone involvement, or acute pancreatitis. Although parathyroid adenoma in the adult population is more common in females, the sex distribution in children is nearly equal.9 The definitive diagnosis of primary hyperparathyroidism requires an elevated serum calcium level with a concurrent elevated PTH level and hypercalciuria.6 Several studies have suggested that two 24-hour urine tests provide substantially more reliable results than a single collection.10 Hypercalciuria has been defined in children as urinary calcium excretion of more than 4 mg/kg per day.11 99m Tc sestamibi scintigraphy, which is the gold standard for identifying and localizing parathyroid adenoma, should follow confirmation of elevated serum calcium and PTH levels. The sestamibi scan will exhibit increased uptake and retention of the technetium radiotracer.9Various mutations have been found to be associated with hyperparathyroidism and parathyroid adenomas. These can be somatic or de novo mutations in the germline. Some common somatic mutations causing single parathyroid adenomas occur in MENIN and PRAD1.Presentation with flank pain led to the diagnosis of nephrolithiasis on renal ultrasonography. Given the development of hypercalciuria in our patient, she underwent blood testing, which revealed hypercalcemia and an elevated PTH level. This constellation of findings prompted concern for hyperparathyroidism and referral to endocrinology. A sestamibi scan confirmed the diagnosis of parathyroid adenoma. The genetic panel for this patient was negative for any genetic abnormalities involved with hyperparathyroidism.Once identified, minimally invasive parathyroid resection tends to be the most curative treatment of hyperparathyroidism caused by an adenoma. Nonsurgical management of hypercalcemia before definitive surgical treatment includes intravenous hydration, calcitonin, furosemide, and cinacalcet. Cinacalcet functions as a “calcimimetic” agent that can reduce PTH levels by enhancing the sensitivity of the calcium-sensing receptor in the parathyroid gland.Postoperatively, patients are at risk for hungry bone syndrome, with reports of 50% incidence. Hungry bone syndrome is a state of profound hypocalcemia that can last for days and is most notably seen after parathyroidectomy or thyroidectomy. The increased PTH secretion by the parathyroid adenoma results in increased bone resorption and suppression of the other parathyroid glands. After removal of the parathyroid adenoma there is rapid decline in PTH, resulting in decreased bone resorption and increased bone formation. This leads to an influx of calcium into the bones and thus a drop in serum calcium levels. In addition, the remaining parathyroid glands can take some time to recover from chronic suppression and may be unable to appropriately respond to the resultant decreasing calcium levels. This can lead to hypocalcemia, hypophosphatemia and hypomagnesemia that can be symptomatic and require supplementation. Optimizing vitamin D levels before surgery can be helpful,5 as well as close postoperative laboratory monitoring. In addition, some cases of primary hyperparathyroidism have reported failed initial surgeries, and contrastingly, others experience spontaneous remission without surgery.5The patient was hospitalized briefly for symptomatic hypercalcemia after her confirmatory diagnosis of parathyroid adenoma. A month later, she underwent adenoma resection of the left inferior parathyroid lobe. Preoperatively she received 2 doses of 50 000 U of ergocalciferol to treat her vitamin D deficiency (received on days –4 and –2 before surgery) with plans to continue weekly for 8 to 12 weeks. Transient hypocalcemia and hypophosphatemia occurred postoperatively due to hungry bone syndrome but were managed successfully with continued high-dose vitamin D, calcitriol, calcium, and phosphorus supplements. Although it is assumed that her renal stone was the result of hyperparathyroidism, it remains unclear why her initial urine studies were normal. Given reports of patients with parathyroid adenomas experiencing spontaneous remission, as well as reports of progressive increase in PTH levels with worsening of symptoms with time, it is speculated that her parathyroid adenoma was not necessarily significantly hyperactive at the time of the initial studies.12,13 She remains in remission to date, nearly 18 months since her adenoma resection, and is followed up every 6 months.Kidney stones in children always warrant additional evaluation and referral to nephrology.Hypercalciuria can often be missed based on the spot urine calcium/creatinine ratio. A 24-hour urine collection is needed if clinical suspicion is strong.Parathyroid adenoma can present as smoldering disease with stone formation before overt hypercalcemia and systemic symptoms develop.Urgent referral to endocrinology is warranted if hypercalcemia is noted in a patient with kidney stone to evaluate for hyperparathyroidism and manage the hypercalcemia.