Idiopathic hypercalciuria (ORPHA:2197)
A rare renal disease characterized by persistent excess urinary calcium excretion in the absence of an underlying systemic disease and hypercalcemia. The condition leads to an increased risk for the formation of kidney stones and nephrocalcinosis, as well as reduced bone mineral density with increased incidence of fractures in some patients.
Epidemiology
Prevalence is estimated at 2.2-6.4% in the pediatric population and is the most common cause of calcium nephrolithiasis in childhood.
Clinical description
Idiopathic hypercalciuria (IH) mainly presents in childhood with variable clinical symptoms including abdominal or back pain, cloudy urine (more evident at the first voiding of the day), sediment in urine collection, gross or microscopic hematuria, urinary tract infections, urinary urgency, incontinence or dysuria. Calcium kidney stones occur frequently as a result of supersaturation of calcium oxalate and calcium phosphate in urine, leading to the formation of mineral plaques in the renal papillary interstitium and subsequent growth of a calcium body. Excessive calcium excretion may also result in decreased bone mineral density and disturbance of bone mineralization.
Etiology
The disorder can be caused by reduced tubular calcium reabsorption (renal IH) or by increased intestinal calcium absorption associated to a vitamin D receptor activation (absorptive IH), or as a result of both. Genetic susceptibility to absorptive IH is correlated to mutations on the ADCY10 gene (1q23.3-q24) and on the 4q33-qter segment, and a history of nephrolithiasis is frequently reported in first-degree relatives. Furthermore, pathological elevation of tissue vitamin D receptor (VDR) level is suggested as a molecular basis of IH, which may elevate intestinal calcium absorption and bone resorption, and decrease renal tubule calcium reabsorption. Environmental factors including dietary habits also influence the disease.
Diagnostic methods
Diagnosis is based on evidence of repeated hypercalciuria in the fasting or fed state, and in the absence of any underlying cause. Hypercalciuria is determined on 24-hour urine collection test, and is often associated with a calcium/creatinine ratio greater than 0.20 mg/mg. Kidney stones may be revealed by ultrasound and high resolution CT imaging of the urinary tract.
Differential diagnosis
Conditions in which urine calcium levels may be increased should be excluded, including hypercalcemia, bone metabolic diseases (e.g. primary hyperparathyroidism, Paget disease), renal tubular acidosis, metabolic acidosis, chronic renal failure, nephrocalcinosis of other origin, long-term immobilization, and drugs affecting bone metabolism (glucocorticoids, diuretics, vitamin D).
Genetic counseling
The disease follows an autosomal dominant inheritance. Genetic counselling should be provided to family members and affected parents, informing them of the 50% risk of reoccurrence. Clinical variability is explained by dietary and other environmental factors.
Management and treatment
Treatment is with dietary management ensuring daily calcium requirements (1,200 mg/day in adults or equivalent reference values for children ), preferably sourced from food, a reduced sodium intake (up to 1.5 g/day in adults or an equivalent quantity in children), moderation of animal protein, and a fluid intake of 3 to 3.5 liters daily depending on climate, lifestyle and working conditions. Thiazide diuretics and potassium citrate are commonly used to prevent persistent symptoms, recurrence of stone formation, development of nephrocalcinosis, and osteopenia and, when dietary adjustments fail, to decrease urinary calcium supersaturation. A urinary calcium: citrate ratio ≥ 0.25 is a risk marker for nephrolithiasis. Monitoring nutritional vitamin D deficiency is recommended but excessive supplementation should be avoided to prevent further excretion of urinary calcium.
Prognosis
The prognosis of IH is usually favorable when treated appropriately. However, persistent hypercalciuria in children may decrease bone formation and lead to poor bone health in adulthood with osteopenia, osteoporosis and increased risks of fractures, whereas recurrent nephrolithiasis may result in progressive renal damage.

                            Last update: 
                            February 2021


                            - Expert reviewer(s): 
                            Pr Gema ARICETA | ERKNet*


                                * European Reference Network