INTRODUCTION — Nephrocalcinosis is characterized by the deposition of calcium in the kidney parenchyma and tubules [1]. Nephrocalcinosis may cause acute or chronic kidney injury or be incidentally detected radiographically in a patient with normal kidney function. Nephrocalcinosis is caused by multiple different conditions, and the kidney prognosis is determined by the underlying cause; whereas most patients with nephrocalcinosis do not progress to end-stage kidney disease, certain underlying conditions, if not effectively treated, may be associated with progressive kidney dysfunction. The pathogenesis, clinical presentation, causes, and treatment of nephrocalcinosis are discussed here.
DEFINITION AND CLASSIFICATION — The term nephrocalcinosis is used to describe the deposition of both calcium oxalate and calcium phosphate [1,2]. Some experts limit the definition of nephrocalcinosis to the deposition of calcium phosphate and refer to the deposition of calcium oxalate as oxalosis [3,4]. For the purposes of this review, we retain the broader definition of nephrocalcinosis to include both calcium phosphate and calcium oxalate. The term oxalosis will refer exclusively to calcium oxalate deposition.
The defining characteristic of nephrocalcinosis is generalized calcium deposition in the kidney [1,2]. Localized calcium deposition that occurs with focal kidney injury is not included in this definition.
Nephrocalcinosis is classified as follows [1,2]:
●Molecular or chemical – A measurable increase in intracellular calcium concentration exists but is not visible microscopically or via radiographic imaging.
●Microscopic – Mineral deposits are visible by light microscopic examination of tissue obtained by biopsy but not by radiographic imaging.
●Macroscopic – Calcification is visible by radiographic imaging.
Molecular nephrocalcinosis is most often observed in patients with overt hypercalcemia and is completely reversed upon correction of the hypercalcemia (see "Clinical manifestations of hypercalcemia"). Microscopic nephrocalcinosis is a precursor of macroscopic nephrocalcinosis but can also be associated with acute kidney injury as occurs in acute phosphate nephropathy following bowel cleansing with sodium phosphate preparations [3]. (See "Acute phosphate nephropathy".)
Nephrocalcinosis can involve the renal medulla or, much less often, the cortex. In the largest reported series of 375 patients with macroscopic nephrocalcinosis, 97 percent involved the medulla [1]. Cortical nephrocalcinosis accounted for less than 3 percent of cases and was usually due to severe underlying cortical disease, such as renal cortical necrosis (often associated with pregnancy) or chronic glomerulonephritis [1,5]. Other causes of cortical nephrocalcinosis include primary and secondary oxalosis (which can also cause medullary nephrocalcinosis) and kidney allograft rejection [6-8]. (See "Acute kidney injury in pregnancy", section on 'Renal cortical necrosis'.)
PATHOGENESIS — Nephrocalcinosis is caused by an increase in the urinary excretion of calcium, phosphate, and/or oxalate [2,9]. The most common cause of nephrocalcinosis is increased urinary calcium excretion with or without hypercalcemia. (See 'Risk factors' below.)
These metabolic abnormalities are also closely associated with nephrolithiasis, and patients frequently present with both conditions. However, for reasons that are not clear, nephrocalcinosis is not always associated with nephrolithiasis, and nephrolithiasis often occurs in the absence of nephrocalcinosis. In addition, nephrocalcinosis often suggests a serious metabolic defect, whereas nephrolithiasis is commonly observed in otherwise healthy individuals [2]. (See "Kidney stones in adults: Epidemiology and risk factors".)
One study evaluated the incidence of nephrocalcinosis in 67 patients with nephrolithiasis (14 with hydroxyapatite, 19 with brushite, and 34 with idiopathic calcium oxalate stones) who did not have the three most common forms of nephrocalcinosis, namely primary hyperparathyroidism, medullary sponge kidney, and distal renal tubular acidosis (RTA) [10]. Nephrocalcinosis was more common among the calcium phosphate stone formers than among the calcium oxalate stone formers (71 and 58 versus 18 percent for hydroxyapatite, brushite, and idiopathic calcium oxalate stones, respectively). In addition, the extent of nephrocalcinosis based upon a scoring system was also more severe in the calcium phosphate stone formers compared with the calcium oxalate stone formers. The exact mechanism for the increase in nephrocalcinosis associated with calcium phosphate nephrolithiasis in the absence of primary hyperparathyroidism, medullary sponge kidney, and distal RTA remains to be determined.
Calcium oxalate and calcium phosphate crystals form when the concentration of the reactants exceeds the saturation limit. In a careful histologic study of intraoperative kidney biopsy specimens from idiopathic calcium oxalate stone formers, calcium phosphate (hydroxyapatite) deposits (Randall's plaques [11]) were primarily noted in the inner medullary (papillary) interstitium in the basement membranes of the thin limbs of the loop of Henle [9,12], where tubular fluid is saturated even under normal circumstances [4,9].
These calcium phosphate plaques can enlarge into the surrounding interstitial tissue or rupture into the tubule lumen serving as a nidus for luminal calcium oxalate stone formation [2]. In vitro studies have shown that calcium phosphate can promote calcium oxalate crystallization. Randall's plaques are also seen in patients with calcium phosphate stones [13].
In the intraoperative biopsy study cited above, the histologic findings were different in patients who had undergone intestinal bypass (bariatric) surgery for obesity and subsequently developed calcium oxalate nephrolithiasis [9]. Crystal deposition was not present in the papillary interstitium as in idiopathic calcium oxalate stone formers. However, crystals were attached to the apical surface of collecting tubule cells or completely filled the tubular lumen, appearing to obstruct a number of inner medullary collecting ducts.
A later series from the same group described the endoscopic findings in the renal papillae in 23 stone formers undergoing percutaneous nephrolithotomy [14]. All kidneys had papillary plaque, which was found in over 90 percent of papillae. Eleven patients had attached stones, which appeared to occur on Randall's plaques.
Oxalate crystals are either homogeneous (composed exclusively of calcium and oxalate) or heterogeneous (composed of calcium, oxalate, and phosphate). In general, homogeneous calcium oxalate crystals form only in the setting of marked hyperoxaluria, such as that which occurs in primary hyperoxaluria or ethylene glycol toxicity. Heterogeneous crystals form in the setting of milder degrees of hyperoxaluria [2,9]. (See "Primary hyperoxaluria" and "Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis".)
PATHOLOGY — The primary histologic finding on kidney biopsy in patients with nephrocalcinosis is tubular, intracellular, and interstitial basophilic calcifications. Calcium phosphate deposits are distinguished from calcium oxalate by positive staining with the von Kossa stain (picture 1) and by the absence of birefringence under polarized light. Tubular atrophy, interstitial fibrosis, and interstitial inflammation with a lymphocytic infiltrate may accompany chronic calcium phosphate or calcium oxalate deposition.
RISK FACTORS — Nephrocalcinosis is associated with conditions that cause hypercalcemia, hyperphosphatemia, and the increased excretion of calcium, phosphate, and/or oxalate in the urine. Hypocitraturia also may contribute, particularly in patients with distal (type 1) renal tubular acidosis (RTA). Citrate normally inhibits crystal formation by forming a soluble complex with calcium [1,15]. (See "Kidney stones in adults: Epidemiology and risk factors", section on 'Low urine citrate'.)
A high urine pH is also observed in patients who have calcium phosphate nephrocalcinosis.
Underlying conditions that have been associated with calcium phosphate crystal formation may be categorized into those that cause the following:
●Hypercalciuria with hypercalcemia
●Hypercalciuria without hypercalcemia
●Hyperphosphaturia
Such categories are useful in determining the specific diseases that underlie newly diagnosed nephrocalcinosis in the individual patient.
Hypercalcemia and hypercalciuria — The following conditions can cause nephrocalcinosis in association with hypercalcemia with hypercalciuria:
●Primary hyperparathyroidism
●Sarcoidosis
●Vitamin D therapy
●Milk-alkali syndrome (see "The milk-alkali syndrome")
●Williams syndrome (see "Williams syndrome")
●Congenital hypothyroidism (see "Clinical features and detection of congenital hypothyroidism")
Primary hyperparathyroidism — Nephrocalcinosis and nephrolithiasis are the most common kidney manifestations of primary hyperparathyroidism [16]. The reported incidence of nephrocalcinosis among patients with primary hyperparathyroidism is between 16 and 22 percent [17]. (See "Primary hyperparathyroidism: Clinical manifestations", section on 'Symptomatic primary hyperparathyroidism'.)
Sarcoidosis — Nephrocalcinosis is common in chronic sarcoidosis and other granulomatous disorders associated with hypercalcemia and hypercalciuria. Nephrocalcinosis is reported in 13 percent of patients with sarcoidosis and in 50 percent of those with known kidney involvement [18,19]. (See "Kidney disease in sarcoidosis", section on 'Epidemiology' and "Kidney disease in sarcoidosis", section on 'Nephrolithiasis and nephrocalcinosis'.)
Hyperabsorption of dietary calcium occurs in up to 50 percent of cases of sarcoidosis. The excess calcium is excreted in the urine, leading to hypercalciuria in approximately 40 percent and, in 2 to 20 percent of cases, hypercalcemia. (See "Kidney disease in sarcoidosis", section on 'Pathogenesis'.)
Nephrocalcinosis in patients with sarcoidosis can also occur in those with hypercalciuria without hypercalcemia. (See 'Hypercalciuria without hypercalcemia' below.)
Vitamin D therapy — Nephrocalcinosis may occur secondary to the administration of vitamin D preparations, which increase both the absorption of ingested calcium and bone resorption, resulting in hypercalcemia and hypercalciuria [1]. This is a particular problem when calcitriol is coadministered with oral phosphate supplements, both of which are commonly used to treat X-linked hypophosphatemic rickets [20-22] and other disorders characterized by hyperphosphaturia and hypophosphatemia. In different series, nephrocalcinosis was detected radiologically in 19 of 24 and 11 of 23 children with X-linked hypophosphatemic rickets [20,22], 3 of 11 children with vitamin D-dependent rickets type I [22], and 26 of 41 children with nephropathic cystinosis [23].
●(See "Etiology of hypercalcemia", section on 'Hypervitaminosis D'.)
●(See "Cystinosis".)
Hypercalciuria without hypercalcemia — The following conditions can cause nephrocalcinosis in association with hypercalciuria without hypercalcemia:
●Distal RTA
●Medullary sponge kidney
●Neonatal nephrocalcinosis and loop diuretics
●Inherited tubulopathies
●Chronic hypokalemia
●Beta thalassemia
●Sarcoidosis
Distal (type 1) renal tubular acidosis — Distal (type 1) RTA is the most common cause of nephrocalcinosis (particularly in children) due to hypercalciuria without hypercalcemia [1,24]. Distal RTA results in a systemic acidosis that requires increased buffering of acid by bone, with the subsequent release of bone calcium and phosphate. Metabolic acidosis is also associated with hypocitraturia, which can promote calcium precipitation in the tubules. (See "Kidney stones in adults: Epidemiology and risk factors", section on 'Low urine citrate'.)
The reported prevalence of nephrocalcinosis in patients with distal RTA ranges from 60 to 80 percent [1,25]. However, it is difficult to interpret this estimate since nephrocalcinosis itself frequently causes defects in distal acidification. (See "Nephrolithiasis in renal tubular acidosis".)
Medullary sponge kidney — Nephrocalcinosis is observed radiographically in 30 to 50 percent of patients with medullary sponge kidney (image 1A-B) [26]. In addition to hypercalciuria, medullary sponge kidney is characterized by hypocitraturia, which contributes to the development of nephrocalcinosis. (See "Medullary sponge kidney".)
Neonatal nephrocalcinosis — Nephrocalcinosis is common in neonates of low birth weight, with a reported incidence that can exceed 60 percent in infants with a birth weight below 1500 g. The most common cause is the prolonged administration of a loop diuretic (most often furosemide). Less common causes include Williams syndrome, RTA, and primary neonatal hyperparathyroidism. (See "Nephrocalcinosis in neonates".)
Loop diuretics — Loop diuretics are widely used in adults and may cause nephrocalcinosis as described in neonates in the preceding section. The risk of nephrocalcinosis appears to be limited to patients taking very high doses for a prolonged period. This issue was addressed in a review of 18 consecutive adults who were treated with furosemide for 3 to 25 years because of weight gain or idiopathic edema [27]. Nephrocalcinosis was detected on kidney ultrasonography in 15 of the patients (all but one were women). The mean dose was 538 mg of furosemide per day (range 120 to 2800 mg/day) compared with 40 to 80 mg/day in the three patients without nephrocalcinosis. (See "Idiopathic edema", section on 'Diuretic-induced edema'.)
Inherited tubulopathies — Multiple inherited tubular disorders directly cause hypercalciuria. Whereas some disorders cause isolated hypercalciuria, others cause concurrent hypercalciuria and hyperphosphaturia.
The following conditions cause isolated hypercalciuria but not hyperphosphaturia (all are discussed elsewhere in UpToDate and links are provided):
●Bartter syndrome, which simulates a chronic low-dose infusion of a loop diuretic, since the defect involves the Na-K-2Cl cotransporter in the thick ascending limb, which is the site of action of loop diuretics. Hypercalciuria is thought to be primarily responsible for the tendency to nephrocalcinosis [28], but chronic hypokalemia also may contribute. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations" and 'Chronic hypokalemia' below.)
●Hypomagnesemic hypercalciuric nephrocalcinosis. (See "Hypomagnesemia: Causes of hypomagnesemia".)
●Autosomal dominant hypocalcemia. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)
The following inherited diseases cause both hypercalciuria and hyperphosphaturia:
●Dent disease (see "Dent disease (X-linked recessive nephrolithiasis)")
●Lowe syndrome (see "Dent disease (X-linked recessive nephrolithiasis)", section on 'Dent disease 2 versus Lowe syndrome')
Chronic hypokalemia — Hypercalciuria and nephrocalcinosis have been observed in chronic hypokalemic states including primary aldosteronism and Liddle's syndrome [29-32]. Nephrocalcinosis and chronic hypokalemia are also seen in distal (type 1) RTA and Bartter syndrome but, as noted above, hypercalciuria is thought to be primarily responsible. Support for this hypothesis comes from the observation that chronic hypokalemia in Gitelman syndrome, which involves a mutation in the thiazide-sensitive sodium-chloride cotransporter in the distal tubule, is associated with hypocalciuria and the absence of nephrocalcinosis [33]. (See 'Sarcoidosis' above and 'Distal (type 1) renal tubular acidosis' above and "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations".)
Beta thalassemia — Nephrocalcinosis was detected in 65 patients at a Northern Italian medical center between 2007 and 2013 [34]. Of these patients, 23 percent had beta thalassemia. All of the patients with beta thalassemia had hypercalciuria, and some were found to have a high fractional excretion of phosphate. In another study of 206 North American patients with thalassemia, 29 percent were noted to have hypercalciuria, and a higher intensity of transfusions was associated with a greater frequency and degree of hypercalciuria [35]. The etiology of hypercalciuria in this population is not clear. Of note, these studies were done prior to the widespread availability of oral chelating agents, which may also be associated with renal tubular injury.
Hyperphosphaturia — Hyperphosphaturia with or without hypercalciuria is a risk factor for nephrocalcinosis. Hyperphosphaturia may occur with or without hyperphosphatemia. Hyperphosphaturia and hyperphosphatemia plus acute kidney failure are observed in tumor lysis syndrome and after ingestion of oral sodium phosphate bowel preparations. These acute disorders are typically characterized by microscopic nephrocalcinosis and are discussed elsewhere. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Hyperphosphatemia' and "Acute phosphate nephropathy".)
Hyperphosphaturia in the absence of hyperphosphatemia (ie, phosphate wasting) usually results from inherited tubulopathies, although acquired forms may be observed in the setting of malignancy or kidney transplantation. (See "Hypophosphatemia: Causes of hypophosphatemia", section on 'Primary renal phosphate wasting' and "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation", section on 'Hypophosphatemia'.)
The hyperphosphaturia can occur as an isolated abnormality or with hypercalciuria in inherited tubulopathies (such as Dent disease and Lowe syndrome mentioned above). (See 'Inherited tubulopathies' above.)
Inherited tubular defects that cause hyperphosphaturia but not hypercalciuria include X-linked hypophosphatemic rickets and autosomal dominant and autosomal recessive hypophosphatemic rickets. These disorders are discussed in detail elsewhere. Treatment of these conditions consists of oral phosphate supplements (which increase phosphate excretion) and calcitriol (which increases calcium excretion), both of which can contribute to the development of nephrocalcinosis. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia" and 'Vitamin D therapy' above.)
Hyperoxaluria — Primary hyperoxaluria is the major risk factor for the development of oxalosis. Primary hyperoxaluria is an autosomal recessive disorder that is characterized by the increased synthesis of oxalate [7,36]. In a series of 95 children with primary hyperoxaluria reported to an international registry, 90 percent had nephrolithiasis at diagnosis and 48 percent had nephrocalcinosis [36]. (See "Primary hyperoxaluria".)
Hyperoxaluria may also be secondary to the increased enteric absorption of oxalate [37]. Fat malabsorption is the most common cause of increased oxalate absorption [37]. The mechanism by which fat malabsorption increases oxalate absorption is via the binding of calcium by free fatty acids in the colon. This decreases the amount of calcium that is available to bind to oxalate and form insoluble calcium oxalate and results in increased oxalate absorption since free oxalate is more easily absorbed compared with calcium-bound oxalate [38].
Fat malabsorption leading to hyperoxaluria and nephrocalcinosis can be seen in a variety of clinical settings, including pancreatic insufficiency, inflammatory bowel disease, bowel resection or jejunoileal or gastric bypass, use of the weight reduction drug orlistat, which causes fat malabsorption by inhibiting gastric and pancreatic lipases [38-41], and cystic fibrosis, which causes pancreatic insufficiency and in which other factors promoting calcium deposition (such as hypercalciuria) may also be present (table 1). (See "Chronic complications of the short bowel syndrome in adults", section on 'Nephrolithiasis' and "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Nephrolithiasis and nephrocalcinosis'.)
Secondary hyperoxaluria may also be due to the chronic ingestion of excessive amounts of oxalate precursors, such as vitamin C, or foods rich in oxalic acid such as rhubarb, parsley, cocoa, nuts, or star fruit (carambola) [42].
CLINICAL PRESENTATION — Nephrocalcinosis is, in most cases, an asymptomatic, chronic, and slowly progressive disease that is discovered as an incidental finding during radiographic imaging of the abdomen or chest. Such imaging may be obtained as part of the evaluation of nephrolithiasis, which often coexists with nephrocalcinosis.
However, occasional patients present with clinical symptoms that are related to nephrocalcinosis or to the causative process (eg, hypercalcemia). These include renal colic and polyuria and polydipsia:
●Renal colic is most often due to associated nephrolithiasis as may occur in patients with chronic hypercalciuria. A less common cause is extrusion of calcified nodules from the interstitium into the calyceal system [1].
●Nocturia, polyuria, and polydipsia due to impaired urinary concentrating ability (ie, nephrogenic diabetes insipidus) as may occur in patients with hypercalcemia, medullary nephrocalcinosis of any cause, or in children with Bartter syndrome in whom the genetic defect impairs loop sodium chloride reabsorption, which is essential for concentrating ability [43].
There are several causes of nephrocalcinosis that are typically acute and present only with kidney failure. These include tumor lysis syndrome, acute phosphate nephropathy, and occasional cases of enteric hyperoxaluria.
●(See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)
●(See "Acute phosphate nephropathy".)
●(See "Chronic complications of the short bowel syndrome in adults", section on 'Nephrolithiasis'.)
Laboratory studies — The urinalysis in patients with nephrocalcinosis may be benign or reveal sterile pyuria or hematuria, especially in the setting of intraluminal stone formation and obstruction [1]. Proteinuria is usually less than 500 mg/day except among patients with Dent disease who often present with significant proteinuria. (See "Dent disease (X-linked recessive nephrolithiasis)".)
Several reports have described an association between erythrocytosis and nephrocalcinosis [44,45]. Erythropoietin levels are increased in most of these patients, which has suggested a possible mechanism of nephrocalcinosis-induced regions of medullary hypoxia [44].
Depending upon the underlying disease, serum calcium and/or phosphate may be increased, and a 24-hour urine collection may show increased excretion of calcium, phosphate, and/or oxalate. However, 24-hour urine collections are not part of the routine work-up of patients with unexplained chronic kidney disease; they are usually obtained if there is a history of nephrolithiasis or after imaging has established the diagnosis of nephrocalcinosis in an attempt to identify treatable predisposing factors.
DIAGNOSIS — Nephrocalcinosis should be included in the differential diagnosis of patients who present with chronic kidney disease, a benign urinalysis, and little or no proteinuria, particularly in those who are hypercalcemic or have a history of one of the above causes of nephrocalcinosis. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting", section on 'Urinalysis' and "Urinalysis in the diagnosis of kidney disease", section on 'Common patterns of abnormal urinary findings'.)
The diagnosis of chronic nephrocalcinosis can only be made by imaging or, much less often, kidney biopsy. In addition to being part of the evaluation for chronic kidney disease, imaging may detect nephrocalcinosis as an incidental finding when performed for indications unrelated to the kidneys or as part of an evaluation for nephrolithiasis. (See 'Imaging' below.)
Imaging — Macroscopic nephrocalcinosis may be detected by multiple imaging techniques, including abdominal plain film, ultrasound, and computed tomographic (CT) imaging [27,46-49]. Calcification is poorly visualized by magnetic resonance imaging [50].
Limited data suggest that ultrasound and CT are more sensitive than abdominal plain film for the detection of nephrocalcinosis, particularly in patients without severe disease. One study, for example, evaluated 62 patients seen at a stone clinic in which an imaging test suggested either nephrocalcinosis or nephrolithiasis (pelvicalyceal calcifications) [46]. All patients underwent abdominal plain film, ultrasound, and CT. Nephrocalcinosis was considered present if at least two radiologists made the diagnosis on ultrasound and/or CT. The sensitivity was 85 to 90 percent with ultrasound, 81 to 86 percent with CT scan, and 63 to 66 percent with abdominal plain film [46].
The highest sensitivity and specificity (92 and 89 percent) were attained when two of the radiologic tests suggested the presence of nephrocalcinosis since there is not always concordance between ultrasound and CT. However, this study had no independent gold standard for the diagnosis. Similar findings were noted in a series of 15 long-term furosemide abusers who had characteristic features of nephrocalcinosis on ultrasound; only 12 had positive findings on CT [27]. (See 'Loop diuretics' above.)
These findings suggest that ultrasound and CT are the preferred imaging tests for the diagnosis of nephrocalcinosis. However, in the absence of a reason to suspect nephrocalcinosis (eg, hypercalcemia or a history of nephrolithiasis), ultrasound is usually the initial imaging test that is performed in patients who present with chronic kidney disease, a bland urinalysis, and little or no proteinuria. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting", section on 'Radiologic studies'.)
Once the diagnosis of nephrocalcinosis has been confirmed, the subsequent evaluation is directed at determining the underlying cause. This evaluation is important since the underlying condition may require treatment for reasons independent of its effect on kidney function (such as primary hyperparathyroidism or sarcoidosis) and because the underlying condition generally determines the kidney prognosis. Whereas some causes of nephrocalcinosis, such as primary hyperoxaluria, commonly result in end-stage kidney disease, others, such as medullary sponge kidney, rarely cause progressive kidney disease. (See "Primary hyperoxaluria", section on 'Clinical and laboratory manifestations' and 'Evaluation subsequent to diagnosis' below and "Medullary sponge kidney", section on 'Prognosis'.)
Evaluation subsequent to diagnosis — Laboratory testing is performed in an attempt to identify possible causes of nephrocalcinosis. Initial testing includes measurement of serum electrolytes, calcium, and phosphate, and the urine pH. If these tests do not suggest a cause (eg, hypercalcemia or distal renal tubular acidosis [RTA]), two 24-hour urine collections should be obtained to measure the excretion of calcium, phosphate, oxalate, citrate, and to assess the completeness of the collection, creatinine.
Based upon the results of these laboratory tests, the following approaches are warranted:
●Patients with hypercalcemia should be evaluated for the cause. (See 'Hypercalcemia and hypercalciuria' above and "Etiology of hypercalcemia" and "Diagnostic approach to hypercalcemia".)
●Hypercalciuria in the absence of hypercalcemia can be caused by a variety of disorders that are discussed above. (See 'Hypercalciuria without hypercalcemia' above.)
●Hyperphosphaturia in the absence of hyperphosphatemia suggests a hereditary form of hypophosphatemic rickets in children and an acquired form due to a tumor or following a kidney transplant in adults. (See 'Hyperphosphaturia' above.)
●In infants, in addition to neonatal primary hyperparathyroidism, one should consider furosemide-induced nephrocalcinosis, Williams syndrome, and distal (type 1) RTA. The last disorder, which can also be caused by nephrocalcinosis, should be suspected in patients with an otherwise unexplained normal anion gap acidosis and a urine pH above 5.6. (See "Nephrocalcinosis in neonates" and "Williams syndrome" and "Nephrolithiasis in renal tubular acidosis" and "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis".)
●Hyperoxaluria suggests either primary or secondary hyperoxaluria (most often due to malabsorption). (See 'Hyperoxaluria' above and "Primary hyperoxaluria".)
If an etiology of nephrocalcinosis is not apparent based upon history, physical examination, and laboratory testing, genetic testing for a monogenic cause of nephrocalcinosis should be considered. Establishing the correct diagnosis in a timely fashion may provide more accurate prognostic information and enable patients to receive effective treatment early in the disease course [51]. (See 'Inherited tubulopathies' above.)
TREATMENT — Therapy is directed at the underlying cause of the nephrocalcinosis. Among patients with hypercalcemia, for example, treatment includes the correction of hypercalcemia by parathyroidectomy in primary hyperparathyroidism and glucocorticoid therapy in sarcoidosis. (See "Primary hyperparathyroidism: Management" and "Kidney disease in sarcoidosis", section on 'Treatment'.)
Measures may be undertaken to reduce the urinary concentration and increase the solubility of the substances (calcium, phosphate, or oxalate) contributing to nephrocalcinosis. Data that support such interventions are extrapolated from studies of patients with nephrolithiasis; no studies have demonstrated a beneficial effect among patients with established nephrocalcinosis. (See "Kidney stones in adults: Prevention of recurrent kidney stones".)
Increasing fluid intake to produce urine output of >2 L/day may be beneficial for all patients with nephrocalcinosis.
Among patients with hypercalciuria, urinary calcium excretion may be reduced by dietary modifications that include restriction of animal protein, restriction of sodium intake to <100 mEq/day, and liberalization of potassium intake. If dietary measures alone do not result in an adequate reduction of hypercalciuria, a thiazide diuretic can be administered in patients who do not have hypercalcemia.
The administration of citrate may increase the solubility of calcium in urine and limit the development of nephrocalcinosis. Among patients who have hypocitraturia and a urine pH less than 7, we give potassium citrate to achieve a normal urinary citrate level. We do not give citrate to patients who have urine pH equal to or greater than 7.
Specific management of the underlying causes of nephrocalcinosis is discussed elsewhere, and links are provided above. Management of obstructing stones is similar to nephrolithiasis that is not associated with nephrocalcinosis and is discussed elsewhere. (See "Kidney stones in adults: Surgical management of kidney and ureteral stones".)
In addition to the specific therapies aimed at nephrocalcinosis, patients should receive general chronic kidney disease therapies. (See "Overview of the management of chronic kidney disease in adults".)
PROGNOSIS — The kidney prognosis of nephrocalcinosis is determined by the underlying cause. While most patients with nephrocalcinosis do not progress to end-stage kidney disease, certain underlying causes, if not effectively treated, are more likely to be associated with progressive kidney dysfunction. These include primary hyperoxaluria, hypomagnesemic hypercalciuric nephrocalcinosis, and Dent disease. On the other hand, patients with medullary sponge kidney or distal renal tubular acidosis (RTA) rarely develop chronic kidney disease [1]. (See "Primary hyperoxaluria" and "Hypomagnesemia: Causes of hypomagnesemia" and "Dent disease (X-linked recessive nephrolithiasis)".)
Once nephrocalcinosis is detected radiographically, it is unlikely to be reversed. However, partial reversal has been reported in patients who have had successful treatment of hypercalciuria and among patients with hyperoxaluria following corrective intestinal surgery [1]. Complete resolution of neonatal nephrocalcinosis is generally observed after furosemide is stopped. (See "Nephrocalcinosis in neonates".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)
SUMMARY AND RECOMMENDATIONS
●Nephrocalcinosis is characterized by the generalized deposition of either calcium phosphate or calcium oxalate in the kidney medulla or cortex. Patients who develop nephrocalcinosis may have acute or chronic kidney injury or may have normal kidney function. Nephrocalcinosis is often incidentally detected by imaging studies that are obtained for reasons unrelated to the kidney. (See 'Introduction' above.)
●The prognosis of nephrocalcinosis depends upon the underlying cause. While most patients do not progress to end-stage kidney disease, patients with primary hyperoxaluria, hypomagnesemic hypercalciuric nephrocalcinosis, and Dent disease often result in end-stage kidney disease. (See 'Prognosis' above.)
●Nephrocalcinosis may be detected by plain film, ultrasound, and computed tomographic (CT) imaging but less often by magnetic resonance imaging. (See 'Imaging' above.)
●The underlying cause of nephrocalcinosis should be determined and treated if possible since the kidney prognosis is determined by the underlying disease. No specific treatment has been shown to prevent progression of nephrocalcinosis. Data extrapolated from studies of individuals with nephrolithiasis provide support for interventions that reduce the urinary concentration and increase solubility of the substances (calcium, phosphate, or oxalate) that contribute to nephrocalcinosis (see 'Treatment' above and "Kidney stones in adults: Prevention of recurrent kidney stones"):
•Among all patients with nephrocalcinosis, we suggest a liberal fluid intake to achieve a urine volume of 2 L/day (Grade 2C).
•Among all patients with nephrocalcinosis and hypercalciuria we suggest modest restriction (approximately 0.7 gram/kg) of dietary intake of animal protein (Grade 2C).
•Among all patients with nephrocalcinosis and hypercalciuria we suggest restriction of dietary sodium intake to <100 mEq/day (approximately 2.3 g of sodium) (Grade 2C).
•Among patients with nephrocalcinosis who have hypocitraturia and urine pH less than 7, we suggest the administration of potassium citrate to achieve normal urinary citrate levels (Grade 2C). Citrate should not be given to patients who have a urine pH equal or greater than 7 even if hypocitraturia is present.
