Nephrocalcinosis

INTRODUCTION — Nephrocalcinosis is characterized by the deposition of calcium salts in the kidney parenchyma and tubules. 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 kidney failure, certain underlying conditions, if not effectively treated, may be associated with progressive chronic kidney disease and sometimes kidney failure.

This topic will review the pathogenesis, causes, clinical presentation, diagnosis, and treatment of nephrocalcinosis. Nephrocalcinosis in neonates is discussed separately. (See "Nephrocalcinosis in neonates".)

DEFINITION AND CLASSIFICATION — The term nephrocalcinosis is used to describe the deposition of calcium oxalate or calcium phosphate in the kidney [1-3]. Some experts limit the definition of nephrocalcinosis to the deposition of calcium phosphate and refer to the deposition of calcium oxalate as oxalosis [4,5]. 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 calcium deposition in the kidney [3]. Very focal or localized calcium deposition that occurs with focal kidney injury is not included in this definition.

Nephrocalcinosis is classified as follows [2,3]:

●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.

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 [4]. (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 [2]. 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 [2,6]. Other causes of cortical nephrocalcinosis include primary and secondary oxalosis (which can also cause medullary nephrocalcinosis) and kidney allograft rejection [7-9].

PATHOGENESIS — Nephrocalcinosis is caused by an increase in calcium, phosphate, and/or oxalate in the kidney tubular fluid [3,10]. The most common cause of nephrocalcinosis is increased urinary calcium excretion with or without hypercalcemia. (See 'Risk factors and causes' 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 [3]. (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) [11]. 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 [12]) were primarily noted in the inner medullary (papillary) interstitium in the basement membranes of the thin limbs of the loop of Henle [10,13], where tubular fluid is saturated even under normal circumstances [5,10].

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 [3]. 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 [14].

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 [10]. 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 [15]. 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.

Calcium oxalate stones may be pure calcium oxalate or an admixture that also contains calcium phosphate. In general, homogeneous calcium oxalate crystals within the kidney parenchyma form only in the setting of markedly high urine oxalate, such as that which occurs in primary hyperoxaluria or ethylene glycol toxicity. Heterogeneous crystals form in the setting of milder degrees of hyperoxaluria [3,10]. (See "Primary hyperoxaluria" and "Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis".)

RISK FACTORS AND CAUSES — 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 inhibits crystal formation by forming a soluble complex with calcium [2,16]. (See "Kidney stones in adults: Epidemiology and risk factors", section on 'Low urine citrate'.)

Underlying conditions that have been associated with nephrocalcinosis may be categorized into those that cause the following:

●High urine calcium with hypercalcemia

●High urine calcium without hypercalcemia

●High urine phosphate

●High urine oxalate

A variety of definitions for "normal" are used for each of these urinary parameters. However, the values for these definitions are arbitrary and additional data suggest a more linear relation for each of these factors. (See "Kidney stones in adults: Epidemiology and risk factors", section on 'High urine calcium' and "Kidney stones in adults: Epidemiology and risk factors", section on 'High urine oxalate'.)

Such categories are useful in determining the specific diseases that underlie newly diagnosed nephrocalcinosis in the individual patient.

High urine calcium with hypercalcemia — The following conditions can cause nephrocalcinosis in association with high urine calcium and hypercalcemia.

The definition of high urine calcium is arbitrary, and the urinary calcium level above which one is considered to be at risk for nephrocalcinosis is not clear, because the relationship between urine calcium and risk of nephrocalcinosis is likely continuous, similar to the relationship between urine calcium and the risk of kidney stone formation. (See "Kidney stones in adults: Epidemiology and risk factors", section on 'High urine calcium'.)

Primary hyperparathyroidism — Nephrocalcinosis and nephrolithiasis are the most common kidney manifestations of primary hyperparathyroidism [17]. The reported incidence of nephrocalcinosis among patients with primary hyperparathyroidism is between 16 and 22 percent [18]. (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 high urine calcium. Nephrocalcinosis is reported in between 5 and 13 percent of patients with sarcoidosis and in 50 percent of those with known kidney involvement [19,20]. (See "Kidney disease in sarcoidosis", section on '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 high urine calcium in approximately 40 percent and, in 2 to 20 percent of cases, hypercalcemia. (See "Kidney disease in sarcoidosis", section on 'Nephrocalcinosis'.)

Nephrocalcinosis in patients with sarcoidosis can also occur in those with high urine calcium without hypercalcemia. (See 'High urine calcium 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 high urine calcium [2]. 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 [21-23] and other disorders characterized by high urine phosphate and hypophosphatemia. In different series, nephrocalcinosis was detected radiologically in 79 and 48 percent of children with X-linked hypophosphatemic rickets [21,23], 27 percent of children with vitamin D–dependent rickets type I [23], and 59 percent of children with nephropathic cystinosis [24].

●(See "Etiology of hypercalcemia", section on 'Hypervitaminosis D'.)

●(See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Complications of phosphate-calcitriol therapy'.)

●(See "Cystinosis".)

●(See "Etiology and treatment of calcipenic rickets in children", section on '1-alpha-hydroxylase deficiency'.)

Other conditions — Other conditions that can cause nephrocalcinosis in association with hypercalcemia and high urine calcium include:

●Milk-alkali syndrome (see "The milk-alkali syndrome")

●Williams syndrome (see "Williams syndrome")

●Congenital hypothyroidism (see "Clinical features and detection of congenital hypothyroidism")

●Idiopathic infantile hypercalcemia (see "Nephrocalcinosis in neonates", section on 'Hypercalcemia')

High urine calcium without hypercalcemia — The following conditions can cause nephrocalcinosis in association with high urine calcium without hypercalcemia.

Distal (type 1) renal tubular acidosis — Distal (type 1) RTA is the most common cause of nephrocalcinosis (particularly in children) due to high urine calcium without hypercalcemia [2,25]. Distal RTA may be acquired and develop as part of an autoimmune disease, such as Sjogren's disease or systemic lupus erythematosus, or secondary to certain medications. Distal RTA may also be inherited. 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 salt 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 [2,26]. 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) [27]. In addition to being characterized by high urine calcium, 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 very high doses of furosemide for 3 to 25 years because of weight gain or idiopathic edema [28]. Nephrocalcinosis was detected on kidney ultrasonography in 15 of the patients (all but one were female). 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 high urine calcium. Whereas some disorders cause isolated high urine calcium, others cause concurrent high urine calcium and high urine phosphate.

The following conditions cause isolated high urine calcium but not high urine phosphate:

●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. High urine calcium is thought to be primarily responsible for the tendency to nephrocalcinosis [29], 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 high urine calcium and high urine phosphate:

●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 — High urine calcium and nephrocalcinosis have been observed in chronic hypokalemic states including primary aldosteronism and Liddle's syndrome [30-33]. Nephrocalcinosis and chronic hypokalemia are also seen in distal (type 1) RTA and Bartter syndrome, but as noted above, high urine calcium 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 [34]. (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 [35]. Of these patients, 23 percent had beta thalassemia. All of the patients with beta thalassemia had high urine calcium, 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 high urine calcium, and a higher intensity of transfusions was associated with a greater frequency and degree of high urine calcium [36]. The etiology of high urine calcium 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.

High urine phosphate — High urine phosphate with or without high urine calcium is a risk factor for nephrocalcinosis. High urine phosphate may occur with or without hyperphosphatemia. High urine phosphate 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".)

High urine phosphate 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 high urine phosphate can occur as an isolated abnormality or with high urine calcium in inherited tubulopathies (such as Dent disease and Lowe syndrome mentioned above). (See 'Inherited tubulopathies' above.)

Inherited tubular defects that cause high urine phosphate but not high urine calcium 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.)

High urine oxalate — 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 [8,37]. 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 [37]. (See "Primary hyperoxaluria".)

High urine oxalate may also be secondary to the increased enteric absorption of oxalate [38]. Fat malabsorption is the most common cause of increased oxalate absorption [38]. The mechanism by which fat malabsorption increases oxalate absorption is via the binding of calcium by free fatty acids. 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 [39].

Fat malabsorption leading to high urine oxalate 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 [39-42]; and cystic fibrosis, which causes pancreatic insufficiency and in which other factors promoting calcium deposition (such as high urine calcium) 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 high urine oxalate 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 spinach, rhubarb, parsley, cocoa, nuts, or star fruit (carambola) [43].

CLINICAL FEATURES

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 or signs that are related to nephrocalcinosis or to the causative process (eg, hypercalcemia). These include the following:

●Renal colic – Renal colic is most often due to associated nephrolithiasis as may occur in patients with chronic high urine calcium. A less common cause is extrusion of calcified nodules from the interstitium into the calyceal system [2].

●Hematuria – Hematuria may be a presenting feature with or without renal colic and is a sign of kidney irritation and movement of associated nephrolithiasis [2].

●Polyuria and polydipsia – Patients may present with polyuria, polydipsia, and nocturia due to impaired urinary concentrating ability (ie, arginine vasopressin resistance [previously called nephrogenic diabetes insipidus]). This 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 [44].

●Acute kidney injury – Several causes of nephrocalcinosis 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" and "Acute phosphate nephropathy" and "Chronic complications of the short bowel syndrome in adults", section on 'Nephrolithiasis'.)

Laboratory findings — 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 [2]. 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)".)

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. (See 'Subsequent evaluation for underlying causes' below.)

Occasionally, there may be laboratory findings that point to specific causes. The presence of a nonanion gap metabolic acidosis and hypokalemia can be seen in patients with nephrocalcinosis due to a distal renal tubular acidosis (RTA). An elevated serum parathyroid hormone level in the context of preserved kidney function and serum calcium above the median of the reference range indicates possible primary hyperparathyroidism as a cause. (See 'Distal (type 1) renal tubular acidosis' above and 'Primary hyperparathyroidism' above.)

Several reports have described an association between erythrocytosis and nephrocalcinosis [45,46]. Erythropoietin levels are increased in most of these patients, which has suggested a possible mechanism of nephrocalcinosis-induced regions of medullary hypoxia [45].

Imaging findings — Patients with nephrocalcinosis may present with the following characteristic imaging findings:

●Abdominal radiography – Abdominal radiography, also called abdominal plain x-ray, may show small, scattered calcifications within the kidney outline (image 2). These calcifications are indicative of calcium deposits in the kidney tissue. Plain abdominal radiographs have limitations in diagnosing nephrocalcinosis accurately, especially when the deposits are small.

●Ultrasonography of the kidneys – On ultrasonography, nephrocalcinosis may appear as bright, hyperechoic areas within the kidney parenchyma. These bright spots represent the calcium deposits in the kidney tissue. There may be evidence of multiple small calcium deposits scattered throughout the kidney cortex and/or medulla.

●Computed tomography of the abdomen – On computed tomography (CT), nephrocalcinosis typically appears as calcium deposits within the kidney. Early detection may be facilitated by determining the Hounsfield units within the kidneys. Nephrocalcinosis can usually be differentiated from kidney stones, which are more localized and appear as well-defined, round, or oval-shaped densities within the kidney collecting system.

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.

DIAGNOSIS

When to suspect nephrocalcinosis — Nephrocalcinosis should be considered in patients who present with chronic kidney disease, a benign urinalysis, and little or no proteinuria, particularly those who are hypercalcemic or have a history of one of the above causes of nephrocalcinosis. In addition, nephrocalcinosis may also be suspected in a patient with recurrent calcium kidney stones. (See 'Risk factors and causes' above.)

Confirming the diagnosis — The diagnosis of nephrocalcinosis can only be made by imaging or, much less often, kidney biopsy. Most cases are diagnosed as an incidental finding during radiographic imaging of the abdomen or chest performed for another indication or for the evaluation of nephrolithiasis.

Macroscopic nephrocalcinosis may be detected by multiple imaging techniques, including abdominal plain film, ultrasound, and computed tomographic (CT) imaging [28,47-50]. If nephrocalcinosis is suspected in a patient, kidney ultrasound and abdominal CT are generally the preferred imaging tests to confirm the diagnosis. However, in the absence of a reason to suspect nephrocalcinosis (eg, hypercalcemia or a history of nephrolithiasis), kidney 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. Calcification is poorly visualized by magnetic resonance imaging [51]. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting", section on 'Radiologic studies'.)

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) [47]. 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 [47].

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 [28]. (See 'Loop diuretics' above.)

Subsequent evaluation for underlying causes — 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 kidney failure, others, such as medullary sponge kidney, rarely cause progressive kidney disease. (See "Primary hyperoxaluria", section on 'Clinical and laboratory manifestations' and "Medullary sponge kidney", section on 'Prognosis'.)

For all patients with confirmed nephrocalcinosis, we perform the following initial evaluation to identify potential underlying causes (algorithm 1):

●History and physical examination, with an assessment of the following:

•History of medical conditions associated with nephrocalcinosis (eg, primary hyperparathyroidism, medullary sponge kidney, sarcoidosis, autoimmune disorders). (See 'Risk factors and causes' above.)

•Family history of kidney tubular dysfunction or kidney stone disease, which may indicate an underlying genetic disorder. (See 'Inherited tubulopathies' above and 'Medullary sponge kidney' above.)

•Review of medications or nutritional intake that increase urinary calcium excretion (eg, loop diuretics, supplemental calcium and vitamin D, topiramate [52]). (See 'Loop diuretics' above and 'Vitamin D therapy' above and "Nephrolithiasis in renal tubular acidosis", section on 'Carbonic anhydrase inhibitors'.)

●Laboratory evaluation, including the following:

•Serum calcium and phosphorus concentration – Measurement of serum calcium is important to determine if hypercalcemia is present. Patients with serum calcium that is elevated or near the upper limit of the reference range should be further evaluated for the cause. (See 'High urine calcium with hypercalcemia' above and "Etiology of hypercalcemia" and "Diagnostic approach to hypercalcemia".)

A low serum phosphorus level may be seen in patients with primary hyperparathyroidism or in patients with urinary phosphate wasting. The serum phosphorus level may be high in patients with nephrocalcinosis and kidney function impairment, such as those with tumor lysis syndrome or after ingestion of oral sodium phosphate bowel preparations. (See 'High urine phosphate' above.)

•Serum creatinine (with determination of estimated glomerular filtration rate [eGFR]) and electrolytes – A reduced eGFR may be present in patients with nephrocalcinosis and kidney function impairment. Hypokalemia and metabolic acidosis can be observed with distal renal tubular acidosis (RTA), while hypokalemia and metabolic alkalosis are features of Bartter syndrome. (See 'Distal (type 1) renal tubular acidosis' above and 'Inherited tubulopathies' above.)

•Urinalysis – A urinalysis is helpful to assess urine pH and to evaluate for hematuria and proteinuria. A urine pH ≥5.5 in a patient with metabolic acidosis may suggest a diagnosis of distal RTA.

•Two 24-hour urine collections to measure the excretion of calcium, phosphate, oxalate, citrate, sodium, potassium, magnesium, and, to assess the completeness of the collection, creatinine.

-High urine calcium in the absence of hypercalcemia can be caused by a variety of disorders that are discussed above. (See 'High urine calcium without hypercalcemia' above.)

-High urine phosphate 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 'High urine phosphate' above.)

-High urine oxalate suggests either primary or secondary hyperoxaluria (most often due to malabsorption). (See 'High urine oxalate' above and "Primary hyperoxaluria".)

●Genetic testing for a monogenic cause of nephrocalcinosis if there is a strong suspicion for an underlying genetic disorder. 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 [53]. (See 'Inherited tubulopathies' above.)

TREATMENT

Treatment of the underlying cause — 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'.)

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".)

General supportive measures — 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. (See "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'Fluid intake'.)

●Among patients with high urine calcium, 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 high urine calcium, a thiazide diuretic can be administered in patients who do not have hypercalcemia. (See "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'Limit sodium intake' and "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'Reduce nondairy animal protein intake' and "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'High urine calcium'.)

●The administration of supplemental alkali 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 or potassium bicarbonate to achieve a normal urinary citrate level. We do not give supplemental alkali to patients who have urine pH equal to or greater than 7. (See "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'Low urine citrate'.)

PROGNOSIS — The kidney prognosis of nephrocalcinosis is determined by the underlying cause. While most patients with nephrocalcinosis do not progress to kidney failure, certain underlying causes, if not effectively treated, are more likely to be associated with chronic kidney disease. These include primary hyperoxaluria, hypomagnesemic hypercalciuric nephrocalcinosis, Dent disease, and distal renal tubular acidosis (RTA) [54]. On the other hand, patients with medullary sponge kidney rarely develop chronic kidney disease [2]. (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 high urine calcium and among patients with high urine oxalate following corrective intestinal surgery [2]. 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

●Overview – Nephrocalcinosis is characterized by the generalized deposition of either calcium phosphate or calcium oxalate in the kidney medulla or, much less often, the cortex. Patients who develop nephrocalcinosis may have acute or chronic kidney injury or may have normal kidney function. (See 'Definition and classification' above.)

●Risk factors and causes – Nephrocalcinosis is associated with conditions that cause hypercalcemia, hyperphosphatemia, and the increased excretion of calcium, phosphate, and/or oxalate in the urine. Underlying conditions that have been associated with nephrocalcinosis may be categorized into those that cause:

•High urine calcium with hypercalcemia (eg, primary hyperparathyroidism, sarcoidosis, vitamin D therapy)

•High urine calcium with normocalcemia (eg, distal renal tubular acidosis [RTA], medullary sponge kidney)

•High urine phosphate (eg, tumor lysis syndrome, inherited tubulopathies)

•High urine oxalate (see 'Risk factors and causes' above)

●Clinical features – In most cases, nephrocalcinosis is an asymptomatic, chronic, and slowly progressive disease. However, occasional patients present with clinical symptoms or signs related to nephrocalcinosis or to the causative process, including renal colic, hematuria, polyuria and polydipsia, or acute kidney injury. The urinalysis may be benign or reveal sterile pyuria or hematuria. Proteinuria is usually <500 mg/day except among patients with Dent disease who often present with significant proteinuria. 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. (See 'Clinical features' above.)

●Diagnosis

•When to suspect – Nephrocalcinosis should be considered in patients who present with chronic kidney disease, a benign urinalysis, and little or no proteinuria, particularly those who are hypercalcemic or have a history of one of the causes of nephrocalcinosis. In addition, nephrocalcinosis may also be suspected in a patient with recurrent calcium kidney stones. (See 'When to suspect nephrocalcinosis' above.)

•Confirming the diagnosis – The diagnosis of nephrocalcinosis can only be made by imaging or, much less often, kidney biopsy. Most cases are diagnosed as an incidental finding during radiographic imaging of the abdomen or chest performed for another indication or for the evaluation of nephrolithiasis. (See 'Confirming the diagnosis' above and 'Imaging findings' above.)

•Subsequent evaluation – Once the diagnosis of nephrocalcinosis has been confirmed, the subsequent evaluation is directed at determining the underlying cause (algorithm 1). 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. (See 'Subsequent evaluation for underlying causes' above and 'Prognosis' above.)

●Treatment – Therapy is directed at the underlying cause of the nephrocalcinosis. 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:

•For all patients with nephrocalcinosis, we suggest sufficient fluid intake to achieve a urine volume of >2 L/day (Grade 2C).

•For all patients with nephrocalcinosis and high urine calcium, we suggest reducing dietary intake of non-dairy animal protein (Grade 2C).

•For all patients with nephrocalcinosis and high urine calcium, we suggest restriction of dietary sodium intake to <100 mEq/day (approximately 2.3 g of sodium) (Grade 2C).

•For patients with nephrocalcinosis who have hypocitraturia and urine pH less than 7, we suggest the administration of potassium citrate or potassium bicarbonate to achieve normal urinary citrate levels (Grade 2C). Alkali should not be given to patients who have a urine pH equal or greater than 7 even if hypocitraturia is present. (See 'General supportive measures' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Sidney Kobrin, MD, who contributed to earlier versions of this topic review.