Updated: Aug 09, 2021
Author: Tibor Fulop, MD, PhD, FACP, FASN; Chief Editor: Vecihi Batuman, MD, FASN 


Practice Essentials

Nephrocalcinosis is a condition in which calcium levels in the kidneys are increased. Most often, the increase in renal calcium is generalized, as opposed to the localized increase observed in calcified renal infarct and caseating granulomas of renal tuberculosis. See the image below.

Axial CT scans from patient with long history of r Axial CT scans from patient with long history of renal tubular acidosis. Images show bilateral medullary nephrocalcinosis (early arterial phase).

Signs and symptoms

Presentation is primarily determined by the underlying etiology, though in many cases the condition remains asymptomatic and is identified only as a radiologic abnormality. The physical findings are nonspecific and reflect the underlying disorders responsible.

Clinical features of hypercalcemic nephropathy may include the following:

  • Relative vasopressin resistance with decreased renal concentrating ability and increased free water diuresis, manifesting as polyuria and polydipsia
  • Renal glycosuria, reduced glucose tubular maximum, aminoaciduria, and nonglomerular proteinuria
  • Reversible hypertension
  • Kidney failure, usually reversible but sometimes not

Clinical features of microscopic nephrocalcinosis (on the basis of animal studies) may include the following:

  • Reduced concentration capacity
  • Increased blood urea nitrogen (BUN)
  • Prolongation of nephron transit time in the distal tubule
  • Acute pyelonephritis or calculous ureteral obstruction with kidney failure

Clinical features of macroscopic nephrocalcinosis (the form most commonly seen) may include the following:

  • Renal colic
  • Hematuria
  • Passage of urinary stones
  • Urinary tract infection
  • Polyuria and polydipsia
  • Hypertension
  • Proteinuria
  • In Dent disease, loss of low-molecular-weight proteins, hypercalciuria, and nephrolithiasis
  • Microscopic pyuria
  • Distal tubular dysfunction with a mild salt-losing defect
  • Proximal tubular dysfunction (unusual)
  • Secondary distal tubular acidosis
  • Kidney failure

See Presentation for more detail.


Laboratory studies that may be useful include the following:

  • Serum calcium, phosphate, and albumin levels
  • Blood urea nitrogen (BUN) and serum creatinine levels
  • Estimated glomerular filtration rate (eGFR)
  • Serum potassium concentration
  • Urinalysis and urine culture
  • Assessment of 24-hour urinary excretion of calcium, oxalate, citrate, and uric acid
  • Urinary magnesium levels
  • Parathyroid hormone and thyroid-stimulating hormone levels

Imaging studies that may be considered include the following:

  • Radiography (eg, kidney-ureter-bladder [KUB])
  • Ultrasonography (more sensitive than conventional radiography)
  • Computed tomography (CT; more effective in detecting calcification)

Magnetic resonance imaging (MRI) offers no advantages over these modalities and is not warranted unless another compelling indication is present.

See Workup for more detail.


Pharmacologic and other nonsurgical treatments for hypercalcemia and hypercalcemic nephropathy include the following:

  • Adequate hydration with an isotonic sodium chloride solution (the single most effective measure for reversing hypercalcemia and protecting the kidneys)
  • Cinacalcet (for correction of hyperparathyroidism)
  • Chemotherapeutic agents (for osteolytic malignancies)
  • Steroids (to decrease intestinal calcium absorption and vitamin-D activity)
  • Hydroxychloroquine (for sarcoid granulomas)
  • Calcitonin or bisphosphonates (to inhibit bone resorption)

Pharmacologic and other nonsurgical treatments for macroscopic nephrocalcinosis include the following:

  • Thiazide diuretics (eg, hydrochlorothiazide)
  • Dietary salt restriction
  • Potassium and magnesium supplementation
  • Citrate supplementation (preferably as potassium citrate)
  • High-dose pyridoxine

Surgery options that may be considered for urinary stones causing obstruction include the following:

  • Percutaneous nephrolithotomy
  • Stent placement
  • Open surgery (rarely necessary)

Parathyroidectomy may be considered for removal of enlarged adenomas.

See Treatment and Medication for more detail.


Nephrocalcinosis is a condition in which calcium levels in the kidneys are increased. There is predominantly interstitial deposit of calcium phosphate or calcium oxalate in the renal cortex and/or medulla. This condition can sometimes overlap with nephrolithiasis, which is characterized by intratubular deposits of calcium.  Calcium deposits can be detected (usually as an incidental finding) through a radiologic examination or via microscopic examination of the renal tissues. The term nephrocalcinosis most often applies to a generalized increase in interstitial renal calcium content, as opposed to the localized increase observed in calcified renal infarct and caseating granulomas of renal tuberculosis.[1]

Nephrocalcinosis has a substantial overlap with hypercalcemia, nephrolithiasis, renal parenchymal damage, and reduced renal function. Therefore, rather being considered a single, distinct disease process, it should be viewed as a helpful finding for several distinct disease processes, one that demands evaluation.[1]

Microscopic nephrocalcinosis is characterized by the presence of microscopic crystalline calcium precipitates in the form of oxalate or phosphate. Patients with macroscopic nephrocalcinosis have larger areas of calcifications, which can be observed on visual or radiologic examination without further magnification.


Hypercalcemic nephropathy (chemical nephrocalcinosis)

Patients with hypercalcemia develop renal function abnormalities. Under these circumstances, the term hypercalcemic nephropathy is more appropriate than is the older term chemical nephrocalcinosis.

Calcium is a critical divalent cation that is transported, along with sodium, potassium, and water, in a complex and regulated manner along the renal tubular epithelium. The cytoplasmic concentration of calcium is tightly regulated and kept very low, being maintained by active extracellular extrusion of calcium and sequestration into the endoplasmic reticulum and mitochondria. Increased extracellular calcium leads to impairment of the calcium messenger system with gross tubular impairment.

The effects of increased calcium have been studied extensively in rats. Rats treated with vitamin D demonstrated mitochondrial swelling and loss of mitochondrial enzyme activities before calcification appeared. Parathyroid extract−induced hypercalcemia was found to cause changes in rat kidneys, predominantly affecting the distal nephron, with focal necrosis of the outer medullary collecting ducts and the ascending limb of the loop of Henle.

Hypercalcemia results in renal vasoconstriction and a reduced glomerular filtration rate. It also interferes with renal tubular functions. Impaired renal concentration ability and resistance to vasopressin are the most common defects observed with hypercalcemia. These changes may be mediated by reduced sodium transport in the loop of Henle (see the image below) and by antidiuretic hormone antagonism via calcium-sensing receptors,[2] or they may be related to medullary prostaglandin synthesis.

Diagram of nephron. Diagram of nephron.

Maximum diluting capacity remains unimpaired. Effectively, the sum effect of this process will be a clinical picture resembling that of nephrogenic diabetes insipidus.

Renal sodium conservation is also impaired because of reduced absorption of sodium chloride in the medullary thick ascending limb and collecting tubule, although this rarely results in gross renal sodium losses. Potassium excretion is increased. Magnesium excretion is also increased, probably due to suppression of parathyroid hormone, which enhances tubular magnesium absorption.[3]

Hypercalcemia increases urinary calcium excretion by increasing the filtered load and reducing tubular absorption. Its effects on phosphate excretion are complex. In experimental animals, pure hypercalcemia reduces phosphate excretion; conversely, in certain cancers, it can be associated with increased phosphate excretion, but the latter occurrence is probably due to the presence of phosphaturic peptides (phosphatonins), which are secreted in some malignancies.[4, 5]

The effects on the acid-base balance are even more complex. Increased renal acid excretion occurs with intravenous (IV) calcium infusions, and metabolic alkalosis has frequently been reported in patients with hypercalcemia. On the other hand, parathyroid hormone decreases hydrogen ion excretion, leading to a distal type of renal tubular acidosis (RTA).

This opposing effect of hypercalcemia and parathyroid hormone has been used in the differential diagnosis of hypercalcemia, because serum bicarbonate is lower and chloride is higher when hyperparathyroidism is the cause of hypercalcemia.

Microscopic nephrocalcinosis

Microscopic nephrocalcinosis has undergone considerable laboratory study. Although this condition theoretically occupies a stage between hypercalcemia and macroscopic nephrocalcinosis, it is difficult to demonstrate in humans, because renal biopsies are not routinely performed in the early stages of metabolic diseases known to lead to the macroscopic stage. However, some elegant human data are now available that demonstrate early stone formation, with blockage of the collecting tubes and subsequent inflammatory response.[6]

At autopsy, healthy human kidneys invariably contain microscopic deposits of calcium in the renal medulla. Microscopic nephrocalcinosis can occur without macroscopic involvement in patients with longstanding hypercalcemia from primary parathyroidism, milk-alkali syndrome, or primary hyperoxaluria.

Different patterns of microscopic nephrocalcinosis have been described. The cortical pattern has been found after parenteral calcium administration. The corticomedullary type involves calcium phosphate deposits that occur in the inner zone of the renal cortex and extend into the medulla. Precipitating factors include excess parathyroid hormone, vitamin D, acetazolamide, magnesium depletion, decreased urinary citrate, and hypothyroid state. Increased plasma calcium is not an essential prerequisite for this type of nephrocalcinosis.

The medullary pattern has been reported in hyaline droplet nephropathy resulting from inhalation of volatile hydrocarbons. The pelvic type affects renal papillae. The deposits usually are calcium phosphate, but calcium oxalate also has been implicated. The underlying mechanism appears to be either increased intestinal absorption or decreased renal excretion of calcium.

Macroscopic nephrocalcinosis

Macroscopic nephrocalcinosis refers to calcium deposition that is visible without magnification and usually is discovered by means of conventional radiography, ultrasonography, or computed tomography (CT) or at autopsy. Macroscopic nephrocalcinosis can affect either the cortex or the medulla, with the latter site being more commonly involved.

Cortical nephrocalcinosis is rare and usually occurs secondary to diffuse cortical disease injury. The calcification can be patchy or confluent. In chronic glomerulonephritis, calcium deposits are found most often in periglomerular tissue and not in the glomerulus. Nephrocalcinosis also has been reported in familial infantile nephrotic syndrome and in Alport syndrome.

Acute cortical necrosis secondary to toxemia of pregnancy, snakebite, or hemolytic-uremic syndrome can lead to patchy cortical nephrocalcinosis. Calcium deposition can start as early as 30 days after cortical necrosis. Chronic pyelonephritis and vesicoureteral reflux are also implicated.[7] Kidney transplantation, primary hyperoxaluria, methoxyflurane abuse, autosomal recessive polycystic kidney disease, and benign nodular cortical nephrocalcinosis may be involved in cortical nephrocalcinosis, albeit rarely.

Medullary nephrocalcinosis assumes the form of small nodules of calcification clustered in each pyramid. Diagnosing the underlying renal disease on the basis of the appearance is difficult. Characteristic exceptions include papillary necrosis due to analgesic abuse and medullary sponge kidneys.[8] In papillary necrosis, the entire papilla may be calcified, whereas in medullary sponge kidney, there is a characteristic band of calcification in the renal pyramids.

It has been suggested that when hypercalcemia is the most important factor, the first foci of calcification develop in the renal tubular cells, whereas when hypercalciuria is the major factor, the initial foci form in the interstitium.

Intraluminal tubular calcium crystals are believed to serve as potential nidi for further buildup of calcium and other stone-forming substances, including oxalate and uric acid. Whether further growth of nephroliths occurs probably depends on a number of additional factors, such as abnormal urine composition, urine flow and volume, and the presence or absence of endogenous inhibitors of crystalline formation in the urine.


Etiologies of cortical calcium deposition in kidneys are as follows:

  • Pyelonephritis
  • Tuberculosis
  • Glomerulonephritis
  • Acute cortical deposits
  • Acute transplant rejection
  • Alport syndrome

Etiologies of medullary calcium deposition in kidneys are as follows:

  • Hyperparathyroidism
  • Distal renal tubular acidosis (RTA)
  • Vitamin D overdose
  • Primary hyperoxaluria
  • Medullary sponge kidney
  • Bartter syndrome
  • ADCK4 mutations

Risk factors for nephrocalcinosis include the following:

  • Persistent hypercalcemia and hyperphosphatemia.
  • Increased urinary excretion of calcium, phosphate, or oxalate
  • Hypocitraturia
  • Chronic hypokalemic states
  • Hyperoxaluria

Primary hyperparathyroidism is the single most common cause of nephrocalcinosis in adults. Although nephrocalcinosis is a relatively rare complication (5%), primary hyperparathyroidism itself is relatively common, especially in the elderly.

Nephrocalcinosis is related more to the duration than to the intensity of hypercalcemia. The classic clinical findings are sometimes referred to as “(abdominal) groans, stones, and bones.” This common phrase is a reminder that patients may present with kidney stones, bone pain, osteoporosis, and pathologic fractures, all of which can result in abdominal discomfort. Rarely, hyperparathyroidism can be associated with multiple endocrine neoplasia type 1 (MEN1).

Patients with chronic hypoparathyroidism are at an increased risk for nephrocalcinosis.[9]

Distal RTA is the second most common cause of medullary nephrocalcinosis. Both the familial form and the secondary form (autoimmune-associated anti-K/H channel antibody) are common.[10] The mechanisms contributing to nephrocalcinosis in distal RTA are hypercalcemia, hypercalciuria, metabolic acidosis, and reduced citrate excretion in the presence of increased urinary pH.[11] Because medullary nephrocalcinosis itself can cause distal RTA, distinguishing the initial insult can be difficult. Kidney function is fairly well maintained.

Other causes of nephrocalcinosis are hypervitaminosis-D states[12] resulting from excessive treatment of hypoparathyroidism, self-administration of vitamins, and the presence of a granulomatous disease, such as sarcoidosis.[13]  Nephrocalcinosis can be among the renal manifestations of primary mitochondrial syndromes (eg, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS] syndrome; Kearns-Sayre syndrome; Leigh syndrome; mitochondrial depletion syndromes).[14]  

In granulomatous disorders, conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol in the granuloma is increased, resulting in an unregulated production of bioactive vitamin D with resultant excessive intestinal absorption of calcium and phosphorus. In addition, cytokines (eg, interleukin [IL]-2) released in these disorders cause dysregulation of calcium homeostasis and activation of osteoclasts, resulting in subacute and chronic hypercalcemia.

Any other cause of hypercalcemia, particularly when associated with hypercalciuria, can contribute to nephrocalcinosis. Etiologies include milk-alkali syndrome (due to excess ingestion of antacids), hyperparathyroidism, and malignant disease (due to bone involvement and humoral factors, including cytokines and parathyroid hormone-related peptide). Idiopathic hypercalciuria,[15, 16] a common metabolic disease, is also known to cause nephrocalcinosis.

Nephrocalcinosis and kidney failure are increasingly recognized as common complications of phosphate supplementation, particularly in the elderly.[17, 18, 19, 20, 21] Other possible risk factors are preexisting kidney failure, high blood pressure, and pharmacologic treatment of high blood pressure (eg, with angiotensin-converting enzyme [ACE] inhibitors or angiotensin-receptor blockers [ARBs]).

Phosphate supplements may contribute to kidney calcifications in children with hypophosphatemic rickets. In vitro studies have shown that an increased urinary concentration of phosphate can result in intratubular crystallization with altered solubility.

Medullary sponge kidney is a common cause of medullary calcification, with calcium lying in dilated collecting ducts rather than in the renal substance. These ectatic outpouchings are believed to be areas of urinary stasis possessing the ideal characteristics for fostering the formation of these calcifying complexes. The calcium deposits are larger and more sharply defined than they are in metabolic disease, and they are uneven in distribution.[8] Associated hemihypertrophy of the body may exist.

Unlike the severe kidney damage with minimal calcification associated with hypercalcemic states, nephrocalcinosis associated with distal RTA and medullary sponge kidney usually is gross, and kidney function is relatively well preserved.

Nephrocalcinosis has been reported in patients receiving antiepileptic drug therapy with topiramate.[22]  Classic analgesic nephropathy, which sometimes manifested as nephrocalcinosis and was characterized pathologically by renal papillary necrosis, has disappeared since the removal of phenacetin from the market internationally.[23]

Other associations with nephrocalcinosis include rapidly progressive osteoporosis due to immobilization, menopause, aging, or steroids.

Medullary calcification can be induced by primary (familial) hyperoxaluria or by secondary hyperoxaluria due to increased intake of oxalates, enhanced absorption resulting from intestinal disease, or ingestion of ethylene glycol or methoxyflurane.[24, 25] Primary hyperoxaluria and ethylene glycol intoxication are also associated with diffuse calcium-oxalate depositions in many other organs, including the eye and the heart.

Chronic hypokalemic states, such as Bartter syndrome, primary hyperaldosteronism, Liddle syndrome, and 11-beta hydroxylase deficiency, are associated with reduced urine citrate excretion and tubular epithelial damage, leading to calcium precipitations. Nephrocalcinosis is most frequently associated with Bartter I, II and V.[26]

 Mutations in ADCK4, one of the genes causing steroid-resistant nephrotic syndrome, usually manifest as focal segmental glomerulosclerosis with onset in late childhood. ADCK4 interacts with the coenzyme Q10 (CoQ10) biosynthesis pathway, and in its early stage this condition is treatable with CoQ10 supplementation.[27]

Autosomal dominant hypophosphatemic rickets and X-linked hypophosphatemic conditions[28] have been associated with abnormal phosphate wastage and nephrocalcinosis due to elevated levels of phosphatonins (fibroblast growth factor 23; secreted frizzled-related protein 4).[4, 5] Nephrocalcinosis is very common (frequency ~80% on ultrasonography) and may be associated with phosphate supplementation for the condition.

Dent disease and familial magnesium-losing nephropathy are rare inherited diseases causing medullary calcification.

Dent disease (also referred to as X-linked recessive hypophosphatemic rickets [in Italy], X-linked recessive nephrolithiasis, and idiopathic low-molecular weight proteinuria with hypercalciuria and nephrocalcinosis [in Japan]), arises from a defect in a gene on the short arm of the X chromosome that codes for the renal chloride channel in the proximal tubule (CLC-5). Mutations in the OCRL-1 gene—normally associated with Lowe syndrome—have been described in cases of clinical Dent disease, expanding the potential for genetic diversity.[29]

Inherited forms of magnesium-losing nephropathy have been described.[30] Familial hypomagnesemia hypercalciuric nephrocalcinosis (FHHNC) is an autosomal recessive disease associated with cation loss through a defect in a renal tight junction protein claudin-16 (paracellin-1)[31, 32, 33]  or claudin-19[34, 35] involved in paracellular transport. Claudin-16/paracellin-1 is dysfunctional in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). However, hypomagnesemia is not a mandatory finding in all kindreds.[36]  Thiazide-type diuretics appears efffective in lessning hypercelcuria and nephrocalcinosis. 

Associated malignancies are not typical in nephrocalcinosis, because patients seldom survive long enough with hypercalcemia to develop them; a possible exception is parathyroid carcinoma.

Familial benign hypercalcemia and hyperthyroidism are not associated with kidney calcification.

Premature sick infants have been observed to develop diffuse nephrocalcinosis (noted in about two thirds of infants with birth weights of < 1500 g), typically when exposed to diuretic therapy or prolonged oxygen therapy. The natural history of this phenomenon is not well understood, and no clearly effective treatment has been established.[37, 38]  Most cases resolve within a year[39, 40] and only a small proportion (< 15%) of stones require interventions.[40]  Urinary tract infections after birth represent another risk factor for slow resolution of these calcifications.

The presence of microscopic calcification in "generic" chronic kidney disease (CKD) is relatively understudied. One study documented progressive worsening of microscopic nephrocalcinosis with worsening stages of CKD (4.6, 14.3, 20.2, and 54.0% in patients with CKD stages 1-2,  3–4, and 5, respectively).  Lower serum bicarbonate level and higher serum parathyroid hormone and calcium levels represent indedendent risk factors for severity.[41]

There has been a growing awareness of the diffusely increased calcifications in patients with advanced kidney failure and end-stage kidney disease.[42] In the uremic environment, the use of large, pharmacologic doses of vitamin-D analogues and calcium-based phosphorus binders appears to accelerate the process. The presence of extraskeletal calcifications seems to be more closely correlated with the calcium-phosphorus product (sometimes referred to as the double product) and total-body calcium overload than with the presence of hypercalcemia. Calcifications in such cases are not limited to the kidneys but may involve multiple organs, including the heart, vascular beds, parenchymal organs, skin, and subcutaneous tissues.


The exact epidemiology and disease burden for nephrocalcinosis is not known. Prematurity-associated calcifications are known to resolve, albeit with significant inter-individual variability.[39]  Younger age in general is very suspicious for underlying genetic disorders, such as Bartter syndrome,[43, 44]  Dent disease or variants of Dent disease,[45]  or amelogenesis imperfecta.[35, 36]  Whole-exome sequencing is a novel and very powerful technology to detect a monogenic cause of nephrocalcinosis and early-onset nephrolithiasis.[46, 47]  In older age groups, acquired processes such as distal renal tubular acidosis are more likely.[11, 48]


The prognosis depends mainly on the etiology of the nephrocalcinosis. Patients with idiopathic hypercalciuria and medullary sponge kidney have the least risk of kidney failure and the best prognosis, whereas patients with primary type 1 hyperoxaluria have the worst prognosis.[49]

The morbidity and mortality associated with nephrocalcinosis depend on the disease associated with the condition rather than on the nephrocalcinosis itself.[50]  The major long-term complication in patients with medullary nephrocalcinosis is kidney failure. Early treatment of reversible causes of kidney failure, such as urinary infections, obstruction, and hypertension, is essential. Once chronic kidney disease has developed, treatment should focus on appropriate management of chronic kidney disease and its complications.

Patient Education

In educating patients about nephrocalcinosis, key points to emphasize include the following:

  • Nephrocalcinosis is usually an incidental finding
  • Hypercalcemia or hypercalciuria are frequently present
  • Nephrocalcinosis is more likely to be a consequence of an underlying abnormality than it is to be the cause



The underlying etiology primarily determines the presentation of nephrocalcinosis, though in many cases the condition remains asymptomatic and is identified only as a radiologic abnormality. The physical findings are nonspecific and reflect the underlying disorders responsible for nephrocalcinosis. Potential clinical features of the 3 types of nephrocalcinosis are described below.

Hypercalcemic nephropathy (chemical nephrocalcinosis)

Hypercalcemic nephropathy is commonly characterized by relative vasopressin resistance with decreased renal concentrating ability and increased free water diuresis (nephrogenic diabetes insipidus), manifesting as polyuria and polydipsia. Other defects, such as renal glycosuria, reduced glucose tubular maximum, aminoaciduria, and nonglomerular proteinuria, have occasionally been reported. Reversible hypertension occurs in approximately 50% of patients as a consequence of increased peripheral vasoconstriction.

Hypercalcemia is also a well-established cause of kidney failure, through direct renal vasoconstriction and volume depletion induced by excessive diuresis. This process usually is reversible, with normal kidney function returning as the hypercalcemia is corrected with volume replacement. However, irreversible failure can occur with long-standing hypercalcemia and is always associated with calcium crystal deposition.

Microscopic nephrocalcinosis

A few studies describe the effects of nephrocalcinosis on kidney function in rats.[51]  Various investigators have observed reduced concentration capacity, increased blood urea nitrogen (BUN), and prolongation of a single nephron transit time in a distal tubule,[52]  though no detailed studies of glomerular filtration or renal tubular function exist in these models. Occasionally, rats with the pelvic type of nephrocalcinosis may develop acute pyelonephritis or calculous ureteral obstruction with kidney failure.

It should be kept in mind, however, that nephrocalcinosis in rats is a poor model for humans because of the high incidence of spontaneous glomerulosclerosis in laboratory rats, the different distribution of calcium in the kidney, and the absence of a rat model for many of the diseases that cause human nephrocalcinosis.

Macroscopic nephrocalcinosis

A wide range of abnormalities can occur with medullary nephrocalcinosis. Calcium nodules may rupture through the papillary epithelium into the calyceal system to become urinary stones and elicit the clinical presentations of renal colic, hematuria, passage of urinary stones, or urinary tract infection. However, macroscopic nephrocalcinosis should not be considered synonymous with urinary stones, because nephrocalcinosis usually implies a more profound metabolic derangement.

The following may be noted:

  • Polyuria and polydipsia may be prominent because of the excess of free water diuresis with reduced renal concentrating ability
  • Hypertension is relatively less common, probably reflecting a reduced ability to conserve sodium
  • Proteinuria may be observed, though it is in the nonnephrotic range and usually below 500 mg/day
  • In Dent disease, loss of low-molecular-weight proteins may exceed 2 g/day; hypercalciuria, nephrolithiasis, and nephrocalcinosis are additional presenting features
  • Microscopic pyuria is common and represents a chronic inflammatory response to medullary calcification
  • Distal tubular dysfunction is common with a mild salt-losing defect; it may become obvious only with profound decrease of oral intake (anorexia) or when another source of salt-water loss (eg, diarrhea or vomiting) emerges
  • Proximal tubular dysfunction is unusual, except for tubular proteinuria and the aminoaciduria of Dent disease
  • Medullary nephrocalcinosis of any etiology can cause secondary distal tubular acidosis related to distal tubular calcium deposition and chronic inflammation in the medulla
  • Patients may present with kidney failure or with features of their underlying disease

Physical Examination

While nephrocalcinosis is a radiologic finding, some features on physical exam may provide hints of underlying genetic abnormality in some cases. Enamel-renal syndrome is characterized by nephrocalcinosis and dental manifestations including enamel defects, gingival hyperplasia, and eruption failures.[53]  Amelogenesis imperfecta (AI) repesents a goup of diseases with tooth enamel defects. It is now recognized that some patients with familial hypercalciuria and hypomagnesemia with nephrocalcinosis caused by claudin-16 mutation will have findings of AI on exam.[35]

Gross bone deformity with rickets can be observed with X-linked hypophosphatemia without proper phosphorus supplementation, although the contribution of phosphate supplementation is debated.[54]  Older individuals (over age 40) often require joint replacement and decompressive laminectomy.[55]


Persistent hypercalcemia can cause dehydration and acute kidney injury. Nephrocalcinosis can lead to progressive chronic kidney disease and eventually end-stage renal disease requiring dialysis.



Diagnostic Considerations

Nephrocalcinosis, though seemingly a simple finding, incorporates numerous potential disease processes in the differential. An effort should be made to describe the location and degree of nephrocalcinosis and to uncover the underlying metabolic abnormality or abnormalities (eg, renal tubular acidosis). In clinical practice, nephrocalcinosis is more commonly encountered in its macroscopic form than in its microscopic form. It must not be considered synonymous with renal stone disease, because it has much broader metabolic implications.

Differential Diagnoses

  • Bartter Syndrome

  • Dent's disease

  • Distal renal tubular acidosis (RTA)

  • Drug exposure (topiramate)

  • Enamel-renal syndrome

  • Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis

  • Hyperoxaluria

  • Medullary Sponge Kidney

  • Prematurity (usually transient)

  • Renal manifestations of primary mitochondrial disorders

  • Sjogren Syndrome

  • X-linked hypophosphatemia



Laboratory Studies

The workup for nephrocalcinosis should include the following studies:

  • Serum calcium
  • Serum phosphate
  • Serum albumin
  • Blood urea nitrogen (BUN) and serum creatinine 
  • Serum potassium
  • Urinalysis and urine culture

Also consider measuring the following:

  • 24-hour urinary excretion of calcium, oxalate, citrate, and uric acid
  • Urinary magnesium
  • Parathyroid hormone
  • Thyroid-stimulating hormone 

Measurement of serum calcium and albumin levels is necessary to establish whether nephrocalcinosis is associated with hypercalcemia. Determining the albumin level is important for interpreting the serum calcium level in the face of hypoalbuminemia: for every 1 g/dL decrease in serum albumin, measured serum calcium decreases by approximately 0.8 mg/dL. The reliability of calcium corrected for albumin has been questioned; ionized calcium should be used to confirm when in doubt.

The serum phosphate level is low in primary hyperparathyroidism with normal kidney function and in hypophosphatemic rickets due to urinary wasting; however, it is typically elevated in nephrocalcinosis associated with kidney insufficiency.

BUN and creatinine levels are elevated when nephrocalcinosis is associated with kidney insufficiency. Many laboratories in the United States now routinely report, along with serum creatinine, an estimated glomerular filtration rate (eGFR), if predicted kidney function falls to less than 60 mL/min/1.73 m2.

The serum potassium concentration may be low when nephrocalcinosis is caused by certain conditions, such as the following:

Urinalysis and urine culture should always be performed to look for evidence of chronic infection. An elevated urinary pH may suggest distal RTA, which may be found when overzealous alkali supplementation for nephrolithiasis prophylaxis has occurred, or may exist in the presence of urea-splitting pathogens in the urine. The type of crystals observed on urine sediment microscopy may provide valuable diagnostic clues about abnormal urine composition.

Assessment of 24-hour urinary excretion of calcium, oxalate, citrate, and uric acid, with simultaneous determination of BUN, creatinine, and protein excretion, can be very helpful.[56]  BUN and creatinine excretions will help to determine the completeness of timed urine collection and aid in calculating measured kidney function.

Excess urinary calcium excretion may be observed in patients with idiopathic hypercalciuria.[56]  Increased urinary oxalate excretion indicates a primary or secondary cause of hyperoxaluria. Patients with nephrocalcinosis generally have low-grade proteinuria of nonglomerular origin. Nephrotic-range proteinuria is not expected in this context and is an indication for further evaluation of underlying kidney disease.

Assessment of urinary magnesium levels may be useful in detecting magnesium-losing nephropathy.

In the presence of hypercalcemia or kidney failure, parathyroid hormone levels should be obtained to rule out primary or secondary hyperparathyroidism.[56] Both primary and secondary hyperparathyroidism may coexist with chronic kidney disease. Thyroid-stimulating hormone levels should be obtained to rule out a thyroid disorder.

Radiography, CT, and Ultrasonography

Despite advances in renal imaging technologies,[57, 58] the correlation between the extent of radiographically demonstrable nephrocalcinosis and the degree of kidney impairment remains limited (see the images below). Plain kidney-ureter-bladder (KUB) radiographs visualize only advanced cases. Furthermore, the diagnostic correlation between currently used techniques is imperfect, and there is considerable interobserver variability with respect to the interpretation of test results.[59]

Excretory urogram obtained at 15 minutes in man wi Excretory urogram obtained at 15 minutes in man with renal papillary necrosis (most likely, patient with diabetes mellitus and repeated urinary tract infections). Image shows bilateral hydronephrosis and hydroureter due to obstruction by sloughed papillae at lower end of ureter.
Plain kidney-ureter-bladder (KUB) radiograph in ma Plain kidney-ureter-bladder (KUB) radiograph in man with renal papillary necrosis (most likely, patient with diabetes mellitus and repeated urinary tract infections). Image shows bilateral renal calcification. Large, sloughed, and calcified renal papilla is present in region of left vesicoureteric junction. Note 2 pelvic phleboliths opposite ischial spine on right.

Ultrasonography (see the image below) is more sensitive than conventional radiography in this setting, but papillary cysts or hilar fat deposition can lead to false-positive results. Ultrasonography is better than x-ray, but has interoperator variability and is not better than computed tomography (CT).

Ultrasonogram of right kidney in woman with nephro Ultrasonogram of right kidney in woman with nephrocalcinosis. Image shows hyperechoic foci in pyramids.

CT is more effective in detecting calcification and can be used to differentiate between medullary and cortical deposition (see the images below).[60] It may also be used to detect defects that are too small to be diagnosed with conventional radiography and can identify deposits even up to 1 mm.

Nonenhanced coronal CT scans through kidneys, show Nonenhanced coronal CT scans through kidneys, showing cortical and medullary nephrocalcinosis (left kidney). Both kidneys appear scarred. Note thinning of renal cortex at upper pole of left kidney. Patient gave long history of chronic pyelonephritis, which is unusual cause of nephrocalcinosis.
Axial CT scans from patient with long history of r Axial CT scans from patient with long history of renal tubular acidosis. Images show bilateral medullary nephrocalcinosis (early arterial phase).

Magnetic resonance imaging (MRI; see the image below) offers no advantages over the aforementioned imaging modalities except for avoidance of radiation exposure. In the absence of other compelling indications, it should not be utilized.

Nephrocalcinosis. Nephrocalcinosis.

For more information, see Nephrocalcinosis Imaging.

Histologic Findings

Histologic findings (see the images below) include crystal deposition, which occurs mainly in the interstitium. The deposits may be observed within or between the tubules. The deposits consist of calcium phosphate or calcium oxalate. Special stains (eg, von Kossa and Pizzolato) may be required for better visualization.

Nephrocalcinosis. Nephrocalcinosis.
Nephrocalcinosis. Nephrocalcinosis.


Approach Considerations

Medical treatment is provided as appropriate for the type of nephrocalcinosis present (see below). Surgical management is indicated in some cases. Dietary interventions can be formulated as part of consultation with an appropriate specialist after the underlying metabolic abnormality has been identified. Management depends mostly on treating the underlying etiology of nephrocalcinosis.

Patients with a primary loin pain–hematuria syndrome experience a poorly understood combination of pain associated with hematuria. Some of these individuals have concurrent nephrocalcinosis that, incorrectly, may be blamed for the generation of pain. However, any associated hypercalciuria or hyperuricosuria should be addressed aggressively for symptomatic control of pain in loin pain–hematuria syndrome.

Pharmacologic and Other Nonsurgical Therapies

Hypercalcemia and hypercalcemic nephropathy

Adequate hydration with an isotonic sodium chloride solution is the single most effective measure for reversing hypercalcemia and protecting the kidneys. This may be combined with furosemide to enhance calcium excretion only if there is evidence of hypervolemia.

Other treatments include the following:

  • Calcium-sensing receptor stimulant cinacalcet (for correction of hyperparathyroidism)
  • Chemotherapeutic agents (for osteolytic malignancies)
  • Steroids (to decrease intestinal calcium absorption and vitamin-D activity)
  • Hydroxychloroquine [61] (for sarcoid granulomas)
  • Calcitonin or bisphosphonates (to inhibit bone resorption)

Calcium-channel blockers have no role in management.

Macroscopic nephrocalcinosis

Thiazide diuretics and dietary salt restriction will reduce renal calcium excretion. Hydrochlorothiazide, the most commonly employed thiazide diuretic, is appropriate to use if the serum calcium level is not high; it may correct coincidental high blood pressure.[62] The usual dose range is 12.5-25 mg/day, though in rare cases, it may be as high as 50 mg/day. However, if hydrochlorothiazide is used, the daily dose should be split into 2 divided doses to cover a full 24-hour period. Chlorthalidone can be used at lower doses but can cause hypokalemia and hypocitraturia.

Potassium and magnesium supplementation will increase the solubility of urinary calcium. Magnesium supplementation may be helpful in magnesium-losing nephropathy.

Citrate supplementation (preferably as potassium citrate) can be used in idiopathic hypercalciuria and in distal renal tubular acidosis (RTA) because it increases urinary citrate excretion, acting as a chelating agent for urinary calcium to decrease stone formation.[63] In type 1 hyperoxaluria, treatment with large doses of pyridoxine can lower oxalate production.

Lessening of nephrocalcinosis may occur over time, especially in idiopathic absorptive hypercalciuria and enteric hyperoxaluria after gastrointestinal bypass surgery. In most other cases, however (eg, when it results from primary hyperoxaluria, distal RTA, papillary necrosis, or magnesium-losing nephropathy), nephrocalcinosis is largely irreversible. Therefore, early detection and treatment are important.

Oral fluid intake to make a daily urine output of at least 2 liters is recommended. Dietary measures include restriction of animal protein to no more than 0.7 mg/kg daily and of sodium to no more than 2.3 g/day.

Surgical Intervention

With copious fluid intake by the patient and appropriate use of pain control, stones passing the mid-ureter and measuring less than 5-7 mm usually pass on their own. Anecdotal evidence suggests that peripheral vasodilators (eg, alpha-blockers and calcium-channel blocker antihypertensive agents) may facilitate stone passage.[64]

Surgery may be required for urinary stones causing obstruction; options include the following:

  • Percutaneous nephrolithotomy
  • Stent placement
  • Open surgery (rarely necessary)

Parathyroidectomy to remove enlarged adenomas is very helpful in primary hyperparathyroidism and results in a low recurrence rate. Attempting to remove calcium nodules from within the renal parenchyma itself has no obvious benefit and is likely to cause harm.


The following consultations may be warranted:

  • Nephrology - For reduced kidney function and associated metabolic abnormalities; electrolyte disorders, including metabolic acidosis, hypercalcemia and hypercalciuria; and recurrent nephrolithiasis
  • Endocrinology - For hypercalcemia, vitamin-D and phosphate disorders, and sarcoid in association with hypercalcemia
  • Rheumatology - For distal RTA associated with rheumatologic disease (eg, Sjögren syndrome or systemic lupus erythematosus)
  • Otorhinolaryngologic or endocrine surgery - For surgical parathyroidectomy (the personal skill and experience of the operating surgeon are important)

Long-Term Monitoring

Efforts are under way to develop a long-term registry of pediatric nephrolithiasis and nephrocalcinosis. A pediatric cohort may be less confounded by co-morbidities of adult ones and demonstrate better the effect of examined processes.



Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications. Recommended agents vary with the underlying cause of the nephrocalcinosis.

Diuretics, Thiazide

Class Summary

Thiazide diuretics are extremely helpful in decreasing calcium excretion in several conditions associated with nephrocalcinosis. Hydrochlorothiazide, the most commonly employed thiazide diuretic, is appropriate to use if the serum calcium level is not high; it may correct coincidental high blood pressure. The usual dose range is 12.5-25 mg/day, though in rare cases it can reach 50 mg/day. However, if hydrochlorothiazide is used, it should be given in 2 divided doses to cover a full 24-hour period.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide inhibits reabsorption of sodium in the distal tubules, causing increased excretion of sodium and water, as well as of potassium and hydrogen ions.


Chlorthalidone inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as of potassium and hydrogen ions. It reduces calcium excretion through direct tubular effects.

Chlorothiazide (Diuril)

A thiazide diuretic, chlorothiazide inhibits sodium-chloride symport, blocking sodium reabsorption in the distal convoluted tubule.

Calcium Metabolism Modifiers

Class Summary

Bisphosphonates are used to treat hypercalcemia and to decrease calcium loss from bone.

Calcitonin is indicated for treatment of hypercalcemia. It maintains calcium homeostasis by increasing the mineral stores in bone and the renal excretion of calcium. Calcitonin also directly inhibits osteoclastic bone resorption. Because of its longer duration of action, salmon calcitonin is preferred to human calcitonin.

Pamidronate (Aredia)

Inhibits bone resorption via actions on osteoclasts or on osteoclast precursors, without significant effects on renal tubular calcium handling. Indicated to treat hypercalcemia.

Alendronate (Fosamax, Binosto)

Alendronate has been successful in treating the pain of polyostotic fibrous dysplasia; it may have some benefit in increasing bone mineral density as well. It offers the additional benefit of oral administration.

Ibandronate (Boniva)

Ibandronate increases bone mineral density and reduces the incidence of vertebral fractures. Ibandronate increases bone mineral density at the spine by 5.7-6.5% and the hip by 2.4-2.8%. It reduces vertebral fractures by 50% with intermittent (nondaily) dosing over 3 years; it has no effects on reduction of nonvertebral fractures. Ibandronate is approved for the treatment and prevention of postmenopausal osteoporosis. It is available as a 150-mg oral tablet and intravenous solution.

Risedronate (Actonel, Atelvia)

Risedronate is a potent antiresorptive agent that does not affect bone mineralization. The inclusion of an amino group within the heterocyclic ring makes risedronate one of the most potent antiresorptive bisphosphonates. As with other bisphosphonates, risedronate inhibits osteoclast formation and activity. Risedronate increases bone mineral density at the spine by 5.4% and the hip by 1.6%. It reduces vertebral fractures by 41% and nonvertebral fractures by 39% over 3 years. It is approved for the treatment and prevention of postmenopausal osteoporosis, male osteoporosis, and glucocorticoid-induced osteoporosis.

Zoledronic acid (Reclast)

Zoledronic acid inhibits bone resorption by altering osteoclast activity and by inhibiting normal endogenous, as well as tumor-induced, mediators of bone degradation. Like other bisphosphonates, zoledronic acid binds to hydroxyapatite crystals in mineralized bone matrix. The binding to calcium phosphates slows the dissolution of hydroxyapatite crystals, as well as inhibits the formation and aggregation of these crystals. It increases bone mineral density at the spine by 4.3-5.1% and at the hip by 3.1-3.5%, as compared with placebo. It reduces the incidence of spine fractures by 70%, hip fractures by 41%, and nonvertebral fractures by 25% over 3 years. Zoledronic acid is approved for the treatment and prevention of postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, osteoporosis in men, and Paget disease of bone. It is contraindicated in patients with severe renal failure.

Calcitonin (Miacalcin, Fortical)

Calcitonin lowers elevated serum calcium in patients with multiple myeloma, carcinoma, or primary hyperparathyroidism. A higher response can be expected when serum calcium levels are high. Onset of action is approximately 2 hours after injection, and activity lasts for 6-8 hours. Calcitonin may lower calcium levels by about 9% for 5-8 days if administered every 12 hours. If it is administered intramuscularly (IM), it should be injected at multiple sites in doses greater than 2 mL.


Class Summary

Pyridoxine (vitamin B-6) deficiency is a known cause of hyperoxaluria. Used to treat nephrocalcinosis, pyridoxine decreases calcium oxalate formation and the subsequent development of kidney stones.

Pyridoxine (Pyri 500, Neuro-K500)

Pyridoxine is involved in the synthesis of gamma-aminobutyric acid (GABA) within the central nervous system (CNS).

Antimalarial Agent

Class Summary

Hydroxychloroquine can be helpful in controlling hypercalcemia due to sarcoid and is utilized as a glucocorticoid-sparing agent.

Hydroxychloroquine (Plaquenil)

Hydroxychloroquine may be most useful in the management of osseous involvement. It inhibits chemotaxis of eosinophils and locomotion of neutrophils, and it impairs complement-dependent antigen-antibody reactions.

Calcimimetic Agent

Class Summary

Calcimimetic agents can be used in primary hyperparathyroidism for temporary control of hypercalcemia if a patient is a poor surgical risk or if surgery is not immediately available. Experience in such settings is limited.

Cinacalcet (Sensipar)

Cinacalcet directly lowers parathyroid hormone (PTH) levels by increasing the sensitivity of calcium-sensing receptors on chief cells of the parathyroid gland to extracellular calcium. It also results in a concomitant serum calcium decrease. It is indicated for hypercalcemia with parathyroid carcinoma.

Alkalinizing Agent, Oral

Class Summary

Oral alkalizing agents are used for urinary alkalization.

Sodium citrate (Bicitra, Oracit)

Sodium citrate treats metabolic acidosis and used as alkalizing agent where long-term maintenance of alkaline urine is desirable.

Potassium citrate (Citra-K)

Potassium citrate is an alkalizing agent indicated for treatment of systemic metabolic acidosis, urinary alkalization, or hypocitraturia. It is administered orally and is metabolized to bicarbonate in the liver. Each 5 mL of Polycitra contains sodium citrate 500 mg, citric acid 334 mg, and potassium citrate 550 mg (amounting to 5 mEq of potassium, 5 mEq of sodium, and 10 mEq of bicarbonate).

Potassium-sparing Diuretics

Class Summary

Potassium-sparing diuretics, in particular amiloride (5-10 mg daily) or triamteren (50-100 mg) daily may be helpful to reduce urinary losses of magnesium or potassium and not burdened by endocrinologic side effects of aldosterone blocker spironolactone.