AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

Section 2 of 11  

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Background

Nephrocalcinosis refers to increased calcium content of the kidneys. This term usually applies to a generalized increase in renal calcium content, as opposed to a localized increase that is observed in calcified renal infarct or caseating renal tuberculosis.

Nephrocalcinosis can be divided into 3 categories based on the different presentations and clinical effects, as follows:

• Chemical nephrocalcinosis: This implies an increased concentration of calcium within renal cells, chiefly the tubular epithelium, causing an adverse effect on renal structure and function.
• Microscopic nephrocalcinosis: This refers to calcium precipitates in crystalline form as oxalate and/or phosphate, but it is only evident microscopically.
• Macroscopic nephrocalcinosis: Large areas of calcification are observed on visual or radiologic examination without magnification.

A certain degree of overlap exists among these despite the differing classification.

Pathophysiology

Chemical nephrocalcinosis

Patients with hypercalcemia develop renal function abnormalities. When no definite evidence of increased renal calcium exists, the term hypercalcemic nephropathy is more appropriate.

Calcium is an important intracellular ion that plays an essential role in tubular transport of sodium, potassium, and water. The cytoplasmic concentration of calcium is very low, and this is 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. Also, parathyroid extract–induced hypercalcemia was found to cause changes in rat kidneys, predominately affecting the distal nephron with focal necrosis of the outer medullary collecting ducts and the ascending limb of the loop of Henle.

The main renal effect of hypercalcemia is on tubular function. Impaired renal concentrating ability and resistance to vasopressin are the most common defects observed with hypercalcemia. This may be mediated by reduced sodium transport in the loop of Henle and antidiuretic hormone antagonism at the level of adenylate cyclase, or it may be related to medullary prostaglandin synthesis. Maximum diluting capacity remains unimpaired.

Sodium conservation is also impaired because of reduced absorption of sodium chloride in the medullary thick ascending limb and collecting tubule, although it rarely results in gross renal sodium loss. Potassium excretion is increased. Magnesium excretion is also increased; the effect probably is due to suppression of the parathyroid hormone, which enhances tubular magnesium absorption. Hypercalcemia increases urinary calcium excretion by increasing the filtered load and reducing tubular absorption. Its effects on phosphate excretion are complex. In experimental animals, hypercalcemia reduces phosphate excretion; conversely, in hypercalcemia due to breast cancer, it increases phosphate excretion. This phenomenon has been associated with the presence of phosphaturic peptides secreted by some malignancies. The effects on the acid-base balance are even more complex.

Metabolic alkalosis, other than that caused by hyperparathyroidism, frequently has been reported in patients with hypercalcemia. Increased renal acid excretion occurs with intravenous calcium infusions, whereas 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 because the concentration of chloride is higher and bicarbonate is lower when hyperparathyroidism is the cause of hypercalcemia.

Microscopic nephrocalcinosis

This form of nephrocalcinosis has been the most elaborately studied in the laboratory. Although microscopic nephrocalcinosis is a theoretical stage between chemical and macroscopic nephrocalcinosis, it seldom is demonstrated as a clinical entity because renal biopsies are not performed in the early stages of metabolic diseases known to lead to the macroscopic stage. However, at necropsy, 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 or milk-alkali syndrome, a malignant disease causing marked hyperphosphatemia that leads to tubular obstruction with calcium phosphate casts and primary hyperoxaluria.

Different patterns of microscopic nephrocalcinosis have been described. The corticomedullary type relates to calcium phosphate deposits in the inner zone of the renal cortex, extending into the medulla. The precipitating factors include excess parathyroid hormone, vitamin D, acetazolamide, magnesium depletion, decreased urinary citrate, and a hypothyroid state. Increased plasma calcium is not an essential prerequisite for this type of nephrocalcinosis. 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. Cortical calcification also has been found after parenteral calcium administration. The medullary pattern has been reported in hyaline droplet nephropathy due to inhalation of volatile hydrocarbons.

Macroscopic nephrocalcinosis

This refers to nephrocalcinosis that is visible without magnification, and it usually is discovered by conventional radiography, ultrasonography, or at autopsy. Macroscopic nephrocalcinosis can affect either the cortex or medulla, with the latter site being more common. Diffuse calcification rarely is observed in chronic glomerulonephritis or long-standing chronic renal disease.

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 usually are found in periglomerular tissue and not in the glomerulus. Nephrocalcinosis also has been reported in familial infantile nephrotic syndrome and 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. Other rare etiologies of cortical nephrocalcinosis include renal transplantation, primary hyperoxaluria, methoxyflurane abuse, autosomal recessive polycystic kidney disease, and benign nodular cortical nephrocalcinosis.

Medullary nephrocalcinosis takes the form of small nodules of calcification clustered in each pyramid. Diagnosing the underlying renal disease based on the appearance is difficult, except in papillary necrosis due to analgesic abuse because the entire papilla may be calcified, and, in medullary sponge kidney, the sharp areas of calcification and the uneven distribution may be conspicuous. It is suggested that the first foci of calcification develop in renal tubular cells or the interstitium when hypercalcemia is the most important factor and in tubular lumen when hypercalciuria is the major factor.

Tubular calcium deposits are believed to form on a nidus whose formation is due to the underlying disorder, uric acid being a common factor. Subsequently, calcium complexes lead to stone growth. There is an ongoing interest in evaluating the presence of secreted stone inhibitors and peptide complexes and their deficiency in renal disorders predisposed to tubular and interstitial calcifications.

Mortality/Morbidity

The morbidity and mortality associated with nephrocalcinosis is dependent on the disease associated with the condition rather than the nephrocalcinosis itself.

CLINICAL

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History

The underlying etiology primarily determines the presentation of nephrocalcinosis, although in most cases it is asymptomatic and is identified as a radiological abnormality. The clinical features of different types of nephrocalcinosis are as follows:

• Clinical features of chemical nephrocalcinosis
• • Hypercalcemia affects renal concentrating ability, manifesting as polyuria and polydipsia.
  • Defects such as renal glycosuria, reduced glucose tubular maximal (Tm), and, occasionally, generalized aminoaciduria have been reported.
  • Proteinuria is usually nonglomerular in hypercalcemic nephropathy.
  • Approximately 50% of patients with hypercalcemia are hypertensive because of increased peripheral vasoconstriction from the effect of calcium on small arteries and increased release of catecholamines. It is rapidly corrected with normocalcemia.
  • Hypercalcemia is also a well-established cause of renal failure, with the most common acute component being due to volume contraction. This volume contraction occurs by an elevated free water diuresis whose mechanism has been shown to involve the inability for vasopressin to function optimally at the tubular level. This usually is reversible, with normal renal function returning as the hypercalcemia is corrected with volume replacement. However, irreversible failure can occur with long-standing hypercalcemia and always is associated with crystal deposition.
• Clinical features of microscopic nephrocalcinosis
• • Few studies describe the effects of nephrocalcinosis on renal function in rats. Various investigators have observed reduced concentrating capacity and increased blood urea nitrogen and prolongation of a single nephron transit time in a distal tubule, but 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 renal failure.
  • Also, 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 diseases causing human nephrocalcinosis.
• Clinical features of macroscopic nephrocalcinosis
• • A wide range of abnormalities can occur with medullary nephrocalcinosis. Calcium nodules commonly rupture through the papillary epithelium into the calyceal system to become urinary stones, and, therefore, the presentation may be that of renal colic, hematuria, a urinary tract infection, or the passage of urinary stones. However, macroscopic nephrocalcinosis should not be considered synonymous with urinary stones because it signifies a metabolic derangement and has broader implications. Episodes of urinary tract infections may occur.
  • Polyuria and polydipsia may be prominent because of reduced renal concentrating ability. As explained previously, these symptoms are contributed to by an excess of free water diuresis.
  • Hypertension is less common because the juxtaglomerular apparatus often is unaffected, and a salt-losing state occasionally may be associated with it.
  • Several cases of medullary nephrocalcinosis of different etiologies have demonstrated erythrocytosis, implying that it may be the cause rather than the underlying disease. However, this needs further investigation. It can also be detected as an incidental finding on conventional radiography or computed tomography scans.
  • Proteinuria may be observed, although it usually is not significant and is less than 500 mg/d.
  • In Dent disease, loss of low–molecular weight protein may exceed 2 g/d. Hypercalciuria, nephrolithiasis, and nephrocalcinosis are some additional presenting features.
  • Microscopic pyuria invariably is found, and it represents a chronic inflammatory response to medullary calcification.
  • Distal tubular dysfunction is common with a mild salt-losing defect, and this defect may become evident when vomiting or anorexia is associated.
  • 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 renal failure or the features of their underlying disease.

Physical

The physical findings are nonspecific and relate mainly to the underlying disorders responsible for nephrocalcinosis.

Causes

• Primary hyperparathyroidism is the single most common cause of nephrocalcinosis in adults. Nephrocalcinosis is related more to the duration than the intensity of hypercalcemia. Nephrocalcinosis occurs in 5% of the cases of hyperparathyroidism. The classical clinical findings are "stone," "bones," and "abdominal groans." This common phrase is a reminder that patients may present with abdominal discomfort, bone pain, pathological fractures, osteoporosis, or osteopenia. A presentation of hyperparathyroidism, albeit rare, can be associated with multiple endocrine neoplasia (MENI).
• 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 Ab) have a high incidence. The contributing mechanisms are hypercalcemia, acidosis, and reduced excretion of citrate in the presence of increased urinary pH. Because medullary nephrocalcinosis also is a cause of distal RTA, reaching a diagnosis to establish the initial insult in this setting is sometimes difficult. Renal function is fairly well maintained.
• Other causes of nephrocalcinosis are hypervitaminosis D due to treatment of hypoparathyroidism or self-administration of vitamins and granulomatous diseases, such as sarcoidosis due to increased conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol within the sarcoid granuloma. In addition, cytokines (IL-2) cause dysregulation of calcium homeostasis and activation of osteoclasts, resulting in subacute and chronic hypercalcemia.
• Even oral phosphate supplements for hypophosphatemia may contribute to renal calcification, whose clinical implications can readily be seen in children with hypophosphatemic rickets; nephrocalcinosis is increasingly being recognized as the most common complication. In vitro studies have shown that an increased urinary concentration of phosphate can result in intratubular crystallization with altered solubility.
• Idiopathic hypercalciuria, one of the common metabolic diseases, also is a known cause of nephrocalcinosis. Hypercalcemia when associated with hypercalciuria is also a contributor to nephrocalcinosis. Etiologies include milk-alkali syndrome (due to excess ingestion of antacids), hyperparathyroidism (which was previously discussed), and malignant disease (bone involvement and humoral factors, including cytokines and PTHrP).
• Medullary sponge kidney is a common cause of medullary calcification in which calcium lies in ectatic collecting ducts rather than the renal substance. These ectatic outpouchings are believed to be areas of urinary stasis in which lies the ideal milieu for formation of these calcifying complexes. The calcium deposits are larger and more sharply defined than in metabolic disease, and they are uneven in distribution. Associated hemihypertrophy of the body may exist. Unlike the severe renal damage with minimal calcification associated with hypercalcemic states, nephrocalcinosis associated with distal RTA and medullary sponge kidney usually is gross, and renal function is relatively well preserved.
• Renal papillary necrosis associated with phenacetin-induced analgesic nephropathy is identified as calcified papillae rather than a speckled pattern.
• Other associations with nephrocalcinosis include rapidly progressive osteoporosis due to immobilization, menopause, senility, or steroids.
• Hyperoxaluria, primary (familial) or secondary to increased intake of oxalates, enhanced absorption due to intestinal disease, or ingestion of ethylene glycol or methoxyflurane can induce medullary calcification. Primary hyperoxaluria, in particular, is associated with deposition/calcifications in many of the body's organs in addition to the kidney, including the eye and the heart.
• Also, chronic hypokalemic states, such as Bartter syndrome, primary hyperaldosteronism, Liddle syndrome, or 11-beta hydroxylase deficiency, can cause damage to the tubular epithelium and low urinary citrate, leading to calcium precipitation.
• Congenital hypothyroidism, Dent disease, and familial magnesium-losing nephropathy are rare inherited diseases causing medullary calcification.
  • Dent disease is a gene defect of the short arm of the X chromosome, coding for renal chloride channel in the proximal tubule (CLC-5). This same defect is seen in X-linked hypophosphatemic rickets, X-linked recessive nephrolithiasis, and idiopathic low—molecular weight proteinuria in Japanese patients.
  • Familial forms of magnesium-losing nephropathy have been described. Familial hypomagnesemia hypocalciuric nephrocalcinosis (FHHNC) is an autosomal recessive disease associated with the cation loss through a defect in renal tight junctions proteins involved in paracellular transport.
• Hypercalcemic diseases that are not often associated with nephrocalcinosis include malignancies because patients seldom survive for an extended period, with the possible exception of parathyroid carcinoma. Also, familial benign hypercalcemia and hyperthyroidism are not associated with renal calcification.
• There have been reports of calcium-based phosphate binders (which are commonly used in patients with kidney disease) being associated with increased calcifications. Data are not conclusive; however, some reports have shown that there may be evidence of increased calcification in the already end-stage kidney when compared to noncalcium based binders, but the degree of calcification was equivocal when looking at other tissue beds, such as the heart and the liver.

DIFFERENTIALS

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Other Problems to be Considered

RTA
Hypercalcemic nephropathy

WORKUP

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Lab Studies

• Serum calcium, phosphate, albumin
• • These are needed to establish whether the nephrocalcinosis is associated with hypercalcemia or normocalcemia. The albumin level is important to determine the true serum calcium level. For every 1-g/dL decrease in the serum albumin, a decrease in serum calcium of approximately 0.8 mg/dL occurs.
  • The serum phosphate is low in primary hyperparathyroidism due to urinary wasting and hypophosphatemic rickets, but it may be elevated in calcinosis associated with renal insufficiency.
• Serum electrolytes, BUN, creatinine: The BUN and serum creatinine are elevated if the nephrocalcinosis has caused renal insufficiency. The serum potassium may be low in certain causes of nephrocalcinosis such as distal RTA, Bartter syndrome, primary hyperaldosteronism, and Liddle syndrome.
• Urinalysis with microscopic examination: The urinalysis should always be performed to look for evidence of chronic infection. An elevated urinary pH is suggestive of a distal RTA but also can be seen in infections with urease-splitting pathogens. Crystals observed on microscopy may provide valuable diagnostic clues.
• Twenty-four–hour urinary excretion of calcium, oxalate, citrate, and protein may be determined. Excess urinary calcium excretion may be observed in patients with idiopathic hypercalciuria. Increased urinary oxalate excretion indicates a primary or secondary cause of hyperoxaluria. Patients with nephrocalcinosis generally have low-grade proteinuria of a nonglomerular etiology. Nephrotic range proteinuria is an indication for further evaluation of the underlying renal disease.
• Parathyroid hormone levels should be obtained to rule out primary hyperparathyroidism.
• Thyroid-stimulating hormone (TSH) levels should be obtained to rule out hypothyroidism.
• Urinary magnesium may be useful in detecting magnesium-losing nephropathy.

Imaging Studies

• Although great imaging detail can be obtained with modern equipment, there remains a poor correlation between the extent of radiographically demonstratable nephrocalcinosis and the degree of renal impairment.
• Ultrasonography is more sensitive than conventional radiography but can produce false-positive results from papillary cysts or hilar fat deposition.
• Computerized tomography scan is more effective in detecting calcification and can be used to locate medullary versus cortical deposition. It also may be used to detect defects that are too small to be diagnosed by conventional radiography.
• Magnetic resonance imaging is not a good tool to establish a diagnosis in the presence of less expensive and alternative methods, as mentioned above; these alternative methods should be used first in the appropriate settings.

Histologic Findings

The histological findings include crystal deposition, which occurs mainly in the interstitium. The deposits may be observed within the tubules or between the tubules. The deposits consist of calcium phosphate or calcium oxalate. Special stains, such as von Kossa and Pizzolato, may be required for better visualization.

TREATMENT

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Medical Care

• Treatment of hypercalcemic nephropathy
• • The successful management of hypercalcemic nephropathy consists of treating the hypercalcemia and its cause.
  • Adequate hydration by isotonic sodium chloride solution, if necessary, is the single most effective measure of protecting the kidney. This may be combined with furosemide to enhance calcium excretion after volume repletion is assured.
  • Other treatments include parathyroidectomy for correction of hyperparathyroidism; chemotherapy for osteolytic malignancies; steroids to decrease intestinal calcium absorption; and plicamycin (also referred to as mithramycin), calcitonin, or bisphosphonates to inhibit bone resorption.
  • Calcium channel blockers have no established role in management.
• Treatment of macroscopic nephrocalcinosis
• • General measures for treatment of medullary nephrocalcinosis may include thiazide diuretics and dietary restriction of calcium and sodium to decrease the urinary calcium excretion and magnesium citrate to increase the solubility of urinary calcium.
  • In type 1 hyperoxaluria, treatment with large doses of pyridoxine can lower oxalate production.
  • Also, magnesium supplementation in magnesium-losing nephropathy may be helpful.
  • Sodium or potassium citrate can be used in distal RTA because this increases urinary citrate and reduces urinary calcium.
  • Over time, lessening of nephrocalcinosis may occur, especially the nephrocalcinosis observed in idiopathic absorptive hypercalciuria and enteric hyperoxaluria treated with bowel surgery. However, most other causes, such as primary hyperoxaluria, distal RTA, papillary necrosis, and magnesium-losing nephropathy, are largely incurable, and the management is limited to decreasing the damage. Therefore, early detection is very important.

Surgical Care

• Surgery may be required for urinary stones causing obstruction, although a number of stones may be passed with no surgical intervention. Percutaneous nephrolithotomy, laser, and shock wave lithotripsy may be required.
• Parathyroidectomy may be needed to control a hyperfunctioning parathyroid gland.
• Attempts to remove calcium nodules from within the renal substance invariably cause damage to renal tissue.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Bisphosphonates

Used to treat hypercalcemia and decrease calcium loss from bone.

Drug Category: Calcitonins

Indicated to treat hypercalcemia. Maintain calcium homeostasis by increasing the mineral stores in bone and renal excretion of calcium. Directly inhibit osteoclastic bone resorption. Salmon calcitonin is preferred over human calcitonin because of its longer duration of action.

Drug Category: Thiazide diuretics

When the delicate balance of calcium needs to be maintained in nephrocalcinosis, thiazide diuretics are useful by decreasing sodium levels and increasing calcium levels. Calcium levels are retained by a decrease in calcium excretion by increasing renal tubular absorption and inhibiting hydroxylation of vitamin D without affecting the parathyroid gland.

Drug Category: Vitamins

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

FOLLOW-UP

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Prognosis

• The prognosis depends mainly on the etiology of the nephrocalcinosis.
• The major long-term complication in patients with medullary nephrocalcinosis is renal failure.
• • Early treatment of reversible causes of renal failure, such as treatment of urinary infections, calculous obstruction, and hypertension, is essential.
  • Once renal failure is established, it must be treated accordingly.
  • Patients with idiopathic hypercalciuria and medullary sponge kidney have the least risk of renal failure and the best prognosis, whereas patients with primary type 1 hyperoxaluria have the worst prognosis.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Nephrocalcinosis, although seemingly simple, is much more complex because it incorporates a large number of diseases. Describing nephrocalcinosis according to its location and degree is best.
• The macroscopic variety of nephrocalcinosis is the form most often observed in clinical practice. Do not consider it synonymous with renal stone disease because it has much broader metabolic implications.

MULTIMEDIA

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Media file 1:  Nephrocalcinosis.
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REFERENCES

Section 11 of 11

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• Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol. Nov 2005;16(11):3389-96.
• Monk RD, Bushinsky DA. Nephrolithiasis and nephrocalcinosis. In: Johnson RJ, Feehally J, eds. Comprehensive Clinical Nephrology. 2^nd ed. Mosby; 2003:731-4.
• Oguzkurt L, Karabulut N, Haliloglu M, Unal B. Medullary nephrocalcinosis associated with vesicoureteral reflux. Br J Radiol. Aug 1997;70(836):850-1. [Medline].
• Sanderson PH. Functional aspects of renal calcification in rats. Clin Sci. 1959;18:67-69.
• Scarpelli DG, Tremblay G, Pearce AGE. A comparative cytochemical and cytologic study of vitamin D induced nephrocalcinosis. Am J Pathol. 1960;36:331-53.
• Weber S, Schneider L, Peters M, Misselwitz J, Rönnefarth G, Böswald M. Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. J Am Soc Nephrol. Sep 2001;12(9):1872-81. [Medline].

Article Last Updated: Feb 1, 2007