Introduction
Background
Nephrocalcinosis was a termed coined by Albright in 1934 to describe the deposition of calcium salts in the renal parenchyma in hyperparathyroidism.1 The term has now acquired more of a radiologic concept, and it is used to describe diffuse, fine, renal parenchymal calcification that is radiologically demonstrable. This appearance is different from that of calcification within the lumen of the collecting system, ureter, and bladder, which represents nephrolithiasis.
Many causes of nephrocalcinosis have been added since the original description. These include the several causes of hypercalcemia and hypercalciuria. Nephrocalcinosis can be subdivided into the cortical type, which is classically the result of acute tubular necrosis (ATN), and the medullary type, which may be an extension of cortical nephrocalcinosis or is seen in isolation with several metabolic disorders.2
In nephrology, the term nephrocalcinosis is applied only to the medullary type. Nephrocalcinosis can be demonstrated on plain radiographs, sonograms, or computed tomography (CT) scans.3,4,5,6,7,8,9 CT scanning is the most accurate and sensitive technique and, therefore, it is the modality of choice.9,10,11
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Top: Plain radiograph of the kidneys in a patient with a long history of renal tubular acidosis (same patient as in bottom image and Image 12 in Multimedia). This image shows bilateral pyramidal calcification that is consistent with nephrocalcinosis. Bottom: Sonograms of the kidneys in the same patient as above show a hyperechoic medulla associated with echogenic foci, some of which are casting shadows.
Axial computed tomography scans obtained from a patient with a long history of renal tubular acidosis (same patient as in Image 11 in Multimedia). These images show bilateral medullary nephrocalcinosis (early arterial phase).
Excretory urogram obtained at 15 minutes in a man with renal papillary necrosis, most likely a patient with diabetes mellitus and repeated urinary tract infections (same patient as in Images 6-7 in Multimedia). This image shows bilateral hydronephrosis and a hydroureter due to obstruction by sloughed papillae at the lower end of the ureter.
Pathophysiology
Disorders of calcium metabolism
Disorders of calcium metabolism, such as hypercalcemia and hypercalciuria, may induce the formation of calcium renal stones and deposition of calcium salts in the renal parenchyma (nephrocalcinosis). The extensive deposition of calcium may lead to chronic tubulointerstitial disease and renal insufficiency. The first signs of damage induced by hypercalcemia are seen at the intracellular level, in the tubular epithelial cells. This results in mitochondrial distortion, and eventually, calcium deposits can be demonstrated within the mitochondria, the cytoplasm, and the basement membrane.
Calcified cellular debris results in occlusion of the tubules, leading to obstructive atrophy of the nephron, nonspecific inflammation, and interstitial fibrosis. Impaired urine drainage through calcified tubules may result in areas of cortical atrophy leading to scarred cortices. A functional abnormality of urine concentration is the earliest detectable renal change. This effect is related to decreased chloride transport in the ascending thick segment of the nephron.
Other defects of tubular function, such as tubular acidosis and salt-losing nephritis, may also occur. The continuing and unchecked deposition of calcium eventually leads to chronic renal insufficiency. Nephrocalcinosis may be complicated by renal stone formation, which adds another element to the causation of renal insufficiency secondary to an obstructive uropathy. The histologic findings include calcium phosphate or calcium oxalate crystal deposits that mainly appear in the renal interstitium, but deposits may also be seen within the renal tubules. Special stains, such as the von Kossa and Pizzolato stains, can be used to specifically depict these deposits.
Causes of cortical nephrocalcinosis
Acute cortical necrosis
Acute cortical necrosis implies death of the renal cortex, with sparing of the renal medulla. This can follow placenta abruptio, placenta previa, septic abortion, transfusion reactions, burns, snake bite, severe dehydration, shock, severe heart failure, and abdominal aortic surgery. In children, the condition may follow dehydration, fever, sepsis, and hemolytic uremic syndrome.
The pathogenesis of acute cortical necrosis is multifactorial and related to a combination of cortical ischemia from vasospasm of small blood vessels, toxic damage to the glomerular capillary endothelium, and primary intravascular thrombosis after an excessive release of thromboplastin. Acute cortical necrosis is usually global, leading to a rapid and permanent renal failure. In focal disease with some sparing of the renal cortex, life can be sustained with dialysis.
Chronic glomerulonephritis
Chronic glomerulonephritis is the second most common cause of cortical nephrocalcinosis after acute cortical necrosis, although radiologic evidence of calcification is rare in both conditions.
Alport syndrome
Alport syndrome involves a hereditary nephropathy that is associated with deafness. This syndrome may cause cortical nephrocalcinosis indistinguishable from that caused by many other etiologies.
Prolonged hypercalcemia and/or hypercalciuria
Prolonged hypercalcemia and/or hypercalciuria may involve conditions such as hyperparathyroidism, vitamin D intoxication, beryllium poisoning, systemic sarcoidosis, milk-alkali syndrome, hyperthyroidism, Addison disease, idiopathic hypercalcemia of infancy, increased bone catabolism associated with myeloma, disseminated metastatic bone disease, leukemia, and immobilization. Most of these result in nephrolithiasis rather than nephrocalcinosis.
Poisoning and toxicity
Ethylene glycol (antifreeze) poisoning can cause marked ballooning and hydropic or vacuolar degeneration of the proximal convoluted tubules. Calcium oxalate crystals are usually found in the tubular lumen in such poisonings. Ethylene glycol can lead to secondary hyperoxaluria. This is actually ATN in which there is destruction of tubular cells
A severe form of primary hyperoxaluria results in the deposition of calcium oxalate crystals in many organs besides the kidneys. The calcific deposits in the convoluted tubules may add a stippled or diffuse increase in the radiopacity to the kidneys. Excessive ingestion of oxalates can give rise to a similar appearance. The metabolic defect is hepatic in origin. Therefore, both renal and liver transplant are required in the treatment of the disease.
Methoxyflurane anesthesia toxicity can cause calcium oxalate deposits in the proximal and distal convoluted tubules. Methoxyflurane anesthesia is a cause of secondary hyperoxaluria.
Other causes
Rejected renal transplants can give rise to cortical necrosis.
Sickle cell disease is a rare cause of cortical nephrocalcinosis. Sickle cell disease is related to infection.
Vitamin B6 (pyridoxine) deficiency can be associated with xanthurenic aciduria that is related to deficiency of the phosphate-dependent enzyme kynureninase. Vitamin B6 (pyridoxine) deficiency is another cause of secondary hyperoxaluria. It is a rare cause of cortical nephrocalcinosis.
Causes of medullary nephrocalcinosis
Hyperparathyroidism
Hyperparathyroidism results in renal lithiasis in 20% of patients, with radiographically detectable nephrocalcinosis in as many as 11% of patients. Both the primary and secondary forms of hyperparathyroidism may affect the kidney, although both lithiasis and nephrocalcinosis are rare in the secondary disease. Nephrocalcinosis in hyperparathyroidism is confined to the lumina of the distal collecting ducts.
Medullary sponge kidney
The pathogenesis of medullary sponge kidney is unknown. Most authors believe this disease is a developmental defect that affects the formation of the collecting tubules. Others suggest it is a progressive degeneration of the collecting tubules that occurs later in life and the primary abnormality is hyperplasia of part of medullary collecting tubules.
Histologic sections show multiple cysts representing dilatated terminal collecting tubules; these measure 1-7 mm. The cysts usually communicate with collecting tubules proximally and with the papillary ducts or calyx distally. Intercommunicating and noncommunicating cysts are occasionally seen. Calculi may be seen within these cysts.
Tuberculosis of the kidneys
Tuberculosis of the kidneys usually spreads via a hematogenous route from pulmonary disease, although it is occasionally secondary to tuberculosis of the gastrointestinal (GI) tract or bone. By the time renal tuberculosis is diagnosed, the primary source of pulmonary infection may be inactive or calcified. The true prevalence of renal tuberculosis is underestimated because radiologic signs may be absent. Moreover, tubercle bacilli are found in 7-29% of urine samples in patients with extrarenal tuberculosis.
The course of renal tuberculosis may be indolent, with the appearance of few, if any, symptoms. The presentation is usually late, and symptoms usually occur as a nonspecific urinary tract infection. Constitutional symptoms usually do not occur or are sparse. Renal tuberculosis is bilateral, although radiologic findings are asymmetric and unilateral in 25% of patients. Ultimately, the kidney becomes atrophic, scarred, densely calcified, and nonfunctioning (autonephrectomy) if the condition is not appropriately treated.
Renal tubular acidosis
Renal tubular acidosis (RTA) includes a group of diseases of diverse etiology. Type I RTA is characterized by abnormalities of hydrogen ion transfer from the blood to the urine in the distal tubules, and type II RTA is characterized by the impairment of bicarbonate conservation by the kidneys. Patients with type I disease are unable to excrete acidic urine and develop profound metabolic conditions, including problems with calcium and phosphate balance. Both nephrocalcinosis and nephrolithiasis eventually develop in 70% of the patients.
The disease may be primary or idiopathic or secondary to a variety of diseases. The primary form (Lightwood syndrome) may be transient and occurs more often in male infants. If these infants survive with treatment, they rarely develop radiologic evidence of nephrocalcinosis. However, a few infants do show spotty renal calcification.
The more common type of primary type I RTA is a chronic disease that is inherited in an autosomal dominant manner (Butler-Albright disease). This type predominantly affects girls aged 2 years or older and adults of both sexes. Nephrolithiasis and nephrocalcinosis affect over 70% of the patients. The secondary form of type I RTA occurs as a result of a variety of causes. These include hypercalcemia; Wilson disease; hyperglobulinemias; and drug toxicity from amphotericin, outdated tetracycline, triamterene, and acetazolamide. Type II RTA does not usually cause calculi.
Renal papillary necrosis
Renal papillary necrosis refers to ischemic necrobiosis of papilla in the medulla of kidney. A number of conditions can cause renal papillary necrosis, all associated with ischemia (hemoglobin S [Hgb S] infection, including that due to tuberculosis, analgesic drugs, cirrhosis). Renal papillary necrosis can be localized or diffuse, and it can be unilateral or bilateral. Early in the disease, renal size and function are preserved, but function may deteriorate with eventual renal failure in the later stages of the disease.
Immobilization
Immobilization may lead to hypercalcemia and hypercalciuria as a result of bone resorption. Immobilized children are particularly prone to calcium metabolic changes because of their active bone growth. Osseous demineralization can occur, and excessive soluble products of calcium and phosphate can precipitate in the renal tubules to form renal calculi. In immobilized patients, the frequency of lithiasis increases with urinary tract infections.
Milk-alkali syndrome
Milk-alkali syndrome is the result of the ingestion of large quantities of calcium. The alkaline urine facilitates the precipitation of calcium-containing calculi. However, this is no longer true in peptic ulcer disease with the use of H2 blockers and the antibiotic treatment of Helicobacter pylori.
Hypervitaminosis D
Excessive vitamin D ingestion (hypervitaminosis D) facilitates increased absorption of calcium from the gut and may cause nephrocalcinosis. A similar complication may occur as a result of treatment of vitamin-resistant rickets in which large doses of vitamin D are used with doses large enough to produce nephrocalcinosis in association with osteomalacia. In this instance, the osseous change is the result of primary disease, and the renal change is the result of treatment. This process is unlike that of type I RTA in which the reverse is true. This is a rare cause of nephrocalcinosis.
Idiopathic hypercalcemia of infancy can produce metabolic changes similar to those of hypervitaminosis D. This condition is related to an inborn error of vitamin D metabolism in which elevated blood levels of vitamin D are present. The affected infants may exhibit dwarfism, elfin facies, mental retardation, and osteosclerosis. Renal failure and hypertension develop secondary to hypercalcemia, hypercalciuria, and nephrocalcinosis.
Sarcoidosis
Sarcoidosis is not infrequently associated with hypercalciuria, which may occur in the absence of hypercalcemia. Both nephrocalcinosis and nephrolithiasis may ensue as a result. Hypercalciuria is due to increased vitamin D absorption from the GI tract, possibly caused by increased sensitivity to vitamin D. When patients present with nephrocalcinosis and nephrolithiasis, pulmonary and mediastinal changes are usually evident. Sarcoid renal granulomas occur but rarely become calcified. This is a rare cause of nephrocalcinosis.
Nephrocalcinosis
Nephrocalcinosis has been described in 16% of preterm infants,12 although a study examining the long-term effects of neonatal nephrocalcinosis on renal function showed spontaneous resolution in 75% of cases and appeared to indicate that nephrocalcinosis is not associated with renal dysfunction in the long term.13 On univariate analysis, gestational age, male sex, duration of ventilation, oxygen dependency, duration and frequency of gentamicin treatment, toxic gentamicin/vancomycin levels, low fluid intake, and postnatal dexamethasone were significantly associated with nephrocalcinosis.12
Nephrocalcinosis has been described in premature infants treated with high doses of furosemide for prolonged periods because of congestive heart failure secondary to patent ductus arteriosus or pulmonary disease.14,15 Both nephrocalcinosis and nephrolithiasis may occur. These complications occur 11-50 days after the commencement of furosemide therapy. The addition of chlorothiazide to furosemide prevents further calculi formation, and it may also lead to the dissolution of existing stones. Therefore, preterm infants who are taking furosemide should be regularly screened with renal ultrasonography. Long-term furosemide abuse can also cause medullary nephrocalcinosis in adults.16,17
Hyperoxaluria
Primary hyperoxaluria is an autosomal recessive disorder involving both excessive production and the urinary excretion of oxalate. Primary hyperoxaluria may cause nephrocalcinosis and nephrolithiasis as a result of deficiency of the enzyme carboligase. Two types are described. In type I, a deficiency of ketoglutarate-glyoxylate carboxylase is observed, and patients present with glycolic aciduria. In type II disease, a deficiency of D-glycerate dehydrogenase occurs, and patients present with 1-glyceric aciduria.
Male and female children are equally affected. They usually present with renal lithiasis and nephrocalcinosis before the age of 5 years. These have a progressive course, and, if untreated, they result in death from renal failure. Associated liver transplantation is required to correct the metabolic defect.
Secondary hyperoxaluria is a much rarer condition, and it is associated with disturbance of bile acid metabolism. The causes of secondary hyperoxaluria include a short small bowel as a result of ileal resection or jejunoileal bypass, Crohn disease, blind loop syndrome, and increased ingestion of green, leafy vegetables. This usually occurs as nephrolithiasis rather than nephrocalcinosis.
Glucose-galactose malabsorption
Soylu et al described an association between hypercalcemia, nephrocalcinosis, and proximal tubular dysfunction, which may be seen in association with glucose-galactose malabsorption, in a 50-day-old girl with glucose-galactose malabsorption who was found to have nephrocalcinosis but no sign of nephrolithiasis.18 The authors noted that most of these abnormalities improved with a glucose-galactose-free diet. The infant was found to have a novel mutation of Na(+)-dependent glucose transporter (SGLT1).
Miscellaneous causes
A variety of conditions can cause bone destruction that is associated with hypercalcemia and hypercalciuria. These include bony metastases, multiple myeloma, Paget disease, Cushing disease, and both hyperthyroidism and hypothyroidism (although the incidence associated with hypothyroidism is low). Chronic paraneoplastic hypercalcemia may also cause nephrocalcinosis.
Sickle cell anemia is a rare cause of nephrocalcinosis. A variety of radiographic renal abnormalities have been associated with sickle cell disease, including renal enlargement, thickening of the renal cortex, focal hypertrophy, papillary necrosis, and changes associated with infection.
Ochronosis (alkaptonuria) is an autosomal recessive disorder involving deficiency of the enzyme homogentisic acid oxidase. It is a rare cause of nephrocalcinosis; renal stone formation is more common.
Frequency
United States
Regarding cases of nephrocalcinosis and nephrolithiasis in children, 64% are associated with an underlying structural renal lesion or urinary tract infection, 10% are associated with hypercalcemia or hypercalciuria, 6% are associated with cystinuria, and 20% are idiopathic (as many as 50% in some series). Oxalosis and miscellaneous conditions may be involved.
In adults, 40% of cases of medullary nephrocalcinosis are attributed to hyperparathyroidism, and 20% are attributed to RTA. The remaining 40% are divided among the other multiple causes. Conversely, 5% of patients with hyperparathyroidism have nephrocalcinosis. The medullary type accounts for 95% of all nephrocalcinosis, whereas 5% represent cortical nephrocalcinosis. In 70% of patients with RTA type I, both nephrocalcinosis and nephrolithiasis eventually develop.
International
No reliable data are available regarding the frequency and prevalence of nephrocalcinosis.
Mortality/Morbidity
Mortality and morbidity depend on the cause of nephrocalcinosis.
- An association with malignant bone disease obviously has a poor prognosis. Unchecked nephrocalcinosis eventually leads to renal dysfunction. Again, the degree of renal impairment depends on the etiology of the nephrocalcinosis. Acute cortical necrosis may lead to a rapid and permanent renal failure. However, in focal disease with some sparing of the renal cortex, life can be sustained, although renal function is impaired.
- Children of both sexes with primary oxaluria usually present with progressive disease, which, if untreated, results in death from renal failure in childhood.
- Some conditions causing nephrocalcinosis are associated with profound metabolic disturbances that have their own associated complications. Growth retardation in children is commonly seen in patients with underlying metabolic disease. Treatment, whether medical or surgical, has its own morbidity and mortality.
Race
No racial or ethnic predilection is observed.
Sex
Males and females are equally affected.
Age
All age groups can be affected, but the disease is more common in childhood than at other times.
Anatomy
The basic unit of renal function is the nephron (see Image below and Image 1 in Multimedia), which consists of the glomerulus; the proximal convoluted tubule; the loop of Henle; and the distal convoluted tubule, which finally drains into the collecting ducts. Anatomically, the glomerulus and proximal convoluted tubules are placed in the renal cortex, whereas the descending loop of Henle enters the medullary tissue. The ascending loop goes back to the cortex, where it drains into the distal convoluted tubule. Finally, the distal convoluted tubule drains into the collecting ducts, which again enter the renal medulla and drain into the calyx.
Diagram of a nephron.
Each normal kidney contains about 1,250,000 nephrons. The gross anatomic renal functioning unit is the lobule, consisting of the medullary pyramid with its base oriented toward the renal cortex and the apex oriented toward the calyx. Its sides are covered by renal cortical columns. At the glomerulus, all the constituents of plasma are filtered, except the cellular elements and the plasma proteins, and are transported via the tubules to the renal sinus. In healthy adults, 180 L of filtrate is formed per day. About 80% of the filtrate is reabsorbed in the proximal convoluted tubule, and 20% is absorbed in the distal tubular structures, dependent on antidiuretic hormone (ADH).
Disorders of calcium metabolism, such as hypercalcemia and hypercalciuria, may cause extensive deposition of calcium within the renal tubules, and chronic tubulointerstitial disease and renal insufficiency may result. Calcified cellular debris results in occlusion of the tubules, leading to obstructive atrophy of the nephron, nonspecific inflammation, and interstitial fibrosis. Impaired urine drainage through calcified tubules may result in areas of cortical atrophy, leading to scarred cortices. Functional abnormality of urine concentration is the earliest detectable renal change (osmolality). This is related to decreased chloride transport in the ascending thick segment of the nephron. Other defects of tubular function, such as tubular acidosis and salt-losing nephritis, may also occur.
Presentation
The clinical presentation of nephrocalcinosis is determined by the underlying etiology. Most cases are asymptomatic, and nephrocalcinosis is identified as a radiologic abnormality. Renal tubular disorders may be first diagnosed on biochemical examination of the urine, which often reveals glycosuria, aminoaciduria, and phosphaturia. Polyuria and polydipsia may be the presenting features, with loss of the concentrating ability of the renal tubules.
With the advent of multichannel analyzers, most cases of hyperparathyroidism are now recognized with routine blood testing. Approximately 50% of the patients with hypercalcemia are hypertensive because of increased vasoconstriction as a result of calcium deposition within the arterioles and because of an increased release of catecholamines. Occasionally, symptoms from recurrent urinary tract infections may be the presenting features. Recurrent abdominal pain and hematuria may be present in children and adults. Associated nephrolithiasis may present acutely with colic.
Preferred Examination
Most cases of nephrocalcinosis are asymptomatic and usually identified on plain abdominal radiographs. Planar radiography provides a useful adjunct to plain radiography. Nonenhanced CT scans can also depict nephrocalcinosis, and its apparent sensitivity and accuracy make CT scanning the modality of choice.
Ultrasonography is noninvasive, ideal for use in young children, quick to perform, and accurate. Early in its course, medullary nephrocalcinosis can be seen as echogenic pyramids before nephrocalcinosis can be identified on plain abdominal radiographs.
Limitations of Techniques
Usually, nephrocalcinosis cannot be detected on plain radiographs until the attenuation exceeds 100 Hounsfield units (HU). Optimal imaging must be used to produce the right factors for radiographic accuracy. The radiation burden with CT scanning is a disadvantage in the young. Ultrasonography remains operator dependent, and its accuracy is affected by the patient's body habitus.
Differential Diagnoses
Autosomal Dominant Polycystic Kidney
Disease
Hyperparathyroidism, Primary
Hyperparathyroidism, Secondary
Nephrolithiasis/Urolithiasis
Rickets
Other Problems to Be Considered
Bartter syndrome
Cystinuria
Hyperoxaluria
Hyperuricuria
Hypomagnesemia-hypercalciuria syndrome
Idiopathic hypercalciuria
RTA (distal)
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Further Reading
Keywords
nephrocalcinosis, male urogenital disease, urologic diseases, kidney disease, medullary sponge kidney, renal lithiasis, urolithiasis, medullary calcification, diffuse renal calcification, nephrolithiasis, medullary nephrocalcinosis, cortical nephrocalcinosis, hypercalcemia, hypercalciuria, hyperoxaluria, Bartter syndrome, hyperparathyroidism, primary, hyperparathyroidism,secondary, Butler-Albright disease
