Nephrocalcinosis 

Nephrocalcinosis is a condition in which calcium levels in the kidneys are increased. This increase can be detected (usually as an incidental finding) through a radiologic exam or via microscopic examination of the renal tissues. The term nephrocalcinosis most often applies to a generalized increase in renal calcium content, as opposed to the localized increase observed in calcified renal infarct and caseating granulomas of renal tuberculosis.^[1]

A diagram of a nephron is shown below.

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

Nephrocalcinosis has a significant 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, demanding further evaluation. See the images below.

Hypercalcemic nephropathy

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, predominately 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. This may be mediated by reduced sodium transport in the loop of Henle and by antidiuretic hormone antagonism via calcium-sensing receptors,^[2] or it may be related to medullary prostaglandin synthesis. Maximum diluting capacity remains unimpaired. Effectively, the sum effect of this will be a clinical picture equivalent to 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; the effect probably is due to suppression of the 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 calcium infusions, and metabolic alkalosis frequently has 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 elaborate laboratory study. Although the condition is a theoretical 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 now exists that demonstrates 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, and primary hyperoxaluria.

Different patterns of microscopic nephrocalcinosis have been described. Cortical calcification 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 due to the 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 through conventional radiography, ultrasonography, or computed tomography (CT) scanning, or at autopsy. Macroscopic nephrocalcinosis can affect either the cortex or medulla, as shown below, with the latter site being more common.

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] Rare etiologies of cortical nephrocalcinosis include renal transplantation, primary hyperoxaluria, methoxyflurane abuse, autosomal recessive polycystic kidney disease, and benign nodular cortical nephrocalcinosis.

Medullary nephrocalcinosis assumes the form of small nodules of calcification clustered in each pyramid. (See first image below.) Diagnosing the underlying renal disease based on the appearance is difficult. Characteristic exceptions include papillary necrosis due to analgesic abuse and medullary sponge kidneys.^[8] (See second and third images below.) In papillary necrosis, the entire papilla may be calcified, while 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, and that when hypercalciuria is the major factor, they form in the interstitium.

Intraluminal tubular calcium crystals are believed to serve as potential nidi for further build-up 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.

Mortality/Morbidity

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