Pathophysiology

Chemical nephrocalcinosis

Patients with hypercalcemia develop renal functional 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 also is impaired because of reduced absorption of sodium chloride in the medullary, thick, ascending limb and collecting tubule, though it rarely results in gross renal sodium loss. Potassium excretion is increased. Magnesium excretion also is 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, though conversely in hypercalcemia due to breast cancer, it increases phosphate excretion. 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. At necropsy, however, normal 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. Raised 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 gross enough to be seen 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 seen in chronic glomerulonephritis or long-standing, chronic, renal disease.

Cortical nephrocalcinosis is rare and usually occurs secondary to diffuse cortical disease. 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 also are 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 from 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. The first foci of calcification have been suggested as developing in renal tubular cells or the interstitium when hypercalcemia is the most important factor and in tubular lumen when hypercalciuria is the major factor.

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.

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 a period of time, lessening of nephrocalcinosis may occur, especially the nephrocalcinosis seen 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, though a number of stones may be passed with no surgical intervention. Percutaneous nephrolithotomy and 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.