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
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.
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.
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
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.