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Hypercalcemic nephropathy (chemical nephrocalcinosis)

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 extractinduced
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. These changes may be mediated by reduced sodium transport in the
loop of Henle (see the image below) and by antidiuretic hormone antagonism via
calcium-sensing receptors, [3] or they may be related to medullary prostaglandin
synthesis.

Diagram of nephron.
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Maximum diluting capacity remains unimpaired. Effectively, the sum effect of this
process will be a clinical picture resembling 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. [4]
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.[5, 6]
The effects on the acid-base balance are even more complex. Increased renal acid
excretion occurs with intravenous (IV) calcium infusions, and metabolic alkalosis has
frequently 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 considerable laboratory study.
Although this condition theoretically occupies a 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 are now
available that demonstrate early stone formation, with blockage of the collecting
tubes and subsequent inflammatory response. [7]
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, or primary hyperoxaluria.
Different patterns of microscopic nephrocalcinosis have been described. The cortical
pattern 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 resulting
from 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 by means of conventional radiography,
ultrasonography, or computed tomography (CT) or at autopsy. Macroscopic
nephrocalcinosis can affect either the cortex or the medulla, with the latter site being
more commonly involved.
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. [8] Renal transplantation, primary
hyperoxaluria, methoxyflurane abuse, autosomal recessive polycystic kidney
disease, and benign nodular cortical nephrocalcinosis may be involved in cortical
nephrocalcinosis, albeit rarely.
Medullary nephrocalcinosis assumes the form of small nodules of calcification
clustered in each pyramid. Diagnosing the underlying renal disease on the basis of
the appearance is difficult. Characteristic exceptions include papillary necrosis due to
analgesic abuse and medullary sponge kidneys. [9] In papillary necrosis, the entire
papilla may be calcified, whereas 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, whereas when hypercalciuria is
the major factor, the initial foci form in the interstitium.
Intraluminal tubular calcium crystals are believed to serve as potential nidi for further
buildup 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.