eMedicine Specialties > Nephrology > Tubulointerstitial Diseases of the Kidney

Nephrocalcinosis

Tibor Fulop, MD, Assistant Professor, Department of Internal Medicine, Division of Nephrology, University of Mississippi Medical Center
Mahendra Agraharkar, MD, MBBS, FACP, FASN, Clinical Associate Professor of Medicine, Baylor College of Medicine, President & CEO, Space City Associates of Nephrology; Rupert Patel, MD, Physician, Division of Nephrology, Houston, Texas; Rajiv Gupta, MD, Assistant Professor, Department of Medicine, Texas A & M University Health Science Center; Consulting Staff, Veterans Affairs Medical Center

Updated: Apr 21, 2009

Introduction

Background

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.

Diagram of a nephron.

Nephrocalcinosis.

Nephrocalcinosis.

Nephrocalcinosis.

Pathophysiology

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.

Nonenhanced coronal computed tomography scans through the kidneys. These images show cortical and medullary nephrocalcinosis (left kidney). Both kidneys appear scarred. Note the thinning of the renal cortex at the upper pole of the left kidney. This patient gave a long history of chronic pyelonephritis, which is an unusual cause of nephrocalcinosis.

Axial computed tomography scans obtained from a patient with a long history of renal tubular acidosis. These images show bilateral medullary nephrocalcinosis (early arterial phase).

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.

Ultrasonogram of the right kidney in a woman with nephrocalcinosis. This image shows hyperechoic foci in the pyramids.

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. This image shows bilateral hydronephrosis and a hydroureter due to obstruction by sloughed papillae at the lower end of the ureter.

Plain kidney, ureters, and bladder (KUB) radiograph in a man with renal papillary necrosis, most likely a patient with diabetes mellitus and repeated urinary tract infections. This image shows bilateral renal calcification. A large, sloughed, and calcified renal papilla is present in the region of left vesicoureteric junction. Note the 2 pelvic phleboliths opposite the ischial spine on the right.

Mortality/Morbidity

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

Clinical

History

The underlying etiology primarily determines the presentation of nephrocalcinosis, although in many cases, the condition remains asymptomatic and is identified only as a radiologic abnormality. Potential clinical features include the following:

• Clinical features of hypercalcemia
  • Relative vasopressin resistance with decreased renal concentrating ability and increased free water diuresis (nephrogenic diabetes insipidus), manifesting as polyuria and polydipsia.
  • Other defects, such as renal glycosuria, reduced glucose tubular maximal, aminoaciduria, and nonglomerular proteinuria have occasionally been reported.
  • Reversible hypertension occurs in approximately 50% of patients, due to increased peripheral vasoconstriction.
  • Hypercalcemia is also a well-established cause of renal failure, due to direct renal vasoconstriction and to volume depletion induced by excessive diuresis. This usually is reversible, with normal renal function returning as the hypercalcemia is corrected with volume replacement. However, irreversible failure can occur with long-standing hypercalcemia and is always associated with calcium crystal deposition.
• Clinical features of microscopic nephrocalcinosis
  • A few studies describe the effects of nephrocalcinosis on renal function in rats.^{[9 ]}Various investigators have observed reduced concentration capacity, increased blood urea nitrogen (BUN), and prolongation of a single nephron transit time in a distal tubule,^{[10 ]} although no detailed studies of glomerular filtration or renal tubular function exist in these models.
  • Occasionally, rats with the pelvic type of nephrocalcinosis may develop acute pyelonephritis or calculous ureteral obstruction with renal failure.
  • However, nephrocalcinosis in rats is a poor model for humans because of the high incidence of spontaneous glomerulosclerosis in laboratory rats, the different distribution of calcium in the kidney, and the absence of a rat model for many of the diseases that cause human nephrocalcinosis.
• Clinical features of macroscopic nephrocalcinosis
  • A wide range of abnormalities can occur with medullary nephrocalcinosis. Calcium nodules may rupture through the papillary epithelium into the calyceal system to become urinary stones and elicit the clinical presentations of renal colic, hematuria, passage of urinary stones, or urinary tract infection. However, macroscopic nephrocalcinosis should not be considered synonymous with urinary stones, because nephrocalcinosis usually implies a more profound metabolic derangement.
  • Polyuria and polydipsia may be prominent because of the excess of free water diuresis with reduced renal concentrating ability. 
  • Hypertension is relatively less common, probably reflecting a reduced ability to conserve sodium.
  • Proteinuria may be observed, although it is in the nonnephrotic range and usually is less than 500 mg per day.
  • In Dent disease, loss of low – molecular weight proteins may exceed 2 grams per day. Hypercalciuria, nephrolithiasis, and nephrocalcinosis are some additional presenting features.
  • Microscopic pyuria is frequently found and represents a chronic inflammatory response to medullary calcification.
  • Distal tubular dysfunction is common with a mild salt-losing defect; this defect may become obvious only with profound decrease of per os intake (anorexia) or when another source salt-water loss emerges, such us diarrhea or vomiting.
  • Proximal tubular dysfunction is unusual, except for tubular proteinuria and the aminoaciduria of Dent disease.
  • Medullary nephrocalcinosis of any etiology can cause secondary distal tubular acidosis related to distal tubular calcium deposition and chronic inflammation in the medulla.
  • Patients may present with renal failure or with features of their underlying disease.

Physical

The physical findings are nonspecific and reflect the underlying disorders responsible for nephrocalcinosis.

Causes

• Primary hyperparathyroidism is the single most common cause of nephrocalcinosis in adults. While nephrocalcinosis is a relatively rare complication (5%), primary hyperparathryroidism is relatively common, especially in the elderly. Nephrocalcinosis itself is related more to the duration than to the intensity of hypercalcemia. The classic clinical findings are sometimes referred to as "(abdominal) groans, stones, and bones." This common phrase is a reminder that patients may present with kidney stones, bone pain, osteoporosis, and pathologic fractures, all of which can result in abdominal discomfort. Rarely, hyperparathyroidism can be associated with multiple endocrine neoplasia type 1 (MEN1).
• Distal RTA is the second most common cause of medullary nephrocalcinosis. The familial form and the secondary form (autoimmune-associated anti-K/H channel antibody) have a high incidence.^{[11 ]}The contributing mechanisms to nephrocalcinosis in distal RTA are hypercalcemia, hypercalciuria, metabolic acidosis, and reduced excretion of citrate in the presence of increased urinary pH. Because medullary nephrocalcinosis can itself be a cause of distal RTA, separating out the initial insult can be difficult. Renal function is fairly well maintained.
• Other causes of nephrocalcinosis are hypervitaminosis-D states^{[12 ]}resulting from excessive treatment of hypoparathyroidism, self-administration of vitamins, and the presence of a granulomatous disease, such as sarcoidosis.^{[13 ]} In granulomatous disorders, there is an increased conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol in the granuloma, resulting in an unregulated production of bioactive vitamin D with resultant excessive intestinal absorption of calcium and phosphorus. In addition, cytokines (IL-2) released in these disorders cause dysregulation of calcium homeostasis and activation of osteoclasts, resulting in subacute and chronic hypercalcemia.
• Any other cause of hypercalcemia, particularly when associated with hypercalciuria, can be a contributor to nephrocalcinosis. Etiologies include milk-alkali syndrome (due to excess ingestion of antacids, in the modern era with CaCO ₃ supplements), hyperparathyroidism, and malignant disease (due to bone involvement and humoral factors, including cytokines and parathyroid hormone – related peptide). Idiopathic hypercalciuria,^{[14 ]}a common metabolic disease, also is known to cause nephrocalcinosis.
• Nephrocalcinosis and renal failure are increasingly being recognized as common complications of phosphate supplementation, particularly in the elderly.^{[15,16,17,18,19 ]}Other possible risk factors are preexisting renal failure, high blood pressure, and the treatment of high blood pressure (with angiotensin-converting enzyme [ACE] inhibitors or angiotensin-receptor blockers). Phosphate supplements may contribute to renal calcifications in children with hypophosphatemic rickets. In vitro studies have shown that an increased urinary concentration of phosphate can result in intratubular crystallization with altered solubility.
• Medullary sponge kidney is a common cause of medullary calcification, with calcium lying in dilated collecting ducts rather than in the renal substance. These ectatic outpouchings are believed to be areas of urinary stasis possessing the ideal milieu for the formation of these calcifying complexes. The calcium deposits are larger and more sharply defined than they are in metabolic disease, and they are uneven in distribution.^{[8 ]}Associated hemihypertrophy of the body may exist. Unlike the severe renal damage with minimal calcification associated with hypercalcemic states, nephrocalcinosis associated with distal RTA and medullary sponge kidney usually is gross, and renal function is relatively well preserved.
• Renal papillary necrosis associated with analgesic nephropathy is identified as calcified papillae rather than as a speckled pattern.
• Other associations with nephrocalcinosis include rapidly progressive osteoporosis due to immobilization, menopause, aging, or steroids.
• Primary (familial) hyperoxaluria, or secondary hyperoxaluria due to increased intake of oxalates, enhanced absorption due to intestinal disease, or ingestion of ethylene glycol or methoxyflurane can induce medullary calcification.^{[20,21 ]}Primary hyperoxaluria and ethylene glycol intoxication is also associated with diffuse calcium-oxalate depositions in many other organs, including the eye and the heart.
• Chronic hypokalemic states, such as Bartter syndrome, primary hyperaldosteronism, Liddle syndrome, and 11-beta hydroxylase deficiency, are associated with reduced urine citrate excretion and tubular epithelial damage, leading to calcium precipitations.
• Autosomal dominant hypophosphatemic rickets and X-linked hypophosphatemic conditions^{[22 ]} have been associated abnormal phosphate wastage and nephrocalcinosis due to elevated levels of phosphatonins (fibroblast growth factor 23; secreted frizzled-related protein 4).^{[4,5 ]}Nephrocalcinosis is very common (~80% on ultrasonography) and may be associated with phosphate supplementation for the condition.
• Dent disease and familial magnesium-losing nephropathy are rare inherited diseases causing medullary calcification.
  • Dent disease arises from a defect in a gene on the short arm of the X chromosome that codes for the renal chloride channel in the proximal tubule (CLC-5). This disease is referred to by several other names in the international literature, including X-linked recessive hypophosphatemic rickets (Italy), X-linked recessive nephrolithiasis, and idiopathic low-molecular weight proteinuria with hypercalciuria and nephrocalcinosis (Japan). Mutations in the OCRL-1 gene — normally associated with Lowe's syndrome — have been described in cases of clinical Dent disease, expanding the potential for genetic diversity.^{[23 ]}
  • Inherited forms of magnesium-losing nephropathy have been described.^{[24 ]}Familial hypomagnesemia hypocalciuric nephrocalcinosis (FHHNC) is an autosomal recessive disease associated with cation loss through a defect in renal tight junctions protein (paracellin-1) involved in paracellular transport.^{[25,26 ]}
• Associated malignancies are not typical in nephrocalcinosis, because patients seldom survive long enough with hypercalcemia to develop them; one possible exception is the parathyroid carcinoma.
• Familial benign hypercalcemia and hyperthyroidism are not associated with renal calcification.
• Premature, sick infants have been observed to develop diffuse nephrocalcinosis (about 2/3 among infants born <1500 g), typically when exposed to diuretic therapy or prolonged O ₂ therapy. There is no clearly effective therapy.^{[27 ]}While these lesions may improve later on,^{[28 ]}the natural history of this phenomenon is not well understood.
• There has been a growing awareness of the diffusely increased calcifications in patients with advanced renal failure and end-stage renal disease.^{[29 ]} In the uremic environment, the presence of large, pharmacologic dose vitamin-D analogs and calcium-based phosphorus binders appear to accelerate the process. It appears that the presence of extraskeletal calcifications is more closely correlated with calcium x phosphorus product (sometimes referred to as the "double product") and total-body calcium overload then with the presence of serum hypercalcemia. Calcifications are not limited to the kidneys but involve multiple organs, including the heart, vascular beds, parenchymal organs, skin, and subcutaneous tissues.

Differential Diagnoses

Other Problems to Be Considered

Hypercalcemic nephropathy
Renal tubular acidosis

Workup

Laboratory Studies

• Serum calcium, phosphate, albumin
  • These are needed to establish whether nephrocalcinosis in a patient is associated with hypercalcemia. Determining the albumin level is important when interpreting the serum calcium level in the face of hypoalbuminemia; for every 1 g/dL decrease in serum albumin, measured serum calcium decreases by approximately 0.8 mg/dL. However, ionized calcium levels remain unchanged. 
  • The serum phosphate is low in primary hyperparathyroidism with normal renal function and in hypophosphatemic rickets due to urinary wasting; however, it is typically elevated in nephrocalcinosis associated with renal insufficiency.
• Serum electrolytes, BUN, creatinine - BUN and serum creatinine are elevated if the nephrocalcinosis is associated with renal insufficiency. Many laboratories in the United States now routinely report, along with serum creatinine, an estimated glomerular filtration rate (eGFR), if predicted renal function falls between 1 and 60 cc/min/1.72 m². The serum potassium may be low when nephrocalcinosis is caused by certain conditions, such as distal RTA, Bartter syndrome, primary hyperaldosteronism and Liddle syndrome.
• Urinalysis with microscopic examination -  Urine analysis and urine culture should always be performed to look for evidence of chronic infection. An elevated urinary pH can be suggestive of distal RTA, can be found when overzealous alkali supplementation for nephrolithiasis prophylaxis has occurred, or can exist in the presence urea-splitting pathogens in the urine. Crystals observed on microscopy may provide valuable diagnostic clues about abnormal urine composition.
• Twenty four – hour urinary excretion of calcium, oxalate, citrate, and uric acid, with simultaneous determination of BUN, creatinine, and protein excretion - Such analyses can be very helpful. BUN and creatinine excretions will help to determine the completeness of timed urine collection and aid in calculating measured renal function. Excess urinary calcium excretion may be observed in patients with idiopathic hypercalciuria. Increased urinary oxalate excretion indicates a primary or secondary cause of hyperoxaluria. Patients with nephrocalcinosis generally have low-grade proteinuria of a nonglomerular etiology. Nephrotic-range proteinuria is not expected in this context and is an indication for further evaluation of underlying renal disease.
• Parathyroid hormone levels - In the presence of hypercalcemia or renal failure, parathyroid hormone levels should be obtained to rule out primary or secondary hyperparathyroidism.
• Thyroid-stimulating hormone (TSH) levels - These should be obtained to rule out a thyroid disorder.
• Urinary magnesium levels - Assessing these may be useful in detecting magnesium-losing nephropathy.

Imaging Studies

Despite advances in renal imaging technologies,^{[30 ]}the correlation between the extent of radiographically demonstrable nephrocalcinosis and the degree of renal impairment remains limited. Plain kidney-ureter-bladder (KUB) radiographs visualize only advanced cases.

Furthermore, the diagnostic correlation between currently used techniques is imperfect, and there is interobserver variability when test results are interpreted.^{[31 ]}

Ultrasonography is more sensitive than conventional radiography, as shown below, but papillary cysts or hilar fat deposition can lead to false-positive results.

Ultrasonogram of the right kidney in a woman with nephrocalcinosis. This image shows hyperechoic foci in the pyramids.

Nonenhanced coronal computed tomography scans through the kidneys. These images show cortical and medullary nephrocalcinosis (left kidney). Both kidneys appear scarred. Note the thinning of the renal cortex at the upper pole of the left kidney. This patient gave a long history of chronic pyelonephritis, which is an unusual cause of nephrocalcinosis.

Axial computed tomography scans obtained from a patient with a long history of renal tubular acidosis. These images show bilateral medullary nephrocalcinosis (early arterial phase).

Histologic Findings

Histologic findings include crystal deposition, which occurs mainly in the interstitium. The deposits may be observed within or between the tubules. The deposits consist of calcium phosphate or calcium oxalate. Special stains, such as von Kossa and Pizzolato, may be required for better visualization.

Treatment

Medical Care

• Treatment of hypercalcemia and hypercalcemic nephropathy
  • Adequate hydration by isotonic sodium chloride solution is the single most effective measure to reverse hypercalcemia and protect the kidneys. This may be combined with furosemide to enhance calcium excretion only after clinical euvolemia or mild hypervolemia has been achieved.  
  • Other treatments include parathyroidectomy or calcium-sensing receptor stimulant cinacalcet (Sensipar), for correction of hyperparathyroidism; chemotherapy, for osteolytic malignancies; steroids, to decrease intestinal calcium absorption and vitamin-D activity; hydroxychloroquine (Plaquenil), for sarcoid granulomas^{[33 ]}; and calcitonin or bisphosphonates, to inhibit bone resorption.
  • Calcium-channel blockers have no role in management.
• Treatment of macroscopic nephrocalcinosis
  • Thiazide diuretics and dietary salt restriction will reduce renal calcium excretion in medullary nephrocalcinosis. Potassium and magnesium supplementation will increase the solubility of urinary calcium.
  • Citrate supplementation (preferably as potassium citrate) can be used in idiopathic hypercalciuria and in distal RTA, because it increases urinary citrate and decreases urinary calcium excretion.^{[34 ]}
  • In type 1 hyperoxaluria, treatment with large doses of pyridoxine can lower oxalate production.
  • Magnesium supplementation in magnesium-losing nephropathy may be helpful.
  • Lessening of nephrocalcinosis may occur over time, especially in idiopathic absorptive hypercalciuria and enteric hyperoxaluria after gastrointestinal bypass surgery. In most other cases, however, such as when it results from primary hyperoxaluria, distal RTA, papillary necrosis, or magnesium-losing nephropathy, nephrocalcinosis is largely irreversible. Therefore, early detection and treatment are important.

Surgical Care

• With copious fluid intake by the patient and the use of pain control, stones passing the midureter and measuring less then 5-7 mm usually pass on their own. Anecdotally, peripheral vasodilators (alpha blockers and calcium-channel blocker antihypertensive agents) are helpful in assisting stone passage.^{[35 ]} Surgery may be required for urinary stones causing obstruction; options include percutaneous nephrolithotomy, laser and shock wave lithotripsy, stent placement, and (rarely) open surgery. 
• Parathyroidectomy to remove enlarged adenomas is very helpful in primary hyperparathyroidism and results in a low recurrence rate.  
• Attempting to remove calcium nodules from within the renal parenchyma itself has no obvious benefit and causes harm.

Consultations

• Nephrology consultation - Reduced renal function and associated metabolic abnormalities; electrolyte disorders, including metabolic acidosis, hypercalcemia and hypercalciuria; and recurrent nephrolithiasis
• Endocrinology consultation: - hypercalcemia, vitamin-D and phosphate disorders, and sarcoid in association with hypercalcemia.
• Rheumatology consultation - distal RTA associated with rheumatology diseases, such us Sj ö gren's syndrome or system lupus erythematosus.
• Ear-nose-throat or endocrine surgery consultation - For surgical parathyroidectomy (the personal skill and experience of the operating surgeon are important)

Diet

Dietary interventions can be formulated, as part of consultation with an appropriate specialist, only after the underlying metabolic abnormality has been identified.

Medication

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Diuretic, Thiazide

Thiazide diuretics are extremely helpful in decreasing calcium excretion in several conditions associated with nephrocalcinosis. Hydrochlorothiazide (HCTZ), the most commonly employed thiazide diuretic, is appropriate to use if the serum calcium level is not high; it may correct coincidental high blood pressure.^{[36 ]}The usual dose range is 12.5-25 mg per day, although in rare cases it can reach up to 50 mg per day. However, if HCTZ is used, the dose should be split in 2 to cover a full 24-hour period.

Hydrochlorothiazide (Esidrix, HydroDIURIL, Microzide)

Inhibits reabsorption of sodium in the distal tubules, causing increased excretion of sodium and water, as well as of potassium and hydrogen ions.

Dosing

Adult

25-50 mg PO divided bid

Pediatric

2-3 mg/kg/d PO divided bid

Interactions

Decreases effects of anticoagulants, antigout agents, and sulfonylureas; may increase toxicity of allopurinol, anesthetics, antineoplastics, calcium salts, loop diuretics, lithium, diazoxide, digitalis, amphotericin B, and nondepolarizing muscle relaxants

Contraindications

Documented hypersensitivity; anuria; renal decompensation

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal disease/failure, hepatic disease, gout, diabetes mellitus, and lupus erythematosus; cross-sensitivity to sulfonamides

Chlorthalidone (Thalitone [US], Apo-Chlorthalidone [Canada])

Inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water as well as potasium and hydrogen ions. Reduces calcium excretion through direct tubular effects.

Dosing

Adult

12.5 - 25 mg/d PO

Pediatric

1 mg/kg/d PO

Interactions

May decrease effect of anticoagulants; increases risk of postural hypotension with coadministration of antihypertensives; increases potential for hypokalemia or hypomagnesemia and subsequent cardiotoxicity when coadministered with ACE inhibitors, digoxin, or corticosteroids; antagonizes sulfonylurea effect by decreasing glucose tolerance; increases risk of hyperglycemia when coadministered with diazoxide; increases lithium serum levels; may antagonize effect of antigout medications by causing hyperuricemia; NSAIDs decrease diuretic effect; probenecid increases thiazide levels

Contraindications

Documented hypersensitivity to drug or related diuretics, renal impairment (clearance less than 30% normal), anuria, breast feeding, diabetes mellitus

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal or liver function impairment; may produce electrolyte abnormalities (hypokalemia, hyponatremia); may increase uric acid or serum lipids; hypomagnesemia may occur

Bisphosphonates

These agents are used to treat hypercalcemia and to decrease calcium loss from bone.

Pamidronate (Aredia)

Inhibits bone resorption via actions on osteoclasts or on osteoclast precursors, without significant effects on renal tubular calcium handling. Indicated to treat hypercalcemia.

Dosing

Adult

Moderate hypercalcemia: 60 mg IV over 4 h initially; alternatively, 90 mg initial single IV infusion over 24 h
Severe hypercalcemia: 90 mg initial IV infusion over 24 h; allow 7 d for retreatment

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; hypocalcemia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor hypercalcemia-related parameters (ie, serum levels of calcium, phosphate, and magnesium); use vein irritation and thrombophlebitis precautions during IV infusion; hypotension or hypertension may occur with higher doses; caution in patients with CKD or ESRD by significantly reducing the dosage

Calcitonins

Calcitonin is indicated to treat hypercalcemia. It maintains calcium homeostasis by increasing the mineral stores in bone and the renal excretion of calcium. Calcitonin also directly inhibits osteoclastic bone resorption. Because of its longer duration of action, salmon calcitonin is preferred over human calcitonin.

Calcitonin (Miacalcin, Osteocalcin, Cibacalcin, Calcimar)

Lowers elevated serum calcium in patients with multiple myeloma, carcinoma, or primary hyperparathyroidism. Can expect a higher response when serum calcium levels are high. Onset of action is approximately 2 h following injection, and activity lasts for 6-8 h. May lower calcium levels for 5-8 d by about 9% if administered q12h. If administered by the IM route, use multiple injection sites with dose >2 mL.

Dosing

Adult

Initial dose for hypercalcemia: 4 IU/kg IM/SC q12h; increase dose to 8 IU/kg q12h if response is not satisfactory after 1-2 d and to 8 IU/kg q6h if response remains unsatisfactory >2 d

Pediatric

Not established

Interactions

May decrease lithium serum levels

Contraindications

Documented hypersensitivity, particularly if sensitive to shellfish.

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Most common adverse effects include nausea and vomiting, facial flushing, and edema at the site of injection; less common adverse effects include hypocalcemia with tetany and glucose intolerance; perform a skin test prior to initiating salmon calcitonin to assess potential for hypersensitivity; there are reports of autoantibody development in up to 50% of treated individuals, although the treatment remained effective; patients with Paget disease should be routinely evaluated with radiography for osteogenic sarcoma

Vitamins

Pyridoxine (vitamin B-6) deficiency is a known cause of hyperoxaluria. Used to treat nephrocalcinosis, pyridoxine decreases calcium oxalate formation and the subsequent development of kidney stones.

Pyridoxine (Nestrex)

Involved in synthesis of GABA within CNS.

Dosing

Adult

1 g IV administered slowly; alternatively, 10-20 mg/d for 3 wk; maintain with 1.5-2.5 mg/d PO

Pediatric

5-20 mg/d PO for 3 wk; maintain with 1.5-2.5 mg/d PO

Interactions

May decrease levodopa effectiveness when used without carbidopa due to enhanced peripheral metabolism; decreases phenytoin and phenobarbital serum levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Seizures have occurred following very high IV doses; long-term administration of high doses may cause neuropathy; safety in pregnancy has not been established for doses exceeding recommended daily allowance

Antimalarial Agent

Hydroxychloroquine can be helpful in controlling hypercalcemia due to sarcoid and is utilized as a glucocorticoid-sparing agent.

Hydroxychloroquine (Plaquenil)

May be most useful in the management of osseous involvement. Inhibits chemotaxis of eosinophils, locomotion of neutrophils, and impairs complement-dependent antigen-antibody reactions.

Dosing

Adult

200-400 mg PO qd with dose decreased by 50% when response noted

Pediatric

Not established

Interactions

Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption

Contraindications

Documented hypersensitivity to 4-aminoquinoline derivatives; psoriasis; retinal and visual field changes attributable to 4-aminoquinolines

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long-term use in children; perform periodic ophthalmologic examinations; test for muscle weakness; retinopathy, tinnitus, nerve deafness, skin eruption, headache, anorexia, nausea, vomiting, and diarrhea may occur

Calcimimetic Agent

These can be used in primary hyperparathyroidism to temporarily control hypercalcemia if a patient is a poor surgical risk or if surgery is not immediately available. Experience in such settings is limited.

Cinacalcet (Sensipar)

Directly lowers parathyroid hormone (PTH) levels by increasing sensitivity of calcium-sensing receptor on chief cell of parathyroid gland to extracellular calcium. Also results in concomitant serum calcium decrease. Indicated for hypercalcemia with parathyroid carcinoma.

Dosing

Adult

30 mg PO qd initially; titrate q2-4wk as needed to normalize calcium levels by sequential doses of 30 mg bid, 60 mg bid, 90 mg bid, and 90 mg tid/qid

Take with meals or immediately after; do not crush, chew or cut tablets

Pediatric

Not established

Interactions

Strong CYP450 2D6 inhibitor; may increase serum levels of CYP 2D6 substrates (eg, flecainide, vinblastine, thioridazine, tricyclic antidepressants); coadministration with CYP450 3A4 inhibitors (eg, ketoconazole, erythromycin, itraconazole) may decrease cinacalcet clearance

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Serum calcium reduction may cause lowered seizure threshold, paresthesia, myalgia, cramping, and tetany; monitor calcium and phosphorus levels closely within 1 wk following initial dose or dose changes, and then monthly (secondary hyperparathyroidism) and q2 mo (parathyroid carcinoma); do not initiate treatment if serum calcium below 8.4 mg/dL; adynamic bone disease may occur if iPTH levels suppressed below 100 pg/mL; caution with hepatic impairment; common adverse effects include nausea and vomiting

Alkalinizing Agent, Oral

These are used for urinary alkalinization.

Sodium citrate (Bicitra, Oracit)

Treats metabolic acidosis and used as alkalinizing agent where long-term maintenance of an alkaline urine desirable.

Dosing

Adult

15-30 mL PO of a sodium citrate and citric acid solution containing 500 mg of sodium citrate and 334 mg of citric acid per 5 mL, usually in divided daily doses.

Pediatric

Infants and children: 2-3 mEq/kg/d PO of a sodium citrate and citric acid solution as in adults; usually administered in 2 equal doses.

Interactions

Decreases therapeutic levels of lithium, chlorpropamide, methotrexate, tetracyclines, and salicylates due to urinary alkalinization; increases toxicity of amphetamines, ephedrine, quinine, and quinidine due to urinary alkalinization

Contraindications

Renal insufficiency and patients on sodium-restricted diet

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Conversion to bicarbonate may be impaired in hepatic failure and in patients who are in shock or are severely ill.

Potassium citrate (Polycitra-K)

Alkalinizing agent indicated for treatment of systemic metabolic acidosis, urinary alkalinization, or hypocitraturia. Administered PO and metabolized to bicarbonate in the liver.

Each 5 mL of Polycitra contains sodium citrate 500 mg, citric acid 334 mg, and potassium citrate 550 mg (each mL contains 1 mEq potassium, 1 mEq sodium, and 2 mEq bicarbonate).

Dosing

Adult

15-30 mL PO pc and hs based on tolerance and response

Pediatric

2-15 mEq/kg/d PO divided pc and hs
Distal RTA: 2 mEq/kg/d PO initially; titrate to maintain serum bicarbonate and urinary calcium excretion within the reference range
Hypocitraturia: 5 mEq/kg/d PO initially; adjust to maintain reference range serum bicarbonate and urine citrate

Interactions

Increased drug effect with potassium-containing medications, potassium-sparing diuretics, ACE inhibitors, or cardiac glycosides (could lead to toxicity); drugs that slow GI transit time (ie, anticholinergics) are expected to increase GI side effects

Contraindications

Documented hypersensitivity; severe renal impairment with oliguria/azotemia; hyperkalemia; untreated Addison disease; acute dehydration

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Frequent monitoring of serum potassium concentration is recommended; caution in CHF, hypertension, edema, or any condition sensitive to sodium or potassium intake
Conversion of citrate to bicarbonate in the liver may be blocked in severe illness, shock, hepatic failure associated with GI distress; high plasma concentrations of potassium may cause death due to cardiac depression, arrhythmias, or arrest

Follow-up

Prognosis

• The prognosis depends mainly on the etiology of the nephrocalcinosis.
• The major long-term complication in patients with medullary nephrocalcinosis is renal failure.
  • Early treatment of reversible causes of renal failure, such as urinary infections, obstruction, and hypertension, is essential.
  • Once chronic renal failure has developed, treatment should focus on the appropriate management of chronic kidney disease and its complications.
  • Patients with idiopathic hypercalciuria and medullary sponge kidney have the least risk of renal failure and the best prognosis, whereas patients with primary type 1 hyperoxaluria have the worst prognosis.

Patient Education

Key points to emphasize include the following:

• Nephrocalcinosis is usually an incidental finding.
• Hypercalcemia or hypercalciuria are frequently present.
• Nephrocalcinosis is more likely to be a consequence of the underlying abnormality than it is to be the cause.

Miscellaneous

Medicolegal Pitfalls

• Nephrocalcinosis, although seemingly a simple finding, incorporates a large number of potential disease processes in the differential. An effort should be made describe the location and degree of nephrocalcinosis and to uncover the underlying metabolic abnormality or abnormalities.
• In clinical practice, nephrocalcinosis is more commonly encountered as macroscopic nephrocalcinosis. Do not consider it synonymous with renal stone disease, because nephrocalcinosis has much broader metabolic implications.
• Patients with a primary loin pain-hematuria syndrome experience a poorly understood combination of pain associated with hematuria. Some of these individuals have co-incidental nephrocalcinosis that, incorrectly, may be blamed for the generation of pain. However, any associated hypercalciuria or hyperuricosuria should be addressed aggressively.

Multimedia

Media file 1: Diagram of a nephron.

Media file 2: Nephrocalcinosis.

Media file 3: Nephrocalcinosis.

Media file 4: Nephrocalcinosis.

Media file 5: Nonenhanced coronal computed tomography scans through the kidneys. These images show cortical and medullary nephrocalcinosis (left kidney). Both kidneys appear scarred. Note the thinning of the renal cortex at the upper pole of the left kidney. This patient gave a long history of chronic pyelonephritis, which is an unusual cause of nephrocalcinosis.

Media file 6: Axial computed tomography scans obtained from a patient with a long history of renal tubular acidosis. These images show bilateral medullary nephrocalcinosis (early arterial phase).

Media file 7: Ultrasonogram of the right kidney in a woman with nephrocalcinosis. This image shows hyperechoic foci in the pyramids.

Media file 8: 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. This image shows bilateral hydronephrosis and a hydroureter due to obstruction by sloughed papillae at the lower end of the ureter.

Media file 9: Plain kidney, ureters, and bladder (KUB) radiograph in a man with renal papillary necrosis, most likely a patient with diabetes mellitus and repeated urinary tract infections. This image shows bilateral renal calcification. A large, sloughed, and calcified renal papilla is present in the region of left vesicoureteric junction. Note the 2 pelvic phleboliths opposite the ischial spine on the right.

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Keywords

nephrocalcinosis, kidney, kidneys, kidney stones, kidney stone, hypercalcemia, hypercalciuria, hyperparathyroidism, nephrolithiasis, urinary stones, urinary stone, medullary nephrocalcinosis, crystal-induced nephropathy, increase in renal calcium content, microscopic nephrocalcinosis, macroscopic nephrocalcinosis, hypercalcemic nephropathy

Contributor Information and Disclosures

Author

Tibor Fulop, MD, Assistant Professor, Department of Internal Medicine, Division of Nephrology, University of Mississippi Medical Center
Tibor Fulop, MD is a member of the following medical societies: American College of Physicians and American Society of Diagnostic and Interventional Nephrology
Disclosure: Nothing to disclose.

Coauthor(s)

Mahendra Agraharkar, MD, MBBS, FACP, FASN, Clinical Associate Professor of Medicine, Baylor College of Medicine, President & CEO, Space City Associates of Nephrology
Mahendra Agraharkar, MD, MBBS, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Nephrology, and National Kidney Foundation
Disclosure: South Shore DaVita Dialysis Center  Ownership interest Other

Rupert Patel, MD, Physician, Division of Nephrology, Houston, Texas
Disclosure: Nothing to disclose.

Rajiv Gupta, MD, Assistant Professor, Department of Medicine, Texas A & M University Health Science Center; Consulting Staff, Veterans Affairs Medical Center
Rajiv Gupta, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, and Society of Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

Medical Editor

James W Lohr, MD, Fellowship Program Director, Professor, Department of Internal Medicine, Division of Nephrology, State University of New York at Buffalo
James W Lohr, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Nephrology, and Central Society for Clinical Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Eleanor Lederer, MD, Consulting Staff, Louisville VA Hospital; Professor of Medicine; Interim Chief of Nephrology; Director of Nephrology Training Program; Director, Metabolic Stone Clinic; Director of Outpatient Clinics, Kidney Disease Program, University of Louisville School of Medicine
Eleanor Lederer, MD is a member of the following medical societies: American Association for the Advancement of Science, American Federation for Medical Research, American Society for Biochemistry and Molecular Biology, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation, and Phi Beta Kappa
Disclosure: Nothing to disclose.

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Amgen Honoraria Speaking and teaching; Ortho Biotech Honoraria Speaking and teaching

Chief Editor

Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System
Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology
Disclosure: Nothing to disclose.

The primary author would like to thank Dr. Gurvinder Suri, Renal Fellow at the University of Mississippi Medical Center - Nephrology Division, for his valuable peer review.

Clinical guidelines:
The American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism. American Association of Clinical Endocrinologists - Medical Specialty Society
American Association of Endocrine Surgeons - Medical Specialty Society. 2005 Jan-Feb. 6 pages. NGC:004187

Clinical trials:
Alkaline Citrate Treatment to Lower the Risk of Nephrocalcinosis in Preterm Infants
International Registry for Primary Hyperoxaluria
Randall's Plaque Study: Pathogenesis and Relationship to Nephrolithiasis
Treatment of Hypoparathyroidism With Synthetic Human Parathyroid Hormone 1-34

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