Jennifer E. Heckman, MD, MPH
Stephen Y. Nakada, MD, FACS
BASICS
DESCRIPTION
• Disorder characterized by deposition of calcium salts in the renal parenchyma
– Calcium oxalate (CaOx)
– Calcium phosphate (CaPhos)
• May be intratubular or interstitial
• May cause renal injury or be incidentally detected
• Associated with multiple conditions
– Renal prognosis dependent on underlying cause
– Often associated with severe metabolic defects
• Can be classified by location:
– Renal medulla (medullary nephrocalcinosis)
– Renal cortex (cortical nephrocalcinosis)
• Can also be classified as:
– Molecular: Measurable increase in intracellular calcium concentration, but not visible microscopically or radiographically
– Microscopic: Visible microscopically
– Macroscopic: Visible radiographically
• Distinct entity from nephrolithiasis (calcifications in collecting system)
• Neonatal nephrocalcinosis is discussed in Section II “Nephrocalcinosis, Neonatal”
EPIDEMIOLOGY
Incidence
Unclear secondary to wide range of etiologies
Prevalence
• Primarily diagnosed in:
– Adults
– Low–birth-weight neonates (60% of preterm infants, frequently caused by loop diuretics)
• Medullary nephrocalcinosis (97–98%), cortical nephrocalcinosis (2–3%)
RISK FACTORS
• Disorders that cause:
– Hypercalcemia
– Hyperphosphatemia
– Hypercalciuria
– Hyperphosphaturia
– Hyperoxaluria
– Hypocitraturia
Genetics
Inherited disorders may lead to risk factors for nephrocalcinosis development (eg, autosomal dominant hypocalcemia, familial hyperoxaluria)
PATHOPHYSIOLOGY
• Caused by increase in urinary excretion of calcium, phosphate, and/or oxalate (1)
– May occur with or without hypercalcemia
– CaOx and CaPhos crystals result from urinary supersaturation
CaOx and CaPhos crystals precipitate, aggregate, and move to interstitium
May result in acute or chronic renal damage and/or lead to calculus formation
Renal ischemia or injury may augment nucleation of CaOx or CaPhos crystals
ASSOCIATED CONDITIONS
• Nephrolithiasis
• Hypercalciuric states:
– Primary hyperparathyroidism (most common cause in adults)
– Sarcoidosis
– Vitamin D intoxication
– Multiple myeloma
– Tuberculosis
– Milk-alkali syndrome
– Distal renal tubular acidosis
– Medullary sponge kidney
– Inherited tubular defects (eg, Bartter syndrome)
– Chronic hypokalemia (eg, primary aldosteronism)
– Chronic immobilization
• Hyperphosphaturic states:
– Tumor lysis syndrome
– Inherited tubular defects
• Hyperoxaluric states:
– Primary oxaluria
– Secondary oxaluria (increased intake or enhanced absorption)
– Fat malabsorptive disorders (eg, pancreatic insufficiency, inflammatory bowel disease)
• Chronic pain
GENERAL PREVENTION
• Avoid hypercalciuric, hyperphosphaturic, and hyperoxaluric states
• Avoid medications that enhance calcium loss (eg, loop diuretics)
DIAGNOSIS
HISTORY
• Most cases are asymptomatic (incidental finding on imaging)
• Occasionally present with symptoms related to underlying cause or associated condition
– Nausea, decreased appetite, abdominal pain, myalgias, polydipsia, lethargy (hypercalcemia)
– Fatigue, edema, mental status changes, seizures (renal failure)
– Renal colic, hematuria (nephrolithiasis)
• Review past medical history and medications
PHYSICAL EXAM
• Nonspecific, many patients are asymptomatic
• Physical findings otherwise a manifestation of underlying disorder
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Used to identify underlying causative disorder
• Serum studies:
– Calcium, phosphate, albumin
– Electrolytes
– BUN, Cr
– Parathyroid hormone (PTH) levels
– Thyroid-stimulating hormone (TSH) levels
– CBC
• Urine studies:
– Urinalysis with microscopy +/– urine culture (if indicated)
– 24-hr urine collection
Imaging
• Can be detected on:
– Abdominal radiograph
Usually only if attenuation >100 Hounsfield units and size >2 mm
Medullary nephrocalcinosis: Stippled calcifications in renal pyramids
Cortical nephrocalcinosis: Thin peripheral band with perpendicular extension; thin, peripheral calcific tracts; or diffuse punctuate calcifications
– Ultrasound
Hyperechoic areas with or without acoustic shadowing
– Computed tomography
Most sensitive and specific
• Pattern and distribution may be suggestive of etiology
• Imaging extent of calcium deposition unrelated to renal functional impairment or prognosis
• Regardless of imaging modality, can be difficult diagnosis, with low levels of intra-observer concordance (2)[B]
Diagnostic Procedures/Surgery
• Radiographic diagnosis (usually incidental finding)
• Rarely, diagnosed on renal biopsy
Pathologic Findings
• Primary histologic finding on renal biopsy:
– Tubular, intracellular, and interstitial basophilic calcifications
• (+) von Kossa stain of calcifications diagnostic of CaPhos
DIFFERENTIAL DIAGNOSIS
• Nephrolithiasis
• Renal calcifications, associated with:
– Chronic ureteropelvic junction obstruction or ureterocele
– Renal infarction
– Renal mass
• Dystrophic calcifications, associated with:
– Renal tuberculosis
– Congenital cystic kidney
• Renal artery calcifications
• Calcification associated with spinal injury
TREATMENT
GENERAL MEASURES
• Treatment directed at underlying etiology
• No specific treatment prevents progression
• Early treatment of reversible causes of renal injury important
• Reduce urinary concentration and increase solubility of calcium, phosphate, and/or oxalate
– Increase fluid intake
Goal urine output >2 L/d
– If hypercalciuria:
Restrict animal protein intake (<0.7 g/kg)
Restrict sodium intake (<100 mEq/d)
– If hypocitraturia and urine pH <7:
Potassium citrate (titrate to normal urinary citrate)
MEDICATION
First Line
Must be tailored to underlying etiology (eg, for hyperparathyroidism, resection of adenoma, treatment of renal tubular acidosis, etc.)
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Surgical intervention may be required, particularly if calcification obstructs collecting system
– Endourologic management
May use in diagnosis (direct visual inspection) (3)[C]
May treat with flexible ureteroscopy/nephroscopy with laser or electrohydraulic lithotripsy (4)[C]
Ureteroscopic laser papillotomy may be safe and effective in patients with chronic flank pain (5)[C]
– Extracorporeal shockwave lithotripsy (ESWL)
Poor fragmentation and evacuation
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
N/A
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Depends on underlying etiology
• Most do not progress to end-stage renal failure
COMPLICATIONS
• Nephrolithiasis
• Obstructive uropathy
– May be associated with sepsis
• Renal infection
• Renal scarring
• Defects in renal tubular function
• Acute renal failure
• Chronic renal failure
FOLLOW-UP
Patient Monitoring
• Urinalysis, 24-hr urine collection
• Renal function testing
• Serum Ca
• Labs to monitor known metabolic abnormalities
• Imaging if symptomatic
Patient Resources
http://www.umm.edu/ency/article/000492.htm
REFERENCES
1. Sayer JA, Carr G, Simmons NL. Nephrocalcinosis: Molecular insights into calcium precipitation within the kidney. Clin Sci (Lond). 2004;106:549–561.
2. Cheidde L, Ajzen SA, Tamer Langen CH, et al. A critical appraisal of the radiological evaluation of nephrocalcinosis. Nephron Clin Pract. 2007;106(3):c119–c124.
3. Miller NL, Humphreys MR, Coe FL, et al. Nephrocalcinosis: Re-defined in the era of endourology. Urol Res. 2010;38(6):421–427.
4. Kerbl K, Clayman RV. Endourologic treatment of nephrocalcinosis. Urology. 2000;56(3):508.
5. Gdor Y, Faddegon S, Krambeck AE, et al. Multi-institutional assessment of ureteroscopic laser papillotomy for chronic flank pain associated with papillary calcifications. J Urol. 2011;185(1):192–197.
ADDITIONAL READING
Monk RD, Bushinsky DA, Chapter 57. Nephrolithiasis and nephrocalcinosis. In: Floege J, Johnson RJ, Feehally J, eds. Comprehensive Clinical Nephrology. 4th ed. Philadelphia, PA: Mosby Elsevier; 2011.
See Also (Topic, Algorithm, Media)
• Calcifications, Renal
• Hypercalcemia, Urologic Considerations
• Hypercalciuria (Absorptive, Renal, and Resorptive)
• Hyperoxaluria
• Hyperparathyroidism, Urologic Considerations
• Hyperphosphatemia and Hypophosphatemia, Urologic Considerations
• Hypocitraturia
• Hypokalemia, Urologic Considerations
• Medullary Sponge Kidney
• Milk-alkali Syndrome
• Nephrocalcinosis, Adult Images 
• Nephrocalcinosis, Neonatal
• Renal Tubular Acidosis
• Tumor Lysis Syndrome
• Urolithiasis, Adult, General Considerations
• Urolithiasis, Calcium Oxalate/Phosphate
• Urolithiasis, Pediatric, General Considerations
CODES
ICD9
• 275.3 Disorders of phosphorus metabolism
• 275.42 Hypercalcemia
• 275.49 Other disorders of calcium metabolism
ICD10
• E83.52 Hypercalcemia
• E83.59 Other disorders of calcium metabolism
• N29 Oth disorders of kidney and ureter in diseases classd elswhr
CLINICAL/SURGICAL PEARLS
• Important to distinguish nephrocalcinosis from nephrolithiasis.
• Management directed at underlying cause of disorder.
• Primarily a radiographic diagnosis, does not typically require surgical intervention.