BASICS
DESCRIPTION
- Nephrocalcinosis (NC) is a condition where calcium salt deposits form in the renal parenchyma.
- NC is related but distinct from nephrolithiasis, where deposits form in the renal collecting system (1).
- Although primarily considered a radiographic diagnosis and often discovered incidentally on radiographic imaging, NC can portend more serious kidney and systemic disease (2).
- Range of symptoms: asymptomatic to vague, nonspecific findings or symptoms related to underlying cause of hypercalcemia
- Descriptive types of NC based on radiographic location (2):
- Medullary type: most commonly related to metabolic disorders; the most common type of NC (95%)
- Cortical type: most commonly associated with renal tubular acidosis and necrosis
- Diffuse
- Microscopic: noted only on histologic examination of renal tissue
EPIDEMIOLOGY
Incidence
Difficult to determine due to multiple etiologies ‚
Prevalence
- 7 " “41% of preterm newborns (3)
- Up to 20% of patients with hyperparathyroidism
ETIOLOGY AND PATHOPHYSIOLOGY
Two primary mechanisms: ‚
- Intratubular NC: crystal adherence to damaged tubular epithelium leading to translocation or obstruction
- Interstitial NC: plaque formation in the ascending loops of Henle and invade the medullary interstitium (4)
Genetics
- Increased prevalence of NC with certain hereditary disorders:
- Dent disease
- Familial hypomagnesemia with hypercalciuria and nephrocalcinosis
- Primary hyperoxaluria
- Bartter syndrome
- Liddle syndrome (5)
RISK FACTORS
- Medullary
- Primary hyperparathyroidism
- Renal tubular acidosis
- Prematurity
- Hereditary disorders
- Hyperthyroidism
- Granulomatous diseases such as sarcoidosis
- Oversupplementation of phosphate and vitamin D
- Multiple myeloma
- Cushing syndrome
- Chronic steroid use
- Metastatic neoplasm
- Medullary sponge kidney
- Milk-alkali syndrome
- Hyperuricemia
- Sickle cell disease
- Cortical
- Renal infarct, ischemia, or toxins
- Hyperoxaluria
- Chronic glomerulonephritis
- Alport syndrome
- Autosomal recessive polycystic kidney disease
- Opportunistic intrarenal infections such as Mycobacterium avium or Pneumocystis carinii pneumonia.
GENERAL PREVENTION
Prevention of preterm birth ‚
COMMONLY ASSOCIATED CONDITIONS
- Hypercalcemia
- Hypercalciuria
- Renal tubular acidosis
- Hyperoxaluria
- Urinary stasis
- Hyperparathyroidism
- Treatment of hypoparathyroidism
- Medullary sponge kidney
- Osteoporosis
DIAGNOSIS
HISTORY
- Preterm birth
- Personal or family history of nephrolithiasis or heritable kidney disease
- Polyuria and polydipsia
- Hematuria
PHYSICAL EXAM
- Often nonspecific
- Blood pressure
- Abdominal exam: may find nonspecific abdominal tenderness related to hypercalcemia or specific tenderness if coexisting symptomatic nephrolithiasis (2)
- Flank exam: may have costovertebral angle tenderness in the presence of coexisting nephrolithiasis or renal infection
DIFFERENTIAL DIAGNOSIS
- Nephrolithiasis
- Urinary tract infection
- Diabetes
- Atherosclerotic kidney disease
- Renal tuberculosis
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Lab: comprehensive metabolic profile; urinalysis with culture; spot urine testing for calcium, oxalate, citrate, magnesium, and uric acid
- Imaging: KUB or US; in adults, consider confirmation with noncontrast CT. (2)
Follow-Up Tests & Special Considerations
- PTH, vitamin D, plasma oxalates, acid " “base status
- In older children and adults: 24-hour urine testing for calcium, citrate, uric acid, magnesium, phosphate, cystine, protein, and oxalate
- Genetic counseling and genetic testing if inherited metabolic disorder is possible
Diagnostic Procedures/Other
Stone analysis in case of concurrent nephrolithiasis ‚
Test Interpretation
Varies based on etiology ‚
TREATMENT
GENERAL MEASURES
- Manage or prevent hypercalcemia.
- Address hyperparathyroidism or other underlying cause.
- In setting of preserved renal function, decrease solute concentration in the urine by maintaining a high-fluid intake across the length of the day. In children, the target daily oral intake of fluid should be >1.5 to 2 L per 1.73 m2 body surface area (5)[C].
MEDICATION
First Line
- For hypercalcemic etiologies in adults:
- Hyperparathyroidism
- Cinacalcet: Start at 30 mg PO BID with food, and then increase every 2 to 4 weeks by an additional 30 mg per dose up to 90 mg PO BID; then may increase to a maximum of 90 mg PO TID " “QID. Dose is titrated to normal serum calcium levels.
- Malignancies: appropriate chemotherapy
- Sarcoid granulomas
- Hydroxychloroquine: 400 mg PO QD " “BID with food; may decrease dose to 200 mg PO QD " “BID if intolerable gastrointestinal effects
- Heightened bone resorption
- Calcitonin-salmon: 4 U/kg IM/SC q12h; increase by 8 U q12h PRN. Dose is titrated to normal serum calcium levels.
- Bisphosphonates
- For hypercalcemia in children:
- Severe hypercalciuria
- Hydrochlorothiazide: 0.5 to 1 mg/kg PO daily dose divided BID (5)[C]
- Crystallization inhibition: Citrate supplementation increases calcium oxalate, cysteine, and uric acid solubility, but pH should be monitored, as higher levels (>7.0) may cause calcium phosphate stone formation (4)[C].
- For infectious etiologies, determine the appropriate antibiotic.
Second Line
Thiazide diuretics are the drug of choice for hypertension; caution in renal impairment ‚
ISSUES FOR REFERRAL
- Nephrologist should be considered in any patient with a hereditary disorder leading to NC or any patient with worsening renal insufficiency or failure.
- Genetic counseling should be considered for any pediatric patient with NC, especially if not a premature infant.
- Dietitian input, from simply counseling patients on a low-sodium diet to formulating a special diet in patients suffering from an underlying metabolic disorder
- Infectious disease specialist in the case of renal infection or opportunistic renal infection (in HIV-positive patients)
ADDITIONAL THERAPIES
Oral Oxalobacter formigenes degrades oxalate in the gastrointestinal tract. Supplementation in patients with hyperoxaluria appears promising and safe (5)[C]. ‚
SURGERY/OTHER PROCEDURES
- Parathyroidectomy for primary hyperparathyroidism related to a hyperfunctioning adenoma
- Renal transplant for patients in end-stage renal failure (4)[C]
- Combined liver " “kidney transplant in patients diagnosed with primary hyperoxaluria type 1 due to defective enzyme that is liver-specific (5)[C]
COMPLEMENTARY & ALTERNATIVE MEDICINE
Oral barley, lemon juice with honey, and tea infused with lady 's mantle have been used for NC treatment but lack sufficient evidence on effectiveness and safety in humans. ‚
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- Hypercalcemia: rarely occurs with NC but could be a medical emergency
- Renal failure: Early, aggressive management is the key for best long-term prognosis.
IV Fluids
Normal saline solution to reverse severe hypercalcemia and restore circulatory volume ‚
Nursing
- Maintain vigilance for signs and symptoms of hypercalcemia such as abdominal pain, bone pain, weakness, and confusion.
- Remain attentive to renal function as demonstrated by urine output, fluid intake, and serial renal laboratories.
- Observe for hypertension with serial blood pressure monitoring.
Discharge Criteria
Kidney function, blood pressure, and electrolytes stable to be managed as an outpatient ‚
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Based on etiology and comorbidities ‚
Patient Monitoring
- Based on etiology
- Patients often need ongoing trending of serum calcium, phosphate, uric acid, and renal function.
DIET
Dietary salt restriction ‚
PATIENT EDUCATION
Based on etiology ‚
PROGNOSIS
- Depends on etiology
- Best prognosis with idiopathic hypercalciuria and reversible disease; worse prognosis with type 1 hyperoxaluria and other inherited metabolic disorders
- Majority of NC in premature neonates resolves (3)[C].
- Primary concern in medullary NC is renal failure.
- Once detected, initial treatment of NC should be focused on potentially reversible etiologies (e.g., infection) and then preventing or treating renal insufficiency.
COMPLICATIONS
Chronic renal failure ‚
REFERENCES
11 Vervaet ‚ BA, Verhulst ‚ A, D 'Haese ‚ PC, et al. Nephrocalcinosis: new insights into mechanisms and consequences. Nephrol Dial Transplant. 2009; 24(7):2030 " “2035.22 Hoppe ‚ B, Kemper ‚ MJ. Diagnostic examination of the child with urolithiasis or nephrocalcinosis. Pediatr Nephrol. 2010;25(3):403 " “413.33 Schell-Feith ‚ EA, Kist-van Holthe ‚ JE, van der Heijden ‚ AJ. Nephrocalcinosis in preterm neonates. Pediatr Nephrol. 2010;25(2):221 " “230.44 Edvardsson ‚ V, Goldfarb ‚ DS, Lieske ‚ JC, et al. Hereditary causes of kidney stones and chronic kidney disease. Pediatr Nephrol. 2013;28(10):1923 " “1942.55 Habbig ‚ S, Beck ‚ BB, Hoppe ‚ B. Nephrocalcinosis and urolithiasis in children. Kidney Int. 2011;80(12):1278 " “1291.
ADDITIONAL READING
National Institutes of Health. Nephrocalcinosis. http://rarediseases.info.nih.gov/gard/7177/nephrocalcinosis/resources/1. Accessed 2014. ‚
CODES
ICD10
- E83.59 Other disorders of calcium metabolism
- N29 Oth disorders of kidney and ureter in diseases classd elswhr
ICD9
275.49 Other disorders of calcium metabolism ‚
SNOMED
- nephrocalcinosis (disorder)
- Medullary nephrocalcinosis (disorder)
- Cortical nephrocalcinosis (disorder)
- Neonatal nephrocalcinosis (disorder)
CLINICAL PEARLS
- Nephrocalcinosis is often found incidentally upon imaging.
- Nephrocalcinosis should be considered a sign of another disease process, more than it should be considered a disease process itself (5).
- Nephrocalcinosis is most common in premature infants receiving neonatal intensive care unit care (pediatric population) and in adults who suffer from hyperparathyroidism.
- Rarely, nephrocalcinosis is associated with inherited metabolic disorders.