Nephrocalcinosis

What is nephrocalcinosis?^{1 2 3}

Nephrocalcinosis is defined as generalised deposition of calcium phosphate and/or calcium oxalate in the kidney, predominantly in the interstitium. Calcifications in renal pyramids, characteristic of medullary nephrocalcinosis, are seen in 98% of nephrocalcinosis patients.

Clinical presentation and course are not dependent on the severity of nephrocalcinosis. The critical feature in nephrocalcinosis is hypercalciuria with or without hypercalcaemia.

Nephrocalcinosis is closely associated with renal stone formation (urolithiasis) resulting from increased urinary calcium levels (hypercalciuria).⁴

Advances in uroendoscopy have led to a further definition: the radiographic demonstration of diffuse, fine renal parenchymal calcifications.⁵

Nephrocalcinosis can be divided into three categories (there is invariably a degree of overlap between the categories):

• Chemical nephrocalcinosis: increased concentration of calcium in renal cells, especially the tubular epithelium, causing adverse effects on renal structure and function - eg, increased excretion of water, sodium, potassium, calcium and magnesium.

• Microscopic nephrocalcinosis: calcium precipitates in crystalline form as oxalate and/or phosphate; however, it is only seen with the aid of a microscope.

• Macroscopic nephrocalcinosis: large areas of calcification can be seen.

Nephrocalcinosis may be associated with renal calculi but is more likely to represent an underlying metabolic disorder. It can also be differentiated into:

• Medullary nephrocalcinosis:
  

  • The most frequent form, characterised by the exclusive involvement of the medullary pyramids.

  • It is usually associated with disordered calcium homeostasis.

• Cortical nephrocalcinosis:
  

  • Rarer and involving all the renal parenchyma.

  • Frequently associated with severe metabolic defects, such as primary hyperoxaluria or end-stage kidney disease.

  • The most frequent causes are chronic glomerulonephritis and acute cortical necrosis.

  • Other causes include haemolytic uraemic syndrome, chronic pyelonephritis, vesicoureteral reflux, renal transplantation and polycystic kidney disease.

Nephrocalcinosis epidemiology

Microscopic nephrocalcinosis is a common incidental finding at post-mortem but macroscopic nephrocalcinosis is uncommon.

What causes nephrocalcinosis? (Aetiology)²

Medullary nephrocalcinosis

• Hypercalcaemia: for example, diet, hyperparathyroidism, vitamin D excess, bone metastases, bone loss from chronic immobilisation and severe osteoporosis, sarcoidosis, idiopathic hypercalcaemia of infancy (Williams' disease).

• Hypercalciuria:
  

  • Altered renal tubular handling - eg, idiopathic hypercalciuria, distal renal tubular acidosis (is associated with low urinary excretion of citrate), hypothyroidism, inherited tubular disorders (eg, Bartter's syndrome and familial magnesium-losing nephropathy), and may follow intensive loop diuretic treatment in premature infants.

  • Hypercalciuria is also a feature of Fanconi's syndrome and proximal renal tubular acidosis; however, these conditions are less commonly associated with nephrocalcinosis.

• Absence of factors in urine (eg, citrate) that help to maintain calcium salts in solution - eg, in conditions causing chronic hypokalaemia (eg, primary hyperaldosteronism).

• Medullary sponge kidney.⁶

Cortical nephrocalcinosis

• Acute renal cortical necrosis: causes include infection, extracorporeal shock wave lithotripsy, haemolytic uraemic syndrome.

• Primary and secondary oxalosis.

• Chronic glomerulonephritis.

• Intrarenal infections in HIV-seropositive patients.

• Chronic pyelonephritis.

• Renal graft rejection.

• Autosomal recessive polycystic disease.

Nephrocalcinosis symptoms (presentation)²

• The underlying aetiology primarily determines the presentation of nephrocalcinosis, although in most cases it is asymptomatic and is identified as an abnormality on imaging of the renal tract.

• Presentation can range from incidental detection on abdominal X-rays or ultrasounds performed for another reason, to life-threatening.

• Hypercalcaemia: polyuria and polydipsia, nausea and vomiting.

• May cause hypertension.

• In medullary nephrocalcinosis, calcium nodules commonly rupture into the calyceal system to form urinary stones and cause renal colic, haematuria, urinary tract infections or the passage of urinary stones.

• May rarely present with features of acute kidney injury or chronic kidney disease.

Presenting symptoms in children include failure to thrive in the first year of life, urinary tract infections, bladder voiding dysfunction or abdominal pain, and psychomotor delay.⁷

Investigations²

Blood tests

• Serum calcium, phosphate, albumin: to establish the presence of hypercalcaemia.

• Serum electrolytes and assessment of renal function.

• Parathyroid hormone levels.

• Thyroid-stimulating hormone (TSH) levels.

Urine investigations

• Urinalysis with microscopy and culture: evidence of urinary tract infection.

• 24-hour urinary excretion of calcium, oxalate, citrate and protein: assessment of hypercalciuria and possible nephrotic syndrome.

• Urinary magnesium: magnesium-losing nephropathy.

Radiology

• Abdominal X-rays: detection of nephrocalcinosis, urinary stones.

• Ultrasound: more sensitive than conventional radiography and can be superior to CT scan in some clinical scenarios (eg, nephrocalcinosis associated with hypoparathyroidism).⁸

• CT scan: more effective in detecting calcification and can be used to differentiate medullary and cortical deposition.

Endoscopy
When calcification in close association with the renal papillae is seen on CT scans, distinguishing nephrolithiasis from nephrocalcinosis may require direct visual inspection using endoscopy.⁵

Renal biopsy
May be required in the assessment of the underlying cause.

Genetic testing
May play an increasing role in nephrocalcinosis presenting in children in the future.⁹

Associated diseases

Nephrocalcinosis and urinary calculi may co-exist. Nephrocalcinosis and calcium nephrolithiasis are considered as two independent pathologies.¹⁰

Common associated conditions include:

• Primary hyperparathyroidism.

• Type 1 (distal) renal tubular acidosis.

• Medullary sponge kidney.

• Furosemide therapy (neonatal).

• Increasing prematurity.

Rarer associated conditions include:

• Phosphate and vitamin D in X-linked hypophosphataemic rickets.

• Hyperphosphatasia.

• Sarcoidosis.

• Tuberculosis.

• Vitamin D intoxication.

• Hypomagnesaemia.

• Bartter's syndrome.

• Glycogen storage disease type 1.

• Prolonged immobilisation.

• Idiopathic hypercalciuria.

• Oculocerebral syndrome.

• Hyperoxaluria.

• Cushing's syndrome.

• Hypothyroidism.

• Acetazolamide.

• Cerebrotendinous xanthomatosis.

• Dent's disease.

Nephrocalcinosis treatment and management¹¹

See also separate Hypercalcaemia article.

• Ensure adequate fluid intake.

• Treatment of the underlying condition - eg, parathyroidectomy to control a hyperfunctioning parathyroid gland.

• Early treatment of reversible causes of renal failure, such as treatment of urinary infections, calculous obstruction and hypertension, is essential.

• Once renal failure is established, it must be treated accordingly. See separate Acute Kidney Injury and Chronic Kidney Disease articles.

• Surgical intervention may be required for significant stone formation in the renal tract, especially if causing obstruction or infection.

• Lithotripsy may cause renal damage, as the calcium deposition is largely parenchymal.

Complications¹¹

May lead to uncontrolled hypertension, renal infection, scarring, renal colic, defects of renal tubular function and chronic kidney disease.

Prognosis

The prognosis depends mainly on the aetiology of the nephrocalcinosis.

Early diagnosis and treatment of the underlying condition in children is associated with catch-up growth and stabilisation of glomerular function in many children but not with the reduction in the degree of nephrocalcinosis in the majority of cases.⁷