Nephronophthisis

Synonyms: juvenile nephronophthisis, medullary cystic disease, Senior-Loken syndrome.

This is an inherited cause of chronic tubulointerstitial nephritis leading to multiple cysts of varying sizes at the corticomedullary junction and medulla. It is autosomal recessive and patients develop end-stage renal failure by adolescence.¹ The protein products, named nephrocystins, which become abnormal in this disorder have primarily a function in cilial structures (making it a "ciliopathy").²

Juvenile form (autosomal recessive) accounts for 10-20% of end-stage renal failure (ESRF) in children. It occurs equally in males and females. The adult form (autosomal dominant) is rare and restricted to the kidney. It presents between the ages of 20 to 40 years with rapidly progressive renal failure.³

Various deletions of the NPH1 gene on chromosome 2 (2q13 region) appear to be responsible for the vast majority (~85%) of the purely renal forms of juvenile nephronophthisis.^4,5 Another possible gene has recently been identified on chromosome 9 (9q22-9q31).⁴

This results from gradual tubular injury.¹

Clinical features

• Age 1 - 3 years
  • Polyuria - decreased concentrating ability with loss of sodium
  • Polydipsia
  • Growth retardation
  • Secondary enuresis
  • Renal impairment
• Renal failure with metabolic acidosis, anaemia, renal osteodystrophy and ESRF
• Once uraemia occurs - patients may have nausea, anorexia and generalised lethargy

Extrarenal manifestations (may be due to a combination of other genetic defects)¹

• Retinal degeneration (Senior-Loken syndrome)⁶
• Retinitis pigmentosa
• Mental retardation
• Skeletal changes
• Cerebellar ataxia
• Liver fibrosis

• Polycystic kidney disease
• Chronic pyelonephritis
• Urinary tract obstruction

• Hyponatremia may occur if sodium intake is reduced for any reason.
• Anaemia and metabolic acidosis are late features.
• Urinalysis - is usually normal; occasionally few cells and casts.
• Ultrasound - multiple small medullary cysts (1 mm to 1 cm in size); early scans may show smooth outline and normal-sized or small kidneys.
• Intravenous pyelogram - the kidneys are small, smooth with reduced function. The nephrogram is prolonged and there are medullary striations due to stasis within the tubules, producing the characteristic "fan shape".
• CT scan of urinary tract - kidneys are small, smooth, and contain medullary cysts. This is more sensitive than USS.¹
• Renal biopsy can confirm the diagnosis.
• Genetic testing looking for homozygous deletions.¹

• Treat symptomatically e.g. correct hypovolaemia
• Treat associated renal failure - usually haemodialysis followed by renal transplantation (the illness does not recur in the transplanted kidney)¹

Most children will develop renal failure by mean age of 13 years. Antenatal diagnosis is only helpful if the specific mutation in a family is already known and can then be tested for.¹ Data from North America on outcomes following renal transplantation in nephronophthisis is very encouraging and suggests that these patients fare better than patients who receive renal transplants for other conditions.⁷