Synonyms: juvenile nephronophthisis, medullary cystic disease

This is an inherited cause of chronic tubulo-interstitial 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 (ESRF) by adolescence.^1,2 The protein products, named nephrocystins, which become abnormal in this disorder, have primarily a function in cilial structures (making it a 'ciliopathy').³

Epidemiology

The 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.⁴

Aetiology

To date, mutations in 12 genes (called NPHP1-NPHP11 and NPHPL1) have been associated with the disease, but these only account for approximately one third of cases so far.⁵ This includes the NPHP1 gene which encodes the protein nephrocystin-1, which is mutated in one fifth of all cases.⁵

Clinical subdivisions⁵

• Infantile - median age of onset 1 year.
• Juvenile - median age of onset 13 years.
• Adolescent - median age of onset 19 years.

Presentation

This results from gradual tubular injury.¹

Clinical features

• Polyuria - decreased concentrating ability with loss of sodium.
• Polydipsia.
• Growth retardation.
• Secondary enuresis.
• Renal impairment.
• Renal failure with metabolic acidosis, anaemia, renal osteodystrophy and end-stage renal failure (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 (Joubert's syndrome).
• Liver fibrosis.

Differential diagnosis

• Polycystic kidney disease
• Chronic pyelonephritis
• Urinary tract obstruction

Investigations

• Hyponatraemia 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 ultrasound scanning.¹
• Renal biopsy can confirm the diagnosis.
• Genetic testing looking for homozygous deletions.¹

Management

• 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).^1,2

Prognosis

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 are very encouraging and suggest that these patients fare better than patients who receive renal transplants for other conditions.⁷

Document references

1. Niaudet P, Nephronophthisis, Orphanet Encyclopedia, March 2004
2. Wolf MT, Hildebrandt F; Nephronophthisis. Pediatr Nephrol. 2011 Feb;26(2):181-94. Epub 2010 Jul 22. [abstract]
3. Simms RJ, Eley L, Sayer JA; Nephronophthisis. Eur J Hum Genet. 2008 Dec 10. [abstract]
4. Scolari F, Viola BF, Ghiggeri GM, et al; Towards the identification of (a) gene(s) for autosomal dominant medullary cystic kidney disease. J Nephrol. 2003 May-Jun;16(3):321-8. [abstract]
5. Hurd TW, Hildebrandt F; Mechanisms of nephronophthisis and related ciliopathies. Nephron Exp Nephrol. 2011;118(1):e9-14. Epub 2010 Nov 11. [abstract]
6. Giridhar S, Padmaraj R, Senguttuvan P; Twins with senior-Loken syndrome. Indian J Pediatr. 2006 Nov;73(11):1041-3. [abstract]
7. Hamiwka LA, Midgley JP, Wade AW, et al; Outcomes of kidney transplantation in children with nephronophthisis: an analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry. Pediatr Transplant. 2008 Dec;12(8):878-82. [abstract]