Familial Juvenile Nephronophthisis (NPH)

Inherited disorder characterized by progressive polyuria preceding the decline of renal function and leading to end-stage renal disease during childhood or adolescence.

Nephronophthisis.

First reported in the literature in 1945 by Smith and Graham, but the first description is attributed to Guido Fanconi, a Swiss pediatrician, in 1951.

Most frequent genetic cause of end-stage renal disease in childhood. Represents approximately 10 to 15% of end-stage renal disease in children.

Four types of nephronophthisis (NPH), often determined by the age at onset of end-stage renal failure. Terminal renal failure develops at median ages of 1 year, 13 years, and 19 years in NPH II, NPH I, and NPH III, respectively. Type IV is variable.

Type I (Familial Juvenile Nephronophthisis; NPH I): Characterized by anemia, polyuria, polydipsia, isosthenuria, and death in uremia. It represent 80% of all NPH cases.

Type II (Infantile Nephronophthisis; NPH II): Characterized by hypertension, respiratory failure, pulmonary hypoplasia, renal failure by age 3 years, hyperkalemic metabolic acidosis, hyperkalemia, oligohydramnios, and neonatal death secondary to pulmonary insufficiency.

Type III (Adolescent Nephronophthisis; NPH III): Adolescent nephronophthisis is considered clearly distinct by clinical and genetic findings than the other types. Most patients suffered from anemia, and onset of terminal renal failure occurred significantly later than in juvenile nephronophthisis.

Type IV (NPH IV): Characterized by a triad of interstitial cell infiltrates, renal tubular cell atrophy with cysts arising from the corticomedullary junction of the kidneys, and renal interstitial fibrosis. Chromosomal localization is reported on a fourth gene locus NPHP4. End-stage renal disease commenced within a wider age range of 11 to 34 years. It usually is considered type III.

Loken Senior Syndrome is characterized by nephronophthisis in association with retinitis pigmentosa or retinal aplasia, which is consistent with Leber Congenital Amaurosis. The association of Leber Congenital Amaurosis (LCA) is present in 15% of all cases affected with nephronophthisis. It is often considered a type III with retinal dysplasia.

Depends on the clinical form. NPH I (80% of cases) is inherited as a recessive trait (linkage for 2q13; possible second locus 9q22-31). NPH II has recessive inheritance (unknown gene localization). NPH III has no linkage for chromosome 2. NPH IV (medullary cystic disease) is transmitted as an autosomal trait (gene map locus 1q21).

Changes are characteristic and include the presence of atrophic tubules, irregularly thickened tubular basement membrane, and focal interstitial fibrosis. As the disease progresses, diffuse tubulointerstitial changes and medullary cysts are found. The biochemical defect underlying the production of the defective tubular basement membrane is unknown.

Confirmed by pathologic renal findings obtained from biopsy.

Patients will complain of polyuria caused by decreased renal concentrating ability. Progressive renal function deterioration follows. Other features of the disease are growth retardation, cerebellar dysfunction, liver involvement, and bone anomalies. Ocular involvement is common. Patients require dialysis or renal transplant; otherwise death occurs in early adulthood.

The hydration status of the patients should be carefully evaluated. Assess all the other characteristic changes associated with chronic renal failure: anemia, thrombocytopenia, electrolyte balance, metabolic acidosis, blood pressure, and susceptibility to infection. In presence of uremia, the coagulation system might be affected and should be checked.

Patients are managed as chronic renal failure patients. Maintain renal function intraoperatively by preventing overt dehydration and cardiovascular depression. According to the type of surgical procedure, invasive monitoring can be helpful for assessing intravascular volume. Patients with arteriovenous shunt for the purpose of dialysis should receive special attention to prevent thrombosis as a result of extrinsic compression. The patency of the shunt should be monitored intraoperatively with a Doppler examination, and the shunt should never be used as intravenous access.

Avoid or reduce the administration of sevoflurane in these patients given the potential production of fluoride anions compound A and their effects on the kidney. The muscular relaxant of choice in the presence of renal failure is cis-atracurium or atracurium. However, other muscular relaxants can be used but in reduced dosage because renal clearance is decreased.

Loken Senior Syndrome: Autosomal recessive disorder characterized by progressive nephronophthisis, with or without medullary cystic disease. Other features include progressive eye disease (retinitis pigmentosa) and ataxia. Apparent during the first year of life. Blindness develops within the first 2 years of life. It is most often associated with tubulointestinal nephropathy and renal cystic disease.