Management of Nephronophthisis
There is currently no curative treatment for nephronophthisis, and management focuses on supportive care, slowing disease progression, and preparing for eventual kidney transplantation when end-stage renal disease develops.
Disease Overview and Classification
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease characterized by chronic tubulointerstitial nephritis that progresses to end-stage renal disease. It can be classified into:
- Infantile form: Progresses to end-stage renal failure before 5 years of age 1
- Juvenile form: Terminal renal failure during the second decade 1
- Adolescent form: Later onset of kidney failure 2
Diagnostic Approach
- Gold standard: Kidney biopsy showing chronic tubulointerstitial changes with thickening of tubular basement membranes 3, 4
- Genetic testing: Identification of mutations in NPHP genes (over 20 genes identified) 5
- Imaging: Kidney ultrasound may show normal-sized kidneys with loss of corticomedullary differentiation and cysts (often appearing after progression to end-stage renal failure) 1
Management Strategy
1. Supportive Care and Monitoring
Regular monitoring of:
- Renal function tests
- Urinalysis
- Blood pressure
- Growth parameters (especially in children)
- Electrolyte balance 4
Kidney biopsy when diagnosis is uncertain 4
2. Blood Pressure Management
First-line therapy: ACE inhibitors or ARBs at maximally tolerated doses for patients with hypertension and proteinuria 6, 4
Consider isosorbide dinitrate for difficult-to-control hypertension, which has shown dramatic improvement in blood pressure control in a case report 7
3. Management of Proteinuria and Edema
ACE inhibitors or ARBs should be up-titrated to maximally tolerated or allowed daily dose as first-line treatment for proteinuria 6
Edema management:
- Dietary sodium restriction (<2.0 g/day) 6, 4
- Diuretics as first-line therapy 6
- If diuretic response is insufficient, add mechanistically different diuretics with careful monitoring for adverse effects (hyponatremia, hypokalemia, GFR reduction, volume depletion) 6
- For potassium-sparing diuretics, ENaC blockers like amiloride are preferable to spironolactone 6
4. Metabolic Management
- Treat metabolic acidosis if serum bicarbonate is <22 mmol/l 6
- Manage dyslipidemia with lifestyle modifications and consider statin therapy, particularly in patients with other cardiovascular risk factors 6
- Dietary protein restriction based on proteinuria level and kidney function:
- 0.8-1 g/kg/day for patients with nephrotic-range proteinuria
- 0.8 g/kg/day for patients with eGFR <60 ml/min/1.73 m² and nephrotic-range proteinuria 4
5. Experimental Therapies
Several potential disease-modifying agents are being investigated:
- Vasopressin receptor 2 antagonists (tolvaptan) - may slow decline in renal function 7, 5
- Cyclin-dependent kinase inhibitors (roscovitine) 5
- Hedgehog agonists (purmorphamine) 5
- mTOR inhibitors (rapamycin) 5
6. Management of Extrarenal Manifestations
15-20% of NPHP patients have extrarenal manifestations requiring specialized care 5:
- Retinal involvement: Ophthalmology evaluation and management
- CNS involvement: Neurological assessment
- Liver involvement: Hepatology consultation and management of liver fibrosis
- Skeletal abnormalities: Orthopedic evaluation
7. Renal Replacement Therapy
- Early referral for kidney transplantation is recommended as the definitive treatment 3
- Dialysis may be required as a bridge to transplantation
Vaccination and Infection Prevention
Recommended vaccines:
- Pneumococcal vaccine
- Annual influenza vaccine
- Herpes zoster vaccination (Shingrix) 4
Consider prophylactic trimethoprim-sulfamethoxazole for patients on immunosuppression 4
Prognosis
Despite management efforts, nephronophthisis inevitably progresses to end-stage renal disease. Early kidney transplantation is fundamental to improving prognosis 3.