Abstract: PUB116
A Child with Increased Serum Creatinine and Polyuria
Session Information
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)
Authors
- Victor, Corinna K., Louisiana State University, Baton Rouge, Louisiana, United States
- Yosypiv, Ihor V., Tulane University School of Medicine, New Orleans, Louisiana, United States
Introduction
Nephronophthisis (NPHP) is a rare autosomal recessive cystic kidney disease and the most frequent genetic cause of end-stage renal disease (ESRD). It is caused by mutations in 11 different genes, denoted nephrocystins (NPHP1-11). The pathomechanism of NPHP involves defects in ciliary function (ciliopathy) and planar cell polarity (PCP). 10-15% of NPHP patients show extrarenal symptoms, including retinal degeneration (Senior-Loken syndrome), cerebellar vermis aplasia (Joubert syndrome), liver fibrosis, and oculomotor apraxia (Cogan syndrome).
Case Description
Blood tests obtained in a 5-year-old boy with a history of developmental delay showed serum creatinine of 1.7 mg/dL. Further Nephrology assessment revealed history of polyuria and polydipsia, which were also present in several family members, high Cystatin C (2.03 mg/dL) and iPTH (500 pg/ml), anemia, low urine specific gravity (1.003) and osmolality (154 mOsm/kg) with normal plasma osmolality and plasma sodium. Vital signs and physical examination were normal. Renal ultrasonography showed bilateral echogenic kidneys and small right kidney. DDAVP challenge did not increase urine osmolality, indicating the kidney’s inability to respond to vasopressin. Renasight gene panel showed two different compound heterozygous likely pathogenic NPHP1 variants, consistent with the diagnosis of NPHP1. Therapy for the manifestations of chronic kidney disease (CKD) was initiated. Family was informed that the patient will evantually progress to ESRD and will need renal replacement therapy in the form of dialysis or a kidney transplant.
Discussion
This case illustrates an incidental diagnosis of a rare ciliopathy, NPHP1, in a 5 year-old boy based on clinical and laboratory features combined with causative gene variant identification. There is currently no curative treatment for nephronophthisis and all patients progress to ESRD. Management includes supportive care and slowing disease progression. NPHP1 encodes nephrocystin-1, which is expressed in the collecting duct at focal adhesions, adherens junctions, and in cilia. Different mechanisms are involved in NPHP signaling ranging from PCP, sonic hedgehog (Shh), Hippo, mTOR, and cAMP signaling. A number of therapeutic interventions appear to be promising, ranging from vasopressin receptor 2 antagonists such as tolvaptan, cyclin-dependent kinase inhibitors such as roscovitine, Shh agonists such as purmorphamine, and mTOR inhibitors such as rapamycin.