Isosorbide dinitrate in nephronophthisis treatment

Abstract

Nephronophthisis is a progressive disease that affects development of the renal tubules and leads to end stage renal disease. Many affected children have isolated renal disease; however, there can be additional manifestations including heart defects, liver fibrosis, brain malformations, and situs inversus. There is no way to slow or modify the disease. We describe a patient who presented at birth with cholestatic jaundice and decreased kidney function, found by exome sequencing to have two NPHP3 variants. Her clinical status deteriorated rapidly, and two disease-modifying agents were given in hopes of slowing disease progression, the arginine vasopressin type II receptor antagonist tolvaptan to stabilize her renal function and isosorbide dinitrate to manage her poorly controlled hypertension. Tolvaptan therapy initiated at 82 days of life had limited effect on the rate of decline in renal function and was insufficient to abrogate the need for dialysis; however, isosorbide dinitrate therapy led to a dramatic improvement in blood pressure control and allowed for the discontinuation of multiple anti-hypertensive agents. This is the first report of the use of tolvaptan and isosorbide dinitrate for nephronophthisis management. We suggest that isosorbide dinitrate may represent a disease-modifying agent in nephronophthisis treatment.

Nephronophthisis: A review of genotype–phenotype correlation

“…Some potential therapeutic interventions have arisen from several lines of investigation into the pathogenesis of NPHP. Various personalized drugs include isosorbide dinitrate and tolvaptan (vasopressin V2 receptor antagonist), dimethyl fumarate, rapamycin (mTOR inhibitor), roscovitine and its analog S‐CR8 (cyclin‐dependent kinases inhibitor), purmorphamine (Shh signalling pathway agonist), paclitaxel, regulation of transcription factor Glis2/NPHP7 by SUMOylation, and FR167653 (p38 MAPK pathway inhibitor) . Despite the many promising interventions that have arisen from preclinical studies, no clinical trials have yet been conducted in NPHP patients.…”

Renal–Hepatic–Pancreatic Dysplasia: An Ultra-Rare Ciliopathy with a Novel NPHP3 Genotype

“…In that case, it was interpreted as a likely pathogenic variant. 10 The variant was rare (not found in GnomAD), predicted to be pathogenic by nine in-silico prediction tools, found in a homozygous state in the patient, previously detected in a Prenatal Oligohydramnios nephronophthisis patient, and the patient's phenotype and the family history were highly consistent with RHPD; therefore, we have interpreted this variant as a pathogenic variant. In the family investigation, the parents were found to be heterozygous for the variant.…”

Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis

“…Nitric oxide is produced by vascular endothelial cells in response to ciliary sensation of shear stress and causes compensatory vasodilatation, a process that is impaired in ciliopathies. Targeting this cilia-specific cause of hypertension was more effective in this patient than classic anti-hypertensive medication ( Strong et al, 2018 ).…”

“…Tolvaptan was shown to be effective in clinical trials ( Torres et al, 2012 , 2017 , 2018 ) and is the first drug registered for treatment of adult ADPKD patients below 55 years of age and at risk of rapidly progressive disease as defined by clinical and/or genetic criteria ( Chebib et al, 2018 ). There are no clinical trials registered for use of Tolvaptan in patients with NPH and there is only one case report in which Tolvaptan is described for the treatment of NPHP3 -related infantile NPH without an effect on the very rapid renal function decline in this specific severe case ( Strong et al, 2018 ). Such an approach could theoretically be used in the case of cystic infantile NPH, although the therapeutic window is small (mean age under 5), while its relevance in juvenile NPH is less apparent.…”

“…In addition, data should be collected to gain insight into ciliopathy-specific symptomatic treatment. For example, in a patient with NPHP3 -related infantile NPH isosorbide dinitrate was used to treat hypertension by restoring nitric oxide generation ( Strong et al, 2018 ). Nitric oxide is produced by vascular endothelial cells in response to ciliary sensation of shear stress and causes compensatory vasodilatation, a process that is impaired in ciliopathies.…”