Use of genomic and functional analysis to characterize patients with steroid-resistant nephrotic syndrome.

BACKGROUND: Children with genetic causes of steroid-resistant nephrotic syndrome (SRNS) usually do well after renal transplantation, while some with idiopathic SRNS show recurrence due to a putative podocyte-toxic factor. Distinguishing different forms of SRNS based on clinical criteria has been difficult. The aim of our study was to test a novel approach that allows categorization of patients into clinically useful subgroups. METHODS: Seventeen patients with clinically confirmed SRNS were analyzed by next-generation sequencing (NGS) of 37 known SRNS genes and a functional assay of cultured human podocytes, which indirectly tests for toxicity of patients' sera by evidenced loss of podocyte focal adhesion complex (FAC) number. RESULTS: We identified a pathogenic mutation in seven patients (41%). Sera from patients with monogenic SRNS caused mild loss of FAC number down to 73% compared to untreated controls, while sera from seven of the remaining ten patients with idiopathic SRNS caused significant FAC number loss to 43% (non-overlapping difference 30%, 95% CI 26-36%, P < 0.001). All patients with recurrent SRNS (n = 4) in the graft showed absence of podocyte gene mutations but significant FAC loss. Three patients had no mutation nor serum podocyte toxicity. CONCLUSIONS: Our approach allowed categorization of patients into three subgroups: (1) patients with monogenic SRNS; (2) patients with idiopathic SRNS and marked serum podocyte toxicity; and (3) patients without identifiable genetic cause nor evidence of serum podocyte toxicity. Post-transplant SRNS recurrence risk appears to be low in groups 1 and 3, but high in group 2.

Acute renal failure in cystic fibrosis: association with inhaled tobramycin therapy.

We describe a 20-year-old patient with cystic fibrosis who developed acute nonoliguric renal failure associated with inhaled tobramycin. Clinical evaluation and renal biopsy findings were consistent with aminoglycoside-induced changes. Renal failure due to inhaled aminoglycosides has not been previously reported. The incidence may rise, however, with the increased use of this treatment modality. Measurable tobramycin levels due to inhalational therapy with conventional dosing in the reported patient indicate that the drug can be systemically absorbed, and renal tubular toxicity may occur.