Introduction:
Сalcineurin inhibitors (CNI) are currently being considered as the first line immunosuppressive treatment for steroid-resistant nephrotic syndrome (SRNS) in children without a proven genetic cause. According to the latest data, CNI could induce remission and improve outcome in some cases with monogenic SRNS. It remains unclear whether children with monogenic SRNS had higher risk of CNI-induced nephrotoxicity (CNIT). The aim of the study was to compare clinical characteristics in children with monogenic and non-genetic SRNS due to focal segmental glomerulosclerosis (FSGS) treated with CNI.
Methods:
A retrospective single-center study was conducted comparing clinical features in 28 children (17F/11M) with monogenic (n=11) and non-genetic (n=17) SRNS with Cyclosporine A (CsA)-induced remission after 12 months of treatment. Kidney biopsy revealed FSGS in all children before genetic testing and start CNI therapy. CNIT was defined by increasing of serum creatinine more than 30% from baseline level. The median of age at onset of SRNS (6.9 vs 5.8 years), disease duration before starting CNI (8.0 vs 7.0 months), baseline serum eGFR (119.0 vs 96.1 ml/min/1.73 m2), CNI dosage (4.2 vs 5.0 mg/kg/d), trough blood CsA levels (138.0 vs 116.1 ng/ml) at the start of CNI treatment and duration of CNI therapy (23 vs 24 months) were similar in two groups of patients (р>0.05). Patients with monogenic SRNS had variants in following genes: LMX1B (n=3), NPHS2 (n=2) and one patient each with variants in COL4A3, C3, ANLN, CRB2, LAMB2, SGPL1 genes.
Results:
The frequency of CNIT (90.9% vs 76.5%, р=0.62), including the incidence of CNIT before the first 6 months of treatment (60% vs 61.5%, р>0.999) in children with monogenic and idiopathic SRNS was comparable. There were no significant difference in the CNI dosage (5.2 vs 5.3 mg/kg/d, р>0.999) and trough blood CsA levels (120.0 vs 128.5 ng/ml, р>0.999), proportion of serum creatinine increasing and eGFR declining from baseline levels (36.5% vs 40.5%; p = 0.337; 24% vs 26%; p = 0.616, respectively) and in the proportion of children with increasing of serum creatinine more than 50% from baseline level (60% vs 69.2% p = 0.685) at the time of acute CNIT in two groups. We did not find any significant differences between children with monogenic and non-genetic SRNS in the proportion of serum creatinine increasing and eGFR declining from baseline levels (26.5% vs 14.2%; p = 0.445; 5.7% vs 3.2%; p = 0.835, respectively) and in the proportion of children with increasing of serum creatinine more than 25% from baseline level (60% vs 30.8% p = 0.222) after CNI dosage adjustment followed by withdrawal of CNI. The frequency of irreversible CNIT with continued decline of eGFR after CNI withdrawal in children with monogenic and idiopathic SRNS was also comparable (36.5% vs 35.3%, р>0.999).
Conclusions:
In spite of using therapeutic dosage and drug monitoring of CsA in all children with monogenic and non-genetic SRNS due to FSGS, the frequency of CNIT was higher than 70% in two groups of patients. The incidence and course of CNIT in patients with monogenic and non-genetic SRNS was similar, which allow us to use CNI to induce remission of the disease in these children. Performing measurement of trough blood CsA levels and serum creatinine is required to make timely dosage adjustment or withdrawal of CNI.
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.