Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage kidney disease (ESKD) in children and young adults. For approximately 30% of children with SRNS results from a genetic cause. In this study, genotype-phenotype correlations in a cohort of 283 pediatric patients with SRNS or early-onset NS (nephrotic syndrome presenting within the first year of life) from 23 major pediatric nephrology centers in China were analyzed. All patients were performed with next-generation sequencing and Sanger sequencing. The overall mutation detection rate was 37.5% (106 of 283 patients). WT1 was the most frequently detected mutation, followed by NPHS1, NPHS2, and ADCK4, and these four major causative genes (WT1, NPHS1, NPHS2, and ADCK4) account for 73.6% of patients with monogenic SRNS. Thirteen of 106 individuals (12.3%) carried mutations in ADCK4 that function within the coenzyme Q10 biosynthesis pathway. In the higher frequently ADCK4-related SRNS, two mutations, c.737G>A (p.S246N) and c.748G>C (p.D250H), were the most prevalent. Our study provides not only definitive diagnosis but also facilitate available targeted treatment for SRNS, and prediction of prognosis and renal outcome. Our indications for genetic testing are patients with FSGS, initial SRNS, cases of positive family history or those with extra-renal manifestations.

This study aims to elucidate the role of Kruppel-like factor (KLF5) and myxovirus resistance 1 (MX1) in the progression of renal fibrosis in lupus nephritis (LN).Methods: First, the expression of KLF5 and MX1 was assessed in the peripheral blood of LN patients and healthy participants. Next, the pathological changes in renal tissues were evaluated and compared in BALB/c and MRL/lpr mice, by detecting the expression of fibrosis marker proteins (transforming growth factor-β [TGF-β] and CTGF) and α-SMA, the content of urine protein, and the levels of serum creatinine, blood urea nitrogen, and serum double-stranded DNA antibody. In TGF-β1-induced HK-2 cells, the messenger RNA levels of KLF5 and MX1 were tested by qRT-PCR, and the protein expression of α-SMA, type I collagen (Col I), fibronectin (FN), and matrix metalloproteinase 9 (MMP9) was measured by western blot analysis. Moreover, the relationship between KLF5 and MX1 was predicted and verified.Results: In renal tissues of MRL/lpr mice and the peripheral blood of LN patients, KLF5 and MX1 were highly expressed. Pearson analysis revealed that KLF5 was positively correlated with MX1. Furthermore, KLF5 bound to MX1 promoter and promoted its transcription level. MRL/lpr mice showed substantial renal injury, accompanied by increased expression of α-SMA, TGF-β, CTGF, Col I, FN, and MMP9. Injection of sh-KLF5 or sh-MX1 alone in MRL/lpr mice reduced renal fibrosis in LN, while simultaneous injection of sh-KLF5 and ad-MX1 exacerbated renal injury and fibrosis. Furthermore, we obtained the same results in TGF-β1-induced HK-2 cells. Conclusion: Knockdown of KLF5 alleviated renal fibrosis in LN through repressing the transcription of MX1.