Clinicopathological characteristics and cyclosporine-responsive proteinuria in nail-patella syndrome with a novel LMX1B mutation.

BACKGROUND

Nephropathy in nail-patella syndrome (NPS) has limited therapeutic options. Progressive nephrotic-range proteinuria often persists despite maximal renin-angiotensin-aldosterone system inhibitor (RAASi) therapy. Calcineurin inhibitors such as cyclosporine A (CsA) are unexplored in NPS. We therefore evaluated the efficacy and safety of CsA in a patient with NPS.

METHODS

A 15-year-old boy with genetically confirmed NPS (novel LMX1B missense variant, c.796T>G, p. W266G) was studied. Clinical, pathological, and follow-up data were analyzed. Bioinformatic screening (GSE12008 dataset) identified LMX1B-regulated podocyte genes. Functional assays (immunofluorescence, dual luciferase reporter, and molecular dynamics analyses) assessed the mutation's impact.

RESULTS

The patient presented with classical NPS features, including nail dysplasia, limited elbow motion, patellar dysplasia, and proteinuria. Kidney biopsy revealed focal glomeruli immaturity with small foci of foamy cells, diffuse foot process effacement, and heterogeneous glomerular basement membrane (GBM) abnormalities (predominantly thinned with segmental thickening and loosening), demonstrating Alport-like kidney pathology. Despite resistance to RAASi and sodium-glucose cotransporter inhibitor (SGLT2i), CsA therapy for 7 months significantly reduced proteinuria from 3.74 to 0.697 g/24 h, increased serum albumin from 28.8 to 39.4 g/L, and maintained normal serum creatinine (54-63 μmol/L). Immunofluorescence analysis of the patient's kidney tissue indicated reduced expressions of PTPRO, NPHS2, and COL4A3. The W266G mutation severely impaired LMX1B binding to the promoters, reducing the transcriptional activity of PTPRO, NPHS2, and COL4A3.

CONCLUSIONS

CsA effectively reduced nephrotic-range proteinuria in genetically confirmed NPS, suggesting the therapeutic potential of calcineurin inhibitors in for NPS-associated nephropathy.