Association of urinary LIF levels with disease prognosis and treatment response to methylprednisolone in IgA nephropathy

Leukemia inhibitory factor (LIF) has been implicated in the production of galactose-deficient IgA1 and development of renal fibrosis, and has emerged in several genome-wide association studies (GWAS) studies as a hotspot gene of IgAN. Therefore, we hypothesis that urinary LIF could predict the renal prognosis and/or treatment response to immunosuppressive therapy in IgAN patients. A prognostic study was conducted in a retrospective cohort of 506 biopsy-confirmed IgAN patients. Baseline urinary LIF concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Kidney disease progression was defined as a 40% decline in eGFR, progression to end-stage kidney disease, or death due to kidney disease. Additionally, a sub-cohort derived from the TESTING trial was used to investigate the association between changes in urinary LIF and the response to methylprednisolone therapy in IgAN patients. Over a median of 35 months of follow-up, 16.6% participants of the prognostic cohort reached the composite kidney progression event. After adjusting for sex, age, eGFR, proteinuria and SBP, elevated levels of urinary LIF/urinary creatinine (uLIF/Cr) were independently associated with an increased risk of kidney progression (per natural log [uLIF/Cr] increment: HR, 2.16; 1.13-4.13; P for trend 0.019). In TESTING sub-cohort, the methylprednisolone group showed a significant greater reduction in uLIF/Cr than the placebo group (41.9% vs. 25.4% at 6th month, P = 0.039; 59.2% vs. 19.8% at 12th month, P < 0.001). The LIF decline group exhibited a significant lower risk of kidney progression compared to LIF non-decline group (adjusted HR 0.431; 0.255-0.730; P for trend 0.002). This study provides strong initial evidence that uLIF/Cr levels are linked to renal prognosis in IgAN. Moreover, reductions in uLIF/Cr may indicate improved outcomes in patients receiving methylprednisolone. Collectively, our findings suggest uLIF/Cr levels may serve as a valuable biomarker for predicting both renal prognosis and treatment response in IgAN patients.