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

Background and Hypothesis 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. Methods 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. Results 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). Conclusion 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.