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

BACKGROUND

Leukemia inhibitory factor (LIF) has been implicated in the production of galactose-deficient immunoglobulin A1 (IgA1) and development of renal fibrosis, and has emerged in several genome-wide association studies as a hotspot gene of IgA nephropathy (IgAN). Therefore, we hypothesize that urinary LIF (uLIF) 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 uLIF concentrations were measured using enzyme-linked immunosorbent assay. Kidney disease progression was defined as a 40% decline in estimated glomerular filtration rate (eGFR), progression to end-stage kidney disease or death due to kidney disease. Additionally, a subcohort derived from the Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) trial was used to investigate the association between changes in uLIF 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 systolic blood pressure, elevated levels of uLIF/urinary creatinine (uLIF/Cr) were independently associated with an increased risk of kidney progression [per natural log (uLIF/Cr) increment: hazard ratio (HR) 2.16; 1.13-4.13; P for trend 0.019]. In TESTING subcohort, the methylprednisolone group showed a significant greater reduction in uLIF/Cr than the placebo group (41.9% vs 25.4% at 6th month, P = .039; 59.2% vs 19.8% at 12th month, P < .001). The LIF decline group exhibited a significant lower risk of kidney progression compared with 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.