Mass spectrometry-based screening identifies circulating immunoglobulinA-α1-microglobulin complex as potential biomarker in immunoglobulin A nephropathy

Background. Immunoglobulin A nephropathy (IgAN) is characterized by predominant IgA deposition in the glomerular mesangium. Previous studies have proved that renal-deposited IgA in IgAN came from circulating IgA1-containing complexes (CICs). Methods. To explore the composition of CICs in IgAN, we isolated CICs from IgAN patients and healthy controls and then quantitatively analyzed them by mass spectrometry. Meanwhile, the isolated CICs were used to treat human mesangial cells to monitor mesangial cell injury. Using the protein content and injury effects, the key constituent in CICs was identified. Then the circulating levels of identified key constituent-IgA complex were detected in an independent population by an in-house-developed enzyme-linked immunosorbent assay. Results. By comparing the proteins of CICs between IgAN patients and controls, we found that 14 proteins showed significantly different levels. Among them, alpha 1-microglobulin content in CICs was associated with not only in vitro mesangial cell proliferation and monocyte chemoattractant protein 1 secretion, but also in vivo estimated glomerular filtration rate (eGFR) levels and tubulointerstitial lesions in IgAN patients. Moreover, we found alpha 1-microglobulin was prone to bind aberrant glycosylated IgA1. Additionally, elevated circulating IgA-alpha 1-microglobulin complex levels were detected in an independent IgAN population and IgA-alpha 1-microglobulin complex levels were correlated with hypertension, eGFR levels and Oxford T- scores in these IgAN patients. Conclusions. Our results suggest that the IgA-alpha 1-microglobulin complex is an important constituent in CICs and that circulating IgA-alpha 1-microglobulin complex detection might serve as a potential noninvasive biomarker detection method for IgAN.

Automated summary

The study identified alpha 1-microglobulin as a key constituent in CICs from IgAN patients, which was associated with mesangial cell injury and aberrant glycosylated IgA1 binding. Elevated levels of circulating IgA-alpha 1-microglobulin complex were detected in an independent IgAN population and were correlated with hypertension, eGFR levels, and Oxford T-scores in these patients. Detection of circulating IgA-alpha 1-microglobulin complex may serve as a potential noninvasive biomarker for IgAN.