Dysregulation of circulating Gas6 is associated with renal disease and inversely proportional to renal function. Low albumin and higher IV iron administration were associated with higher Gas6 levels, suggesting a possible connection between inflammation and oxidative stress mediated by iron. Protein S levels were also elevated in CKD patients, but the relevance of this finding needs to be further investigated.

Glomerulonephritis (GN) is a typical lesion in autoantibody and immune complex disorders, including SLE. Because the Gas6/Axl pathway has been implicated in the pathogenesis of many types of GN, targeting this pathway might ameliorate GN. Consequently, we have studied the efficacy and mechanism of R428, a potent selective Axl inhibitor, in the prevention of experimental anti-GBM nephritis. Axl upregulation was investigated with Sp1/3 siRNA in the SV40-transformed mesangial cells. For Axl inhibition, a daily dose of R428 (125 mg/kg) or vehicle was administered orally. GN was induced with anti-GBM sera. Renal disease development was followed by serial blood urine nitrogen (BUN) determinations and by evaluation of kidney histology at the time of sacrifice. Axl-associated signaling proteins were analyzed by Western blotting and inflammatory cytokine secretion was analyzed by Proteome array. SiRNA data revealed the transcription factor Sp1 to be an important regulator of mesangial Axl expression. Anti-GBM serum induced severe nephritis with azotemia, protein casts and necrotic cell death. R428 treatment diminished renal Axl expression and improved kidney function, with significantly decreased BUN and glomerular proliferation. R428 treatment inhibited Axl and significantly decreased Akt phosphorylation and renal inflammatory cytokine and chemokine expression; similar effects were observed in anti-GBM antiserum-treated Axl-KO mice. These studies support a role for Axl inhibition in glomerulonephritis.

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Identifying surrogate markers of renal allograft outcome and biomarkers of acute and chronic graft injury is a critical issue for the transplant community. Measurement of serum creatinine and biopsy remain the current gold standards for the evaluation of renal allografts. These tests have significant limitations in predicting which patients are destined for immune tolerance or immune-mediated graft loss, and aiding in the management of long-term immunosuppression. The goal of biomarkers is to diagnose rejection early, determine prognosis and tailor immunosuppressive therapy in a noninvasive, cost-effective manner. Biomarker research has focused on primary areas of kidney injury, the tubules and the cells that infiltrate them. This article reviews biomarkers currently under investigation in the setting of renal allograft transplantation.

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