Kidney injury molecule 1 (KIM-1): a potential biomarker of acute kidney injury and tubulointerstitial injury in patients with ANCA-glomerulonephritis

Abstract

Background: Kidney injury molecule 1 (KIM-1) is a transmembrane glycoprotein expressed by proximal tubular cells, recognized as an early, sensitive and specific urinary biomarker for kidney injury. Blood KIM-1 was recently associated with the severity of acute and chronic kidney damage but its value in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis with glomerulonephritis (ANCA-GN) has not been studied. Thus, we analyzed its expression at ANCA-GN diagnosis and its relationship with clinical presentation, kidney histopathology and early outcomes.

Methods: We assessed KIM-1 levels and other pro-inflammatory molecules (C-reactive protein, interleukin-6, tumor necrosis factor α, monocyte chemoattractant protein-1 and pentraxin 3) at ANCA-GN diagnosis and after 6 months in patients included in the Maine-Anjou registry, which gathers data patients from four French Nephrology Centers diagnosed since January 2000.

Results: Blood KIM-1 levels were assessed in 54 patients. Levels were elevated at diagnosis and decreased after induction remission therapy. KIM-1 was associated with the severity of renal injury at diagnosis and the need for kidney replacement therapy. In opposition to other pro-inflammatory molecules, KIM-1 correlated with the amount of acute tubular necrosis and interstitial fibrosis/tubular atrophy (IF/TA) on kidney biopsy, but not with interstitial infiltrate or with glomerular involvement. In multivariable analysis, elevated KIM-1 predicted initial estimated glomerular filtration rate (β = -19, 95% CI -31, -7.6, P = .002).

Conclusion: KIM-1 appears as a potential biomarker for acute kidney injury and for tubulointerstitial injury in ANCA-GN. Whether KIM-1 is only a surrogate marker or is a key immune player in ANCA-GN pathogenesis remain to be determined.

Keywords: ANCA; KIM-1; glomerulonephritis; tubulointerstitial injury; vasculitis.

Figure 1:

KIM-1 levels in ANCA-GN. (A) KIM-1 levels between ANCA-GN patients and HC. (B) KIM-1 levels at the time of ANCA-GN diagnosis and after induction remission treatment (6 months) (after exclusion of patients without KIM-1 levels assessment at 6 months). (C) KIM-1 levels at the time of ANCA-GN diagnosis and after induction remission treatment (6 months) (after exclusion of patients without KIM-1 levels detectable at diagnosis, and without KIM-1 levels assessment at 6 months).

Figure 2:

KIM-1 levels according to relevant outcomes. (A) Evolution of eGFR overtime. (B) Need for KRT during follow-up. (C) Need for early KRT (within 30 days from diagnosis). (D) Renal survival (ESKD). (E) Patient survival (death).

Figure 3:

Correlation between KIM-1 levels and ANCA-GN presentation. Correlation has been assessed with Spearman method. Correlation coefficient ranges from –1 (dark red) to +1 (dark blue). *P-value <.05. “% normal glom.,” “% crescentic glom.” and “% sclerotic glom.” refer to the amount for glomerular involvement on kidney biopsy. IFTA: interstitial fibrosis/tubular atrophy on kidney biopsy.

Figure 4:

KIM-1 levels and histological lesions found on kidney biopsy. KIM-1 levels according to the severity of ATN (A), the amount of IF/TA (B), the severity of interstitial infiltrate (C), Berden classification (D) and Renal Risk Score (E). IF/TA was scored quantitatively as in the Banff classification [31], and trichotomized in three classes: ≤5%, 5%–25%, >25%. ATN was scored as previously defined [32] (n1 = loss of brush border, n2 = tubular epithelial cells in the lumen, vacuolization of tubular cells, n3 = exposure of basal membranes/epithelial necrosis). Interstitial infiltrate was scored semi-quantitatively as in Banff classification [31] (i1: ≤25%, i2: 25%–50%, i3: ≥50%), without i0 stage because no patients were found with the absence of infiltration.