Glomerular macrophage index (GMI) in kidney transplant biopsies is associated with graft outcome

Abstract

Background: Macrophages in renal transplants have been shown to participate in antibody-mediated rejection and are associated with impaired renal function. We calculated the glomerular macrophage index (GMI) in a large transplant biopsy cohort, studied its quantity in different diagnostic groups, to clarify its possible impact on graft survival.

Methods: GMI, defined as the mean number of macrophages in 10 glomeruli, was prospectively quantified in 1440 renal transplant biopsies over a 10-year period. The main histopathological diagnoses were grouped into eight disease entities, and GMI was compared to normal transplant biopsies as the reference group. The impact of GMI on graft survival was analyzed.

Results: GMI was highest in chronic (mean 9.4) and active (9.7) antibody mediated rejections (ABMR), mixed rejections (7.6), and recurrent or de novo glomerulonephritis (7.5) and differed significantly from normal transplants (1.3) in almost all diagnostic groups. Hazard ratios for graft loss were significantly increased for all biopsies with GMI ≥1.9 compared to GMI < .5 (reference group) in an adjusted Cox regression model and increased with higher GMI levels. Biopsies with GMI ≥ 4.6 had < 60% 10-year graft-survival, compared to > 80% with GMI ≤ 1.8.

Conclusion: GMI levels were predictive of graft loss independent of histological diagnoses and may guide clinicians to decide follow-up and therapy.

Keywords: glomerular macrophage index; graft outcome; macrophage; rejection; renal transplant biopsies.

FIGURE 1

Light microscopy of CD68 positive macrophages in glomeruli. Light microscopy showing CD68 positive monocytes/macrophages in the glomeruli. (A) Biopsy with a low number of positive cells (n = 2) in the glomerular capillaries. (B) Biopsy specimen with a high number of positive cells (n = 28). Arrows = immune‐positive cells, arrowheads = cell fragments or processes not identified as positive cells. Bar = 100 micrometer

FIGURE 2

Range of GMI‐levels for different diagnostic groups. The different diagnostic groups are shown in Table 1. Extremely high GMI levels (>25) were leaved out of the figure to improve the visibility of the median levels in the groups.

FIGURE 3

Kaplan‐Meier estimates of death‐censored graft survival after biopsy, according to GMI‐levels at biopsy. Increasing levels of GMI showed a statistically significant association with worse graft outcomes. Low levels (<1.9) have a 10‐year graft survival of >80%, intermediate levels (1.9–4.5) have a graft survival around 70%, and GMI ≥ 4.6 have a 10‐year graft survival between 50% and 60%. Further, a GMI ≥ 4.6 predict poor graft survival already 1 year after biopsy

FIGURE 4

GMI‐levels at different biopsy times after transplantation. The figure shows that GMI increased with time after transplantation but was high in the first month after transplantation. There were statistically significant differences between the GMI levels at different time points after transplantation (p < .01)