Evaluation of CD68⁺ macrophages in relation to kidney outcomes in immunoglobulin light-chain amyloidosis.

Abstract

The clinical course of systemic amyloidosis reflects the equilibrium between amyloid deposition and clearance, which varies across disease contexts. The mechanisms underlying amyloid clearance in vivo remain unclear, though experimental data implicate macrophage-mediated phagocytosis. Here we evaluated the impact of CD68⁺ macrophage infiltration in diagnostic kidney biopsies on kidney outcomes in immunoglobulin light-chain amyloidosis (AL) and examined the prognostic value of amyloid regression among patients with deep hematological response following chemotherapy. Kidney biopsies from 708 consecutive patients with kidney AL treated at the United Kingdom National Amyloidosis Centre between 2000-2022 and achieved a deep and sustained hematologic response to chemotherapy were retrospectively stained with anti-CD68 antibody. Macrophage infiltration was scored on a scale of 0-3 and the relationship between macrophage score, interstitial fibrosis and tubular atrophy (IFTA) and kidney survival was evaluated. Among 396 patients in the cohort who had serial serum amyloid P component (SAP) scans at diagnosis and at two-years of follow-up, the relationship between change in amyloid burden and long-term kidney outcomes was characterized. At five years, cumulative incidence of renal replacement therapy (RRT) was 14%, 22%, 40%, and 52% across macrophage scores 0-3 respectively. On multivariable Cox regression analysis, each one-point macrophage score increase independently and significantly predicted higher risk of RRT (hazard ratio 1.31, 95% confidence interval 1.09-1.56) alongside baseline estimated glomerular filtration rate, proteinuria, and IFTA. In two-year landmark analysis, amyloid accumulation by SAP scintigraphy conferred a significant nine-fold increased risk of RRT versus amyloid regression (9.44, 3.25-27.39) Hematologic complete response was strongly associated with amyloid regression and prolonged renal survival. In AL amyloidosis, kidney CD68⁺ macrophage infiltration at diagnosis is independently associated with risk of progression to RRT even among patients with deep hematologic response. Regression of amyloid is associated with prolonged kidney survival. These findings highlight kidney CD68⁺ macrophage infiltration and subsequent SAP-defined amyloid regression as complementary predictors of kidney outcome in AL amyloidosis.