The Significance Of Glomerular Macrophage In IgA Nephropathy With Endocapillary Hypercellularity

IgAN is diagnosed by the presence of dominant or co-dominant IgA deposits within mesangium,and is the most common primary glomerulonephritis and an important cause of end-stage renal disease in China.Patients with IgAN have diverse clinicopathological manifestations and poor prognosis.In order to accurately predict the prognosis of the disease,the international nephrologist group proposed the pathological MEST of Oxford classification based on evidence in 2009.Endocapillary hypercellularity(E)is associated with disease progression and represents a poor prognosis in patients w-ho not treated with immunosuppressive agents,which defined as increased number of cells in glomerular capillaries that resulted in capillary luminal narrowing.Obviously this definition is subjective so that E score suffered from poor to moderate reproducibility even among experienced hands and its use in clinical and research is limited.Therefore,a study proposed to replace E with the objective number of glomerular macrophage,and found that E lesion is correlated with glomerular macrophages and macrophages could be used to evaluate the presence or absence of E lesions.However,this study is limited by its small sample size of patients with E lesion.The number of infiltrating glomerular inflammatory cells are generally small,and macrophages are the main type of infiltrating cells.However,there are few related studies and the sample size is also small.The aim of this study is to investigate the infiltrating macrophages in the glomeruli and the correlation between glomerular macrophages and E lesion.Whether glomerular macrophage number,which is a more objective,more reproducible and robust parameter,is conducive to determine E.In addition,the clinicopathological and prognostic characteristics and potential pathogenesis of in IgAN with massive glomerular macrophages infiltration were explored.Part 1 Glomerular macrophage for the evaluation of endocapillary hypercellularity in IgA nephropathyBackground and objectiveEndocapillary hypercellularity(E),which has been identified by the Oxford classification as one of histologic lesions that bear therapeutic and prognostic significance in IgA nephropathy(IgAN),suffers from poor reproducibility caused the limitation in clinical practice.We aimed to explore whether the number of glomerular macrophage is conducive to the determination of E score.MethodA total of 62 patients with IgAN-El and 75 patients with IgAN-EO were retrospectively selected.Immunohistochemistry against CD68 was performed in biopsy samples to identify macrophages.The relationships between the mean glomerular macrophage number and clinicopathological features were analyzed by Pearson's rank correlation or Spearman's rank correlation.The diagnostic efficacy of the mean numbers and the maximal numbers of glomerular macrophages for differentiating E1 from EO was evaluated and compared by receiver operating characteristics(ROC)curve.ResultsAn increased glomerular macrophages were found in IgAN patients with E,crescents(C),necrosis(N)compared with those without(respectively 4.2(2.3-6.0),2.4(1.1-4.4),3.1(1.8-5.5)cells/glomerulus).The mean number of glomerular macrophages was significantly associated with E%(r=0.725,P<0.000);modestly with mesangial hypercellularity,C and N lesion(respectively r=0.199,P=0.02;r=0.205,P=0.016;r=0.284,P=0.001);but not with segmental glomerulosclerosis,tubular atrophy and interstitial fibrosis.Additionally,both the mean numbers of glomerular macrophages and E%were associated with proteinuria and hematuria but not renal function.The mean glomerular macrophage was relatively superior to the maximal glomerular macrophage(area under the curve 0.904 vs.0.87;sensitivity 98.4%vs.82.3%;specificity 74.7%vs.72.0%;P=0.096)for differentiating El from E0.ConclusionGlomerular macrophage numbers are strongly positive associated with endocapillary hypercellularity in IgAN.The glomerular macrophage number is helpful for the determination of E with high diagnostic efficacy.Part 2 IgA nephropathy with endocapillary hypercellularity and massive macrophage infiltrationBackground and objectiveMassive glomerular macrophage infiltration is a rare histologic feature in IgA nephropathy with endocapillary hypercellularity(IgAN-E).We aimed to characterize the clinicopathological features and outcome of these cases and to explore its potential pathogenesis.MethodThe 95th percentile of the mean number of glomerular CD68+ cells from 62 IgAN-E cases was defined as the threshold of massive macrophage infiltration.Patients with biopsies that met the threshold were enrolled as the study group and those whose biopsies did not met were included as the control group.Clinicopathological features and follow-up data were evaluated in both groups.Immunohistochemical staining was performed with the cell biomarker of CD68,iNOS,CD163,CD3 and CD20.Abnormal glycosylated IgA1(Gd-IgA1)was immunofluorescently stained with KM55,and overlapped with IgA.ResultsThe median number of glomerular CD68+ cells in 62 IgAN-E patients was 4.2(2.3-6.1)cell/glomerulus,with 95th percentile of 14.A total of 38 patients were enrolled in the case group,including 17 males and 21 females;the mean age was 36±17 years.Compared with 59 control group,patients in the study group showed significantly higher proteinuria,cholesterol,and triglyceride,lower albumin levels,increased E%but less glomerulosclerosis,tubular atrophy and interstitial fibrosis at time of renal biopsy(all P<0.05);higher percentage of immunosuppressive treatment(90%vs 42%,P<0.001)and worse renal prognosis(P=0.002)during follow-up.The glomerular infiltrating inflammatory cells in the study group were mainly CD68' and CD 163+ cells(M2 macrophages),which both were positively correlated with E%but not renal function.The co-localization of KM55 and IgA in the renal samples of the two groups confirmed that the IgA deposit in glomeruli was Gd-IgA1.ConclusionIgAN-E with massive glomerular macrophage infiltration patients have distinctive clinicopathological features,showing a more active clinicopathological findings and worse renal prognosis as compared those without.