A New Diagnostic Algorithm for Antibody‐Mediated Microcirculation Inflammation in Kidney Transplants

We studied the significance of microcirculation inflammation in kidney transplants, including 329 indication biopsies from 251 renal allograft recipients, who were mostly nonpresensitized (crossmatch negative). Glomerulitis (g) and peritubular capillaritis (ptc) were often associated with antibody‐mediated rejection (65% and 75%, respectively), but were also found in other diseases in the absence of donor‐specific antibody (DSA): T‐cell‐mediated rejection (ptc, g), glomerulonephritis (g) and acute tubular necrosis (ptc). To develop rules for reducing the nonspecificity of microcirculation inflammation and defining the best grading thresholds associated with DSA, we built and validated a decision tree to predict DSA. The decision tree revealed that g + ptc sum (addition of g‐score plus ptc‐score) was the best predictor of DSA, followed by time posttransplant, then C4d, which had a small role. Late biopsies with g + ptc > 0 showed higher frequency of DSA compared to early biopsies with g + ptc > 0 (79% vs. 27%). Microcirculation inflammation in early biopsies was often false positive (antibody‐independent). The decision tree predicted DSA with higher sensitivity and accuracy than C4d staining. Microcirculation inflammation sum score predicted graft failure independently of time, C4d and transplant glomerulopathy. Thus any degree of microcirculation inflammation in late kidney transplant biopsies strongly indicates presence of DSA and predicts progression to graft failure.

[1]  P. Halloran,et al.  Inflammation Lesions in Kidney Transplant Biopsies: Association with Survival Is Due to the Underlying Diseases , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[2]  X. Jouven,et al.  Significance of C4d Banff Scores in Early Protocol Biopsies of Kidney Transplant Recipients with Preformed Donor‐Specific Antibodies (DSA) , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[3]  R. Munivenkatappa,et al.  Glomerular Inflammation in Renal Allografts Biopsies After the First Year: Cell Types and Relationship With Antibody-Mediated Rejection and Graft Outcome , 2010, Transplantation.

[4]  J. Lunz,et al.  A Critical Appraisal of Methods to Grade Transplant Glomerulitis in Renal Allograft Biopsies , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[5]  K. Famulski,et al.  An Integrated View of Molecular Changes, Histopathology and Outcomes in Kidney Transplants , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[6]  P. Halloran,et al.  NK Cell Transcripts and NK Cells in Kidney Biopsies from Patients with Donor‐Specific Antibodies: Evidence for NK Cell Involvement in Antibody‐Mediated Rejection , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[7]  Jeff Reeve,et al.  A molecular classifier for predicting future graft loss in late kidney transplant biopsies. , 2010, The Journal of clinical investigation.

[8]  M. Stegall,et al.  Significance and Implications of Capillaritis During Acute Rejection of Kidney Allografts , 2010, Transplantation.

[9]  C. Legendre,et al.  Antibody‐Mediated Microcirculation Injury Is the Major Cause of Late Kidney Transplant Failure , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[10]  L C Racusen,et al.  Banff ’09 Meeting Report: Antibody Mediated Graft Deterioration and Implementation of Banff Working Groups , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[11]  P. Halloran,et al.  Cluster Analysis of Lesions in Nonselected Kidney Transplant Biopsies: Microcirculation Changes, Tubulointerstitial Inflammation and Scarring , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[12]  P. Halloran,et al.  Endothelial transcripts uncover a previously unknown phenotype: C4d-negative antibody-mediated rejection , 2010, Current opinion in organ transplantation.

[13]  P. Halloran,et al.  De Novo Donor‐Specific Antibody at the Time of Kidney Transplant Biopsy Associates with Microvascular Pathology and Late Graft Failure , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  E. Thervet,et al.  Outcome of Subclinical Antibody‐Mediated Rejection in Kidney Transplant Recipients with Preformed Donor‐Specific Antibodies , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[15]  G. Jhangri,et al.  Endothelial Gene Expression in Kidney Transplants with Alloantibody Indicates Antibody‐Mediated Damage Despite Lack of C4d Staining , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[16]  G S Jhangri,et al.  Peritubular Capillaritis in Renal Allografts: Prevalence, Scoring System, Reproducibility and Clinicopathological Correlates , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[17]  D. Nochy,et al.  Determinants of Poor Graft Outcome in Patients with Antibody‐Mediated Acute Rejection , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[18]  M. Kamoun C4d and C3d Staining in Biopsies of ABO‐ and HLA‐Incompatible Renal Allografts: Correlation with Histologic Findings , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[19]  D. Kerjaschki,et al.  The Cellular Lesion of Humoral Rejection: Predominant Recruitment of Monocytes to Peritubular and Glomerular Capillaries , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[20]  D. Wishart,et al.  Transplant Glomerulopathy, Late Antibody‐Mediated Rejection and the ABCD Tetrad in Kidney Allograft Biopsies for Cause , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[21]  O. Djurdjev,et al.  Glomerular monocytes predict worse outcomes after acute renal allograft rejection independent of C4d status. , 2005, Kidney international.

[22]  A. Magil Infiltrating cell types in transplant glomerulitis: relationship to peritubular capillary C4d deposition. , 2005, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[23]  S. Cramer,et al.  International variation in histologic grading is large and persistent feedback does not improve reproducibility. , 2004, The American journal of surgical pathology.

[24]  T. Larson,et al.  Overcoming a Positive Crossmatch in Living‐Donor Kidney Transplantation , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[25]  M. Fishbein,et al.  Antibody‐Mediated Rejection Criteria – an Addition to the Banff ′97 Classification of Renal Allograft Rejection , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[26]  A. Magil,et al.  Monocytes and peritubular capillary C4d deposition in acute renal allograft rejection. , 2003, Kidney international.

[27]  R. Colvin,et al.  Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification. , 2002, Journal of the American Society of Nephrology : JASN.

[28]  A. Zachary,et al.  Cohort study of the prognostic significance of acute transplant glomerulitis in acutely rejecting renal allografts. , 2001, Transplantation.

[29]  R. Colvin,et al.  Chronic humoral rejection: identification of antibody-mediated chronic renal allograft rejection by C4d deposits in peritubular capillaries. , 2001, Journal of the American Society of Nephrology : JASN.

[30]  H. E. Hansen,et al.  The Banff 97 working classification of renal allograft pathology. , 1999, Kidney international.

[31]  P. Halloran,et al.  Pathologic features of acute renal allograft rejection associated with donor-specific antibody, Analysis using the Banff grading schema. , 1996, Transplantation.

[32]  G. Riethmüller,et al.  Vascular deposition of complement‐split products in kidney allografts with cell‐mediated rejection , 1991, Clinical and experimental immunology.

[33]  G. Einecked,et al.  Banff 07 Classification of Renal Allograft Pathology : Updates and Future Directions , 2008 .

[34]  P. Halloran,et al.  The significance of the anti-class I antibody response. I. Clinical and pathologic features of anti-class I-mediated rejection. , 1990, Transplantation.