The significance of histological diagnosis in renal allograft biopsies in 2014

In 2014, the renal allograft biopsy still represents the best available diagnostic ‘gold’ standard to assess reasons for allograft dysfunction. However, it is well recognized that histological lesion observed in the biopsy is of limited diagnostic specificity and that the Banff classification as the international diagnostic standard represents mere expert consensus. Here, we review the role of the renal allograft biopsy in different clinical and diagnostic settings. To increase diagnostic accuracy and to compensate for lack of specificity, the interpretation of biopsy pathology needs to be within the clinical context, primarily defined by time post‐transplantation and patient‐specific risk profile. With this in mind, similar histopathological patterns will lead to different conclusions with regard to diagnosis, disease grading and staging and thus to patient‐specific clinical decision‐making. Consensus generation for such integrated diagnostic approach, preferably including new molecular tools, represents the next challenge to the transplant community on its way to precision medicine in transplantation.     

Inflammation in areas of fibrosis: The DeKAF prospective cohort

Inflammation in areas of fibrosis (i‐IFTA) in posttransplant biopsy specimens has been associated with decreased death‐censored graft survival (DC‐GS). Additionally, an i‐IFTA score ≥ 2 is part of the diagnostic criteria for chronic active TCMR (CA TCMR). We examined the impact of i‐IFTA and t‐IFTA (tubulitis in areas of atrophy) in the first biopsy for cause after 90 days posttransplant (n = 598); mean (SD) 1.7 ± 1.4 years posttransplant. I‐IFTA, present in 196 biopsy specimens, was strongly correlated with t‐IFTA, and Banff i. Of the 196, 37 (18.9%) had a previous acute rejection episode; 96 (49%) had concurrent i score = 0. Unlike previous studies, i‐IFTA = 1 (vs 0) was associated with worse 3‐year DC‐GS: (i‐IFTA = 0, 81.7%, [95% CI 77.7 to 85.9%]); i‐IFTA = 1, 68.1%, [95% CI 59.7 to 77.6%]; i‐IFTA = 2, 56.1%, [95% CI 43.2 to 72.8%], i‐IFTA = 3, 48.5%, [95% CI 31.8 to 74.0%]). The association of i‐IFTA with decreased DC‐GS remained significant when adjusted for serum creatinine at the time of the biopsy, Banff i, ci and ct, C4d and DSA. T‐IFTA was similarly associated with decreased DC‐GS. Of these indication biopsies, those with i‐IFTA ≥ 2, without meeting other criteria for CA TCMR had similar postbiopsy DC‐GS as those with CA TCMR. Those with i‐IFTA = 1 and t ≥ 2, ti ≥ 2 had postbiopsy DC‐GS similar to CA TCMR. Biopsies with i‐IFTA = 1 had similar survival as CA TCMR when biopsy specimens also met Banff criteria for TCMR and/or AMR. Studies of i‐IFTA and t‐IFTA in additional cohorts, integrating analyses of Banff scores meeting criteria for other Banff diagnoses, are needed.     

Banff 2011 Meeting Report: New Concepts in Antibody‐Mediated Rejection

The 11th Banff meeting was held in Paris, France, from June 5 to 10, 2011, with a focus on refining diagnostic criteria for antibody‐mediated rejection (ABMR). The major outcome was the acknowledgment of C4d‐negative ABMR in kidney transplants. Diagnostic criteria for ABMR have also been revisited in other types of transplants. It was recognized that ABMR is associated with heterogeneous phenotypes even within the same type of transplant. This highlights the necessity of further refining the respective diagnostic criteria, and is of particular significance for the design of randomized clinical trials. A reliable phenotyping will allow for definition of robust end‐points. To address this unmet need and to allow for an evidence‐based refinement of the Banff classification, Banff Working Groups presented multicenter data regarding the reproducibility of features relevant to the diagnosis of ABMR. However, the consensus was that more data are necessary and further Banff Working Group activities were initiated. A new Banff working group was created to define diagnostic criteria for ABMR in kidneys independent of C4d. Results are expected to be presented at the 12th Banff meeting to be held in 2013 in Brazil. No change to the Banff classification occurred in 2011.     

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.     

抗体介导的排斥反应与临床

随着器官移植体液免疫理论的发展与抗体检测技术的进步,抗体介导的排斥反应(AMR)已逐渐被认识和引起关注。其治疗难度大、逆转率较低,已成为导致移植物失功的重要原因。本文较为系统地介绍了AMR的免疫机制、诊断与防治进展,以及供者特异性抗体的检测技术和临床意义,从而提出供者特异性抗体是引起移植物排斥反应特别是慢性排斥反应的主要原因,移植受者需常规监测抗体以利及时干预和治疗。     

Diagnosing skin rejection in vascularized composite allotransplantation: advances and challenges

Refinements in microsurgical techniques coupled with advances in immunosuppressive and immunomodulatory protocols have enabled broader clinical application of vascularized composite allotransplantation (VCA) with encouraging immunological, functional, and esthetic results. However, skin rejection remains a significant obstacle and a serious complication for VCA recipients. Clinical and histopathological features of rejection in VCA have been described in a number of studies, which led to the development of an international consensus on the classification guidelines of rejection in the context of VCA. Nevertheless, currently available diagnostic modalities still have several limitations and shortcomings that can pose a significant diagnostic challenge, particularly when signs of rejection are found to be equivocal. In this review, we provide a critical analysis of these advances and challenges in diagnosing skin rejection. Specifically, we highlight the gaps in understanding of rejection mechanisms, the shortfalls in correlating cellular, molecular, and clinicopathologic markers with rejection grades, deficiencies in defining chronic rejection, and antibody‐mediated rejection after VCA, as well as providing an outlook on novel concepts, such as the utilization of advanced computational analyses and cross‐disciplinary diagnostic approaches.     

Clinical significance of isolated v lesions in paediatric renal transplant biopsies: muscular arteries required to refute the diagnosis of acute rejection

Intimal vascular lesions are considered features of acute T‐cell‐mediated rejection yet can occur in the absence of tubulointerstitial inflammation, termed isolated ‘v’ lesions. The clinical significance of these lesions is unclear. The diagnosis requires a biopsy with the presence of arteries. The frequency of adequate biopsies was analysed in 89 renal transplant biopsies from 57 paediatric renal allograft recipients, and the incidence of isolated endarteritis was determined. 60 (67%) biopsies contained an artery and of these, isolated ‘v’ lesions occurred in 6 (10%). 5 (83%) biopsies with isolated ‘v’ lesions were associated with positive DSA, suggesting that these lesions may represent acute antibody‐mediated rejection. Patients with vessel‐negative biopsies had an increased decline in eGFR (median ?20.5, IQR ?24.4 to 1.2 ml/min/1.73 m² vs. ?9.6, IQR ?78.7 to ?6.8 ml/min/1.73 m²; P = 0.01). Patients with vessel‐negative biopsies were more likely to have repeat biopsy for ongoing allograft dysfunction, (25.0% vs. 2.4%; P < 0.01). The data suggest that isolated ‘v’ lesions are more common than previously thought. A significant proportion of biopsies classified as ‘normal’ or ‘borderline change’ in the absence of a large vessel may represent undiagnosed acute rejection. This may result in suboptimal therapy with possible adverse effects on renal outcome.