Search

Background: Antibody‐mediated rejection (AMR) often leads to chronic kidney allograft damage and is a critical cause of allograft failure. The Banff classification, used to diagnose AMR, has become complex and challenging for clinicians. A Banff‐based histologic chronicity index (CI) was recently proposed as a simplified prognostic indicator. Its reliability and reproducibility have not been externally validated. Methods: This study investigated 71 kidney allograft biopsies diagnosed with AMR. Interobserver reproducibility of the recently proposed CI and its components (cg, cv, ct, and ci) were assessed. The association between CI and allograft failure was analyzed, and CI cut‐off values were evaluated by Cox proportional hazards regression and Kaplan–Meier estimator with log‐rank test. Results: The study confirmed the association of CI with allograft failure, but also revealed that the assessment of CI varied between pathologists, impacting its reproducibility as a prognostic tool. Only 49 (69.0%) of the biopsies showed complete agreement on the proposed cut‐off value of CI < 4 or CI ≥ 4. Furthermore, this cut‐off did not reliably stratify allograft failure. Notably, the cg score, which carries significant weight in the CI calculation, had the lowest agreement between observers (kappa =.281). Conclusions: While a simplified prognostic indicator for AMR is needed, this study highlights the limitations of CI, particularly its poor interobserver reproducibility. Our findings suggest that clinicians should interpret CI cautiously and consider establishing their own cut‐off values. This study underscores the need to address interobserver reproducibility before CI can be widely adopted for AMR management. [ABSTRACT FROM AUTHOR]

Prolonged survival in preclinical renal xenotransplantation demonstrates that early antibody mediated rejection (AMR) can be overcome. It is now critical to evaluate and understand the pathobiology of late graft failure and devise new means to improve post xenograft outcomes. In renal allotransplantation the most common cause of late renal graft failure is transplant glomerulopathy—largely due to anti‐donor MHC antibodies, particularly anti‐HLA DQ antibodies. We evaluated the pig renal xenograft pathology of four long‐surviving (>300 days) rhesus monkeys. We also evaluated the terminal serum for the presence of anti‐SLA class I and specifically anti‐SLA DQ antibodies. All four recipients had transplant glomerulopathy and expressed anti‐SLA DQ antibodies. In one recipient tested for anti‐SLA I antibodies, the recipient had antibodies specifically reacting with two of three SLA I alleles tested. These results suggest that similar to allotransplantation, anti‐MHC antibodies, particularly anti‐SLA DQ, may be a barrier to improved long‐term xenograft outcomes. [ABSTRACT FROM AUTHOR]

Chronic antibody‐mediated rejection of kidney transplantation is a major cause of late‐stage graft loss. Donor‐specific antibodies are the main cause of antibody‐mediated rejection; in particular, de novo donor‐specific antibodies are a risk factor for chronic active antibody‐mediated rejection. The level of de novo donor‐specific antibodies tends to increase with time throughout long‐term graft survival. Donor‐specific antibodies induce humoral rejection through complement activation, which results in tissue injury and coagulation. Additionally, complement activation promotes the migration of inflammatory cells through the innate immune response, causing endothelial injury. This inflammatory response may cause persistent glomerulitis and peritubular capillaritis, leading to fixed pathological lesions that impair graft function. No treatment has been established for chronic antibody‐mediated rejection, a condition in which antibody‐mediated rejection becomes irreversible. Thus, antibody‐mediated rejection must be detected and treated while it is still reversible. In this review, we discuss the development of de novo donor‐specific antibodies and the mechanisms leading to chronic antibody‐mediated rejection and summarize the current treatment options and the latest biomarkers for detecting chronic antibody‐mediated rejection at an earlier stage. [ABSTRACT FROM AUTHOR]

With the development of organ transplantation in clinical practice, allograft pathology has been constantly developing and advancing. The convening of Banff conference on allograft pathology and the establishment of Banff classification on allograft pathology (Banff classification) are pivotal milestones in the development of international allograft pathology. Since then, Banff classification on pathological diagnosis of various transplant organs have been continually updated and improved. Ultrastructural pathological observation by electron microscope plays an irreplaceable role in the early diagnosis of antibody-mediated rejection, recurrent disease and de novo disease of renal allograft. Early detection and rational treatment help to maintain the long-term survival of renal allograft and reduce the failure of renal allograft. In this article, the basic definition of electron microscope and the ultrastructural pathological diagnosis, the research history and main progress on electron microscope diagnosis on Banff classification for renal allograft pathology were introduced, and typical pathological changes, specific terminology and diagnostic criteria of electron microscope diagnosis on renal allograft biopsy were summarized, aiming to provide reference for clinical and basic research of organ transplantation. [ABSTRACT FROM AUTHOR]

There have been recent significant advances in short‐term outcomes in renal transplantation, however, long‐term allograft survival remains a challenge. With reported incidences as high of 74.5% of chronic graft loss in patients with biopsies showing transplant glomerulopathy (TG), this syndrome represents an important factor for chronic allograft complications. In this review we show an overview of the novel mechanistic insights into pathogenesis of TG, as well as a brief description of the pathology, diagnosis and newer prognostic indices within TG diagnosis. These data raise intriguing roles for cell‐mediated immunity and podocyte stress in TG as well as reinforce previous associations of TG with ABMR. We also delve into management strategies for TG and report the paucity of existing clinical trial data for this prevalent condition in renal transplants. [ABSTRACT FROM AUTHOR]

Summary: Proteinuria and transplant glomerulopathy (TG) are common in kidney transplantation. To date, there is limited knowledge regarding proteinuria in different types of TG and its relationship to allograft survival. A retrospective cohort analysis of TG patients from indication biopsies was performed to investigate the relationship of proteinuria, histology, and graft survival. One hundred and seven (57.5%) out of 186 TG patients lost their grafts with a median survival of 14 [95% confidence interval (CI) 10–22] months after diagnosis. Proteinuria ≥1 g/24 h at the time of biopsy was detected in 87 patients (46.8%) and the median of proteinuria was 0.89 (range 0.05–6.90) g/24 h. TG patients with proteinuria ≥1 g/24 h had worse 5‐year graft survival (29.9% vs. 53.5%, P = 0.001) compared with proteinuria <1 g/24 h. Proteinuria was associated with graft loss in univariable Cox regression [hazard ratio (HR) 1.25, 95% CI, 1.11–1.41, P < 0.001], and in multivariable analysis (adjusted HR 1.26, 95% CI 1.11–1.42, P < 0.001) independent of other risk factors including creatinine at biopsy, positive C4d, history of rejection, and Banff lesion score mesangial matrix expansion. In this cohort of TG patients, proteinuria at indication biopsy is common and associated with a higher proportion of graft loss. [ABSTRACT FROM AUTHOR]

Introduction: Chronic active antibody‐mediated rejection (cAMR) is a major determinant of late allograft failure. Rituximab/immunoglobulins (IVIg) + plasma exchange (PLEX) showed controversial results in cAMR treatment. Tocilizumab (TCZ), a humanized anti‐interleukin 6 receptor antibody, has been recently used as rescue therapy in patients non‐responsive to rituximab/IVIg/PLEX with favorable outcomes. Whether TCZ acts "per se" or requires a priming effect from previous treatments is currently unknown. Methods: Fifteen patients with cAMR were treated with TCZ as a first‐line therapy and followed for a median time of 20.7 months. Results: Despite the majority of patients experiencing advanced transplant glomerulopathy (TG) at diagnosis (60% with cg3), glomerular filtration rate and proteinuria stabilized during the follow‐up, with a significant reduction in donor‐specific antibodies. Protocol biopsies after 6 months demonstrated significant amelioration of microvascular inflammation and no TG, C4d deposition, or IF/TA progression. Gene‐expression and immunofluorescence analysis showed upregulation of three genes (TJP‐1, AKR1C3, and CASK) involved in podocyte, mesangial, and tubular restoration. Conclusion: Tocilizumab adopted as a first‐line approach in cAMR was associated with early serological and histological improvements and functional stabilization even in advanced TG, suggesting a role for the use of TCZ alone with the avoidance of unnecessary previous immunosuppressants. [ABSTRACT FROM AUTHOR]

Background Peritubular capillaritis (ptc), reported by the ptc score, is a major feature of kidney allograft rejection and microvascular inflammation (MVI). MVI sum scores (ptc + glomerulitis score ≥2) are accepted diagnostic surrogates of human leucocyte antigen (HLA)–antibody interaction. However, low-grade inflammation is common and ptc scores (number of leucocytes/capillary) may not mirror all aspects of ptc morphology. Recently we observed a relationship of the diffuse extent of ptc (inflammation of >50% of the renal cortex) with graft loss and significantly higher donor-specific antibody levels, suggesting potential inclusion of diffuse ptc as an additional surrogate of antibody–antigen interaction. Methods We sought to assess how a combination of ptc score and extent in low-grade inflammation (ptc1) affects transplant glomerulopathy (TG) and graft loss risk. Patients (n  = 616) were assessed for MVI in first indication biopsies. Cases with a ptc score of 1 but diffuse extent (ptc1diffuse, g-score = 0, n  = 26) were considered additional surrogates of HLA–antibody interaction and compared with MVI ≥2 and MVI <2. Results The ptc1diffuse and MVI score ≥2 subjects had worse graft survival (42% and 59%) compared with an MVI score <2 (70%) (P = 0.002). The incorporation of ptc1diffuse in the MVI score ≥2 increased the receiver operating characteristics curve for TG [area under the curve (AUC) 0.602; P = 0.008] compared with a Banff MVI score ≥2 (AUC 0.56; P = 0.12); cases with baseline TG were excluded. In multivariate analysis, ptc1diffuse remained independently related to TG (odds ratio 3.89; P = 0.008) and graft loss (hazard ratio 2.64; P = 0.001) even after inclusion of all rejection episodes. Conclusion An integrated view of ptc morphology including diffuse ptc in MVI is superior for TG and graft loss risk assessment. [ABSTRACT FROM AUTHOR]

Background/Aims: We aimed to explore the associations between clinical parameters and long-term allograft outcomes in transplant glomerulopathy (TG) in a large retrospective cohort with long follow-up. Methods: Clinical and laboratory data at biopsy from 180 cases of TG with an estimated glomerular filtration rate (eGFR)> 15ml/min/1.73m2 from January 2004 to December 2016 at our center were retrospectively analyzed. The main outcome of this study was initiation of replacement therapy or an eGFR declined to < 15 ml/min/1.73m2. Results: During a median follow-up of 5 years (interquartile range 2.6-8.2 years), 117 cases (65.0%) achieved the combined event. Kaplan-Meier method yielded the 1-year and 5-year cumulative renal allograft survival rates after a histopathologic diagnosis of TG were 84% (95% confidence interval [CI] 81-87%) and 33% (95% CI 27–39%) respectively. In univariate analysis, allograft outcome differed significantly by eGFR, proteinuria, blood hemoglobin level, urinary retinol-binding protein (urRBP) and urinary N-acetyl-β-D-glucosaminidase (urNAG) level at the time of biopsy. Multivariate Cox analysis revealed that a higher level of eGFR was the most powerful predictor of allograft survival. Compared with those with eGFR≥60, the hazard ratio (HR) increased from 4.50 (95% CI: 1.03-19.71, p=0.0462) for patients with eGFR between 30 and 59 ml/min/1.73m2 to 9.14 (95% CI 1.97-42.45, P=0.0047) when eGFR decreased to 15 to 29 ml/min/1.73m2. Additionally, proteinuria and higher urRBP values (≥2.85mg/dl) were found to confer much worse survival rates for TG patients in multivariate Cox analysis. Male sex (HR 0.48, P=0.02) and HCV infection (HR 1.78, P=0.0499) were also found to be independent risk factors for worse allograft survival. Conclusion: Five clinical features—impaired renal function, higher proteinuria, higher urRBP level, male sex and HCV infection—are independent predictors of an unfavorable renal allograft outcome. urRBP is a simple and useful parameter that can add invaluable information for the clinical follow-up of patients with TG. [ABSTRACT FROM AUTHOR]

Chronic-active antibody-mediated rejection (CAABMR) is associated with poor kidney graft survival and has no clear effective treatment. Forty-one cases of CAABMR were detected in indication graft biopsies and evaluated according to current Banff classification. We investigated the impact of concurrent donor-specific antibodies (DSA) and their characteristics, together with non-adherence regarding immunosuppression on CAABMR histopathological phenotypes and prognosis. Twenty-four (59%) patients had detectable DSA at biopsy, with 15 of them being considered non-adherent. Graft function at biopsy was similar in DSA (+) and (−) patients. DSA (+) patients had significantly higher tubulointerstitial inflammation (i and ti) and acute humoral (g+ptc+v+C4d) composite score than DSA (−). DSA (+)/non-adherent cases presented additionally with increased microvascular inflammation (ptc and v), besides having a distinctively lower ah score. C1q DSA strength was higher ( P  = .046) in non-adherent patients and correlated closely with C4d score ( P  = .002). Lower graft function and ah score, higher proteinuria and ci + ct score, and, separately per each model, DSA (+) (HR = 2.446, P  = .034), DSA (+)/non-adherent (HR = 3.657, P  = .005) and DSA (+)/C1q (+) (HR = 4.831, P  = .003) status were independent predictors of graft failure. CAABMR with concomitant DSA pose a higher risk of graft failure. Adherence should be evaluated, and histopathological phenotyping and DSA characterization may add critical information. [ABSTRACT FROM AUTHOR]

Background Immune responses to tissue-restricted self-antigens are thought to play a role in chronic rejection after solid organ transplantation. De novo development of antibodies (Abs) to vimentin have been reported to be associated with interstitial fibrosis/tubular atrophy after kidney transplant, and it has been suggested that immunoglobulin isotype switching of Abs to vimentin may occur during this process. We aimed to determine the correlation between immunoglobulin isotype switching of Abs to vimentin and development of transplant glomerulopathy (TG) after kidney transplant, and to determine whether citrullinated modification of vimentin is required for de novo anti-vimentin development. Methods Sera were collected from 24 patients with TG (diagnosed on biopsy), 24 matched stable kidney transplant recipients (KTxRs) and 22 normal healthy subjects who did not undergo transplant. Serum vimentin Abs concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Immunoglobulin isotypes of anti-vimentin were determined using isotype-specific Abs conjugated with horseradish peroxidase. Samples were considered positive to vimentin Abs if the values were above mean + 2 × standard deviations of the levels in the healthy control subjects. Specificities of anti-vimentin for mutated citrullinated vimentin and anti-mutated citrullinated vimentin were measured by ELISA. Results In this retrospective analysis of 24 KTxRs with TG, 16/24 (67%) patients with biopsy-proven TG developed Abs to vimentin (645 ± 427 ng/ml). In contrast, only 4/24 (17%) stable KTxRs had detectable Abs to vimentin (275 ± 293 ng/ml; p = 0.001). Of the patients with TG, 15/24 (63%) developed Abs to vimentin of IgG isotype (572 ± 276 ng/ml), whereas only 6/24 (25%) stable KTxRs (310 ± 288 ng/ml) had anti-vimentin of IgG isotype (p = 0.002). However, no significant difference was noted in the concentration of IgM isotype anti-vimentin between KTxRs with TG (9/24 [38%], 407 ± 401 ng/ml) and stable KTxRs (5/24 [21%], 348 ± 439 ng/ml; p = 0.631). The serum concentration of Abs specific for the mutated form of citrullinated vimentin was not significantly different between KTxRs with TG and stable KTxRs. Conclusions Patients with biopsy-proven TG demonstrated significantly increased levels of anti-vimentin Abs of the IgG isotype compared with stable KTxRs. Anti-vimentin in stable KTxRs was primarily of IgM isotype. Therefore, the observed isotype switching of anti-vimentin from IgM to IgG isotype strongly suggests ongoing immune responses to vimentin in KTxRs diagnosed with TG. Furthermore, as opposed to patients with rheumatoid arthritis (who develop immune responses primarily to citrullinated vimentin), KTxRs diagnosed with TG developed immune responses to non-citrullinated vimentin, suggesting that modification of vimentin protein via citrullination is not required for the de novo anti-vimentin response seen in patients with TG. [ABSTRACT FROM AUTHOR]

Pediatric renal transplant recipient survival continues to improve, but ABMR remains a significant contributor to graft loss. ABMR prognostic factors to guide treatment are lacking. C4d staining on biopsies, diagnostic of ABMR, is associated with graft failure. Persistent C4d+ on follow-up biopsies has unknown significance, but could be associated with worse outcomes. We evaluated a retrospective cohort of 17 pediatric renal transplant patients diagnosed with ABMR. Primary outcome at 12 months was a composite of ≥50% reduction in eGFR, transplant glomerulopathy, or graft failure. Secondary outcome was the UPCR at 12 months. We used logistic and linear regression modeling to determine whether persistent C4d+ on follow-up biopsy was associated with the outcomes. Forty-one percent reached the primary outcome at 12 months. Persistent C4d+ on follow-up biopsy occurred in 41% and was not significantly associated with the primary outcome, but was significantly associated with the secondary outcome (estimate 0.22, 95% CI 0.19-0.25, P < .001), after controlling for confounding factors. Persistent C4d+ on follow-up biopsies was associated with a higher UPCR at 12 months. Patients who remain C4d+ on follow-up biopsy may benefit from more aggressive or prolonged ABMR treatment. [ABSTRACT FROM AUTHOR]

Peritubular capillary C4d (ptc-C4d) usually marks active antibody-mediated rejection, while pseudolinear glomerular capillary C4d ( GBM-C4d) is of undetermined diagnostic significance, especially when seen in isolation without concurrent ptc-C4d. We correlated GBM-C4d with structural GBM abnormalities and active antibody-mediated rejection in 319 renal transplant and 35 control native kidney biopsies. In kidney transplants, ptc-C4d was associated with GBM-C4d in 97% by immunofluorescence microscopy ( IF) and 61% by immunohistochemistry ( IHC; P < 0.001). Transplant glomerulopathy correlated with GBM-C4d ( P < 0.001) and presented with isolated GBM-C4d lacking ptc-C4d in 69% by IF and 40% by IHC. Strong isolated GBM-C4d was found post year-1 in repeat biopsies with transplant glomerulopathy. GBM-C4d staining intensity correlated with Banff cg scores (rs = 0.45, P < 0.001). Stepwise exclusion and multivariate logistic regression corrected for active antibody-mediated rejection showed significant correlations between GBM duplication and GBM-C4d ( P = 0.001). Native control biopsies with thrombotic microangiopathies demonstrated GBM-C4d in 92% ( IF, P < 0.001) and 35% ( IHC). In conclusion, pseudolinear GBM-C4d staining can reflect two phenomena: (i) structural GBM changes with duplication in native and transplant kidneys or (ii) active antibody-mediated rejection typically accompanied by ptc-C4d. While ptc-C4d is a dynamic 'etiologic' marker for active antibody-mediated rejection, isolated strong GBM-C4d can highlight architectural glomerular remodelling. [ABSTRACT FROM AUTHOR]

Transplant glomerulopathy is mainly due to chronic antibody-mediated rejection and actually represents a major cause of long-term allograft failure. The lack of effective treatment remains a serious problem in transplantation. A retrospective and uni-center study was performed in 48 kidney allograft recipients with transplant glomerulopathy between January 2010 and December 2015. Median time for diagnosis was 7.1 (3.6-11.8) years post-transplant. Light microscopy showed severity of transplant glomerulopathy in the majority of patients (cg1=10.4%; cg2=20.8%; cg3=68.8%). Moderate microvascular inflammation was present in 56.3% (g+ptc≥2), and almost half of recipients (51.1%) were C4d positive in immunofluorescence. Female gender ( P=.001), age ( P=.043), renal dysfunction ( P=.002), acute rejection episodes ( P=.026), and anti- HLA class II antibodies ( P=.004) were associated with kidney allograft failure. Treatment of transplant glomerulopathy was performed in 67.6% of patients. The histologic and laboratory features that led to a therapeutic intervention were score ptc ( P=.021), C4d ( P=.03), and the presence of anti- HLA antibodies ( P=.029), whereas score ah ( P=.005) was associated with conservative measure. The overall cumulative kidney allograft survival at 10 years was 75%. Treatment of transplant glomerulopathy was ineffective to improve long-term kidney allograft survival. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Chronic antibody mediated rejection (CAMR) is a major therapeutic challenge for achieving long-term graft survival; treatment options are limited to several anti-humoral interventions. MATERIAL and METHODS: Efficacy of rituximab combination therapy was retrospectively investigated by comparison with a historical control group for allograft function at six month and overall graft survival/dysfunction. The inclusion criterion was biopsy proven chronic AMR according to the Banff 2007 classification. Nineteen patients found eligible, rituximab group had nine patients (rituximab, plasmapheresis and low dose IVIG); control group had ten recipients. Predictive factors for graft failure also investigated according to Banff scores and renal functions. RESULTS: None of the outcomes were exposed significant efficacy of rituximab, although better treatment response at sixth month (55% vs. 40%, p=0.51), fewer overall graft failures (33% vs. 60%, p=0.25) and dysfunctions (66% vs. 80%, p=0.52). Overall, 47% of patients suffered graft failure. Advanced transplant glomerulopathy was found in 90% of biopsies (all scored ≥2). Peritubular capillaritis score (1.67±0.87 vs. 0.70±0.94, p=0.04) and interstitial inflammation score (1.78±0.44 vs. 1.00±0.47, p=0.004) were significantly higher in recipients who suffered graft failure. CONCLUSION: Rituximab could not sufficiently prevent further deterioration of allograft and failed to improve allograft survival in CAMR, especially after settlement of the irreversible transplant glomerulopathy. [ABSTRACT FROM AUTHOR]

Desensitization with intravenous immunoglobulin (IVIG) and rituximab can improve transplantation rates in broadly sensitized kidney transplant recipients. However, long-term outcomes are lacking. Here we analyze long-term outcomes in living donor kidney transplant recipients desensitized with this regimen and compare them to low-risk recipients. Living donor kidney transplants that took place between July 2006 and December 2010 were considered retrospectively. The primary end point of the study was death-censored allograft survival at last follow-up. Secondary end points included patient survival, incidence of rejection, glomerular filtration rate (GFR), and proteinuria. There were 66 sensitized and 111 lowrisk patients included. Average follow-up was 68 months. There was no difference in long-term patient or graft survival. The rate of rejection was similar in the groups with more early rejection in the sensitized group and more late rejection in the low-risk group. There was more antibodymediated rejection in the sensitized group. Estimated GFR was similar during the follow-up period. Risk factors for rejection included a positive cross-match (HR: 2.4 CI: 1.35-4.40) and age (HR: 0.97 CI: 0.95-0.99). Desensitization with IVIG and rituximab has good long-term results with graft outcomes similar to non-HLA-sensitized patients despite higher immunologic risk. [ABSTRACT FROM AUTHOR]

The low sensitivity of C4d immunoreactivity in peritubular capillaries ( PTCs) hinders its use in the diagnosis of chronic active antibody-mediated rejection ( CAAMR). C4d-negative CAAMR was defined in the 2013 Banff classification, which included the expression of endothelial-associated transcripts ( ENDATs). We previously showed that the ENDAT caveolin-1 ( CAV-1) is a distinct feature of CAAMR. In this study, we investigated the prognostic value of CAV-1 immunoreactivity in PTCs in kidney transplant patients. Ninety-eight kidney transplant recipients were included in this study. The prognostic value of CAV-1 immunoreactivity in PTCs was evaluated by double immunostaining for CAV-1 and pathologische Anatomie Leiden endothelium ( PAL-E, a PTC marker) in the PTCs of kidney allograft biopsy samples. The patients were divided into two groups: CAV-1/ PAL-E<50% and CAV-1/ PAL-E≥50%. Kaplan-Meier curves showed that CAV-1/ PAL-E≥50% patients had a significantly worse prognosis than that of CAV-1/ PAL-E<50% patients (log-rank; P<.001). C4d staining of PTCs was not associated with the development of graft failure (log-rank; P=.345), whereas in a multivariate Cox regression analysis, CAV-1 immunoreactivity in PTCs was independently associated with graft failure (hazard ratio: 11.1; P=.0324). CAV-1 immunoreactivity in PTCs may serve as a prognostic marker for kidney allograft survival. [ABSTRACT FROM AUTHOR]

Transplant glomerulopathy (TG) is generally accepted to result from repeated episodes of endothelial activation, injury and repair, leading to pathological abnormalities of double contouring or multi-layering of the glomerular basement membrane. TG is a major sequel of chronic active antibodymediated rejection (cABMR), from pre-existing or de novo anti-HLA antibodies. Hepatitis C infection, thrombotic microangiopathy or other factors may also contribute to TG development. TG prevalence is 5-20% in most series, reaching 55%, in some high-risk cohorts, and is associated with worse allograft outcomes. Despite its prevalence and clinical significance, few well-studied treatment options have been proposed. Similar to desensitization protocols, plasmapheresis with or without immunoabsorption, high-dose intravenous immunoglobulin, rituximab, bortezomib and eculizumab have been proposed in the treatment of TG due to cABMR individually or in various combinations. Robust clinical trials are urgently needed to address this major cause of allograft loss. This review summarizes the current knowledge of the epidemiology, etiology, pathology, and the preventive and treatment options for TG secondary to cABMR. [ABSTRACT FROM AUTHOR]

Background The C1q-binding properties of donor specific antibodies (DSA) may be related to antibody-mediated rejection and poor outcome. Methods We retrospectively studied 35 kidney transplant recipients with transplant glomerulopathy (TG) and de novo DSA (dnDSA). C1q dnDSA were measured in the serum stored at renal biopsy and the association among C1q-fixing dnDSA, C4d deposition and graft loss was examined. Results Of the 35 patients with dnDSA and TG, 15 (42.9%) had C1q-positive dnDSA and 20 (57.1%) had C1q-negative dnDSA. Ten out of 15 patients with C1q-positive dnDSA (66.6%) and 5 with C1q-negative dnDSA (25%) had C4d positive staining renal biopsies (P = 0.02), being the C1q-negative dnDSA/C4d-negative TG 42.9% of the total. The C1q-positive dnDSA group has significantly higher IgG DSA Class II MFI than the C1q-negative dnDSA group (P = 0.004). Patients with C4d deposits have significantly higher IgG DSA MFI for both Class I and Class II than those without C4d deposits (P = 0.02). We found a trend toward higher graft loss in the C1q-positive dnDSA group (60%) versus the C1q-negative dnDSA group (40%) without a statistical significance (P = 0.31). Conclusion Our study provides further characterization of TG associated with dnDSA. The major part of dnDSA-associated TG was C1q-negative and the presence of C1q-fixing dnDSA did not significantly correlate with graft outcome. [ABSTRACT FROM AUTHOR]

The pathological classification of rejection in renal allografts ( Banff classification) has undergone substantial evolution for more than 20 years, and has been the diagnostic gold standard in clinical practice. The 2013 updated Banff classification encompasses a revised scheme of antibody-mediated rejection ( ABMR) that consists of donor-specific antibody ( DSA) positivity, characteristic histological manifestations for both acute and chronic ABMR, and DSA-induced endothelial cell injury which is represented by either C4d positivity, microvascular inflammation or expression of activated endothelial gene transcripts. Other modified criteria include a C4d positivity threshold, and histological definition of transplant glomerulitis and transplant glomerulopathy. Morphologically, glomerulonephritis, either recurrent or de novo, can be challenging to differentiate from ABMR-mediated transplant glomerulitis. Endothelial arteritis by itself does not warrant the diagnosis of acute T-cell mediated rejection; ABMR should also be considered based on the DSA test results. With regard to polyomavirus BK-associated nephropathy, immunohistochemical examination using anti-simian virus ( SV) 40 antibody can be a promising method to assess the quantitative viral load of polyomavirus BK and graft survival. In summary, the 2013 updated Banff classification strictly defines ABMR with histopathological and serological criteria irrespective of C4d positivity. Inclusion of gene expression data relevant to ABMR highlights that the Banff criteria have entered the era of 'Seeing the Unseen' schemes, reflecting recent advances in understanding the molecular events in allograft injury. [ABSTRACT FROM AUTHOR]

Outcome of patients with transplant glomerulopathy ( TG) is poor. Using B-cell targeting molecules represent a rational strategy to treat TG during chronic antibody-mediated rejection. In this pilot study, 21 patients with this diagnosis received four doses of intravenous immunoglobulins and two doses of rituximab ( IVIG/ RTX group). They were retrospectively compared with a untreated control group of 10 patients. At 24 months post-biopsy, graft survival was similar and poor between the treated and the untreated group, 47% vs. 40%, respectively, p = 0.69. This absence of response of IVIG/ RTX treatment was observed, regardless the phenotype of TG. Baseline estimated glomerular filtration rate ( eGFR) and decline in eGFR during the first six months after the treatment were risk factors associated with 24-month graft survival. The IVIG/ RTX therapy had a modest effect on the kinetics of donor-specific alloantibodies at M24, compared to the untreated group, not associated with an improvement in graft survival. The mean number of adverse events per patient was higher in the IVIG/ RTX group than in the control group (p = 0.03). Taken together, IVIG/ RTX treatment for severe TG during chronic antibody-mediated rejection does not seem to change the natural history of TG and is associated with a high incidence of adverse events. [ABSTRACT FROM AUTHOR]

Introduction Transplant glomerulopathy ( TG) is the characteristic lesion of chronic antibody-mediated rejection ( AMR). However, in some patients presents with no circulating HLA antibodies or C4d positivity. Aim Patients with TG accomplishing criteria for chronic AMR were compared to patients with isolated TG. Patients and Methods We reviewed late (>6 months) graft biopsies performed between 2007 and 2010 (n = 75). Biopsies with C4d-negative TG and no circulating donor-specific antibody were called isolated TG (n = 12), and chronic AMR was defined according to Banff consensus (n = 17). HLA antibodies were evaluated by Luminex technology. Immunohistochemistry was performed to quantify graft infiltrating cells. Results Patients with isolated TG were older (52 ± 14 vs. 35 ± 14; p = 0.0048), received grafts from older donors (54 ± 16 vs. 41 ± 18; p = 0.0554), and displayed a lower inflammation in the glomerular (g-score: 0.5 ± 0.5 vs. 1.0 ± 0.9; p = 0.0865; CD3 positive cells/glomeruli: 1.5 ± 2.9 vs. 4.4 ± 4.1; p = 0.0147), interstitial (i-score: 1.2 ± 0.9 vs. 1.9 ± 1.0; p = 0.0685; CD45 positive cells/hpf: 18 ± 11 vs. 57 ± 68; p = 0.0132), and peritubular capillary (ptc-score 0.2 ± 0.6 vs. 1.1 ± 0.9; p = 0.0089; CD45 positive cells/hpf: 3.7 ± 3.1 vs. 10.1 ± 7.4; p = 0.0290) compartments. Fifteen grafts were lost and graft survival was significantly lower in patients with chronic AMR (p = 0.0122). Conclusion Isolated TG is associated with less severe allograft inflammation and with a better outcome than chronic AMR. [ABSTRACT FROM AUTHOR]

Glomerular diseases of the transplanted kidney are the most important cause of poor long- term outcome. The estimation of the magnitude of this problem and an elucidation of pathogenic mechanism is essential for improvement of graft survival. This study from the Indian subcontinent aims (i) to determine the incidence of transplant glomerulopathy ( TG) and thrombotic microangiopathy ( TMA) in a large cohort of indicated renal transplant biopsies, (ii) to evaluate the histological and ultrastructural features of TG and TMA, and (iii) to assess the relationship between the two glomerular lesions. Of a total of 1792 indication renal transplant biopsies received over 5 years (2006-2010), 266 biopsies (of 249 patients) had significant glomerular pathology and were further analyzed along with immunofluorescence, electron microscopy ( EM), and C4d immunohistochemistry. TG is the most common glomerular lesion followed by TMA seen in 5.97% and 5.08% of allograft biopsies, respectively, which constitutes 40.23% and 34.2% of biopsies with significant glomerular lesions. Pathologic antibody-mediated rejection ( AMR) is associated with both TG and TMA in 71% and 46.5%, respectively. A coexistent TG was found in 18.4% of biopsies with TMA. Endothelial swelling with subendothelial widening, a feature of TMA, is also seen in early TG by EM. Our findings support the concept that TG evolves from a smoldering TMA of various causes. [ABSTRACT FROM AUTHOR]

Aim Transplant glomerulopathy ( TG) is included as one of the criteria of chronic active antibody-mediated rejection (c- AMR) in Banff 09 classification. In this report, we discuss the clinical and pathological analyses of cases of TG after renal transplantation. Patients TG was diagnosed in 86 renal allograft biopsy specimens ( BS) obtained from 50 renal transplant patients followed up at our institute between January 2006 and October 2012. We retrospectively reviewed the data of these 86 BS and 50 patients. Results Among the 50 patients, 42 (84%) had a history of acute rejection ( AR); of these, 30 (60%) had acute antibody-mediated rejection (a- AMR). Among the 86 BS of TG, the TG was mild in 35 cases (cg1 in Banff classification), moderate in 28 cases (cg2) and severe in 23 cases (cg3). Peritubular capillaritis was present in 74 BS (86%), transplant glomerulitis in 65 (76%), interstitial fibrosis and tubular atrophy ( IF/ TA) in 71 (83%), thickening of the peritubular capillary ( PTC) basement membrane in 72 (84%), and interstitial inflammation in 40 (47%). C4d deposition in the PTC was present in 49 BS (57%); 39 of these 49 BS showed diffuse C4d deposits in the PTC ( C4d3), while the remaining 10 BS showed focal deposits ( C4d2). Diffuse C4d deposition in the glomerular capillaries ( GC) was seen in 70 BS (81%), while focal C4d deposition in the GC was seen in 9 (11%). In the assay using plastic beads coated with HLA antigen performed in 67 serum samples obtained in the peri-biopsy period, circulating ant- HLA alloantibody was detected in 55 (82%); in 33 of the 55 (49%) samples, donor-specific antibodies ( DSA) were detected. Among our study, the findings in 22 BS (26%) fully met the criteria for c- AMR in Banff '09 classification, including TG, C4d deposition in the PTC and presence of DSA, while those in 27 BS were suspicious of c- AMR. Deterioration of the renal allograft function after the biopsies was seen in 31 patients (62%), of which 11 lost their graft. Conclusions We suggest that histopathological changes of transplant glomerulopathy might be accompanied by inflammation of the microvasculature, such as transplant glomerulitis and peritubular capillaritis, thickening of the peritubular capillary basement membrane, and circulating anti- HLA antibodies. C4d deposition in the PTC is not always present in biopsy specimens of TG. We speculated that C4d deposition in the GC, rather than that in the PTC might be a more characteristic manifestation of TG. Many of the patients with TG had a history of AR. Anti- HLA antibody Class II, particularly when the antibody was DSA Class II, appeared to be associated with the development of TG. The prognosis of grafts exhibiting TG was not too good even under the currently used immunosuppressive protocol. [ABSTRACT FROM AUTHOR]

The diagnosis of an antibody-mediated rejection (AMR) is made when there is evident histologic injury in the presence of detectable donor-specific alloantibodies (DSA) and diffuse peritubular capillary C4d staining (C4d-pos). In the presence of only detectable DSA or C4d-pos, the tissue injury is currently considered 'presumptive' for antibody causation. In acute antibody-mediated rejection (AAMR), diagnostic morphologic features include microvascular inflammation (MVI), specifically glomerulitis and peritubular capillaritis. In the case of chronic active AMR (CAAMR), these inflammatory lesions have progressed to chronic microvascular injury, transplant glomerulopathy (TG) and peritubular capillary basement membrane multilayering (PTCBMML). Either TG or PTCBMML is sufficient morphological evidence for a diagnosis of CAAMR. Unfortunately, these lesions are not specific. MVI, TG, and PTCBMML are found in the setting of cell-mediated immunity, as well as in association with non-alloimmune mechanisms. The available treatments for AMR and CMR are different, and it is important to ascertain the dominant mechanism when approaching an individual patient. At present, no gold standard exists to establish the specific pathogenesis in the more ambiguous cases. We detail here the differential diagnosis of MVI, TG, and PTCBMML. [ABSTRACT FROM AUTHOR]

The C4d staining as a special tissue marker for humoral immunity has served criteria of pathological diagnosis for antibody-mediated rejection ( ABMR) in Banff classification since 2003. However, the sensitivity and specificity of C4d staining have been questioned, and recently, C4d-negative ABMR has been more focused in renal allograft pathology. The aim of this study was to make certain of C4d staining for ABMR that was diagnosed by clinical and morphological findings. C4d staining was employed by immunofluorescence. This study included 14 patients with acute ABMR and 16 with chronic active ABMR. Eight of acute ABMR were ABO-blood-type-incompatible renal transplantation ( ABOin RTx) pre-treated by DFPP and splenectomy or rituximub. In acute ABMR after ABOin RTx, C4d staining along peritubular capillary ( PTC) was positive in five of them (62.5%). Only one graft biopsy of five acute ABMR with donor-specific antibody ( DSA) showed C4d positive. We assembled 16 graft biopsies showing typical transplant glomerulopathy and thickened PTC basement membrane with peritubular capillaritis as a suspicious pathological chronic active ABMR. Four of eight DSA-positive patients were C4d negative in PTC; however, three of four DSA-positive and C4d-negative patients in PTC chronic active ABMR were C4d positive in only glomerular capillaries. C4d positivity could not come to a specific marker of ABMR diagnosing based on clinically and ordinary morphological findings. [ABSTRACT FROM AUTHOR]

Transplant glomerulopathy ( TG) is involved in the criteria of chronic active antibody-mediated rejection (c- AMR) in Banff '09 classification. Patients TG was diagnosed in 58 renal allograft biopsy specimens ( BS) from 37 renal transplant patients. Results Among 58 BS of TG, 27 BS were mild (cg1), 16 were moderate (cg2), and 15 were severe (cg3). Peritubular capillaritis was present in 49 (84%), transplant glomerulitis was seen in 47 BS (81%), interstitial fibrosis and tubular atrophy in 47 (81%) and the thickening of the peritubular capillary ( PTC) basement membrane ( PTCBM) in 44 (76%), and interstitial inflammation was present in 26 BS (45%). C4d deposition in PTC was presented in 32 BS (55%). The circulating anti- HLA alloantibody was detected in 38 times (76%), of which 27/38 (54%) were donor-specific antibodies. Deterioration of renal allografts' function after biopsies was seen in 12 patients (32%) with six of them lost their graft. Conclusions We suggest that histopathological changes of TG accompanying by transplant glomerulitis, peritubular capillaritis, the thickening of the PTCBM, and circulating anti- HLA antibodies might indicate c- AMR, even if C4d deposition in PTC is negative. The prognosis of the graft exhibiting TG was relatively good under the present immunosuppression protocol in short time. [ABSTRACT FROM AUTHOR]

B cells have many possible mechanisms by which they can affect allograft survival, including antigen presentation, cytokine production, immune regulation, and differentiation into alloantibody-producing plasma cells. This report reviews the last mechanism, which the authors regard as most critical for the long-term survival of allografts, namely, the promotion of chronic rejection by alloantibodies. Chronic humoral rejection characteristically arises late after transplantation and causes transplant glomerulopathy, multilamination of peritubular capillary basement membranes, and C4d deposition in PTCs and glomeruli. Circulating antidonor human leukocyte antigen class II antibodies are commonly detected and may precede the development of graft injury. Prognosis is poor, especially when recognized after graft dysfunction has developed. Improved detection and treatment are critically needed for this common cause of late graft loss. [ABSTRACT FROM AUTHOR]

Kidney transplant glomerulopathy (TG) has a poor outcome as there are no known effective therapies. Therefore, we investigated whether rituximab therapy (RTx) could halt progression of established TG. Fourteen kidney-transplant patients (nine of whom were men), with median age of 54 (range: 30–74) years, of whom seven had biologic markers for HCV infection, underwent a kidney biopsy (KB) at 118 months post-transplant because of impaired allograft function, associated with albuminuria (95–13430 mg/day), within nephrotic-range albuminuria in seven patients. KBs showed no evidence of acute cellular rejection but showed TG. Donor-specific anti-HLA antibodies were present in six cases. When diagnosis of TG was made, patients were placed on rituximab therapy (RTx) (2–4 injections of 375 mg/m2 week), and other concurrent immunosuppression treatments were not modified. By last follow up post-RTx (30 months), seven (50%) patients had lost their kidney within 6–26 months and the other seven had stable creatinine (182 vs. 161 μmol/l; NS), and albuminuria had decreased from 2660 to 500 mg/day ( P = 0.03). There was prolonged B-cell lymphopenia (from 71 to 0/mm3) whereas immunoglobulin G, A, M levels remained stable, and four patients (28.5%) experienced severe infectious complications. We conclude that long-term RTx in kidney-transplant patients with TG is associated with allograft function/stabilization in 50% of cases. [ABSTRACT FROM AUTHOR]

Abstract: The important role of preformed human leukocyte antigen (HLA) antibodies in the outcome of organ transplants has been well demonstrated for the past 40 years. During this same period, the significance of HLA antibody formation after transplantation was largely ignored. Only in the past 10 years has become increasingly clear that HLA antibodies formed posttransplantation are the major cause of allograft failure. We provide here an updated review of the critical evidence implicating HLA antibodies in chronic rejection. It has now also been shown that antibodies formed soon after transplantation are much more toxic to the graft than antibodies formed after the first year. This is likely a result of adaptation of the graft after the first year, possibly through endothelial cell replacement. On the basis of this new finding, a policy of monitoring for antibody development after 3, 6, 9, and 12 months, with yearly checks thereafter, is suggested. Another important new development is the use of bortezomib, a fresh new agent for the removal of antibodies. Because this is the first agent to act on plasma cells, its use is promising. Early data on successful removal of antibodies are reviewed here. [Copyright &y& Elsevier]

Introduction: Transplant glomerulopathy (TG) is involved in the criteria of chronic active antibody-mediated rejection (c-AMR) in Banff 07 classification. In this report, we discuss the clinico-pathological analysis of TG cases after renal transplantation, and analysis of whether all TG cases are applied to c-AMR. Patients: Transplant glomerulopathy, defined by double contours of glomerular basement membranes, was diagnosed in 13 patients from 13 renal transplant patients followed-up in our institute between January 2007 and April 2008. We retrospectively reviewed these 13 patients. Results: Among 13 cases of TG, three cases were mild (cg1 in Banff classification), four were moderate (cg2), and six were severe (cg3). Transplant glomerulitis and interstitial inflammation were present in all 13 biopsies, and peritubular capillaritis was present in 12 of 13 biopsies, interstitial fibrosis/tubular atrophy in 13, and the thickening of the peritubular capillary (PTC) basement membrane in 11. PTC C4d deposition was presented in six cases, three out of six cases had diffuse C4d deposits in PTC, and the remainder had focal deposits. By assaying with plastic beads coated with human leukocyte antigen (HLA) in 12 cases, the circulating anti-HLA alloantibody was detected in all 12 patients of which only 3 of 12 were donor-specific antibodies (DSA). In our cases, there was no patient who fully met criteria for c-AMR in Banff classification, which included TG, C4d deposition in PTC, and existence of DSA, but seven patients were diagnosed suspicious for c-AMR. Seven cases (54%) had proteinuria at the time of the biopsies and the severity of proteinuria was associated with the severity of TG. Deterioration of renal allografts’ function after biopsies was seen in seven (54%), and two of them lost their graft. Conclusions: We suggest that histopathological changes of TG accompanied by transplant glomerulitis, peritubular capillaritis, the thickening of the peritubular capillaries basement membrane, and circulating anti-HLA antibodies may indicate c-AMR, even if C4d deposition in PTC is negative. The severity of TG may be associated with proteinuria, reduced graft function, and reduced graft survival. [ABSTRACT FROM AUTHOR]

The Banff 2017 report permits the diagnosis of pure chronic antibody-mediated rejection (cAMR) in absence of microcirculation inflammation. We retrospectively investigated renal allograft function and long-term outcomes of 67 patients with cAMR, and compared patients who received antihumoral therapy (cAMR-AHT, n = 21) with patients without treatment (cAMRwo, n = 46). At baseline, the cAMR-AHT group had more concomitant T-cell-mediated rejection (9/46 (19.2%) vs. 10/21 (47.6%); p = 0.04), a higher g-lesion score (0.4 ± 0.5 versus 0.1 ± 0.3; p = 0.01) and a higher median eGFR decline in the six months prior to biopsy (6.6 vs. 3.0 mL/min; p = 0.04). The median eGFR decline six months after biopsy was comparable (2.6 vs. 4.9 mL/min, p = 0.61) between both groups, and three-year graft survival after biopsy was statistically lower in the cAMR-AHT group (35.0% vs. 61.0%, p = 0.03). Patients who received AHT had more infections (0.38 vs. 0.20 infections/patient; p = 0.04). Currently, antihumoral therapy is more often administered to patients with cAMR and rapidly deteriorating renal function or concomitant TCMR. However, long-term graft outcomes remain poor, despite treatment. [ABSTRACT FROM AUTHOR]

The true incidence of positive C4d staining in the peritubular capillaries of biopsies with chronic allograft nephropathy (CAN) and transplant glomerulopathy (TGP) remains controversial. We retrospectively reviewed all transplant biopsies performed at Saint Louis University Hospital between June 2002 and May 2004. We examined the incidence of positive C4d staining in the peritubular capillaries of biopsy specimens with pure CAN with or without features of TGP. We identified 54 biopsies in 43 patients showing CAN. The average age was 46 ± 13 years. The average creatinine at the time of biopsy was 308 ± 211 μmol/l (3.5 ± 2.4 mg/dl). Twenty (37%) biopsies exhibited features consistent with TGP. Only two biopsies had positive C4d staining in the peritubular capillaries. The C4d positive biopsies were from two different patients; one patient had donor specific antibodies (DSA) against HLA class 1 at the time of biopsy and the other patient had no detectable DSA. None of the TGP biopsies showed peritubular C4d staining. C4d staining of the peritubular capillaries appears to be rare in patients with pure CAN with and without TGP features. [ABSTRACT FROM AUTHOR]

Immunologic risk factors and glomerular C4d deposits in chronic transplant glomerulopathy. Background. Chronic transplant glomerulopathy is an uncommon cause of chronic transplant dysfunction of unknown pathogenesis. We evaluated the epidemiologic, clinical, and histologic features of chronic transplant glomerulopathy. To determine the possible contribution of humoral immune responses, we assessed glomerular deposition of C4d. Methods. From a cohort of 1111 kidney transplants (1983 to 2001) with at least 6 months of graft function, we identified 18 cases with chronic transplant glomerulopathy (1.6%) showing double contours of the glomerular basement membrane (GBM) on light microscopy. To assess the risk factors, this group was compared with 739 patients with stable function using multivariate Cox regression analysis. Paraffin sections of 11/18 biopsies were stained with polyclonal C4d antibodies. Sera of 13/18 patients could be tested for antidonor human leukocyte antigen (HLA) antibodies by enzyme-linked immunosorbent assay (ELISA). Patients with chronic allograft nephropathy without chronic transplant glomerulopathy or predominant cyclosporine nephrotoxicity were used as controls. Results. Chronic transplant glomerulopathy was diagnosed at a median of 8.3 (range 2.6–12.5) years posttransplantation. Panel reactive antibodies at time of transplantation, RR 1.23 (1.05–1.45) per 10% increase, and late acute rejection episodes, RR 7.6 (1.8–31.7), were independently associated with chronic transplant glomerulopathy. We found glomerular C4d deposits in 10/11 biopsies showing chronic transplant glomerulopathy and in only 2/13 controls. Peritubular capillary C4d deposits and donor-specific anti-HLA antibodies were demonstrated in 4 and 3 of the 10 patients with glomerular C4d deposits, respectively. [ABSTRACT FROM AUTHOR]

Abstract: Transplant glomerulopathy (TGP) is a unique disease entity with characteristic pathological findings. Although ultrastructural studies for TGP have been performed, histogenesis of TGP is not fully understood. The present study was designed to investigate the relation of complement fragment C4d to the histogenesis of TGP. Nine cases of isolated TGP were randomly selected. A commercially available monoclonal antibody against complement fragment C4d was used in allograft biopsies. To evaluate the extent and severity of deposition of the C4d complement in the glomerular and peritubular capillaries, indirect immunofluoresce method was performed on frozen sections. Intense deposition of C4d in the glomerular basement membrane and peritubular capillaries was found in association with morphological appearance of TGP. Peritubular capillaries were affected in all the patients, showing splitting and multilayering of peritubular capillary basement membrane. These changes, which diffusely affect most capillaries, and their severity pattern were quite similar in each patient. In early stages of all patients with cellular rejection, C4d was not detected in the glomerular and peritubular capillaries. In addition, no C4d deposition was detected in all zero-hour biopsies without diagnostic abnormality. These findings suggest that C4d deposition in the glomerular and peritubular capillaries might be associated with the pathogenesis of TGP in renal transplantation. [ABSTRACT FROM AUTHOR]

Discusses the role of indirect allorecognition in graft rejection. Mechanisms of allorecognition and graft rejection; Indirect alloreactivity to donor HLA-DR peptides in renal transplant recipients with chronic allograft dysfunction; T-cell proliferative response to the peptides in primed and control animals.

Transplant glomerulopathy develops through multiple mechanisms, including donor-specific antibodies, T cells and innate immunity. This study investigates circulating small RNA profiles in serum samples of kidney transplant recipients with biopsy-proven transplant glomerulopathy. Among total small RNA population, miRNAs were the most abundant species in the serum of kidney transplant patients. In addition, fragments arising from mature tRNA and rRNA were detected. Most of the tRNA fragments were generated from 5′ ends of mature tRNA and mainly from two parental tRNAs: tRNA-Gly and tRNA-Glu. Moreover, transplant patients with transplant glomerulopathy displayed a novel tRNA fragments signature. Gene expression analysis from allograft tissues demonstrated changes in canonical pathways related to immune activation such as iCos-iCosL signaling pathway in T helper cells, Th1 and Th2 activation pathway, and dendritic cell maturation. mRNA targets of down-regulated miRNAs such as miR-1224-5p, miR-4508, miR-320, miR-378a from serum were globally upregulated in tissue. Integration of serum miRNA profiles with tissue gene expression showed that changes in serum miRNAs support the role of T-cell mediated mechanisms in ongoing allograft injury. [ABSTRACT FROM AUTHOR]

Banff 2013 criteria recommend performing ultrastructural studies with electron microscopy (EM) in kidney transplant biopsies if the technology is available. We sought to determine the impact of EM on enhancing diagnostic findings in pediatric kidney transplant biopsies and the prognostic information gained from the additional findings. All kidney transplant biopsies since routine EM use started on June 1, 2014, until October 31, 2016, were reviewed. Primary outcome measures included the positive yield frequency of EM use defined as an upgraded diagnosis based on EM findings relative to light microscopy, and 12‐month kidney allograft outcome of progression to ESRD or doubling of serum creatinine stratified by transplant glomerulopathy (TG) status on EM. Eighty unique kidney transplant biopsies were reviewed. EM studies were completed for 61 biopsies (76%). Complication rate was low (3.7%). In 61 biopsies where EM was completed, EM findings included foot process fusion (62%), endothelial cell swelling (38%), subendothelial lucencies (31%), and glomerular basement membrane duplication (41%). EM confirmed FSGS recurrence in three cases. In the remaining 58 cases, there was a positive yield of 31% where 18 biopsies were upgraded to a worse category after TG identification on EM. Kidney allograft outcome was poor regardless whether TG was detected early on EM or advanced on LM. Routine EM use in analyzing pediatric kidney transplant biopsies proved safe and provided valuable additional diagnostic information in almost one‐third of cases. Additional studies are needed to determine if clinical interventions for early TG identified on EM can improve long‐term outcomes. [ABSTRACT FROM AUTHOR]

Background: We investigated clinical outcomes and molecular signatures of transplant glomerulopathy (TG) stratified by microvascular inflammation (MVI) and donor‐specific antibody (DSA) status. Methods: We performed a retrospective review of 749 kidney transplant patients who received a for‐cause kidney biopsy from 2009 to 2014. We classified TG as MVI positive (MVI+) or MVI negative (MVI−), and with or without DSA. We obtained gene expression profiles for 44 biopsies by Affymetrix HuGene 1.0 ST expression arrays. Results: A total of 100 patients had TG; 49 were MVI+, and 51 were MVI−. After a median post‐biopsy follow‐up of 2.08 years (range 0.43‐4.59), Kaplan‐Meier survival analysis demonstrated worse allograft survival in MVI+ TG patients compared with MVI− TG patients (P = 0.01), and time to graft failure was significantly shorter in MVI+ patients (1.08 ± 1.01 years vs 2.3 ± 1.8 years; P = 0.002). DSA status did not affect graft survival within MVI+ or MVI− groups. Analysis of pathogenesis‐based transcripts (PBT) showed that MVI+ TG biopsies had increased expression of gamma interferon and rejection (GRIT) and DSA‐associated transcripts (DSAST), as observed in antibody‐mediated rejection. MVI− TG biopsies had increased expression of cytotoxic and regulatory T cell‐ and B cell‐associated transcripts but not GRIT or DSAST. DSA status had no effect on expression of any PBTs studied in MVI− TG biopsies. Conclusions: Graft survival in TG is significantly worse in the presence of MVI. Gene expression profiles of MVI+ TG resemble antibody‐mediated rejection while gene expression profiles of MVI− TG resemble cell‐mediated rejection regardless of DSA status. [ABSTRACT FROM AUTHOR]

Background: Transplant glomerulopathy (TG) is an important cause of late graft loss. The role of angiotensin type 1‐receptor antibodies (AT1R‐Ab) in TG is not known. Methods: All the TG cases (N = 137) between January 2007 and December 2014 (N = 1410) were analyzed. Donor‐specific anti‐HLA antibodies (DSA) at the time of biopsy and AT1R‐Ab IgG (positive, >17 UI/mL; "at risk," 10‐17 UI/mL; negative, <10 UI/mL) in pre‐transplant sera (PT‐Ab) and at biopsy time (BT‐Ab) were studied. Results: AT1R‐PT‐Ab+ and AT1R‐BT‐Ab+ patients were 16.5% (51.5% "at risk") and 11.5% (27.4% "at risk"), respectively. Clinical correlations were found between AT1R‐Ab and HCV infection, number of transplants, and age. Considering Banff scores, ptc was higher in DSA+ patients vs AT1R‐PT‐Ab+ (P = 0.002) or AT1R‐BT‐Ab+ (P = 0.001) without differences in g and chronicity score (ci + ct); cg showed lower scores in DSA+ patients vs AT1R‐BT‐Ab+ (P = 0.001). Graft survival was not influenced by the presence of AT1R‐Ab, AT1‐R‐Ab titer or MFI, but we observed a longer graft survival in patients with both AT1R‐BT‐Ab+ or "at risk" and DSA+ vs patients positive only for DSA (P = 0.02), for AT1R‐BT‐Ab (P = 0.019) or AT1R‐BT‐Ab "at risk" (P = 0.039). Conclusion: AT1R‐Ab showed no independent prognostic role in TG in this pilot analysis. [ABSTRACT FROM AUTHOR]

B cells have many possible mechanisms by which they can affect allograft survival, including antigen presentation, cytokine production, immune regulation, and differentiation into alloantibody-producing plasma cells. This report reviews the last mechanism, which the authors regard as most critical for the long-term survival of allografts, namely, the promotion of chronic rejection by alloantibodies. Chronic humoral rejection characteristically arises late after transplantation and causes transplant glomerulopathy, multilamination of peritubular capillary basement membranes, and C4d deposition in PTCs and glomeruli. Circulating antidonor human leukocyte antigen class II antibodies are commonly detected and may precede the development of graft injury. Prognosis is poor, especially when recognized after graft dysfunction has developed. Improved detection and treatment are critically needed for this common cause of late graft loss. [ABSTRACT FROM AUTHOR]