Transplant Glomerulopathy Research Articles

Microvascular Inflammation of Kidney Allografts and Clinical Outcomes.

The heterogeneous clinical presentation of graft microvascular inflammation poses a major challenge to successful kidney transplantation. The effect of microvascular inflammation on allograft outcomes is unclear. We conducted a cohort study that included kidney-transplant recipients from more than 30 transplantation centers in Europe and North America who had undergone allograft biopsy between 2004 and 2023. We integrated clinical and pathological data to classify biopsy specimens according to the 2022 Banff Classification of Renal Allograft Pathology, which includes two new diagnostic categories: probable antibody-mediated rejection and microvascular inflammation without evidence of an antibody-mediated response. We then assessed the association between the newly recognized microvascular inflammation phenotypes and allograft survival and disease progression. A total of 16,293 kidney-transplant biopsy specimens from 6798 patients were assessed. We identified the newly recognized microvascular inflammation phenotypes in 788 specimens, of which 641 were previously categorized as specimens with no evidence of rejection. As compared with patients without rejection, the hazard ratio for graft loss was 2.1 (95% confidence interval [CI], 1.5 to 3.1) among patients with microvascular inflammation without evidence of an antibody-mediated response and 2.7 (95% CI, 2.2 to 3.3) among patients with antibody-mediated rejection. Patients with a diagnosis of probable antibody-mediated rejection had a higher risk of graft failure beyond year 5 after biopsy than those without rejection (hazard ratio, 1.7; 95% CI, 0.8 to 3.5). Patients with a diagnosis of either newly recognized microvascular inflammation phenotype had a higher risk of progression of transplant glomerulopathy during follow-up than patients without microvascular inflammation. Microvascular inflammation in kidney allografts includes distinct phenotypes, with various disease progression and allograft outcomes. Our findings support the clinical use of additional rejection phenotypes to standardize diagnostics for kidney allografts. (Funded by OrganX. ClinicalTrials.gov number, NCT06496269.).

Corrigendum to “Quantitative scoring of progression in transplant glomerulopathy using digital pathology may be superior to Banff cg scoring.” Kidney International 2023;103:365–377

Corrigendum to “Quantitative scoring of progression in transplant glomerulopathy using digital pathology may be superior to Banff cg scoring.” Kidney International 2023;103:365–377

Innate Immune Cells, Memory T Cells, and Interferon Gamma Responses Characterize Transplant Glomerulopathy of Chronic Antibody-Mediated Rejection

Innate Immune Cells, Memory T Cells, and Interferon Gamma Responses Characterize Transplant Glomerulopathy of Chronic Antibody-Mediated Rejection

Early and Late Microvascular Inflammation Have Differing Etiological Causes and Clinical Expression.

Microvascular inflammation (MVI) is an important pathological feature of antibody-mediated rejection (AMR). How posttransplant time affects its clinicopathological expression is little understood. This retrospective, single-center study screened 3398 kidney transplant biopsies and dichotomized 202 MVI ≥ 2 (Banff glomerulitis + peritubular capillaritis ≥ 2) samples by 9-mo median incidence time for comparison. The prevalence of MVI ≥ 2 was 12.4% in transplant kidneys, which failed more frequently than propensity-matched normal controls (n = 202; P < 0.001). Epidemiological risk factors for early MVI ≥ 2 were delayed graft function, prior AMR, and circulating donor-specific antibodies (DSAs+). Prior recipient sensitization occurred in 72.3%. Early MVI ≥ 2 was classified AMR in 65.3% and cellular rejection in 34.7%, and demonstrated excellent functional recovery and graft survival comparable to normal control kidneys. Late MVI ≥ 2 was predicted by younger (18 = 29 y) age, female recipient, living-donation, prior methylprednisolone, cyclosporine (versus tacrolimus, levels <5 ng/mL), absent antiproliferative therapy, and DSA+ using multivariable epidemiological modeling. Nonadherence caused 49.5%, with iatrogenic minimization responsible for 47.5%, usually for recipient infection. Late MVI ≥ 2 was because of AMR in 93.1%, and characterized by greater interstitial fibrosis, tubular atrophy, complement degradation split-product 4d (C4d) staining of peritubular capillaries+, endothelial C4d staining of glomerular capillaries+, transplant glomerulopathy and vasculopathy scores, DSA strength, and graft failure than early MVI ≥ 2 or normal transplant kidneys. Death-censored graft survival in 149 unique MVI ≥ 2 kidneys was independently determined by nonadherence, serum creatinine, proteinuria, DSA+, Banff C4d staining of peritubular capillaries+, and chronic interstitial fibrosis scores. MVI score and time lost significance using multivariable Cox regression. The changing expression of MVI ≥ 2 over time is best explained by differences in underimmunosuppression and microvascular injury from AMR impacting allograft function and survival.

262.8: Correlation of early ultrastructural findings, microvascular HLA-DR, and VEGF expression in renal allografts with acute rejection types: Impact on transplant glomerulopathy and interstitial fibrosis.

262.8: Correlation of early ultrastructural findings, microvascular HLA-DR, and VEGF expression in renal allografts with acute rejection types: Impact on transplant glomerulopathy and interstitial fibrosis.

205.5: Not all transplant glomerulopathy related to chronic antibody-mediated rejection.

205.5: Not all transplant glomerulopathy related to chronic antibody-mediated rejection.

Outcomes of Early Thrombotic Microangiopathy in Renal Transplantation.

Alternate complement dysregulation postrenal transplantation can result in thrombotic microangiopathy (TMA). There is a scarcity of data regarding outcomes based on the timing of TMA post-transplant, coupled with a lack of follow-up biopsy findings post TMA diagnosis. This study aims to assess allograft and patient outcomes in individuals developing early TMA, defined within 4months post-transplantation, and explore any differences in follow-up surveillance biopsies compared to a non-TMA group. This is a single center retrospective study between January 1, 2002 and October 10, 2019. Patients who developed TMA within 4months post-transplantation were compared to a propensity matched non-TMA group. Thirty-one patients developed TMA within 4months of renal transplantation. Index TMA biopsy featured noticeable glomerular, and vascular lesions along with acute tubular injury. Four-month surveillance biopsy showed significant glomerulitis, transplant glomerulopathy and chronic interstitial fibrosis as compared to non-TMA group. However, at 1year, these differences were no longer significant. There was no significant difference in patient survival (TMA vs. non-TMA, p=0.083); however, death censored graft survival was significantly lower in the TMA group (p<0.001). TMA patients had a significantly lower estimated glomerular filtration rate at 4months and at 1year as compared to the non-TMA group. Early onset TMA post renal transplant leads to decreased renal function and lower graft survival. Early recognition and prompt treatment may help in reducing the adverse outcomes.

Probable antibody-mediated rejection in kidney transplantation is a rare and challenging phenotype to define: Findings from a single-center study

The Banff 2022 consensus introduced probable antibody-mediated rejection (AMR), characterized by mild AMR histologic features and human leukocyte antigen (HLA) donor-specific antibody (DSA) positivity. In a single-center observational cohort study of 1891 kidney transplant recipients transplanted between 2004 and 2021, 566 kidney biopsies were performed in 178 individual HLA-DSA–positive transplants. Evaluated at time of the first HLA-DSA–positive biopsy of each transplant (N = 178), 84 of the 178 (47.2%) of first biopsies were scored as no AMR, 22 of the 178 (12.4%) as probable AMR, and 72 of the 178 (40.4%) as AMR. The majority (77.3%) of probable AMR cases were first diagnosed in indication biopsies. Probable AMR was associated with lower estimated glomerular filtration rate (mL/min/1.73m2) than no AMR (20.2 [8.3-32.3] vs 40.1 [25.4-53.3]; P = .001). The one-year risk of (repeat) AMR was similar for probable AMR and AMR (subdistribution hazard ratio (sHR), 0.99; 0.42-2.31; P = .97) and higher than after no AMR (sHR, 3.05; 1.07-8.73; P = .04). Probable AMR had a higher five-year risk of transplant glomerulopathy vs no AMR (sHR, 4.29; 0.92-19.98; P = 06), similar to AMR (sHR, 1.74; 0.43-7.04; P = .44). No significant differences in five-year risk of graft failure emerged between probable AMR and AMR (sHR, 1.14; 0.36-3.58; P = .82) or no AMR (sHR, 2.46; 0.78-7.74; P = .12). Probable AMR is a rare phenotype, however, sharing significant similarities with AMR in this single-center study. Future studies are needed to validate reproducible diagnostic criteria and associated clinical outcomes to allow for defining best management of this potentially relevant phenotype.

#2403 Impact of pregnancy on kidney transplant recipients

Abstract Background and Aims Kidney transplantation (KT) provides an opportunity to increase fertility in women with chronic kidney disease and gestational desire. Lack of knowledge about obstetric complications and implications for the graft may lead to discourage pregnancy for these women. Although the incidence of pregnancy is rising in women receiving KT, the impact that it may have on the graft function is unknown. Method We conducted an observational, retrospective, single-centre study of a cohort of kidney transplant recipients (KTR) who became pregnant between 2007 and 2022. Clinical and analytical parameters were evaluated before, during and after pregnancy. The main aim was to assess the long-term impact of pregnancy on the graft by analysing renal function 3 years after pregnancy. Results We included 25 women receiving a KT between 1990 and 2018, among which 72% (n = 18) were transplanted from a deceased donor. 2 women (8%) received a combined liver-kidney transplant and 2 women (8%) a simultaneous pancreas-kidney transplant. Maintenance immunosuppression before conception included teratogenic drugs in 68% of cases [12 of them (48%) received mycophenolate mofetil and 5 of them (20%), mTOR inhibitors]. Planned withdrawal was only applied in 50.0% of pregnancies (n = 15). 30 pregnancies were identified (5 patients had 2 post-transplant pregnancies). Median age at gestation was 35 years [interquartile range (IQR) 33-39]. 5 conceptions required assisted reproductive technology. The main complications were gestational hypertension in 4 KTR (13.3%) and preeclampsia in 7 pregnancies (23.3%). 60% of neonates (n = 18) were preterm births (36 [IQR 34-37] weeks of pregnancy at birth) and 44% (n = 12) had low birth weight (2530 [IQR 2283-2950] grams). No foetal malformations were described. Due to physiological changes, a significant increase in estimated glomerular filtration rate (eGFR) was observed in the first and the second trimester of pregnancy (61 [IQR 50-91] ml/min and 70 [IQR 50-90] ml/min, respectively vs. baseline eGFR 59 [IQR 47-77] ml/min; p 0.001]. However, eGFR was equal to the previous one in the third trimester of pregnancy (60 [IQR 44-69] ml/min vs. 59 [IQR 47-77] ml/min; p 0.322). Median proteinuria remained below 0.5 g/day throughout pregnancy, without significant variation. Immunosuppression regimen during pregnancy was mainly based on a combined therapy of steroids, calcineurin inhibitors and azathioprine (21 KTR, 70%). Tacrolimus dose increase (median 63.6% [IQR 33.3-90.0%]) was necessary to maintain proper drug levels throughout gestation. Kidney graft function showed a decline in the first and second year after pregnancy compared to baseline function (54 [IQR 35-77] ml/min and 55 [IQR 36-75] ml/min vs. 59 [IQR 47-77] ml/min; p 0.018 and p 0.021, respectively]. Nevertheless, by the third year post-pregnancy, eGFR was similar to the baseline function (62 [IQR 43-73] ml/min vs. 59 [IQR 47-77] ml/min; p 0.365]. Likewise, annual eGFR variation was comparable during 3 years before (+1.0 ml/min/year) and 3 years after pregnancy (−0.9 ml/min/year), hence no worsening was observed after gestation (p 0.78). No differences were observed in proteinuria either (baseline proteinuria 0.17 [IQR 0.13-0.3] g/day vs. third-year proteinuria 0.21 [IQR 0.15-0.34] g/day; p 0.938). Only 5 women had a baseline serum creatinine above current recommendations for pregnancy (&amp;gt;1.5 mg/dl) and only 3 women presented baseline proteinuria &amp;gt; 0.5 g/day. In this group (n = 7), pregnancy occurred later after KT (96.0 [IQR 80.9-213.0] vs. 46.0 [IQR 16.0-67.5] months; p 0.024). The only 2 graft losses in the cohort were in this group. Both were attributed to transplant glomerulopathy, and they occurred at years 3 and 5 after pregnancy. On the other side, in this group there were no other baseline differences or obstetrical complications [Table 1]. Conclusion Pregnancy does not normally affect graft function and it stabilises within 3 years after gestation. It is important to increase data on women with suboptimal graft function to determine the direct implications that pregnancy may have on these KTRs.

Absence of IL-6 Receptor Blockade Effect on the Outcomes of Transplant Glomerulopathy in the Absence of Anti-HLA Donor-specific Antibodies.

Transplant glomerulopathy (TG) is the hallmark of chronic antibody-mediated rejection but often occurs without anti-HLA donor-specific antibodies (DSAs) in the assumption that other DSAs may be the effectors of the tissue injury. Recently, we reported a positive effect of interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ) in TG/DSA+. In the present study, we investigate the effect of TCZ in a cohort of TG cases without detectable anti-HLA DSAs. Single-center retrospective analysis of TG cases without anti-HLA DSAs (TG/DSA) treated with TCZ for chronic antibody-mediated rejection as first-line therapy evaluated through clinical, protocol biopsies, and gene expression analyses was included. Differently from TG/DSA+, TG/DSA- showed a progressive reduction in the estimated glomerular filtration rate at 12 mo and after that with no significant modification in microvascular inflammation or C4d+. No upregulation in tight junction protein-1, aldo-keto reductase family 1 member C3, and calcium/calmodulin-dependent serine protein kinase, documented in TG/DSA+, was noted in post-TCZ biopsies. The reduction of microvascular inflammation was associated with natural killer-cell reduction in TG/DSA+, whereas TG/DSA- tends to maintain or increase periglomerular/interstitial infiltration. In the absence of anti-HLA DSAs, TG behavior seems not to be modified by IL-6 receptor blockade. These results are at variance with observational studies and previous trials with IL-6 inhibitors in TG associated with anti-HLA DSAs. These data may fuel the hypothesis of different mechanisms underlying TGs (including the potentially different roles of natural killer cells) and suggest carefully selecting patients with TG for clinical trials or off-label treatment based on their antidonor serologic status.

Late graft failure of pig-to-rhesus renal xenografts has features of glomerulopathy and recipients have anti-swine leukocyte antigen class I and class II antibodies.

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.

Antibody-mediated Rejection in Kidney Transplant: An Unmastered Area

Antibody-mediated rejection (ABMR) remains a significant cause of allograft failure in patients with kidney transplantation. Despite successful strategies to treat ABMR, irreversible injury in the form of transplant glomerulopathy commonly manifests months to years later. Treatment for ABMR is not standardized, and treatment guidelines vary among different transplant centers. The outcomes for patients at risk for ABMR have not significantly changed over the years. This is largely because of an incomplete understanding of the mechanisms of injury responsible for different phenotypes of ABMR. Establishing relevant surrogate endpoints to facilitate more informative studies will likely allow for a more accurate determination of prognosis and pave the way for new and effective therapeutic approaches. This article aims to summarize the current understanding of the mechanism of injury in ABMR and highlight current diagnostic approaches and treatment strategies.

Transplant glomerulopathy: A brief narrative review in the light of informed literature

Transplant glomerulopathy is characterized by a post-transplant morphologic insult. It occurs as a consequence of chronic, periodic injury of endothelial cells triggered by chronic hepatitis C virus (HCV) infection, donor-specific antibodies (DSA), cell-mediated injury or thrombotic microangiopathy. The disease might not be overt; however, it often presents with obvious symptoms, such as proteinuria (nephrotic range), hypertension, and deteriorating glomerular filtration rate (GFR). Histopathology is the mainstay diagnostic tool for transplant glomerulopathy patients and electron microscopy serves the purpose to early diagnosis. The classic histopathological feature of the disease is glomerular basement membrane thickening with reduplication on light or electron microscopy without immune complex deposits. Conventional therapeutic regimens include intravenous immunoglobulins (IVIG), plasmapheresis and splenectomy, and lately rituximab, eculizumab and bortezomib. Transplant glomerulopathy patients usually have positive history for acute rejection, resulting mostly in antibody-mediated rejection. DSAs against class II is specifically linked with transplant glomerulopathy. Unfortunately, the prognosis of kidney allografts is dismal even under existing immunosuppressive regimens.

Multiomic profiling of transplant glomerulopathy reveals a novel T-cell dominant subclass

Kidney transplant (KTx) biopsies showing transplant glomerulopathy (TG) (glomerular basement membrane double contours (cg) > 0)) and microvascular inflammation (MVI) in the absence of C4d staining and donor-specific antibodies (DSA)s do not fulfill the criteria for chronic active antibody-mediated rejection (CA-AMR) diagnosis and do not fit into any other Banff category. To investigate this, we initiated a multicenter intercontinental study encompassing 36 cases, comparing the immunomic and transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA-/C4d- with 22 classified as CA-AMR DSA+/C4d+ through novel transcriptomic analysis using the NanoString Banff-Human Organ Transplant (B-HOT) panel and subsequent orthogonal subset analysis using two innovative 5-marker multiplex immunofluorescent panels. Nineteen genes were differentially expressed between the two study groups. Samples diagnosed with CA-AMR DSA+/C4d+ showed a higher glomerular abundance of natural killer cells and higher transcriptomic cell type scores for macrophages in an environment characterized by increased expression of complement-related genes (i.e., C5AR1) and higher activity of angiogenesis, interstitial fibrosis tubular atrophy, CA-AMR, and DSA-related pathways when compared to samples diagnosed with cg+MVI DSA-/C4d-. Samples diagnosed with cg+MVI DSA-/C4d- displayed a higher glomerular abundance and activity of T-cells (CD3+, CD3+CD8+, and CD3+CD8-). Thus, we show that using novel multiomic techniques, KTx biopsies with cg+MVI DSA-/C4d- have a prominent T-cell presence and activity, putting forward the possibility that these represent a more T-cell-dominant phenotype.

The Physiopathologic Roles of Calcium Signaling in Podocytes.

Calcium (Ca2+) plays a critical role in podocyte function. The Ca2+-sensitive receptors on the cell surface can sense changes in Ca2+ concentration, and Ca2+ flow into podocytes, after activation of Ca2+ channels (such as transient receptor potential canonical (TRPC) channels and N-type calcium channels) by different stimuli. In addition, the type 2 ryanodine receptor (RyR2) and the voltage-dependent anion channel 1 (VDAC1) on mitochondrial store-operated calcium channels (SOCs) on the endoplasmic reticulum maintain the Ca2+ homeostasis of the organelle. Ca2+ signaling is transmitted through multiple downstream signaling pathways and participates in the morphogenesis, structural maintenance, and survival of podocytes. When Ca2+ is dysregulated, it leads to the occurrence and progression of various diseases, such as focal segmental glomerulosclerosis, diabetic kidney disease, lupus nephritis, transplant glomerulopathy, and hypertensive renal injury. Ca2+ signaling is a promising therapeutic target for podocyte-related diseases. This review first summarizes the role of Ca2+ sensing, Ca2+ channels, and different Ca2+-signaling pathways in the biological functions of podocytes, then, explores the status of Ca2+ signaling in different podocyte-related diseases and its advances as a therapeutic target.

Histopathological diagnoses revealed by indication-based renal allograft biopsies: a retrospective analysis

Objectives: Although there have been several advances in post-solid organ transplantation immunosuppression medications over the last two decades, the long-term survival of renal allografts did not significantly improve. Renal allograft biopsy is a helpful tool for determining the cause of graft dysfunction and adjusting patient management. Methods: Patients who received kidney transplantation and underwent allograft biopsy in Istinye University Hospital between January 2017 and January 2023 constituted the target population of this study. Demographic parameters, clinical data and biopsy indications, and histopathological assessment results of the patients were retrospectively analyzed. Results: Overall, 74 patients were included. The histopathology results included acute T-Cell mediated rejection (TCMR) (n = 15, 20%), tubular atrophy/chronic allograft nephropathy (IFTA) (n = 11, 15%), calcineurin inhibitor (CNI) toxicity (n = 2, 3%), chronic antibody-mediated rejection (ABMR) (n = 2, 3%), borderline pathology (n = 10, 13.5%), normal histology (n = 5, 6.5%), transplant glomerulopathy (TG) (n = 5, 6.5%), acute ABMR (n = 4, 5%), acute tubular necrosis (n = 7, 9%), polyomavirus nephropathy (n = 3, 4%) and non-specific changes (n = 10, 13.5%). The C4d was positive in 12% (n = 9) of the graft biopsies. In 73% (n = 54) of cases, the treatment strategy was changed based on biopsy results. Among all patients, 19 (25.6%) lost their grafts during follow-up. Conclusions: According to the histopathological analysis results, acute TCMR, IFTA, and borderline pathology were the most common causes of renal graft dysfunction. Renal allograft biopsy led to a remarkable change in treatment strategies in a significant number of cases.

#4610 LACK OF EFFICACY AND SAFETY OF ECULIZUMAB FOR TREATMENT OF ANTIBODY-MEDIATED REJECTION FOLLOWING RENAL TRANSPLANTATION

Abstract Background and Aims We evaluated the efficacy and safety of eculizumab in comparison with plasmapheresis and intravenous immunoglobulin therapy in renal transplant recipients diagnosed with antibody-mediated rejection (AMR). Method This was a multicenter, open-label, prospective, randomized analysis. The patients were randomized by therapy type (eg, eculizumab infusions or standard of care [SOC]: plasmapheresis/intravenous immunoglobulin). The patients (ie, eculizumab arm: 7 patients, SOC arm: 4 patients) were evaluated for the continued presence of donor-specific antibodies (DSAs) and C4d (staining on biopsy), as well as histologic evidence, using repeat renal biopsy after treatment. Results The allograft biopsies revealed that eculizumab did not prevent the progression to transplant glomerulopathy. Cases of AMR were diagnosed in the early post-transplantation period in 2 patients (eculizumab arm: 1 patient, SOC arm: 1 patient) and in the late period in 9 patients. Most of the reports show that eculizumab, in combination with other therapeutic measures such as PP and/or IVIG, effectively reversed rejection. However, eculizumab alone could not treat AMR effectively. Only 2 patients in the SOC arm experienced rejection reversal, and no graft losses occurred in either group. After AMR treatment, the DSA titers generally decreased compared to titers taken at the time of AMR diagnosis. There were no serious adverse effects in the eculizumab arm. Conclusion Eculizumab alone cannot treat AMR effectively and does not prevent acute AMR from progressing to chronic AMR or transplant glomerulopathy. However, it should be considered as a potential alternative therapy because it may be associated with decreased DSA levels.

The Trend of Serum Creatinine Does Not Predict Follow-Up Biopsy Findings Among Kidney Transplant Recipients With Antibody-Mediated Rejection.

We included all cases of AMR at our program between March 2016 and July 2020 who had a follow-up biopsy after the index biopsy, with initial diagnosis of AMR. We trended the Scr and change in Scr (delta Scr) and its association with being a responder (microvascular inflammation, MVI ≤1) or nonresponder (MVI >1), as well as graft failure. A total of 183 kidney transplant recipients were included, 66 in the responder group and 177 in the nonresponder group. The MVI scores and sum chronicity scores, along with transplant glomerulopathy scores, were higher in the nonresponder group. However, Scr at index biopsy was similar in responders (1.74 ± 0.70) versus nonresponders (1.83 ± 0.65; P = 0.39), as were the delta Scr at various time points. After adjustment for multiple variables, delta Scr was not associated with being a nonresponder. Also, delta Scr value at follow-up biopsy compared with index biopsy among responders was 0 ± 0.67 (P = 0.99) and among nonresponders was -0.01 ± 0.61 (P = 0.89). Being a nonresponder was significantly associated with an increased risk of graft failure at the last follow-up in univariate analysis but was not in multivariate analysis (hazard ratio 1.35; 95% confidence interval, 0.58-3.17; P = 0.49). We found that Scr is not a good predictor of the resolution of MVI, supporting the utility of follow-up biopsies after treatment of AMR.

Quantitative scoring of progression in transplant glomerulopathy using digital pathology may be superior to Banff cg scoring

Antibody-mediated rejection (ABMR) is a major cause of kidney allograft failure. Biopsy-based surrogate endpoints reflecting ABMR progression on sequential biopsies that predict long-term outcome offer the potential to make treatment trials for ABMR feasible. However, the Banff transplant glomerulopathy (TG) scoring system (chronic glomerular injury score [cg]) relies on relatively crude and arbitrary ordinal grades and has low inter-observer concordance that currently limits its usefulness as a surrogate endpoint for ABMR progression in clinical drug trials. Here, we describe and validate a novel quantitative method for quantifying progression of TG in ABMR. Using digital pathology in sequential biopsies from 75 patients at various stages of ABMR, we scored all capillaries in the most affected glomeruli for basement membrane duplication that were correlated with allograft function, outcome, Banff lesion scores, and gene expression. Our digital scoring reflected TG progression better than the categorical Banff cg score and correlated with Banff ABMR and chronicity lesions, but not transcript changes. In multivariate analysis, the delta change between biopsies with serum creatinine and mean percent duplicated glomerular basement membranes was significantly associated with graft loss. Neither the delta in any Banff lesion scores (including cg) nor in gene expression was associated with outcome. Receiver operating characteristic curve analysis showed that the digital pathology approach was superior to the conventional score for predicting graft failure. Thus, our digital pathology-based approach for scoring TG accurately assessed progression in TG. However, further validation as a potential surrogate endpoint in clinical trials for the treatment of ABMR is warranted.

Data-Driven Chronic Allograft Phenotypes: A Novel and Validated Complement for Histologic Assessment of Kidney Transplant Biopsies.

No validated system currently exists to realistically characterize the chronic pathology of kidney transplants that represents the dynamic disease process and spectrum of disease severity. We sought to develop and validate a tool to describe chronicity and severity of renal allograft disease and integrate it with the evaluation of disease activity. The training cohort included 3549 kidney transplant biopsies from an observational cohort of 937 recipients. We reweighted the chronic histologic lesions according to their time-dependent association with graft failure, and performed consensus k-means clustering analysis. Total chronicity was calculated as the sum of the weighted chronic lesion scores, scaled to the unit interval. We identified four chronic clusters associated with graft outcome, based on the proportion of ambiguous clustering. The two clusters with the worst survival outcome were determined by interstitial fibrosis and tubular atrophy (IFTA) and by transplant glomerulopathy. The chronic clusters partially overlapped with the existing Banff IFTA classification (adjusted Rand index, 0.35) and were distributed independently of the acute lesions. Total chronicity strongly associated with graft failure (hazard ratio [HR], 8.33; 95% confidence interval [CI], 5.94 to 10.88; P<0.001), independent of the total activity scores (HR, 5.01; 95% CI, 2.83 to 7.00; P<0.001). These results were validated on an external cohort of 4031 biopsies from 2054 kidney transplant recipients. The evaluation of total chronicity provides information on kidney transplant pathology that complements the estimation of disease activity from acute lesion scores. Use of the data-driven algorithm used in this study, called RejectClass, may provide a holistic and quantitative assessment of kidney transplant injury phenotypes and severity.