Diagnosis Of Transplant Glomerulopathy Research Articles

Archetype Analysis Identifies Distinct Profiles in Renal Transplant Recipients with Transplant Glomerulopathy Associated with Allograft Survival.

Transplant glomerulopathy, a common glomerular lesion observed after kidney transplant that is associated with poor prognosis, is not a specific entity but rather the end stage of overlapping disease pathways. Its heterogeneity has not been precisely characterized to date. Our study included consecutive kidney transplant recipients from three centers in France and one in Canada who presented with a diagnosis of transplant glomerulopathy (Banff cg score ≥1 by light microscopy), on the basis of biopsies performed from January of 2004 through December of 2014. We used an unsupervised archetype analysis of comprehensive pathology findings and clinical, immunologic, and outcome data to identify distinct groups of patients. Among the 8207 post-transplant allograft biopsies performed during the inclusion period, we identified 552 biopsy samples (from 385 patients) with transplant glomerulopathy (incidence of 6.7%). The median time from transplant to transplant glomerulopathy diagnosis was 33.18 months. Kidney allograft survival rates at 3, 5, 7, and 10 years after diagnosis were 69.4%, 57.1%, 43.3%, and 25.5%, respectively. An unsupervised learning method integrating clinical, functional, immunologic, and histologic parameters revealed five transplant glomerulopathy archetypes characterized by distinct functional, immunologic, and histologic features and associated causes and distinct allograft survival profiles. These archetypes showed significant differences in allograft outcomes, with allograft survival rates 5 years after diagnosis ranging from 88% to 22%. Based on those results, we built an online application, which can be used in clinical practice on the basis of real patients. A probabilistic data-driven archetype analysis approach applied in a large, well defined multicenter cohort refines the diagnostic and prognostic features associated with cases of transplant glomerulopathy. Reducing heterogeneity among such cases can improve disease characterization, enable patient-specific risk stratification, and open new avenues for archetype-based treatment strategies and clinical trials optimization.

Clinical, Histological, and Molecular Markers Associated With Allograft Loss in Transplant Glomerulopathy Patients.

We aimed to investigate the clinical, histopathological, and molecular factors associated with allograft loss in transplant glomerulopathy (TGP) patients. Of the 525 patients who underwent clinically indicated kidney biopsies, 52 (10%) had diagnosis of TGP. Gene expression profiles of 28 TGP and 11 normal transplant kidney biopsy samples were analyzed by Affymetrix HuGene 1.0 ST expression arrays. Over a median follow up of 23 months (1-46 months) after the diagnosis of TGP by biopsy, 17 patients (32%) lost their allografts at a median of 16 months (1-44 months). There was no difference between the 2 groups in terms of any demographic variables, serum creatinine, panel reactive antibody levels, donor-specific antibody frequency, or mean fluorescence intensity values. Patients who lost their allograft had a significantly higher median spot protein to creatinine ratio 2.81 (1.20-6.00) compared to no graft loss patients 1.16 (0.15-2.53), (P < 0.01), and a trends toward a higher mean chronic glomerulopathy (cg) score (1.65 ± 0.93 vs 1.11 ± 0.93) (P = 0.05). There was also no difference in microvascular inflammation or any other Banff injury scores between the 2 groups. Although 117 gene transcripts were upregulated in both groups, 86 and 57 were upregulated in graft loss and functioning allograft groups, respectively. There were significantly increased levels of intragraft endothelial cell-associated transcripts, gene transcripts associated with complement cascade, interleukins and their receptors and granulysin in graft loss patients compared to patients with a functioning allograft. Our results demonstrate differential intragraft gene expression profiles in TGP patients with allograft loss.

Transplant glomerulopathy: Evolution of morphologically distinct changes

AbstractTransplant glomerulopathy: Evolution of morphologically distinct changes. The study was undertaken to redefine morphological appearance and clinical implications of the diagnosis of transplant glomerulopathy (TGP). Fifty-seven renal transplant biopsy specimens from thirty patients with the diagnosis of TGP were evaluated. Multiple repeat biopsies in several cases enabled us to follow the pattern of the evolution of the changes. Transplant dysfunction manifested itself 8 days to 13 years post-transplantation by proteinuria and/or elevated creatinine level. The earliest recognizable morphological change was the swelling of endothelial and mesangial cells. This stage was called evolving TGP. The intermediate stage was characterized by enlarged glomeruli with lobular simplification, spongy matrix, and glomerular basement membrane (GBM) deformities. The advanced stage of TGP showed pronounced GBM changes (reduplication, interposition). These light microscopic changes were associated with vascular rejection. Immunofluorescence showed significant glomerular deposition of IgM (83% of biopsies) and fibrinogen (66%). Electron microscopy at an early stage showed subendothelial widening with cellular debris and focal endothelial damage with fibrin deposition. In the advanced stage, complex GBM changes developed as a reparative response to the capillary wall injury. Effacement of foot processes was a constant finding at all stages. In follow-up, twenty-three allografts failed (77%), five patients are stable, and two died due to other causes. TGP has specific morphology with an attendant poor long-term prognosis for the allograft.Glomérulopathie du transplant: Evolution de changements morphologiquement distincts. Cette étude a été entreprise pour redéfinir l'aspect morphologique et les implications cliniques du diagnostic de glomérulopathie du transplant (TGP). Cinquante-sept spécimens biopsiques de transplants rénaux provenant de trente malades porteurs du diagnostic de TGP ont été évaluées. Des biopsies répétées de multiples fois dans plusieurs cas nous ont permis de suivre l'aspect évolutif des modifications. Le dysfonctionnement du transplant se manifestait lui-même de 8 jours à 13 ans après la transplantation par une protéinurie et/ou un niveau de créatinine élevé. La modification morphologique reconnaissable le plus précocement était un gonflement des cellules endothéliales et mésangiales. Ce stade était appelé TGP en apparition. Le stade intermédiaire était caractérisé par des glomérules de taille accrue, avec une simplification lobulaire, une matrice spongieuse, et des déformations de la membrane basale glomérulaire (GBM). Le stade avancé de TGP présentait des modifications prononcées de la GBM (déboublement, interposition). Ces modifications en microscopie optique étaient associées à un rejet vasculaire. L'immunofluorescence révélait des dépôts glomérulaires significatifs d'IgM (83% des biopsies) et de fibrinogène (66%). La microscopie électronique à un stade précoce révélait un épaississement sous-endothélial avec des débris cellulaires et des lésions endothéliales focales avec dépôts de fibrine. Au stade avancé, des modifications complexes de la GBM se développaient à titre de réponse réparative aux altérations de la paroi capillaire. L'effacement des pédicelles était un fait constant à tous les stades. Lors du suivi, vingt trois allogreffes ont échoué (77%), cinq malades sont stables, et deux sont décédées d'autres causes. TGP a une morphologie spécifique avec un pronostic associé à long terme défavorable pour l'allogreffe.