Thrombotic Microangiopathy in the Renal Allograft:Results of the TMA Banff Working Group Consensus on Pathologic Diagnostic Criteria

The Banff community summoned the TMA Banff Working Group to develop minimum diagnostic criteria (MDC) and recommendations for renal transplant TMA (Tx-TMA) diagnosis, which currently lacks standardized criteria. Using the Delphi method for consensus generation, 23 nephropathologists (panelists) with &gt;3 years of diagnostic experience with Tx-TMA were asked to list light, immunofluorescence, and electron microscopic, clinical and laboratory criteria and differential diagnoses for Tx-TMA. Delphi was modified to include 2 validations rounds with histological evaluation of whole slide images of 37 transplant biopsies (28 TMA and 9 non-TMA). Starting with 338 criteria in R1, MDC were narrowed down to 24 in R8 generating 18 pathological, 2 clinical, 4 laboratory criteria, and 8 differential diagnoses. The panelists reached a good level of agreement (70%) on 76% of the validated cases. For the first time in Banff classification, Delphi was used to reach consensus on MDC for Tx-TMA. Phase I of the study (pathology phase) will be used as a model for Phase II (nephrology phase) for consensus regarding clinical and laboratory criteria. Eventually in Phase III (consensus of the consensus groups) and the final MDC for Tx-TMA will be reported to the transplantation community.</p

Delphi:A Democratic and Cost-Effective Method of Consensus Generation in Transplantation

The Thrombotic Microangiopathy Banff Working Group (TMA-BWG) was formed in 2015 to survey current practices and develop minimum diagnostic criteria (MDC) for renal transplant TMA (Tx-TMA). To generate consensus among pathologists and nephrologists, the TMA BWG designed a 3-Phase study. Phase I of the study is presented here. Using the Delphi methodology, 23 panelists with &gt;3 years of diagnostic experience with Tx-TMA pathology listed their MDC suggesting light, immunofluorescence, and electron microscopy lesions, clinical and laboratory information, and differential diagnoses. Nine rounds (R) of consensus resulted in MDC validated during two Rs using online evaluation of whole slide digital images of 37 biopsies (28 TMA, 9 non-TMA). Starting with 338 criteria the process resulted in 24 criteria and 8 differential diagnoses including 18 pathologic, 2 clinical, and 4 laboratory criteria. Results show that 3/4 of the panelists agreed on the diagnosis of 3/4 of cases. The process also allowed definition refinement for 4 light and 4 electron microscopy lesions. For the first time in Banff classification, the Delphi methodology was used to generate consensus. The study shows that Delphi is a democratic and cost-effective method allowing rapid consensus generation among numerous physicians dealing with large number of criteria in transplantation.</p

Hypoxia-inducible factor-1α (HIF-1α) and autophagy in polycystic kidney disease (PKD)

Cyst expansion in polycystic kidney disease (PKD) results in localized hypoxia in the kidney that may activate hypoxia-inducible factor-1α (HIF-1α). HIF-1α and autophagy, a form of programmed cell repair, are induced by hypoxia. The purposes were to determine HIF-1α expression and autophagy in rat and mouse models of PKD. HIF-1α was detected by electrochemiluminescence. Autophagy was visualized by electron microscopy (EM). LC3 and beclin-1, markers of autophagy, were detected by immunoblotting. Eight-week-old male heterozygous (Cy/+) and 4-wk-old homozygous (Cy/Cy) Han:SPRD rats, 4-wk-old cpk mice, and 112-day-old Pkd2WS25/− mice with a mutation in the Pkd2 gene were studied. HIF-1α was significantly increased in massive Cy/Cy and cpk kidneys and not smaller Cy/+ and Pkd2WS25/− kidneys. On EM, features of autophagy were seen in wild-type (+/+), Cy/+, and cpk kidneys: autophagosomes, mitophagy, and autolysosomes. Specifically, autophagosomes were found on EM in the tubular cells lining the cysts in cpk mice. The increase in LC3-II, a marker of autophagosome production and beclin, a regulator of autophagy, in Cy/Cy and cpk kidneys, followed the same pattern of increase as HIF-1α. To determine the role of HIF-1α in cyst formation and/or growth, Cy/+ rats, Cy/Cy rats, and cpk mice were treated with the HIF-1α inhibitor 2-methoxyestradiol (2ME2). 2ME2 had no significant effect on kidney volume or cyst volume density. In summary, HIF-1α is highly expressed in the late stages of PKD and is associated with an increase in LC3-II and beclin-1. The first demonstration of autophagosomes in PKD kidneys is reported. Inhibition of HIF-1α did not have a therapeutic effect

Prognostic significance of glomerular and tubulointerstitial morphometry in idiopathic membranous nephropathy

The purpose of our study was to investigate the prognostic value of clinical and pathological, in particular glomerular and tubulointerstitial morphometric variables in idiopathic membranous nephropathy (IMN). We prospectively followed 60 Caucasian patients diagnosed with idiopathic membranous nephropathy for at least 2 years or until primary outcome (≥50% permanent decrease in estimated glomerular filtration rate or death). Glomerular and tubulointerstitial morphometric variables at the time of renal biopsy were analyzed with respect to this outcome. Univariate analysis revealed that significant negative prognostic factors for this outcome were higher cholesterol and smaller albumin concentrations, higher creatinine and maximal 24-h proteinuria, higher grade of nephroangiosclerosis, higher glomerular basement membrane thickness and glomerulopathy index, higher interstitial fibrosis and tubular atrophy percentage and higher injury score. In multivariate analysis, only the maximal 24-h proteinuria and interstitial fibrosis and tubular atrophy percentage were independent predictors of this outcome. The results suggest that morphometric analysis, mainly quantitative measurement of interstitial fibrosis and tubular atrophy percentage, injury score, glomerular basement membrane thickness and glomerulopathy index could be used as an additional method for risk stratification of patients with idiopathic membranous nephropathy

Impact of Consensus Definitions on Identification of Glomerular Lesions by Light and Electron Microscopy

Introduction: In 2020, a working group of 13 renal pathologists published consensus definitions for 47 individual glomerular lesions found on light microscopy (LM) and 47 glomerular lesions and 9 normal structures found on electron microscopy (EM). Methods: To test the impact of these definitions on identification of these lesions and structures, 2 surveys were circulated to all members of the Renal Pathology Society (RPS), each having 32 images (19 LM, 13 EM) and accompanying questions with 5 multiple-choice answers, one being the consensus choice of the working group. The first survey (survey 1 [S1]), answered by 297 RPS members, was sent in September 2020, before publication of the consensus definitions. The second (survey 2 [S2]), with images of the same lesions and structures (but not the same images) and the same questions and multiple choices in different order, was sent in April 2020, 5 months after the publication of the definitions. Results: S2 was taken by 181 RPS members; 64% also took S1 and 61% reported having read the definitions paper (def. paper). Mean agreement with the consensus answers increased modestly between the 2 surveys (65.2% vs. 72.0%, P = 0.097); the increase was greater and significant when only respondents to S2 who read the def. paper were considered (65.2% vs. 74.8%, P = 0.026). Furthermore, in S2 agreement with consensus answers was greater among respondents who read this paper versus those who did not (66.9% vs. 74.8%, P < 0.0001). Conclusions: Publication of the consensus definitions modestly improved interobserver agreement in identification of glomerular lesions

Impact of Consensus Definitions on Identification of Glomerular Lesions by Light and Electron Microscopy

Introduction: In 2020, a working group of 13 renal pathologists published consensus definitions for 47 individual glomerular lesions found on light microscopy (LM) and 47 glomerular lesions and 9 normal structures found on electron microscopy (EM). Methods: To test the impact of these definitions on identification of these lesions and structures, 2 surveys were circulated to all members of the Renal Pathology Society (RPS), each having 32 images (19 LM, 13 EM) and accompanying questions with 5 multiple-choice answers, one being the consensus choice of the working group. The first survey (survey 1 [S1]), answered by 297 RPS members, was sent in September 2020, before publication of the consensus definitions. The second (survey 2 (S2]), with images of the same lesions and structures (but not the same images) and the same questions and multiple choices in different order, was sent in April 2020, 5 months after the publication of the definitions. Results: S2 was taken by 181 RPS members; 64% also took 51 and 61% reported having read the definitions paper (def. paper). Mean agreement with the consensus answers increased modestly between the 2 surveys (65.2% vs. 72.0%, P = 0.097); the increase was greater and significant when only respondents to S2 who read the def. paper were considered (65.2% vs. 74.8%, P = 0.026). Furthermore, in S2 agreement with consensus answers was greater among respondents who read this paper versus those who did not (66.9% vs. 74.8%, P < 0.0001). Conclusions: Publication of the consensus definitions modestly improved interobserver agreement in identification of glomerular lesions

Corrigendum: Thrombotic Microangiopathy in the Renal Allograft: Results of the TMA Banff Working Group Consensus on Pathologic Diagnostic Criteria

[This corrects the article DOI: 10.3389/ti.2023.11590.]

Corrigendum: Delphi: A Democratic and Cost-Effective Method of Consensus Generation in Transplantation

[This corrects the article DOI: 10.3389/ti.2023.11589.]