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

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

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.].

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 >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.

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 >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.

Measurement of Complement Activation via Plasma-Soluble C5b-9 Comparison with Terminal Complement Complex Staining in a Series of Kidney Biopsies.

INTRODUCTION: With the emergence of therapeutic complement inhibitors, there is a need to identify patients with complement-driven inflammation. C5b-9 is the terminal product of the three complement pathways and therefore a marker of total complement activation. We present a pilot study which aims to assess whether plasma soluble C5b-9 (sC5b-9) correlates with terminal complement complex (TCC) staining in kidney tissue. The secondary aim was to assess the utility of plasma sC5b-9 as part of routine workup in kidney patients undergoing kidney biopsy. METHODS: Thirty-seven patients undergoing kidney biopsy had plasma sC5b-9 and TCC staining on kidney tissue performed. Additional blood markers including creatinine, haemoglobin, CRP, factor H, factor I, and midkine levels were also taken. These parameters were correlated with the histological diagnoses. Patients were divided into a diseased group (n = 31) and a control group (n = 6) consisting of transplanted kidneys with minor or no changes. Of the biopsies in the control group, 50% were performed as per protocol, and the other 50% were performed due to clinical need. RESULTS: There was no correlation found between plasma sC5b-9 and TCC kidney staining. Elevated sC5b-9 levels were found in a heterogeneous group of patients but were associated with higher CRP and lower haemoglobin levels. Overall, there was more TCC kidney staining in the diseased group compared with the control group, and a trend was observed of diabetic, primary membranous nephropathy, and amyloidosis patients having more intense glomerular and peritubular/interstitial staining. CONCLUSION: Plasma sC5b-9 as a marker of total complement activation does not correlate with TCC kidney staining. This discordance suggests that plasma sC5b-9 and TCC staining are distinct markers of disease. TCC staining reflects chronicity and tissue deposition of complement over time. Conversely, plasma sC5b-9 concentrations change rapidly and reflect systemic complement activation. Complement activation was present in a heterogeneous group of kidney disease, indicating the underlying role of complement in many disorders.

A novel missense LIPA gene mutation, N98S, in a patient with cholesteryl ester storage disease.

Lysosomal acid lipase plays an important role in maintaining cellular cholesterol homeostasis. Complete absence of lysosomal acid lipase activity results in Wolman disease and usually death in infancy, whereas partial deficiency of lysosomal acid lipase results in cholesteryl ester storage disease (CESD). We describe a 26 year-old female with CESD who presented with recurrent right upper quadrant abdominal pain. Abnormal liver function tests and a subsequent liver biopsy revealed features consistent with CESD. Sequencing of the LIPA gene revealed that she was a compound heterozygote for the previously reported exon 8 splice junction mutation and a novel missense mutation (N98S) in exon 4. The splice junction mutation allows some (approximately 3%) normal splicing to occur, and therefore gives rise to residual lysosomal acid lipase activity. Asn98 in lysosomal acid lipase is highly conserved among species and mutation of this residue could influence catalytic activity or accessibility to the active site. In summary, we describe a CESD patient compound heterozygous for the LIPA exon 8 splice junction mutation and a novel missense mutation, N98S.

Refinement of immunohistologic parameters for Her2/neu scoring validation by FISH and CISH.

The conventional method of scoring Her2/neu immunostaining is recognized to result in a high false-positive rate among 2+ cases when compared with results obtained with fluorescence in situ hybridization (FISH); however, costs and convenience dictates that immunohistochemistry remains the screening test for Her2/neu status in patients with breast cancer. We describe refined criteria for scoring of Her2/neu on the basis of anatomic localization rather than the subjective assessment of intensity. The presence of a circumferential tram track pattern that results from the staining of apposing cell membranes in >25% of the tumor cells was necessary for a 3+ score (Her2/neu overexpressed) and the presence of the tram track pattern in <25% was scored 2+ (equivocal); granular and fragmented membrane staining was scored 1+ (negative). The tram track pattern of Her2/neu overexpression showed 100% concordance with gene amplification. FISH and CISH testing in selected cases from the other categories validated the revised scoring method. These criteria reduced the numbers of equivocal staining cases that required FISH testing.

Aortic valve lipoma.

Cardiac lipoma (especially on the aortic valve) is extremely rare. We report a patient suffering from shortness of breath, chest pain, and recent presyncopal episodes who was found to have a mass on the aortic valve with mild aortic regurgitation. The patient had an uneventful aortic valve replacement.