The Banff 2022 Kidney Meeting Work Plan: Data-driven refinement of the Banff Classification for renal allografts.

The XVIth Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from September 19 to 23, 2022, as a joint meeting with the Canadian Society of Transplantation. In addition to a key focus on the impact of microvascular inflammation and biopsy-based transcript analysis on the Banff Classification, further sessions were devoted to other aspects of kidney transplant pathology, in particular T cell-mediated rejection, activity and chronicity indices, digital pathology, xenotransplantation, clinical trials, and surrogate endpoints. Although the output of these sessions has not led to any changes in the classification, the key role of Banff Working Groups in phrasing unanswered questions, and coordinating and disseminating results of investigations addressing these unanswered questions was emphasized. This paper summarizes the key Banff Meeting 2022 sessions not covered in the Banff Kidney Meeting 2022 Report paper and also provides an update on other Banff Working Group activities relevant to kidney allografts.

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.

Proliferative glomerulonephritis with monoclonal IgG deposits: a unique case with a clinical course of over 46 years.

BACKGROUND: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a rare entity first described in 2004. We present a case of PGNMID with recurrent hematuria and nephrotic range proteinuria with three biopsies over 46 years. CASE PRESENTATION: A 79-year-old Caucasian female presents with a history of two separate episodes of biopsy-proven recurrent GN over a course of 46 years. Both biopsies from 1974, and 1987 were reported as membranoproliferative GN (MPGN). The patient presented in 2016 for the third time with symptoms of fluid overload, slight worsening in renal function, and proteinuria along with glomerular hematuria. A third kidney biopsy was performed, and the final diagnosis was proliferative glomerulonephritis with monoclonal IgG/κ deposits. CONCLUSION: With three renal biopsies obtained over 46 years, our case opens a unique window into the natural history of PGNMID. The three biopsies demonstrate the immunologic and morphologic evolution of PGNMID in the kidney.

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.

Epitope Spreading: The Underlying Mechanism for Combined Membranous Lupus Nephritis and Anti-GBM Disease?

Membranous lupus nephritis associated with anti-GBM antibodies is a rare entity, particularly in lupus nephritis patients who are serologically negative for ANA and anti-dsDNA with normal complement levels. We present an unusual case of a patient initially diagnosed with anti-GBM disease whose repeat biopsy demonstrated combined focal proliferative and membranous lupus nephritis (III + V). The first biopsy showed a granular linear pattern, and the second biopsy had multiple electron dense deposits in the subendothelial, epithelial, and mesangial regions along with podocyte effacement. Experimental research suggests that the sequential histopathological transition observed may reflect the action of immunological rearrangement and epitope spreading.

Kidney Pathology of Tropical and Nontropical Infectious Diseases in the Pediatric Population.

OBJECTIVES: To review kidney pathology of tropical and nontropical infectious diseases in the pediatric population. METHODS: We review 4 tropical and 2 nontropical infectious diseases that affect the kidneys of children in terms of their direct and indirect pathogenetic mechanism in inducing kidney damage. RESULTS: We demonstrate clinical manifestations, pathogenesis, kidney pathology, and laboratory diagnostic methods for (1) renal cryptococcosis, which represents involvement of a pure direct pathway; (2) schistosomiasis and dengue fever as examples of dual direct and indirect pathways; and (3) congenital syphilis, visceral leishmaniasis, and Chagas disease, which represent indirect pathways. CONCLUSIONS: Infective agents affect the kidneys of children mainly through indirect mechanisms, such as through immunological mechanisms as part of an antigenic response. A direct mechanism of kidney injury, however, is less known within the medical community simply because the direct mechanism is rarely encountered in nontropical countries. In some infectious diseases, both indirect and direct pathways are responsible in inducing 2 sets of morphologically separate kidney lesions.

A Case of Lansoprazole-Induced Bullous Pemphigoid After Zantac Recall.

Proton pump inhibitors (PPIs) are the mainstay of treatment for many gastric acid-related diseases with a relatively safe drug profile. One of the rare side effects is PPI-induced bullous pemphigoid. We describe a case of new-onset bullous pemphigoid on initiation of lansoprazole for esophagitis after a nationwide Zantac recall. This condition can improve with the cessation of PPI and the use of corticosteroids. However, it poses a significant challenge to the management of gastroesophageal reflux disease by limiting available pharmacologic options. In addition, this case highlights the negative effects of a drug recall.

Case Report: Renal Failure due to Focal Segmental Glomerulosclerosis in a Patient with Murine Typhus.

Murine typhus is a flea-borne rickettsiosis caused by Rickettsia typhi. When severe, endothelial dysfunction can lead to acute kidney injury secondary to prerenal azotemia or acute tubular necrosis. Here, we describe an unusual cause of kidney injury during the course of murine typhus-focal segmental glomerulosclerosis.

Lymphoma-Associated Monoclonal Cryoglobulinemic Glomerulonephritis and Relationship with Hepatitis C Virus Infection: A Case Report.

We report a case of type I cryoglobulinemic glomerulonephritis in a patient with chronic hepatitis C who presented with acute renal failure. The renal biopsy revealed membranoproliferative GN (MPGN) due to cryoglobulinemia with unexpected monoclonal Kappa restriction on immunofluorescence microscopy, suggesting an underlying hematopoietic malignancy. The bone marrow biopsy revealed presence of marginal zone lymphoma. Our case raises awareness regarding possibility of monoclonality in the renal biopsy of HCV-infected patients and exemplifies the crucial role the renal biopsy plays in detecting lymphoid malignancies where clinical features are ambiguous.

The Impact of Renal Tissue Procurement at Bedside on Specimen Adequacy and Best Practices.

Objectives: Renal biopsy is the gold standard for the diagnosis of both native and allograft renal diseases. We studied the impact of tissue procurement at bedside (TPB) omission on the adequacy of renal biopsies. Methods: We compared 120 renal biopsies collected during 2015 using TPB with 111 renal biopsies collected during 2016 when TPB was discontinued. Adequacy criteria were applied as follows: by light microscopy, 10 glomeruli and two arteries for allograft biopsies and seven glomeruli for native biopsies. At least one glomerulus was considered adequate for immunofluorescence and electron microscopy in both groups. Results: The rate of inadequacies in allograft biopsies increased significantly, from 12.50% to 21.61% (P < .05), when TPB was discontinued. Conclusions: Elimination of TPB service had a negative impact on allograft specimen adequacy. Repeat biopsies add cost and delay patient care. Institutions should take this into consideration when considering omission of TPB.

Florid Proliferation of Hyalinized Vessels in a Spermatic Cord STAT6 Positive Solitary Fibrous Tumor and Its Potential Clinical Implications.

A solitary fibrous tumor (SFT) arising in the paratesticular region is a rare event. Typically most SFTs present as a lung mass and have a characteristic microscopic appearance. Although uncommon, SFTs may present at just about any anatomical site. Here we present a case of a SFT arising along the right spermatic cord, with histologic features mimicking a cellular angiofibroma. We describe the diagnostic immunohistochemical markers useful for arriving at its diagnosis. We also summarize our current understanding of the structural and molecular features that make up SFTs and discuss how these features may help us better understand the pathophysiology of pluripotent mesenchymal stem cell differentiation.

Role of the efflux transporters BCRP and MRP1 in human placental bio-disposition of pravastatin.

The expression and activity of human placental transporters during pregnancy could be altered by several factors including pathological changes associated with preeclampsia. The aims of this study were to identify the placental efflux transporters involved in the bio-disposition of pravastatin, determine the protein expression of these transporters and their encoding genes as well as the activity of pravastatin uptake in placentas obtained from patients with preeclampsia. ATP-dependent uptake of [3H]-pravastatin by trophoblast tissue apical and basal membrane vesicles exhibited sigmoidal kinetics. The curved shapes of Eadie-Hofstee plots indicate that more than one placental transporter are involved in the uptake of pravastatin. ATP-dependent uptake of [3H]-pravastatin into vesicles expressing MRP1-5, BCRP, and P-gp, as well as the results of inhibition studies suggest that BCRP and MRP1 are the major placental efflux transporters responsible for the in vitro uptake of pravastatin. Compared to placentas from healthy pregnancies, preeclamptic placentas had increased number of syncytial knots with increased expression of BCRP in their apical membrane and increased expression of MRP1 in the cytoplasm of the syncytiotrophoblast and in cytoplasm of syncytial knots. There was a concomitant increase in ABCC1 but not in ABCG2 gene expressions in preeclamptic placentas. ATP-dependent uptake of [3H]-pravastatin by vesicles prepared from apical membranes of preeclamptic placentas was similar to the uptake by vesicles prepared from placentas obtained after uncomplicated pregnancies (13.9 ±â€¯6.5 vs 14.1 ±â€¯5.8 pmol·mg protein-1 min-1). The transporter-specific changes in the expression of BCRP and MRP1 in preeclamptic placentas did not affect the efflux activity of transporters localized on the apical membrane of the syncytiotrophoblast.

Bile Cast Nephropathy in Cirrhotic Patients: Effects of Chronic Hyperbilirubinemia.

OBJECTIVES: The aim of this study was to determine the prevalence of bile cast nephropathy (BCN) in autopsied cirrhotic patients and to correlate BCN with clinical and laboratory data to direct attention to this underrecognized renal complication of liver failure. METHODS: We assessed 114 autopsy cases of cirrhosis for the presence of renal intratubular bile casts using Hall stain for bile. Presence of bile casts was correlated with etiology of cirrhosis, clinical and laboratory data, and histologic findings. RESULTS: Bile casts were identified in 55% of cases. The most common etiology of cirrhosis was hepatitis C virus (HCV) infection (52%), and serum creatinine ( P = .02) and serum urea nitrogen ( P = .01) were significantly higher in the Hall-positive group. Conjugated bilirubin was below 20 mg/dL in 90%, and levels below 10 mg/dL were noted in 80% of cases. CONCLUSIONS: To our knowledge, this is the largest study of BCN in human subjects and a first report describing the association of BCN with HCV-related cirrhosis. We demonstrated that in the face of protracted chronic hyperbilirubinemia, bile casts are formed at much lower bilirubin levels than previously thought. Furthermore, we proposed an algorithm to assist in better identification of bile casts.

Levamisole-Adulterated Cocaine Nephrotoxicity: Ultrastructural Features.

OBJECTIVES: The issue of levamisole-adulterated cocaine is emerging as a rapidly growing public health concern due to an increasing number of reports describing its role in cutaneous vasculitis and agranulocytosis. Of note, levamisole is recognized as a contaminant in 69% of the cocaine used within the United States. METHODS: We describe a patient who was a chronic cocaine user and developed systemic vasculitis characterized by polyarthralgia, bullous skin lesions, agranulocytosis, and antineutrophil cytoplasmic antibody-positive rapidly progressive glomerulonephritis. RESULTS: The skin biopsy specimen demonstrated leukocytoclastic vasculitis. The renal biopsy specimen revealed pauci-immune necrotizing and crescentic glomerulonephritis and unusual deposits with medium electron density composed of granules, microspherules, and rare single fibrils on electron microscopy. CONCLUSIONS: The electron microscopic features of levamisole-adulterated cocaine toxicity are novel findings that are presented for the first time, to our knowledge, in this report.

Renal medullary carcinoma as an incidental finding in a horseshoe kidney: case report and literature review.

Renal medullary carcinoma is rare and extremely aggressive neoplasm that typically affects young patients of African decent who demonstrate sickle cell trait or disease. Since the original description in 1995, only few cases have been reported outside the United States. A 29 year-old Canadian male of Afro-Caribbean decent with sickle cell trait developed right-sided hemiparesis due to brain infarct. During the clinical work-up, a 3 cm renal tumor was detected in a horseshoe kidney. The patient died suddenly 2 weeks after the presentation of massive non-neoplastic pulmonary thromboembolism, confirmed at autopsy. The final diagnosis of renal medullary carcinoma was established after the autopsy. Due to the small size of the tumor and the limited metastatic spread only to the regional lymph nodes, the tumor was considered an incidental finding, and not the primary cause of patient's death.

Four miniature kidneys: supernumerary kidney and multiple organ system anomalies.

More than 350 years after Martius's first reported case in 1656, supernumerary kidney (SNK) continues to fascinate the world of medicine, generating new ideas in the domain of embryogenesis. Association of a normal kidney with a second or third ipsilateral smaller kidney is an extremely rare anomaly with only a total of 81 cases reported until today. We are reporting a case of SNK, clinically diagnosed as right hydronephrosis, associated with an ipsilateral ectopic ureter, a contralateral partially duplicated ureter, and a multiseptate gallbladder. Pathologic examination of the nephrectomy revealed 4 miniature kidneys, joining a dilated ureter through 4 separate conduits. Our patient is the first reported case of SNK with absent ipsilateral normal kidney, presence of more than 3 kidneys on 1 side, and associated anomaly in the gallbladder. This case represents a unique combination of rarities, suggesting insights in the domain of molecular embryology.

Evaluating the accuracy of functional biomarkers for detecting histological changes in chronic allograft nephropathy.

The most common cause of late kidney transplant failure is chronic allograft nephropathy (CAN). Much research has focused on identifying biomarkers (or correlates) that would predict subsequent CAN and allow timely intervention. Functional biomarkers such as serum creatinine and estimated glomerular filtration rate (eGFR) have been widely adopted, even though they have not been rigorously evaluated as surrogate markers. This study evaluated serum creatinine and eGFR for predicting the early histopathological changes seen in transplant protocol biopsies (TPB). We prospectively followed 289 kidney transplant patients in the Southern Alberta Transplant Program who had TPB at 6-12 months post-transplant. Tissue samples (n = 280) were independently examined by renal pathologists. The ability of serum creatinine or eGFR to predict the threshold level for abnormal histopathology was evaluated by calculating the area under the receiver operator characteristic curve. Serum creatinine and eGFR had poor predictive value (most confidence intervals included 0.5, indicating no predictive ability) for ten individual histological measurements (Banff 97 scores), and the Chronic Allograft Damage Index. We conclude that serum creatinine and eGFR have a limited clinical role in predicting the early histopathological changes that precede CAN and should not be used for this purpose.