Mignano, Salvatore

ABSTRACT Background Diagnostic interpretation of kidney allograft biopsies using the Banff classification remains variable, but the determinants of this variability are not fully defined. We performed a global, fully digital multi-reader study to identify the principal drivers of disagreement in Banff-based assessment. Methods Thirty-six kidney transplant biopsies were independently scored by 67 renal pathologists on a standardized digital platform. Readers assessed Banff lesions on hematoxylin and eosin, periodic acid–Schiff, and Jones’ silver stains; final diagnostic categories were assigned using prespecified Banff-based decision rules. Interobserver agreement was quantified with Gwet’s agreement coefficient (AC) statistics. Determinants of diagnostic agreement were evaluated using pairwise mixed-effects logistic regression, and reader similarity was examined by principal component analysis (PCA) with post hoc molecular annotation. Results Agreement for final diagnostic categories was moderate (Gwet’s AC1, 0.55; 95% CI, 0.47–0.63). Lesion-level agreement varied substantially, with lowest agreement for selected threshold-dependent inflammatory or semi-quantitative lesions, including interstitial inflammation in areas of IFTA, peritubular capillaritis and arteriolar hyalinosis. Diagnostic concordance differed markedly across biopsies, indicating strong case-level heterogeneity. In pairwise models, differences in active inflammatory and vascular lesion scoring were the strongest correlates of diagnostic disagreement; reader experience and geography contributed minimally. Principal component analysis showed reader variation was organized along two dominant axes: a rejection-calling threshold axis linked mainly to tubulointerstitial inflammatory injury, and a T cell-mediated (TCMR/TI) and antibody-mediated/microvascular (AMR/MVI) inflammation-oriented phenotypic classification axis. Conclusion Interobserver variation in Banff-based kidney transplant biopsy assessment is structured rather than random and driven mainly by how readers threshold and integrate key inflammatory lesion compartments rather than experience or geographic location.

Background: Vascular endothelial growth factor inhibitors (VEGF-I) are frequently used for cancer treatment. VEGF-I can cause proteinuria and acute kidney injury (AKI) with thrombotic microangiopathy (TMA) as a commonly described pathology, but other glomerular pathologies are not well characterized. We aim to describe the clinical characteristics and glomerular lesions associated with VEFG-I in a single center cohort. Methods: We performed a retrospective chart review of patients treated with VEGF-I and underwent kidney biopsies from 2010 to 2022 at the Mayo Clinic, Rochester, MN. Biopsy findings were reviewed by our pathologists. Data on patients’ characteristics, clinical course, and outcomes were abstracted. Descriptive statistics were used to report relevant patient characteristics and findings. Results: From 2010 to 2022, 19 kidney biopsies were performed for kidney dysfunction in patients on VEGF-I. Eleven had complete data, with a median age of 62 years (interquartile range 58–66 years); renal cell carcinoma (RCC) was the most common cancer (4 of 11 patients). TMA was noted in 8 of the 11 biopsies, with proteinuria as the most frequent indication for biopsy in these cases. Three patients had findings other than TMA. One developed anti-phospholipase A2 receptor negative membranous nephropathy; VEGF-I and pembrolizumab were discontinued, and prednisone improved proteinuria. Another patient had known cryoglobulinemia with nephrotic range proteinuria which was exacerbated by VEGF-I peaking at 11 g/day. Despite stopping VEGF-I and treating with prednisone and rituximab, kidney dysfunction progressed to end stage kidney disease (ESKD). A third patient had IgA nephropathy with concurrent diabetic changes, but proteinuria progressed even after stopping VEGF-I. Conclusion: In this case-series of patients treated with VEGF-I undergoing kidney biopsy, we describe the pathological characteristics, clinical course, and outcomes of patients with pathologies other than TMA. Our study adds information to the sparse literature on patients with renal dysfunction after receiving VEGF-I.

Abstract Background and Aims Immune-checkpoint inhibitors (ICI) are antineoplastic therapies that unleash the immune-system and have revolutionized cancer outcomes. Though they are a drug class with great potential, their effects are not always limited to the malignant cells and can cause a spectrum of immune-related adverse events (irAEs). Roughly 5% of patients will experience acute kidney injury (AKI) with acute interstitial nephritis (AIN) being the predominant pathologic lesion. Glomerular and vascular lesions are thought to be rare and, as a result, not well-defined. We aim to document glomerular and vascular pathology in this context at our institution. Method We performed a retrospective review of internal native renal biopsies from 2010-2022 that had known ICI treatment. Standard processing of renal biopsies included light microscopy (LM), immunofluorescence (IF), and electron microscopy (EM). We reviewed the biopsies and pathology reports, as well as clinical data from patient electronic medical records. Results Our search yielded 32 kidney biopsies; of those, most had AIN (27/32), 8 cases had glomerular pathology, and 1 case had arterial endotheliitis. Of the cases with glomerular pathology, 4 had subacute glomerular thrombotic microangiopathy (TMA). Among the cases with TMA, 2 were also treated with vascular endothelial growth factor inhibitor (VEGFi),1 with gemcitabine, and 1 with BRAF-inhibitor therapy. Further, only one of these patients had complement testing, which did not reveal definitive deficiency. One patient had proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), IgG-κ. One patient had IgA nephropathy (IgAN) and another had membranous nephropathy (MN). Most patients were biopsied for rising serum creatinine (SCr) (median: 1.6 mg/dL; range: 0.55-5.5); 1 had nephrotic-range proteinuria (median urine protein/creatinine ratio (UPCR): 0.3; range: 0.12-5.64). One, with thin basement membrane disease, had significant hematuria (>100 RBC/hpf). Five patients had irAEs in other organs. 7/9 patients died or entered hospice care (median: 14 months post-biopsy; range: 2-48 months) due to malignancy progression. Of the deceased patients, 2 were dialysis-dependent. Of the living patients, 1 has dialysis-independent chronic kidney disease (CKD). Conclusion Overall, glomerular and vascular pathology due to ICI-use appears rare though difficult to isolate since other drugs and neoplasia can cause similar lesions. In our cohort, TMA was the most common glomerular lesion, though direct causation due to ICI is difficult to prove. In all patients with TMA, we identified concurrent use of other known causative drugs. IgAN and MN have been reported in association with neoplasia. PGNMID has been reported in a variety of malignant and nonmalignant conditions, and ICI-use could be a triggering factor. In conclusion, the patterns of glomerular injury seen in our cohort may be secondary to other concurrent risk factors other than ICI use. Arterial endotheliitis appears to be a rare but significant secondary effect to ICI-use.