Significance of clinical-immunological patterns and diagnostic yield of biopsies in microscopic polyangiitis and granulomatosis with polyangiitis.

BACKGROUND: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are the two major antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). OBJECTIVES: To characterize a homogenous AAV cohort and to assess the impact of clinicopathological profiles and ANCA serotypes on clinical presentation and prognosis. Clinical differences in GPA patients according to ANCA serotype and the diagnostic yield for vasculitis of biopsies in different territories were also investigated. RESULTS: This retrospective study (2000-2021) included 152 patients with AAV (77 MPA/75 GPA). MPA patients (96.1% myeloperoxidase [MPO]-ANCA and 2.6% proteinase 3 [PR3]-ANCA) presented more often with weight loss, myalgia, renal involvement, interstitial lung disease (ILD), cutaneous purpura, and peripheral nerve involvement. Patients with GPA (44% PR3-ANCA, 33.3% MPO, and 22.7% negative/atypical ANCA) presented more commonly with ear, nose, and throat and eye/orbital manifestations, more relapses, and higher survival than patients with MPA. GPA was the only independent risk factor for relapse. Poor survival predictors were older age at diagnosis and peripheral nerve involvement. ANCA serotypes differentiated clinical features in a lesser degree than clinical phenotypes. A mean of 1.5 biopsies were performed in 93.4% of patients in different territories. Overall, vasculitis was identified in 80.3% (97.3% in MPA and 61.8% in GPA) of patients. CONCLUSIONS: The identification of GPA presentations associated with MPO-ANCA and awareness of risk factors for relapse and mortality are important to guide proper therapeutic strategies in AAV patients. Biopsies of different affected territories should be pursued in difficult-to-diagnose patients based on their significant diagnostic yield.

Kidney biopsy in lupus nephritis after achieving clinical renal remission: paving the way for renal outcome assessment.

The role of repeat kidney biopsy in lupus nephritis (LN) with renal remission is unclear. The aim of this study was to assess this role in a real-life scenario. This retrospective, single-centre study included 56 patients with LN diagnosed from 1998 to 2019, with an initial kidney biopsy (KB1) at the onset of LN and a second kidney biopsy (KB2) after achieving renal remission. A total of 51 (91.1%) patients were women with a median age of 29.9 years [interquartile range (IQR) 23.4-40.6] at the time of LN diagnosis. KB2s were performed after 41.1 months (IQR 30.1-52.5) of KB1. At the time of KB2, complete renal response was achieved in 51 (91.1%) patients. The median activity index decreased from a baseline value of 6.5 (IQR 2.8-11) to 0 (IQR 0-2) (P < .001). The chronicity index worsened from 1 (IQR 0-2) to 2 (IQR 1-3) (P = .01). In patients with proliferative/mixed forms at KB2, the chronicity index median value increased to 3 (IQR 1.5-4), as well as interstitial fibrosis and tubular atrophy [Formula: see text]25%, from 5.4% to 13.5%. Persistent histological active LN (activity index ≥2) was present in 11 (19.6%) KB2s. There were no differences when comparing immunological parameters between both groups (activity index ≥2 versus <2) at KB2, nor in the percentage of patients who presented renal flare. Immunosuppressive treatment was withdrawn in 35 (62.5%) patients and maintained/switched in 21 (37.5%). Afterward, new renal flare occurred in 9 patients per group (25.7% and 43%, respectively), after a median time of 39 months (IQR 6.5-55) and 7 months (IQR 6-30), respectively. There was no difference in the number of patients who developed chronic kidney disease [n = 14 (25%)] according to the treatment. In conclusion, KB2 provides valuable information to guide immunosuppressive maintenance therapy.

The extent of tubulointerstitial inflammation is an independent predictor of renal survival in lupus nephritis.

BACKGROUND AND OBJECTIVE: Lupus nephritis (LN) is a major complication in patients with systemic lupus erythematosus (SLE). Tubulointerstitial injury is an inflammatory process that, if not attenuated, can promote renal damage. Despite this, the current 2003 ISN/RPS "glomerulocentric" classification does not include a score for tubulointerstitial injury. We sought to establish predictors for tubulointerstitial injury and to determine their influence on renal outcomes. METHODS: This is a retrospective study of a cohort of 166 patients with biopsy-proven LN diagnosed in a Spanish referral center, with a median follow-up of 86 months. Chronic tubulointerstitial lesions were defined as interstitial fibrosis and tubular atrophy (IF/TA), whereas tubulointerstitial inflammation (TII) was defined as an acute interstitial lesion. Activity (0-24) and chronicity (0-12) indices were assigned. OUTCOME: Composite outcome, defined as advanced CKD or development of kidney failure. RESULTS: The prevalence of tubulointerstitial lesions was 69.3%. Eighty-one of the biopsies had features of tubulointerstitial inflammation and only 6 of these 81 (7%) patients had moderate/severe tubulointerstitial inflammation. The incidence of interstitial fibrosis and tubular atrophy was 56.6%. Renal survival was shorter in patients with moderate/severe as compared with absent/mild interstitial fibrosis and tubular atrophy (median: 15-19 years, p = 0.009). In the Cox regression model, the grade of interstitial fibrosis and tubular atrophy was independently associated with shorter renal survival (hazard ratio: 3.9, 95% CI 1.4-10.5; p = 0.008) after adjusting for degree of IF/TA and hypertension or diabetes. CONCLUSIONS: The extent of tubulointerstitial inflammation emerged as an independent predictor of renal survival after adjusting for the grade of interstitial fibrosis and tubular atrophy and co-morbid conditions including hypertension or diabetes. Regarding disease duration at the time of renal biopsy, no significant association was found between the interstitial fibrosis and tubular atrophy groups. The results reported herein need to be validated in future studies to include also groups of patients who usually have a worse prognosis. Consensus on histological classification is needed to aid in defining prognosis.

Simultaneous presentation of granulomatosis with polyangiitis (GPA) and immunoglobulin G4-related disease (IgG4-RD). Leaving an open question: widening the spectrum of a single disease or real overlap?

Because of a similar organ involvement and histopathological features, IgG4-related disease (IgG4-RD) may mimic some forms of granulomatosis with polyangiitis (GPA). However, several cases of clear coexistence or overlap of both diseases have been reported. We describe a case of a 47-year-old man presenting with a renal mass and a nasal crusting showing histopathological features of IgG4-RD in both territories. Cytoplasmic/proteinase 3 (PR3) antineutrophil cytoplasmic antibodies (ANCA) were positive and the patient subsequently developed kidney failure and nephritic syndrome that led to a renal biopsy re-evaluation revealing changes compatible with segmental necrotising glomerulonephritis and GPA. Remission induction therapy with prednisone and rituximab was started and clinical and laboratory parameters returned to normal. After administering a maintenance regimen based in rituximab 500 mg every six month the patient remained asymptomatic during 4 years of follow-up and free of prednisone the last 18 months. Although coexistence or overlap of GPA and IgG4-RD may be established in some clinical scenarios, the possibility of widening the spectrum of a single disease is also postulated.

Use of De Novo mTOR Inhibitors in Hypersensitized Kidney Transplant Recipients: Experience From Clinical Practice.

BACKGROUND: It is commonly believed that mTOR inhibitors (mTORi) should not be used in high-immunological risk kidney transplant recipients due to a perceived increased risk of rejection. However, almost all trials that examined the association of optimal-dose mTORi with calcineurin inhibitor (CNI) have excluded hypersensitized recipients from enrollment. METHODS: To shed light on this issue, we examined 71 consecutive patients with a baseline calculated panel reactive antibody (cPRA) ≥50% that underwent kidney transplantation from June 2013 to December 2016 in our unit. Immunosuppression was based on CNI (tacrolimus), steroids and alternatively mycophenolic acid (MPA; n = 38), or mTORi (either everolimus or sirolimus, n = 33, target trough levels 3-8 ng/mL). RESULTS: Demographic and immunological risk profiles were similar, and almost 90% of patients in both groups received induction with lymphocyte-depleting agents. Cox-regression analysis of rejection-free survival revealed better results for mTORi versus MPA in terms of biopsy-proven acute rejection (hazard ratio [confidence interval], 0.32 [0.11-0.90], P = 0.031 at univariable analysis and 0.34 [0.11-0.95], P = 0.040 at multivariable analysis). There were no differences in 1-year renal function, Banff chronicity score at 3- and 12-month protocol biopsy and development of de novo donor-specific antibodies. Tacrolimus trough levels along the first year were not different between groups (12-mo levels were 8.72 ± 2.93 and 7.85 ± 3.07 ng/mL for MPA and mTORi group respectively, P = 0.277). CONCLUSIONS: This single-center retrospective cohort analysis suggests that in hypersensitized kidney transplant recipients receiving tacrolimus-based immunosuppressive therapy similar clinical outcomes may be obtained using mTOR inhibitors compared to mycophenolate.

Hepatic epithelioid hemangioendothelioma: An international multicenter study.

BACKGROUND AND AIMS: Hepatic epithelioid hemangioendothelioma is an ultra-rare hepatic vascular tumor, diagnosed more frequently in females. The knowledge about this tumor derives mainly from small case series with sub-optimal treatment outcomes. The aim of this study is to identify the clinical and radiological issues helpful to develop an international prospective registry. METHODS: We conducted an international multicentric and retrospective study of patients with hepatic hemangioendothelioma. The clinical, pathological and radiological images collected during follow-up were reviewed. Central radiological revision was performed and 3 patterns of contrast were defined. RESULTS: Between 1994 and 2016, 27 patients with hepatic hemangioendothelioma were identified in three institutions but the final diagnosis was hepatic angiosarcoma in one. The majority were females, median age was 38.7-years and 17 patients were asymptomatic at diagnosis. No patient had Two out of ten (20%) patients had surgical specimens with positive macro-vascular invasion and 50% had extrahepatic disease, and the most frequent pattern was the progressive-central-contrast-uptake. After a median follow-up of 6.7-years, the 5- and 10-year survival rates are 91.5% and 51.9%, respectively. CONCLUSIONS: This multicentric study shows the heterogeneous profile of patients with hepatic hemangioendothelioma, reflecting the need to establish a reference network in order to better characterize these patients and ultimately develop a personalized treatment strategy.

Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA), a deadly malignancy of the bile ducts, can be classified based on its anatomical location into either intrahepatic (iCCA) or extrahepatic (eCCA), each with different pathogenesis and clinical management. There is limited understanding of the molecular landscape of eCCA and no targeted therapy with clinical efficacy has been approved. We aimed to provide a molecular classification of eCCA and identify potential targets for molecular therapies. METHODS: An integrative genomic analysis of an international multicenter cohort of 189 eCCA cases was conducted. Genomic analysis included whole-genome expression, targeted DNA-sequencing and immunohistochemistry. Molecular findings were validated in an external set of 181 biliary tract tumors from the ICGC. RESULTS: KRAS (36.7%), TP53 (34.7%), ARID1A (14%) and SMAD4 (10.7%) were the most prevalent mutations, with ∼25% of tumors having a putative actionable genomic alteration according to OncoKB. Transcriptome-based unsupervised clustering helped us define 4 molecular classes of eCCA. Tumors classified within the Metabolic class (19%) showed a hepatocyte-like phenotype with activation of the transcription factor HNF4A and enrichment in gene signatures related to bile acid metabolism. The Proliferation class (23%), more common in patients with distal CCA, was characterized by enrichment of MYC targets, ERBB2 mutations/amplifications and activation of mTOR signaling. The Mesenchymal class (47%) was defined by signatures of epithelial-mesenchymal transition, aberrant TGFß signaling and poor overall survival. Finally, tumors in the Immune class (11%) had a higher lymphocyte infiltration, overexpression of PD-1/PD-L1 and molecular features associated with a better response to immune checkpoint inhibitors. CONCLUSION: An integrative molecular characterization identified distinct subclasses of eCCA. Genomic traits of each class provide the rationale for exploring patient stratification and novel therapeutic approaches. LAY SUMMARY: Targeted therapies have not been approved for the treatment of extrahepatic cholangiocarcinoma. We performed a multi-platform molecular characterization of this tumor in a cohort of 189 patients. These analyses revealed 4 novel transcriptome-based molecular classes of extrahepatic cholangiocarcinoma and identified ∼25% of tumors with actionable genomic alterations, which has potential prognostic and therapeutic implications.

Successful use of nonantigen-specific immunoadsorption with antihuman Ig-columns in kidney graft antibody-mediated rejection.

INTRODUCTION: Nonantigen-specific immunoadsorption (IA) has proven to be effective in acute antibody-mediated rejection (aAMR). However, there is a lack of solid studies evaluating the safety and efficacy of IA with antihuman Ig-columns in aAMR. For chronic-active AMR (cAMR), no studies have evaluated the efficacy of nonantingen-specific IA with antihuman Ig-columns. The purpose of this study was to evaluate the role of nonantigen-specific IA with antihuman Ig-columns in the treatment of both aAMR and cAMR in kidney transplantation. MATERIAL AND METHODS: In retrospective and observational study, kidney graft and recipient survival rates were assessed after treatment of aAMR and cAMR with nonantigen-specific IA with Ig-Flex columns (Therasorb) between January 2012 and May 2018. Protocols included nonantigen-specific IA, rituximab, intravenous immunoglobulin, and rescue plasma exchange, if necessary. RESULTS: The study included 14 patients with AMR (acute in 9, chronic active in 5). For aAMR, mean follow-up was 13 ± 6 months, and patient and graft survival were, respectively, of 100% and 83%, with a mean increase in estimated glomerular filtration rate (eGFR) of 7.98 ± 12.96, 10.18 ± 16.71, and 11.43 ± 13.85 mL/min/1.72 m2 (P > .05) at 3, 12 months after treatment, and at the end of follow-up, respectively. For cAMR, mean follow-up was 14 ± 8 months, and patient and graft survival were, respectively, of 100% and 60%, with an average increase in eGFR of 4.30 ± 7.86, 5.64 ± 10.47, and 14.5 ± 7.86 mL/min/m2 (P > .05) at 3, 12 months after IA treatment, and at the end of the follow-up, respectively, although 40% did not respond and required chronic hemodialysis. CONCLUSION: Nonantigen-specific IA with Ig-Flex columns was safe and effective for aAMR treatment in kidney transplantation. In cAMR, IA with Ig-Flex columns was associated with a satisfactory kidney graft survival, suggesting that IA could potentially offer some benefits supporting its indication in cAMR.

Urine cytology suspicious for urothelial carcinoma: Prospective follow-up of cases using cytology and urine biomarker-based ancillary techniques.

BACKGROUND: Urine cytology results that are suspicious for urothelial carcinoma (UC) are challenging. The objective of this study was to elucidate the clinical significance of such results in patients who have a negative cystoscopy. METHODS: In this prospective study, 83 patients who had urine cytology that was suspicious of UC and a negative cystoscopy underwent a second cystoscopy and urine evaluation by cytology, UroVysion fluorescence in situ hybridization (FISH) assay, FGFR3 (fibroblast growth factor receptor 3) and TERT (telomerase reverse transcriptase) mutations and an 8-gene expression classifier (GEC). Results from all techniques were compared with patients' clinical outcomes. RESULTS: The presence of tumor was identified in 41% of patients; of these, 82% had tumors identified at their second evaluation (76% high-grade [HG] tumors), and 18% had tumors identified at a later follow-up (50% were HG tumors). After The Paris System for Reporting urinary Cytology (TPS) reclassification, 53 cytology results still had an indeterminate diagnosis (13 were suspicious for HGUC, and 40 had atypical urothelial cells (AUCs)]. Complete results from second evaluations using urine cytology, cytology-TPS, FISH, and GEC were available for 6 cases that were suspicious for HGUC and 34 cases that had AUCs. The sensitivity of these techniques to detect HG tumors in cases that were suspicious for HGUC was 100%, except for cytology-TPS, for which the sensitivity was 50%. The sensitivity of cytology and cytology-TPS to detect HG tumors in cases with AUCs was 33%, whereas the sensitivity of fluorescence in situ hybridization and GEC in these cases was 83% and 75%, respectively, to detect HG tumors at the second evaluation. CONCLUSIONS: The current results indicate the relevant clinical significance of indeterminate urine cytology findings and strongly suggest the use of complementary evaluations by urine biomarker-based, ancillary techniques to elucidate their significance.