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.

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.

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.

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.

Emerging PD-1 and PD-1L inhibitors-associated myopathy with a characteristic histopathological pattern.

BACKGROUND AND OBJECTIVE: Drug-induced myopathy is among the most common causes of muscle disease. An association has recently been described between programmed death-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors and immune-related adverse events (irAE) affecting the muscle. Here, we report the clinical and pathological findings of nine unrelated patients with PD-1 and PD-L1 inhibitors-associated myopathy. METHODS: We retrospectively analyzed 317 muscle biopsies performed for diagnostic purposes from January 2017 to June 2019. Patients were attended in two tertiary centers and muscle biopsies were performed and analyzed by two myology experts. Muscle biopsies were frozen in cooled isopenthane, cryostat sectioned and stained. Immunohistochemistry studies were also performed as a routine procedure in our lab. RESULTS: We identified 9 patients receiving anti-PD-1 or PD-L1 inhibitors consulting for either muscle weakness, asthenia, myasthenic-like syndrome or other muscle related-symptoms, along with biopsy-proven inflammatory myopathy. One had concomitant myocarditis. In most of the cases muscle biopsy showed a marked phenomenon of necrosis, macrophagy and muscle regeneration with perivascular inflammatory infiltrates with a large component of macrophagic cells. A tendency to perifascicular atrophy was also noticed. The expression of MHC class I antigens predominated in the perifascicular zones. Raised muscle enzymes were detected in 7 patients. CONCLUSION: A characteristic clinic-pathological pattern, including a myasthenia gravis-like syndrome plus myositis was found in patients receiving PD-1 and PD-1 L inhibitors. A large component of macrophages resembling granulomas seems to be the pathological hallmark of the syndrome. Further information is required to understand the wide spectrum of immune-related adverse events involving the muscle during or after treatment with anti-PD-1 inhibitors, but the pathological picture seems to be characteristic.

Combination of calcineurin and mTOR inhibitors in kidney transplantation: a propensity score analysis based on current clinical practice.

INTRODUCTION: The TRANSFORM study demonstrated that an immunosuppression based on a combination of calcineurin inhibitors and de-novo mTOR inhibitors (mTORi) is safe and effective in kidney transplant recipients. However, data that validate this approach in clinical practice are currently missing. MATERIALS AND METHODS: Analysis of 401 kidney transplant recipients transplanted from June 2013 to December 2016. All patients received tacrolimus with prednisone in combination with either mycophenolate (n = 186) or mTORi (either everolimus or sirolimus, n = 215). A propensity score to receive mTORi was calculated based on the inverse probability of treatment weighting (IPTW) from the following parameters: age and sex of donor and recipient, BMI, previous transplants, diabetes, cPRA, dialysis before transplantation, dialysis vintage, type of donor, ABO-incompatibility, HLA-mismatches, induction and ischemia time. Median follow-up was 2.6 [1.9; 3.7] years. RESULTS: Cox-regression analysis suggests good results for mTORi versus MPA in terms of 1-year biopsy-proven acute rejection (BPAR, P = 0.063), 1-year graft loss (P = 0.025) and patient survival (P < 0.001). Results observed for BPAR and graft failure were largely attributed to those patients that would have been excluded by the TRANSFORM because of some exclusion criteria (52.9% of the population, P = 0.003 for 1-year BPAR and P = 0.040 for graft loss). In patients who met selection criteria for TRANSFORM, no effect of treatment for BPAR or graft failure was observed, while the beneficial effect on overall survival persisted. CONCLUSIONS: In a real-life setting, a protocol based on de-novo mTORi with tacrolimus and prednisone could be employed as a standard immunosuppressive regimen and was associated with good outcomes.

Clinical Features of Primary and Systemic Metastatic Intraocular Lymphomas in Spanish Patients.

OBJECTIVES: To describe and compare clinical findings in different subtypes of biopsy-proven intraocular lymphomas (IOLs). DESIGN: Retrospective, observational case series. METHODS: The clinical and pathologic features in IOLs at the Hospital Clinic of Barcelona from 1995 to 2018 were retrospectively studied. RESULTS: Twenty-one patients, 12 men (57%), median age 60 (interquartile range, IQR: 18 years), and a median follow-up of 30 (IQR 60) months were included. Eleven patients had primary vitreo-retinal lymphoma (PVRL, 52%), 4 had primary uveal lymphoma (PUL, 19%), and 6 had systemic metastatic retinal lymphomas (SMRLs, 28%). Diffuse large B-cell lymphoma was the main IOL subset in PVRL (91%) and in SMRL (83%), whereas extranodal marginal zone lymphoma was the only type in PUL (100%). Survival rate was 44% in PVRL and 20% in SMRL at 5 years (p=0.047). One patient had flow cytometry of two different vitreous humour samples. With them, flow cytometry was performed in a total of 11 samples, yielding 7 positive samples. CONCLUSIONS AND RELEVANCE: Even though PVRL is the most frequent IOL subtype, our findings suggest that PUL and SMRL should be considered as potential IOL causes. Overall survival was poor in PVRL and even shorter in SMRL patients.

An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents.

BACKGROUND & AIMS: Cirrhosis and chronic inflammation precede development of hepatocellular carcinoma (HCC) in approximately 80% of cases. We investigated immune-related gene expression patterns in liver tissues surrounding early-stage HCCs and chemopreventive agents that might alter these patterns to prevent liver tumorigenesis. METHODS: We analyzed gene expression profiles of nontumor liver tissues from 392 patients with early-stage HCC (training set, N = 167 and validation set, N = 225) and liver tissue from patients with cirrhosis without HCC (N = 216, controls) to identify changes in expression of genes that regulate the immune response that could contribute to hepatocarcinogenesis. We defined 172 genes as markers for this deregulated immune response, which we called the immune-mediated cancer field (ICF). We analyzed the expression data of liver tissues from 216 patients with cirrhosis without HCC and investigated the association between this gene expression signature and development of HCC and outcomes of patients (median follow-up, 10 years). Human liver tissues were also analyzed by histology. C57BL/6J mice were given a single injection of diethylnitrosamine (DEN) followed by weekly doses of carbon tetrachloride to induce liver fibrosis and tumorigenesis. Mice were then orally given the multiple tyrosine inhibitor nintedanib or vehicle (controls); liver tissues were collected and histology, transcriptome, and protein analyses were performed. We also analyzed transcriptomes of liver tissues collected from mice on a choline-deficient high-fat diet, which developed chronic liver inflammation and tumors, orally given aspirin and clopidogrel or the anti-inflammatory agent sulindac vs mice on a chow (control) diet. RESULTS: We found the ICF gene expression pattern in 50% of liver tissues from patients with cirrhosis without HCC and in 60% of nontumor liver tissues from patients with early-stage HCC. The liver tissues with the ICF gene expression pattern had 3 different features: increased numbers of effector T cells; increased expression of genes that suppress the immune response and activation of transforming growth factor ß signaling; or expression of genes that promote inflammation and activation of interferon gamma signaling. Patients with cirrhosis and liver tissues with the immunosuppressive profile (10% of cases) had a higher risk of HCC (hazard ratio, 2.41; 95% confidence interval, 1.21-4.80). Mice with chemically induced fibrosis or diet-induced steatohepatitis given nintedanib or aspirin and clopidogrel down-regulated the ICF gene expression pattern in liver and developed fewer and smaller tumors than mice given vehicle. CONCLUSIONS: We identified an immune-related gene expression pattern in liver tissues of patients with early-stage HCC, called the ICF, that is associated with risk of HCC development in patients with cirrhosis. Administration of nintedanib or aspirin and clopidogrel to mice with chronic liver inflammation caused loss of this gene expression pattern and development of fewer and smaller liver tumors. Agents that alter immune regulatory gene expression patterns associated with carcinogenesis might be tested as chemopreventive agents in patients with cirrhosis.

Postinfectious Acute Glomerulonephritis in Renal Transplantation: An Emergent Aetiology of Renal Allograft Loss.

Despite the high incidence of posttransplant infections, postinfectious acute glomerulonephritis (PIAGN) in renal allograft is a rare entity, without effective treatment and a bad prognosis. We describe two cases of PIAGN: the first one was developed 2 years after kidney transplantation, secondary to Staphylococcus aureus bacteremia with presence of extracapillary proliferation in biopsy. The patient was treated with methylprednisolone and plasma exchanges without response, remaining dialysis dependent. The second case was reported 5 years after kidney transplantation, secondary to influenza A infection. Kidney biopsy showed an IgA-dominant PIAGN and methylprednisolone boluses were initiated without clinical response, suffering a progressive worsening and loss of kidney graft. Due to the aggressive clinical course of this entity, PIAGN should be considered in the differential diagnosis of acute kidney graft failure in the context of an infection. Elderly patients have a higher risk of more severe acute renal dysfunction, requiring dialysis in a great proportion of cases.

Time association between hepatitis C therapy and hepatocellular carcinoma emergence in cirrhosis: Relevance of non-characterized nodules.

BACKGROUND & AIMS: Despite direct-acting antivirals being highly effective at eradicating hepatitis C virus infection, their impact on the development of hepatocellular carcinoma (HCC) remains controversial. We analyzed the clinical and radiological outcome of cirrhotic patients treated with interferon-free regimens to estimate the risk of developing HCC. METHODS: This was a retrospective multicenter study focusing on cirrhotic patients treated with direct-acting antivirals until December 2016. Clinical and radiologic characteristics were collected before the start of antiviral therapy, at follow-up and at HCC development. Diagnosis of HCC was centrally validated and its incidence was expressed as HCC/100 person-years. RESULTS: A total of 1,123 patients were included (60.6% males, 83.8% Child-Pugh A) and 95.2% achieved a sustained virologic response. Median time of follow-up was 19.6 months. Seventy-two patients developed HCC within a median of 10.3 months after starting antiviral treatment. HCC incidence was 3.73 HCC/100 person-years (95% CI 2.96-4.70). Baseline liver function, alcohol intake and hepatic decompensation were associated with a higher risk of HCC. The relative risk was significantly increased in patients with non-characterized nodules at baseline 2.83 (95% CI 1.55-5.16) vs. absence of non-characterized nodules. When excluding these patients, the risk remained increased. CONCLUSION: These data expose a clear-cut time association between interferon-free treatment and HCC. The mechanisms involved in the increased risk of HCC emergence in the short term require further investigation. LAY SUMMARY: In this cohort of cirrhotic patients, interferon-free therapies achieved a high rate of sustained virologic response (>95%); however, we reported a risk of de novo hepatocellular carcinoma of 3.73 per 100 person-years and a clear-cut time association with antiviral therapy. The time association between starting direct-acting antivirals and developing hepatocellular carcinoma, together with the association with the presence of non-characterized nodules at baseline ultrasound, suggests that antiviral therapy elicits a mechanism (probably immune-related) that primes the growth and clinical recognition of hepatocellular carcinoma early during follow-up. As a result, short-term liver cancer risk is significantly increased.

Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial.

OBJECTIVE: Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognostic factors with B level of evidence. DESIGN: Tumour tissue from 188 patients randomised to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene expression profiling, targeted exome sequencing (19 known oncodrivers), immunohistochemistry (pERK, pVEGFR2, Ki67), fluorescence in situ hybridisation (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time to recurrence equalled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test. RESULTS: BIOSTORM recapitulates clinicopathological characteristics of STORM. None of the biomarkers tested (related to angiogenesis and proliferation) or previously proposed gene signatures, or mutations predicted sorafenib benefit or recurrence. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p of interaction=0.04). These sorafenib RFS responders were significantly enriched in CD4+ T, B and cytolytic natural killer cells, and lacked activated adaptive immune components. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors. CONCLUSION: In BIOSTORM, only hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene signatures predicted sorafenib benefit. A newly generated multigene signature associated with improved RFS on sorafenib warrants further validation. TRIAL REGISTRATION NUMBER: NCT00692770.

The development of a predictive model of graft function in uncontrolled donors after circulatory death: validity of a pulsatile renal preservation machine cut-off value for kidney acceptance.

BACKGROUND: The criteria for kidney suitability in uncontrolled donors after circulatory death (uDCD) procured after regional normothermic perfusion are based on macroscopic appearance and renal haemodynamic values with final renal resistance (FRR). However, these criteria have not been analysed to predict the future graft function. This study presents a model to predict the outcome in uDCD kidneys and define the predictive FRR value. METHODS: All uDCD kidney transplants performed in our hospital from 2004 to 2016 were included. Donors and recipients and pre-transplantation data are described. The endpoint was glomerular filtration rate (GFR) ≥30 mL/min at 6 months after transplantation. RESULTS: A total of 194 recipients were included. FRR in donors ≥60 years old was (mean ± SD) 0.27 ± 0.11 versus 0.22 ± 0.09 mmHg/mL/min in donors <60 years (P = 0.042). Kidney survival was 88.2% versus 84% at 12 months and 60.7% versus 30.8% at 120 months (P = 0.067). For the group of recipients from donors ≥60 years, the FRR was 0.37 ± 0.08 mmHg/mL/min in the GFR <30 mL/min group versus 0.18 ± 0.06 mmHg/mL/min in the GFR ≥30 mL/min group (P < 0.001). The value FRR ≥0.3 mmHg/mL/min predicts 59-79% of GFR <30 mL/min [odds ratio = 2.16, 95% confidence interval (CI) 1.80-6.40; P < 0.001]. The predictive accuracy of FRR for GFR by ROC curve was 0.968 (95% CI). The best cut-off for FRR was 0.3 mmHg/mL/min to predict GFR at 6 months with a sensitivity of 67%, specificity of 100%, positive predictive value of 83% and negative predictive value of 92%. CONCLUSIONS: Our results suggest that in uDCD donors the combination of donor age ≥60 years together with FRR ≥0.3 mmHg/mL/min could predict poor outcome at 6 months after transplantation in low immunological risk recipients.