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A 75-year-old male developed acute kidney injury KDIGO stage 3 a few weeks after Whipple surgery was performed for a distal cholangiocarcinoma. Kidney biopsy revealed oxalate nephropathy. This was attributed to post-Whipple malabsorption, poor compliance with pancreatic enzyme replacement therapy, and daily intake of vitamin C supplements. Pancreatic enzyme replacement therapy was resumed and calcium carbonate initiated, with an improvement in glomerular filtration rate. Unfortunately, due to oncological progression, best supportive care was initiated. We review the pathophysiology and conditions predisposing to secondary hyperoxaluria and oxalate nephropathy. This diagnosis should be considered among the main causes of acute kidney injury following pancreatectomy, with important therapeutic implications.

Background Most studies on tumour progression from precursor lesion toward gallbladder adenocarcinoma investigate lesions sampled from distinct patients, providing an overarching view of pathogenic cascades. Whether this reflects the tumourigenic process in individual patients remains insufficiently explored. Genomic and epigenomic studies suggest that a subset of gallbladder cancers originate from biliary intraepithelial neoplasia (BilIN) precursor lesions, whereas others form independently from BilINs. Spatial transcriptomic data supporting these conclusions are missing. Moreover, multiple areas with precursor or adenocarcinoma lesions can be detected within the same pathological sample. Yet, knowledge about intra-patient variability of such lesions is lacking. Methods To characterise the spatial transcriptomics of gallbladder cancer tumourigenesis in individual patients, we selected two patients with distinct cancer aetiology and whose samples simultaneously displayed multiple areas of normal epithelium, BilINs and adenocarcinoma. Using GeoMx digital spatial profiling, we characterised the whole transcriptome of a high number of regions of interest (ROIs) per sample in the two patients (24 and 32 ROIs respectively), with each ROI covering approximately 200 cells of normal epithelium, low-grade BilIN, high-grade BilIN or adenocarcinoma. Human gallbladder organoids and cell line-derived tumours were used to investigate the tumour-promoting role of genes. Results Spatial transcriptomics revealed that each type of lesion displayed limited intra-patient transcriptomic variability. Our data further suggest that adenocarcinoma derived from high-grade BilIN in one patient and from low-grade BilIN in the other patient, with co-existing high-grade BilIN evolving via a distinct process in the latter case. The two patients displayed distinct sequences of signalling pathway activation during tumour progression, but Semaphorin 4 A ( SEMA4A ) expression was repressed in both patients. Using human gallbladder-derived organoids and cell line-derived tumours, we provide evidence that repression of SEMA4A promotes pseudostratification of the epithelium and enhances cell migration and survival. Conclusion Gallbladder adenocarcinoma can develop according to patient-specific processes, and limited intra-patient variability of precursor and cancer lesions was noticed. Our data suggest that repression of SEMA4A can promote tumour progression. They also highlight the need to gain gene expression data in addition to histological information to avoid understimating the risk of low-grade preneoplastic lesions.

ObjectiveTo determine whether immune deposit (ID) resorption in per-protocol repeat kidney biopsies in patients with proliferative lupus nephritis (PLN) correlates with histological response and/or predicts renal relapse.MethodsTwenty-eight patients with PLN (class III/IV±V) who underwent a per-protocol repeat kidney biopsy after a median time of 18.4 [11.5–29.2] months (i.e., performed irrespectively of the clinical response) were included in this retrospective study. We assessed IgG, IgA, IgM, C3, and C1q IDs by direct immunofluorescence using a semi-quantitative scale (0–3) at three sites (mesangial, subendothelial, subepithelial). We computed a total Ig score (0–27; 3 Ig subclasses x 3 sites x score 0–3) and a total C score (0–18; 2 C molecules x 3 sites x score 0–3). Activity index (AI) was measured according to the NIH scoring system. Renal relapse was defined as the reappearance of a urinary protein/creatinine ratio (uPCR) >1 g/g, following a clinical response with uPCR <0.5 g/g, prompting a biopsy and/or therapy modification.ResultsTotal Ig and C scores substantially decreased from the diagnostic (median [IQR]: 7.25 [5.00–10.00] and 6.00 [5.00–9.25], respectively) to the repeat biopsy (3.50 [0.75–6.00] and 2.50 [0.00–4.62]; p<0.001), with significant reductions for IgG, IgA, C3, and C1q (table 1). Significant resorption was observed in the mesangial (from 3.25 [0.00–5.25] to 0.00 [0.00–2.00]; p=0.005 for Ig and from 4.75 [3.00–6.00] to 0.00 [0.00–2.00]; p<0.001 for C) and subendothelial (from 0.00 [0.00–4.62] to 0.00 [0.00–0.00]; p=0.006 for Ig and from 0.00 [0.00–4.25] to 0.00 [0.00–0.00]; p=0.027 for C) sites, but not in the subepithelial site. There was no significant correlation between the decrease in AI and total Ig and C. Of seven relapsing patients, none had achieved a decrease of ≥75% in the total Ig ID score (table 2).ConclusionsResorption of mesangial and subendothelial Ig and C IDs is attainable upon treatment and does not necessarily correlate with AI score reductions. Assessment of ID scores could serve as a valuable tool for determining the early treatment response and informing subsequent treatment adjustments.Conflicts of interestIP has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia, Bristol Myers Squibb, Elli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Otsuka, and Roche. The other authors declare that they have no conflicts of interest related to this work. The funders had no role in the design of the study, the analyses or interpretation of data, or the writing of the manuscript.Abstract O39 Table 1Immune deposits at baseline and per-protocol repeat biopsies. All values represent the sum scores on a semi-quantitative scale, ranging from 0 to 3 (0 = absent, 1 = minimal, 2 = moderate, 3 = extensive), for the evaluation of immune deposits (IgA, IgG, IgM, C3, and C1q) at three distinct sites: mesangial, subendothelial, and subepithelial. IQR, Interquartile range; SD, Standard deviationAbstract O39 Table 2Contingency table for renal relapses versus total Ig decrease by ≥75% from baseline Renal relapse (+) Renal relapse (-) Total Ig reduction ≥75% 0 10 Total Ig reduction <75% 7 11 Fisher’s exact test P=0.026

SummaryA 36-year-old male patient, who was an agricultural farmer and had a diagnosis of bicuspid aortic valve and coarctation, was admitted with symptoms of fever, fatigue, and shortness of breath that lasted for a month, in March 2017. Examination revealed dyspnea and bilateral rales and rhonchi in lung auscultation. A 3/6 systolic murmur was heard in the mesocardiac focus. The laboratory tests showed a white blood cell count of 15.14×103/µl, erythrocyte sedimentation rate of 36 mm/h, and C-reactive protein of 26 mg/l. An echocardiogram showed mobile vegetation (30×10 mm) on the aortic valve and severe aortic and tricuspid valve insufficiency. All blood cultures that are taken from the patient with the diagnosis of infective endocarditis were negative and C. burnetii phase I IgG antibody was positive at 1/32768 titer. As far as we know, herein, we present a case of endocarditis due to C. burnetii, which is the third case that is reported in Turkey.

Coronavirus disease-2019 (COVID-19) associated pneumonia may progress into acute respiratory distress syndrome (ARDS). Some patients develop features of macrophage activation syndrome (MAS). Elevated levels of IL-6 were reported to be associated with severe disease, and anti-IL-6R tocilizumab has been shown to be effective in some patients. This retrospective multicenter case–control study aimed to evaluate the efficacy of tocilizumab in hospitalized COVID-19 patients, who received standard of care with or without tocilizumab. Primary outcome was the progression to intubation or death. PSMATCH (SAS) procedure was used to achieve exact propensity score (PS) matching. Data from 1289 patients were collected, and study population was reduced to 1073 based on inclusion–exclusion criteria. The composite outcome was observed more frequently in tocilizumab-users, but there was a significant imbalance between arms in all critical parameters. Primary analyses were carried out in 348 patients (174 in each arm) after exact PS matching according to gender, ferritin, and procalcitonin. Logistic regression models revealed that tocilizumab significantly reduced the intubation or death (OR 0.40, p = 0.0017). When intubation is considered alone, tocilizumab-users had > 60% reduction in odds of intubation. Multiple imputation approach, which increased the size of the matched patients up to 506, provided no significant difference between arms despite a similar trend for intubation alone group. Analysis of this retrospective cohort showed more frequent intubation or death in tocilizumab-users, but PS-matched analyses revealed significant results for supporting tocilizumab use overall in a subset of patients matched according to gender, ferritin and procalcitonin levels.

Background Tubulo-interstitial Nephritis and Uveitis (TINU) syndrome is a rare oculo-renal inflammatory disease. Renal tubular defects are usually found, but full proximal tubular abnormalities have rarely been described. Case presentation We report the case of a 55-year old woman, native from Morocco, presenting with bilateral, non-granulomatous, anterior uveitis, mild renal insufficiency, leucocyturia and glycosuria. Further work-up showed hypophosphatemia and hyperphosphaturia, hypouricemia and hyperuricosuria, and hyper aminoaciduria, consistent with Fanconi syndrome. A kidney biopsy was obtained and showed diffuse interstitial infiltrates with tubular necrosis. The patient improved after the initiation of a corticosteroid therapy, with tapering dose. Conclusions We reviewed the literature and found nine similar cases. This association mostly occurs in adult woman, without current evidence for an ethnic predilection, unlike previously reported. The renal prognosis seems favorable after corticosteroid therapy, even in case of severe renal injury. Nonetheless mild tubular defects may persist after treatment or spontaneous remission.

Background/Objectives: Cardiac implantable electronic device-related infective endocarditis (CIED-RIE) is a serious condition with significant morbidity and mortality. Although recent advances in imaging and therapeutic approaches have improved management, diagnosing and treating CIED-RIE continues to be challenging. This study aimed to identify factors associated with mortality in CIED-RIE patients. Methods: We conducted a retrospective, multicenter international study of adult patients diagnosed with CIED-RIE between January 2014 and June 2024. Data on demographics, clinical presentation, microbiological findings, imaging results, treatment modalities, and outcomes were collected and analyzed to determine predictors of short-term mortality. Results: A total of 197 patients (mean age: 65.3 ± 14.4 years; 75.1% male) were included. The most common device type was permanent pacemaker (48.2%). Staphylococcus species were the predominant pathogens (62.4%). Surgical intervention was performed in 67.5% of patients, and 90-day mortality occurred in 19.3%. Multivariable analysis identified higher Charlson comorbidity index (HR: 1.31), tricuspid valve involvement (HR: 2.35), vegetation size ≥ 10 mm (HR: 2.53), pulmonary embolism (HR: 3.92), and absence of surgical intervention (HR: 2.90) as independent predictors of increased 90-day mortality. Conclusions: Early identification of high-risk patients and prompt multidisciplinary management, including surgical intervention when indicated, are critical to improving outcomes in patients with CIED-RIE.

Background Alport syndrome and ANCA-associated vasculitis are both rare diseases. The co-existence of these two conditions has never been reported. There is no obvious pathogenic link between these two glomerular diseases. The management of this case highlights the importance of a systematic approach when investigating the unexpected unfavourable evolution of a known glomerulopathy. Case presentation A-17 year old caucasian boy with a genetically proven X-linked Alport syndrome presented with progressive dyspnea, fatigue and pallor. His blood tests showed a severe anemia (Hb 6.9 g/dl) with acute worsening of kidney function (serum creatinine, normal 9 months earlier, was now 3.6 mg/dl). Microscopic hematuria and proteinuria also worsened. He soon developed signs of alveolar hemorrhage. Serological tests showed the presence of perinuclear ANCA with anti MPO specificity. Kidney biopsy showed a necrotizing and crescentic glomerulonephritis. Pulses of methylprednisolone were given in combination with plasmapheresis. The patient further received 6 pulses of cyclophosphamide, followed by maintenance oral azathioprine. During the 15-months follow up he remained well with serum creatinine back to normal, and some residual proteinuria and hematuria ascribed to Alport syndrome. Conclusion We report a young patient with the coexistence of Alport syndrome and ANCA associated vasculitis. Clinicians should be aware of the possibility of a second acquired disease in a patient with a known kidney disease, genetic in this case. This coexistence is very rare, but should be considered even if both diseases are rare, if the evolution is atypical for the single (known) primary disease. The diagnosis of the added vasculitis prompted in our case the initiation of immunosuppressive drugs, with a favourable outcome.

ObjectivesBecause a significant fraction of patients with lupus nephritis (LN) develops renal impairment, there is a need to better understand the mechanisms underlying disease progression. Here, we assessed for cellular senescence in the LN kidney, and its association with disease severity and outcome.MethodsWe enumerated the number of cells positive for p16INK4a protein, a marker of cellular senescence, by immunohistochemistry followed by digital quantification, on renal biopsies from 40 patients with active LN. We tested for an association of p16INK4a with renal fibrosis, CD8+ T cell infiltration, systemic disease and renal function at baseline and at 5 years.ResultsThe presence of p16INK4a-positive cells was significantly associated with lower estimated glomerular filtration rate at baseline and 5 years post-treatment, independently of patient demographics and systemic disease parameters. It was also associated with higher baseline renal fibrosis and CD8+ T cell infiltration. Interestingly, we observed marked spatial co-distribution of glomerular p16INK4a-positive cells with CD8+ T cells.ConclusionWe demonstrate, for the first time, that LN biopsies characterised by renal impairment display increased p16INK4a-positive cells, associated with higher fibrosis and CD8+ T cell infiltration. Cellular senescence may represent a kidney-intrinsic disease mechanism and potentially, a novel therapeutic target in LN.

In the Balkan and Taiwan, the relationship between exposure to aristolochic acid and risk of urothelial neoplasms was inferred from the A>T genetic hallmark in TP53 gene from malignant cells. This study aimed to characterize the TP53 mutational spectrum in urothelial cancers consecutive to Aristolochic Acid Nephropathy in Belgium. Serial frozen tumor sections from female patients (n=5) exposed to aristolochic acid during weight-loss regimen were alternatively used either for p53 immunostaining or laser microdissection. Tissue areas with at least 60% p53-positive nuclei were selected for microdissecting sections according to p53-positive matching areas. All areas appeared to be carcinoma in situ. After DNA extraction, mutations in the TP53 hot spot region (exons 5-8) were identified using nested-PCR and sequencing. False-negative controls consisted in microdissecting fresh-frozen tumor tissues both from a patient with a Li-Fraumeni syndrome who carried a p53 constitutional mutation, and from KRas mutated adenocarcinomas. To rule out false-positive results potentially generated by microdissection and nested-PCR, a phenacetin-associated urothelial carcinoma and normal fresh ureteral tissues (n=4) were processed with high laser power. No unexpected results being identified, molecular analysis was pursued on malignant tissues, showing at least one mutation in all (six different mutations in two) patients, with 13/16 exonic (nonsense, 2; missense, 11) and 3/16 intronic (one splice site) mutations. They were distributed as transitions (n=7) or transversions (n=9), with an equal prevalence of A>T and G>T (3/16 each). While current results are in line with A>T prevalence previously reported in Balkan and Taiwan studies, they also demonstrate that multiple mutations in the TP53 hot spot region and a high frequency of G>T transversion appear as a complementary signature reflecting the toxicity of a cumulative dose of aristolochic acid ingested over a short period of time.