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OBJECTIVE: This study was undertaken to characterize kidney and urine antibody-secreting cells (ASCs) from patients with active lupus nephritis, before and after induction therapy. METHODS: We included patients with biopsy-proven active lupus nephritis and performed anti-CD138 staining of kidney biopsy samples to visualize ASCs. We performed single-cell gene expression profiling on sorted ASCs from fresh biopsy samples using multiplex reverse transcriptase-polymerase chain reaction. We used a gene set that allowed for the study of ASC maturation from plasmablasts to long-lived plasma cells. We quantified urine ASCs from untreated patients with lupus nephritis at diagnosis and after 6 months of prospective follow-up during induction therapy. RESULTS: The number of kidney CD138+ ASCs in 46 untreated patients with lupus nephritis was correlated with a low estimated glomerular filtration rate and with tubulointerstitial damage. Most kidney ASCs from 3 untreated patients had a plasmablast molecular signature; in contrast, in 4 patients with refractory lupus nephritis, the kidney ASCs were mainly long-lived plasma cells, representing an ASC transcriptional profile similar to that in the bone marrow of 2 healthy donors. Some urine ASCs with a plasmablast signature were detected in patients with untreated active lupus nephritis. The presence of urine ASCs at 6 months was associated with treatment failure. CONCLUSION: Our results suggest potential for ASC-directed therapy in refractory lupus nephritis.

Pulmonary-renal syndrome refers to the combination of elevated plasma creatinine concentration and/or abnormal urinalysis with diffuse alveolar hemorrhage, and involves both an urgent diagnostic approach and care. We report the case of a 24-year-old man presenting with diffuse alveolar hemorrhage as well as a nephritic syndrome associating kidney failure, moderate hypertension, hematuria and selective glomerular proteinuria. The initial high suspicion of anti-glomerular basement membrane (GBM) disease or ANCA-associated vasculitis justified intravenous pulse-corticotherapy in association with plasma exchange. Renal biopsy was remarkable for an IgA nephropathy, lesions of active thrombotic microangiopathy (TMA) and a positive staining for complement factor C4d. Because anti-GBM and ANCA antibodies returned negative, plasma exchange was discontinued, but oral corticosteroids were maintained to prevent alveolar hemorrhage recurrence. In the absence of renal function recovery, hemodialysis was initiated. TMA lesions are frequently seen in IgA nephropathy and are associated with a poorer prognosis. Complement activation seems to be involved in the development of those lesions and contributes to disease progression. Conversely, alveolar hemorrhage in the setting of IgA nephropathy is uncommon. It is thought to result from non-specific mucosal hemorrhage, an immune complex mediated basement membrane damage and an IgA-mediated capillaritis against basement membrane antigens.

Background Oxalate nephropathy is a potentially underestimated cause of kidney failure characterized by massive deposition of calcium oxalate crystals in the renal parenchyma. The prevalence and modes of presentation of this entity are ill-defined. Methods Here we report on the largest consecutive series of cases of adult oxalate nephropathy diagnosed on native kidney biopsies from January 2010 to December 2018 in the UCLouvain Kidney Disease Network. Results We screened 2265 native kidney biopsies and identified 22 cases (1%) of oxalate nephropathy. Patients had a mean age at diagnosis of 61 years (±20) and presented either with acute on chronic kidney disease (CKD) (62%) or with acute kidney injury (AKI) (38%). Mean serum creatinine at biopsy was 8.0 ± 4.5 mg/dl. Kidney biopsies showed abundant calcium oxalate crystal deposits, associated with acute interstitial nephritis and tubular necrosis, and variable degrees of interstitial fibrosis and tubular atrophy. Chronic pancreatitis and gastric bypass were the most common causes of oxalate nephropathy (48%). During a mean follow-up of 29 months, half of the patients (52%) progressed to kidney failure, all within the month following diagnosis. Higher serum creatinine level at presentation and interstitial fibrosis and tubular atrophy score were associated with progression to kidney failure. Conclusion Oxalate nephropathy is the cause of kidney disease in 1% of consecutive native kidney biopsies and typically presents as acute on CKD or AKI. The prognosis of the disease is poor, with a high rate of kidney failure within the first month after the diagnosis., Graphical abstract

Objectives In patients with LN, clinical and histological responses to treatment have been shown to be discordant. We investigated whether per-protocol repeat kidney biopsies are predictive of LN relapses and long-term renal function impairment. Methods Forty-two patients with incident biopsy-proven active proliferative (class III/IV±V) LN from the database of the UCLouvain were included in this retrospective study. Per-protocol repeat biopsies were performed after a median [interquartile range (IQR)] time of 24.3 (21.3–26.2) months. The National Institutes of Health activity index (AI) and chronicity index (CI) scores were assessed in all biopsies. Results Despite a moderate correlation between urinary protein/creatinine ratios (UPCR) and AI scores at repeat biopsy (r = 0.48; P = 0.001), 10 patients (23.8%) with UPCR 3). High AI scores (continuous) in repeat biopsies were associated with an increased probability and/or shorter time to renal relapse (n = 11) following the repeat biopsy [hazard ratio (HR) = 1.2, 95% CI: 1.1, 1.3; P = 0.007], independently of proteinuria levels. High CI scores (continuous) in repeat biopsies were associated with a sustained increase in serum creatinine levels corresponding to ≥120% of the baseline value (HR = 1.8, 95% CI: 1.1, 2.9; P = 0.016) through a median (IQR) follow-up time of 131.5 (73.8–178.2) months, being also the case for acute tubulointerstitial inflammation and interstitial fibrosis/tubular atrophy in repeat but not baseline biopsies. Conclusion Our results highlight the usefulness of per-protocol repeat biopsies, herein performed after a median time of 24 months from baseline, as an integral part of the treatment evaluation, also in patients showing adequate clinical response.

1. L’OBSERVATION : Une femme, âgée de 64 ans, était hospitalisée à la fin du mois d’avril pour dyspnée évoluant depuis un mois. Dans ses antécédents, on notait un reflux gastro-œsophagien, une hypothyroïdie substituée, des migraines, une hypertension artérielle, une hypercholestérolémie et une arthrodèse lombaire. Elle était fonctionnaire, ne fumait pas et consommait de l’alcool de manière occasionnelle. Elle appréciait les balades en forêt. Son traitement comportait : propanolol 40 mg/j, oméprazole 20 mg/j, L-thyroxine 25 μg/j, acide folique 4 mg/j. Fin mars, après une chute de la 11e marche d’un escalier, elle présentait une fracture et une plaie du poignet, nécessitant une attelle plâtrée puis une chirurgie de l’extenseur de l’index droit. C’est en revoyant l’orthopédiste à la consultation de contrôle post-opératoire qu’elle mentionnait pour la première fois une dyspnée de grade 3, associée à des douleurs thoraciques d’effort. Elle était donc hospitalisée en cardiologie où un bilan était réalisé : ECG montrant des ondes T négatives de V1 à V3, échographie cardiaque retrouvant une discrète hypertension artérielle pulmonaire (HTAP), angioscanner pulmonaire négatif, coronarographie normale. Une anémie macrocytaire (hémoglobine : 7,2 g/L) était découverte. Le bilan biologique montrait également une carence en folate substituée. Une gastroscopie mettait en évidence une petite ulcération antrale traitée par oméprazole. Il existait un syndrome inflammatoire (CRP : 200 mg/L), pour lequel les prélèvements bactériologiques (hémocultures, culture urinaire) restaient stériles. [...] Titre en anglais : Dyspnea in a 64 year-old woman

Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, causing urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy. Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and oxalate nephropathy, whose diagnosis is frequently delayed and prognosis too often poor. Fortunately, novel promising targeted therapeutic approaches are on the horizon in patients with primary hyperoxaluria. Patients with secondary hyperoxaluria frequently have long-standing hyperoxaluria-enabling conditions, a fact suggesting the role of triggers of acute kidney injury such as dehydration. Current standard of care in these patients includes management of the underlying cause, high fluid intake and use of calcium supplements. Overall, prompt recognition of hyperoxaluria and associated oxalate nephropathy is crucial, because optimal management may improve outcomes.

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.

Resume La granulomatose induite par les agents anti-tumor necrosis factor (anti-TNF) est un effet secondaire rare, mais pas exceptionnel, de ce traitement. Les organes le plus souvent atteints sont les poumons, les ganglions lymphatiques et la peau. L’atteinte renale est exceptionnelle. L’examen histologique montre habituellement des granulomes non caseeux. Certains des signes biologiques decrits habituellement dans la sarcoidose sont tres rares dans la granulomatose induite. Nous rapportons un cas de granulomatose se manifestant par une hypercalcemie severe et symptomatique, associee a une insuffisance renale aigue, chez une femme traitee par etanercept pour une polyarthrite rhumatoide. Sept jours apres l’admission, elle a presente une pneumopathie interstitielle hypoxemiante. Les analyses microbiologiques se sont averees negatives, y compris la recherche de mycobacteries et mycoses. Le tableau etant suggestif de granulomatose secondaire au traitement par etanercept, celui-ci a ete arrete. La biopsie renale, effectuee 30 jours apres l’admission, a revele une nephrite interstitielle aigue avec des depots de cristaux calciques. L’evolution a ete favorable apres arret de l’etanercept et traitement par cortisone, avec une reversibilite des lesions pulmonaires et une recuperation totale de la fonction renale trois semaines apres l’admission. La presentation clinique de la granulomatose secondaire aux agents anti-TNF peut etre extremement variable. Notre observation montre qu’une hypercalcemie symptomatique et potentiellement fatale peut survenir. L’atteinte renale est inhabituelle. Ce cas souligne la difficulte diagnostique de cette entite, ainsi que l’importance d’un suivi rapproche chez les patients recevant ce traitement. L’arret du medicament conduit a la resolution des lesions dans la majorite des cas.

TO THE EDITOR : Several reports of newly diagnosed or relapses of immune-mediated renal diseases following vaccination with anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA and AstraZeneca vaccines recently emerged in the litterature. [...]

With oxygenation proposed as a resuscitative measure during hypothermic models of preservation, the aim of this study was to evaluate the optimal start time of oxygenation during continuous hypothermic machine perfusion (HMP). In this porcine ischemia‐reperfusion autotransplant model, the left kidney of a ±40 kg pig was exposed to 30 minutes of warm ischemia prior to 22 hours of HMP and autotransplantation. Kidneys were randomized to receive 2 hours of oxygenation during HMP either at the start (n = 6), or end of the perfusion (n = 5) and outcomes were compared to standard, nonoxygenated HMP (n = 6) and continuous oxygenated HMP (n = 8). The brief initial and continuous oxygenated HMP groups were associated with superior graft recovery compared to either standard, nonoxygenated HMP or kidneys oxygenated at the end of HMP. This correlated with significant metabolic differences in perfusate (eg, lactate, succinate, flavin mononucleotide) and tissues (eg, succinate, adenosine triphosphate, hypoxia‐inducible factor‐1α, nuclear factor erythroid 2‐related factor 2) suggesting superior mitochondrial preservation with initial oxygenation. Brief initial O2 uploading during HMP at procurement site might be an easy and effective preservation strategy to maintain aerobic metabolism, protect mitochondria, and achieve an improved early renal graft function compared with standard HMP or oxygen supply shortly at the end of HMP preservation.

Introduction: Though there is currently no approved treatment for COVID-19, potential medications include lopinavir and doxycycline. Lopinavir is a broad-spectrum protease inhibitor successfully used during the SARS outbreak. Doxycycline is an antibiotic with immunomodulatory effects, which successfully treats dengue hemorrhagic fever. Comparing lopinavir combined with doxycycline with other commonly implemented COVID-19 treatment regimens is of medical significance. Methods: We conducted a retrospective study comparing two cohorts. One cohort strictly adhered to a treatment protocol of lopinavir combined with doxycycline (Lop/Dox), while the other cohort (Others) applied protocols based on combinations of favipiravir, hydroxychloroquine, and azithromycin. The outcomes evaluated were death from coronavirus and intubation. Results: During the study period, 161 and 114 patients were followed in the Lop/Dox cohort and the Others cohort, respectively. The Lop/Dox cohort was older and had lower O2 saturation at admission. The proportion of patients needing intubation did not differ between the cohorts (Lop/Dox, 15∙5%; Others, 16∙7%). The overall fatality rate likewise did not differ (12∙4%) in Lop/Dox and 8∙7% in the Others cohort). Older age and elapsed time between the onset of symptoms and hospitalization, O2 saturation at admission, and the lymphocyte to white blood cell ratio were independent risk factors for poor outcomes of the illness. Conclusion: This study showed that lopinavir plus doxycycline therapy is an effective treatment amongst moderate to severe COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is commonly associated with kidney damage, and the angiotensin converting enzyme 2 (ACE2) receptor for SARS-CoV-2 is highly expressed in the proximal tubule cells. Whether patients with COVID-19 present specific manifestations of proximal tubule dysfunction remains unknown. To test this, we examined a cohort of 49 patients requiring hospitalization in a large academic hospital in Brussels, Belgium. There was evidence of proximal tubule dysfunction in a subset of patients with COVID-19, as attested by low-molecular-weight proteinuria (70-80%), neutral aminoaciduria (46%), and defective handling of uric acid (46%) or phosphate (19%). None of the patients had normoglycemic glucosuria. Proximal tubule dysfunction was independent of pre-existing comorbidities, glomerular proteinuria, nephrotoxic medications or viral load. At the structural level, kidneys from patients with COVID-19 showed prominent tubular injury, including in the initial part of the proximal tubule, with brush border loss, acute tubular necrosis, intraluminal debris, and a marked decrease in the expression of megalin in the brush border. Transmission electron microscopy identified particles resembling coronaviruses in vacuoles or cisternae of the endoplasmic reticulum in proximal tubule cells. Among features of proximal tubule dysfunction, hypouricemia with inappropriate uricosuria was independently associated with disease severity and with a significant increase in the risk of respiratory failure requiring invasive mechanical ventilation using Cox (adjusted hazard ratio 6.2, 95% CI 1.9-20.1) or competing risks (adjusted sub-distribution hazard ratio 12.1, 95% CI 2.7-55.4) survival models. Thus, our data establish that SARS-CoV-2 causes specific manifestations of proximal tubule dysfunction and provide novel insights into COVID-19 severity and outcome., Graphical abstract

Sneddon's syndrome is a rare, noninflammatory thrombotic vasculopathy characterized by the combination of livedo racemosa, recurrent stroke, and histopathological skin lesions of endarteritis obliterans. Although multiorgan involvement suggests its systemic nature, detailed pathological description of affected organs - including the kidney - is exceptional. We report a case of Sneddon's syndrome with chronic kidney disease, associated with features of endarteritis obliterans in the skin and the kidney. The clinical presentation of our patient is compared to previously reported cases of Sneddon's syndrome with biopsy-proven kidney disease. We also discuss the differential diagnosis, pathophysiological mechanisms, relationship with antiphospholipid syndrome, and management of patients with Sneddon's syndrome and kidney disease. This clinical observation supports the systemic nature of Sneddon's syndrome and provides insights into the mechanisms by which this rare but probably underdiagnosed disease alters kidney function. .

Background Renal fibrosis is a feared complication of Lupus Nephritis (LN), and is associated with irreversible loss of kidney function. In our previous experiments, we found that intrarenal infiltration by immune effectors in LN correlates with the development of renal fibrosis. Here, we wondered whether cellular senescence, through its typical secretome (known as senescence-associated secretory phenotype or SASP) or through the accumulation of functionally incompetent cells, are part of the renal functional impairment and fibrotic process in LN. Methods Microarray data (Illumina HumanHT-2 v4 Expression BeadChip), obtained by our group from 32 human LN kidney biopsies and 8 controls were mined using GeneSpring software in order to study the expression of SASP-associated transcripts. Senescent cells were identified in human LN kidney biopsies using an anti-p16 antibody (Roche Diagnostics). Evaluation of glomerular activity and chronicity indices, glomerular and interstitial fibrosis was performed using conventional or quantitative scores on HE- PAS- and Red Sirius-stained sections. Clinical and biological data were retrieved from the medical files of the patients. Results Mining of microarray data obtained from 32 LN kidney biopsies indicated that SASP-associated transcripts (e.g. IGFB4, VCAM1, TGFb2, COL1A2, MMP7) were significantly overexpressed in kidney biopsies characterized by the presence of adaptive immune cell infiltrates in the interstitium and lower renal function. Expression of SASP-associated transcripts correlated significantly with the expression of b galactosidase (GLB1), a key regulator of the senescence process. In a pilot experiment, we stained LN renal biopsy sections using anti-p16 antibodies, in order to detect the presence of senescent cells. We found a positive stain in podocytes and renal tubular cells from 8 LN patients. The number of positive cells correlated positively with the number of intrarenal CD8-positive cells and the amount of fibrosis in these samples, while it correlated negatively with renal function (eGFR). Conclusion Our data show that the presence of senescent podocytes and renal tubular cells in LN kidney biopsies correlates with fibrotic changes and impaired renal function. Characterization of senescent cells in a larger cohort of LN biopsies is ongoing. Our observations are in line with the hypothesis that inflammation-accelerated senescence links the presence of activated adaptive immune effectors in the lupus kidney and the development of fibrosis.

Background In patients with Lupus Nephritis (LN), clinical response to treatment and renal histopathology have been shown to be discordant. We investigated whether per-protocol repeat renal biopsies are predictive of LN relapses and long-term impairment of renal function. Methods Forty-two patients with an incident biopsy-proven active proliferative (class III/IV ± V) LN from the LN database of the Universite catholique de Louvain were included in the present retrospective study. Per-protocol repeat kidney biopsies were performed in all patients after a median time of 24.3 (IQR: 21.3–26.2) months. The NIH activity index (AI) and chronicity index (CI) scores were assessed in both baseline and repeat biopsies. Results Despite a moderate correlation between urinary protein/creatinine (U-P/C) ratios and AI scores at repeat biopsy (r=0.48; P=0.001), ten patients (23.8%) with U-P/C ratios 3; figure 1). High AI scores in repeat biopsies were associated with an increased probability and/or shorter time to renal relapse (N=11) following the repeat biopsy (HR: 1.2; 95% CI: 1.1–1.3; P=0.007), independently of proteinuria levels. High NIH CI scores in repeat biopsies were associated with a sustained increase in serum creatinine levels corresponding to ≥120% of the baseline value (HR: 1.8; 95% CI: 1.1–2.9; P=0.016) through a median follow-up time of 131.5 (IQR: 73.8–178.2) months. Baseline AI/CI scores were not predictive of these outcomes. Conclusions Our results highlight the usefulness of per-protocol repeat biopsies as an integral part of the treatment evaluation, also in patients who have shown adequate clinical response.

A 74-year-old man was admitted to the nephrology ward for acute kidney injury (AKI). His medical history was remarkable for hypertension, coronary artery bypass grafting, early-onset gouty arthropathy, and slowly progressive stage IIIb chronic kidney disease of probable vascular origin. His medications included amlodipine, ramipril, furosemide, moxonidine, aspirin, simvastatin, omeprazole, and allopurinol. The patient further mentioned he had been taking a “rejuvenating powder” ordered on the Internet a week beforehand. Since starting the intake of this powder, he had been complaining of nausea, anorexia, and fatigue. Upon questioning, he mentioned a decrease in urine output for 3 days before admission. He denied any abdominal or flank pain, dysuria, and hematuria. Vitals signs were normal and physical examination unremarkable except for numerous tophi and hand and foot deformations related to gouty arthropathy. A kidney biopsy was performed [...]

Despite optimal anticoagulation and blood pressure control, patients with antiphospholipid syndrome (APS) nephropathy frequently progress to kidney failure, and recurrence after transplantation is common. The mTORC (mechanistic target of rapamycin complex) pathway was recently identified as a potential intermediate and a therapeutic target in vascular lesions associated with APS nephropathy. However, these results were derived from the retrospective analysis of a small cohort of patients receiving sirolimus after kidney transplantation. Therefore, they warranted external validation and the demonstration of the potential benefit of sirolimus in native kidney APS nephropathy. We report a patient with active APS nephropathy lesions occurring on native kidneys, in which endothelial mTORC activation was substantiated at the molecular level. Treatment with sirolimus was shown on a repeat kidney biopsy to successfully inhibit the AKT/mTORC pathway and was associated with significant improvement in kidney function and lesions of vasculopathy. Drug tolerance was excellent during the entire follow-up. This case validates and extends previous observations in kidney transplant recipients and demonstrates that endothelial activation of the AKT/mTORC pathway occurs in the damaged renal vasculature of native kidneys in APS nephropathy. These findings further support the potential of precision medicine and the use of mTORC activation as a biomarker of disease activity and as therapeutic target in patients with APS nephropathy.

Purpose Urinary tract infection (UTI) is the most common bacterial infection among infectious complications in kidney transplant recipients (KTR). After transplantation, infections can result from surgical complications, donor-derived infections, pre-existing recipient infections, and nosocomial infections. Post-transplant infection is still a major cause of morbidity, mortality, graft dysfunction and rejection. In this paper, we aimed to review a few compelling questions in kidney transplantation (KTX). Methods To identify relevant clinical questions regarding KTX and UTI a meeting was conducted among physicians involved in the KT program in our hospital. After discussion, several clinically relevant questions related to UTI after KTX. The 5 first rated in importance were judged generalizable to other clinical settings and selected for the purposes of this review. Results Nearly half of the patients present in the first three months of transplant with UTI. The most common uropathogens in post-transplant UTIs are Escherichia coli, Klebsiella pneumoniae, and Enterococcus faecalis. Risk factors for UTI include female sex, advanced age, recurrent UTI before transplant, prolonged urethral catheterization, delayed graft function, and cadaveric kidney transplant. Conclusion The incidence of post-transplant UTI is similar in both developed and developing countries. E.coli is the most common pathogen in most of studies. Cadaveric donor and post-dialysis transplantation are defined as independent risk factors for post-transplant UTI. Further studies are still required to identify risk factors after kidney transplantation and UTI's importance for graft function and patient outcome.

Rationale & Objective Membranous nephropathy (MN) is characterized by the deposition of immune complexes along glomerular basement membranes. M-Type phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A), exostosin 1 and 2 (EXT1/2), and neural epidermal growth factor-like 1 protein (NELL-1) have been identified as established or potential podocyte antigens in MN. We investigated the association of podocyte antigen staining with MN clinical phenotype and outcomes. Study Design Multicenter retrospective cohort study. Setting & Participants 177 consecutive patients with MN unrelated to lupus erythematosus, identified after screening of 3,875 native kidney biopsies performed in the Belgian UCLouvain Kidney Disease Network from 2000 through 2018. Predictor Positive immunostaining for podocyte antigens on archived kidney biopsy samples. Outcomes Association with different phenotypes (baseline characteristics of patients and pathologic findings on kidney biopsy), time to cancer and to kidney failure. Analytical Approach Kaplan-Meier estimates and Cox regression analyses to assess time to cancer and kidney failure. Results 177 patients were followed up for a median of 4.0 (IQR, 1.3-8.0) years. Diagnosis of PLA2R-positive (PLA2R+), THSD7A+, and double-negative (PLA2R−/THSD7A−) MN was made in 117 (66.1%), 6 (3.4%), and 54 (30.5%) patients, respectively. Progression to kidney failure was similar in all groups. Although the number of patients with THSD7A+ MN was small, they showed a higher incidence (50%) and increased risk for developing cancer during follow-up (adjusted HR, 5.0 [95% CI, 1.4-17.9]; P = 0.01). 8% and 5% of patients with double-negative MN stained positively for EXT1/2 and NELL-1, respectively. Most patients with EXT1/2+ MN were women, had features of systemic autoimmunity, and showed glomerular C1q deposits. Limitations Retrospective design; small number of patients in the THSD7A group; lack of evaluation of immunoglobulin G subclasses deposition. Conclusions Our real-world data describe the relative prevalence of subgroups of MN and support the hypothesis that a novel classification of MN based on podocyte antigen staining may be clinically relevant.

ObjectivesChronic renal impairment remains a feared complication of lupus nephritis (LN). The present work aimed at identifying mechanisms and markers of disease severity in renal tissue samples from patients with LN.MethodsWe performed high-throughput transcriptomic studies (Illumina HumanHT-12 v4 Expression BeadChip) on archived kidney biopsies from 32 patients with LN and eight controls (pretransplant donors). Histological staging (glomerular and tubular scores) and immunohistochemistry experiments were performed on the same and on a replication set of 37 LN kidney biopsy samples.ResultsA group of LN samples was identified by unsupervised clustering studies based on their gene expression features, that is, the overexpression of transcripts involved in antigen presentation, T and B cell activation. These samples were characterised by a significantly lower estimated glomerular filtration rate (eGFR) at the time of biopsy (T0) compared with the other systemic lupus erythematosus samples. Yet, apparent disease duration at T0, double-stranded DNA antibody titres at T0 and other relevant characteristics (serum C3, proteinuria, histological scores, numbers of previous flares) were not different between groups.Immunohistochemistry studies confirmed the association between interstitial infiltration by adaptive immune effectors and decreased renal function in the same and in a replication group of LN kidney biopsies. This was associated with transcriptomic, histological and immunohistochemical evidence of renal tubular cell involvement.ConclusionInterstitial infiltration of LN kidney biopsies by adaptive immune effectors is associated with impaired renal tubular cell function and decreased eGFR. These results open new perspectives in evaluating and treating patients with LN, focusing on intrarenal mechanisms of immune cell activation.

De novo thrombotic microangiopathy (TMA) can occur after kidney transplantation. An abnormality of the alternative pathway of complement must be suspected and searched for, even in presence of a secondary cause. We report the case of a 23-year-old female patient who was transplanted with a kidney from her mother for end-stage renal disease secondary to Hinman syndrome. Early after transplantation, she presented with 2 episodes of severe pyelonephritis, associated with acute kidney dysfunction and biological and histological features of TMA. Investigations of the alternative pathway of the complement system revealed atypical haemolytic uremic syndrome secondary to complement factor I mutation, associated with mutations in CD46 and complement factor H related protein genes. Plasma exchanges followed by eculizumab injections allowed improvement of kidney function without, however, normalization of creatinine.

Cushing syndrome (CS) is a rare disease in children, frequently associated with subtle or periodic symptoms that may delay its diagnosis. Weight gain and growth failure, the hallmarks of hypercortisolism in pediatrics, may be inconsistent, especially in ACTH-independent forms of CS. Primary pigmented nodular adrenocortical disease (PPNAD) is the rarest form of ACTH-independent CS, and can be associated with endocrine and nonendocrine tumors, forming the Carney complex (CNC). Recently, phenotype/genotype correlations have been described with particular forms of CNC where PPNAD is isolated or associated only with skin lesions. We present four familial series of CS due to isolated PPNAD, and compare them to available data from the literature. We discuss the clinical and molecular findings, and underline challenges in diagnosing PPNAD in childhood.

Context: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine, usually benign, tumors. Currently, the only reliable criterion of malignancy is the presence of metastases. Objective: The aim of this study was to identify genes associated with malignancy in PPGLs. Design: Transcriptomic profiling was performed on 40 benign and 11 malignant PPGLs. Genes showing a significantly different expression between benign and malignant PPGLs with a ratio $4 were confirmed and tested in an independent series by quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry was performed for the validated genes on 109 benign and 32 malignant PPGLs. Functional assays were performed with hPheo1 cells. Setting: This study was conducted at the Department of Pathology of the Erasmus MC University Medical Center Rotterdam Human Molecular Genetics laboratory of the de Duve Institute, University of Louvain. Patients: PPGL samples from 179 patients, diagnosed between 1972 and 2015, were included. Main outcome measures: Associations between gene expression and malignancy were tested using supervised clustering approaches. Results: Ten differentially expressed genes were selected based on messenger RNA (mRNA) expression array data. Contactin 4 (CNTN4) was overexpressed in malignant vs benign tumors [4.62-fold; false discovery rate (FDR), 0.001]. Overexpression at the mRNA level was confirmed using qRTPCR (2.90-fold, P=0.02; validation set: 4.26-fold, P=0.005). Consistent findings were obtained in The Cancer Genome Atlas cohort (2.7-fold; FDR, 0.02). CNTN4 protein was more frequently expressed in malignant than in benign PPGLs by immunohistochemistry (58% vs 17%; P=0.002). Survival after 7 days of culture under starvation conditions was significantly enhanced in hPheo1 cells transfected with CNTN4 complementary DNA. Conclusion: CNTN4 expression is consistently associated with malignant behavior in PPGLs.

Les sarcomes cardiaques primitifs sont extrêmement rares et de pronostic sombre. L’existence du sarcome intimal, tumeur mésenchymateuse maligne affectant principalement l’artère pulmonaire et l’aorte, est rapportée au niveau du cœur mais reste encore débattue. Nous rapportons le cas d’un sarcome intimal développé chez une patiente de 70 ans, avec ses caractéristiques macroscopiques, microscopiques et moléculaires. [Cardiac intimal sarcoma: A case report of a rare tumor with peculiar histopathological findings] Primary cardiac sarcomas are rare tumors with poor prognosis. Intimal sarcoma, a mesenchymal malignant tumor described mainly in the great vessels, may rarely involve the heart. Herein we describe the case of a 70-years-old female who was found to have a left atrial mass during an investigation of a new onset dyspnea. The patient underwent surgery and the resected mass was found to be an intimal sarcoma. The objectives of this report were to describe a case of this rare disease entity and to discuss its pathological and molecular findings based on relevant literature.

Renal diseases are frequently associated with monoclonal gammopathies. Heavy chain deposition disease (HCDD) is an extremely rare condition, one of the 3 entities of monoclonal immunoglobulin deposition disease (MIDD). It is characterized by the presence of nodular glomerulosclerosis and glomerular and tubular deposition of monoclonal HC without associated light chains (LC). Here, we reported a case of HCDD associated with other manifestations, e.a. pulmonary fibrosis and cutis laxa. A 38-year-old Polish woman was referred to the emergency room for a 2-month history of fatigue, 10 kg weight gain and NYHA II dyspnea. She has been treated in 2014 by corticosteroids for a nephrotic syndrome responsible to acute renal failure, attributed to a minimal change glomerulonephritis, evolving with time to a progressive decrease of her renal function. In addition, she presented a 3-year history of skin changing appearance with premature ageing of the face, neck, chest, arms and feet. On physical examination, she looked much older than her age, with a sagging of the skin and a lack of elasticity that predominates in the neck, axillary regions, back and abdomen. She had peripheral edema and a blood pressure at 160/90 mmHg. Initial lab tests revealed a terminal stage chronic renal failure (creatinine, 10.24 mg/dL) with microcytic anemia (hemoglobin, 7.2 g/dL), hypogammaglobulinemia (IgG, 5 g/L) with a discreet IgG Lambda M-protein and low C3 levels. Both kappa and lambda light chains were elevated with a normal kappa/lambda ratio, and associated to a significant proteinuria (4.78 g/L) with excess lambda LC and micro-hematuria. Kidney biopsy confirmed the presence of nodular glomerulosclerosis with peritubular anti-IgG staining and 'powdery punctate' deposits along the inner aspect of the tubular basement membranes, confirming the diagnosis of HCDD. IgG and C3 deposits were also reported on skin biopsies, in addition to elastic fibers degenerative changes responsible for cutis laxa. Functional pulmonary evaluation revealed a marked restrictive syndrome with a decreased diffusion capacity suggesting an interstitial lung disease, probably related to the elastolysis seen in cutis laxa. Bortezomib-based chemotherapy was started, with the prospect to collect stem cells later on, and in case of complete hematological response, proceed to kidney transplantation. Monoclonal gammapathies are rarely found in patients under the age of 40, and can be associated with numerous clinical manifestations such as MGRS. HCDD is an extremely rare condition, in which patients presented with nephrotic syndrome, hematuria and hypertension, develop progressive renal failure, but can be successfully treated with chemotherapy.

We describe the case of a 64-year-old woman admitted for fever of unknown origin, who developed nephrotic syndrome during hospitalisation and pulmonary infiltrates. Renal biopsy disclosed intracapillary glomerular invasion by intravascular large B cell lymphoma. Clinical and biological evolution was favourable after rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone (R-CHOP) treatment and autologous stem cell transplant. Two years after diagnosis the patient was considered in remission.

We report the case of a 43-year-old man, suffering from ankylosing spondylitis and treated with Infliximab 5 mg/kg every 2 months, with an excellent disease control. During a follow-up consultation, an incipient renal insufficiency is detected. A urine analysis showed haematuria and proteinuria and a renal puncture-biopsy revealed an image of IgA nephropathy.Several cases of IgA nephropathy have been reported in the literature associated with ankylosing spondylitis. Some of them occur in patients treated with antitumour necrosis factor, but it is unclear whether this pathology is caused by the treatment or whether treatment failed to prevent its occurrence.Our clinical case highlights the importance of regular monitoring of renal function in patients with ankylosing spondylitis, as well as urinary spotting.The question of whether the disease itself, the treatment or other factors such as immune dysregulation could be held responsible for kidney disease will be addressed in the discussion.

Background: The aim of this feasibility study was to determine an alternative oxygenation technique (easy, cheap, and compatible with air transport) for membrane oxygenation during hypothermic machine perfusion (HMP) to improve early graft function in a porcine ischemia-reperfusion autotransplant model. Methods: The left kidney of a ±40- kg pig was exposed to 30 minutes of warm ischemia before 22 hours of preservation and autotransplantation. In the experimental group, oxygenation of the perfusate during HMP was obtained by direct bubble and 30-minute surface oxygenation at start and 1-hour end ischemic (n = 4) and outcome measures compared with historical HMP without active oxygenation (n = 6), 22-hour continuous oxygenated HMP (HMPO2) (n = 8), and 2-hour HMPO2 + 20-hour HMP (n = 6) using membrane oxygenation in both historical oxygenated control groups. Results: Brief bubble and 30-minute surface oxygenation of the perfusate effectively maintained supraphysiological Po2 levels during the first 2 hours of HMP with improved flow dynamics. Although the metabolic profile of the perfusate (ie, flavin mononucleotide) and tissue (ie, glutamate, ATP) after brief O2 uploading at the start of HMP seemed to be slightly better with the use of a membrane oxygenator compared with bubble and interrupted surface oxygenation, both techniques yielded similar, superior early graft function when compared with HMP without active oxygenation. Conclusions: The data presented in this feasibility study support the conclusion that brief bubble and intermittent surface oxygenation could be an alternative oxygenation technique during HMP to achieve an improved kidney graft function compared with HMP without active oxygenation and similar functional outcome when compared with membrane HMPO2.

Background:In patients with lupus nephritis (LN), clinical response to treatment and renal histopathology have been shown to be discordant. No clinical or laboratory markers have to date been shown to reliably portend renal prognosis, in particular renal function impairment.Objectives:To investigate whether per-protocol repeat renal biopsies are predictive of LN relapses and long-term impairment of renal function.Methods:Forty-two patients with an incident biopsy-proven active proliferative (class III/IV ± V) LN from the LN database of the Université catholique de Louvain were included in the present retrospective study. Per-protocol repeat kidney biopsies were performed in all patients after a median time of 24.3 (IQR: 21.3–26.2) months. The NIH activity index (AI) and chronicity index (CI) scores were assessed in both baseline and repeat biopsies. We defined acute glomerular lesions as cellular proliferation, fibrinoid necrosis or karyorrhexis, cellular crescents, hyaline thrombi or wire loops, and leucocyte infiltration, and chronic glomerular lesions as glomerular sclerosis and fibrous crescents, in alignment with the NIH activity and chronicity indices. Similarly, we defined acute tubulointerstitial lesions as mononuclear cell infiltration and chronic tubulointerstitial lesions as interstitial fibrosis and tubular atrophy.Results:Despite a moderate correlation between urinary protein/creatinine (U-P/C) ratios and AI scores at repeat biopsy (r=0.48; P=0.001), ten patients (23.8%) with U-P/C ratios 3). High AI scores in repeat (but not baseline) kidney biopsies were associated with an increased probability and/or shorter time to renal relapse (N=11) following the repeat biopsy (HR: 1.2; 95% CI: 1.1–1.3; P=0.007), independently of proteinuria levels. This association remained significant for the NIH activity index items within the glomerular but not the tubulointerstitial compartment of the kidney biopsies. High NIH CI scores in repeat (but not baseline) kidney biopsies were associated with a sustained increase in serum creatinine levels corresponding to ≥120% of the baseline value (HR: 1.8; 95% CI: 1.1–2.9; P=0.016) through a median follow-up time of 131.5 (IQR: 73.8–178.2) months, being the case also for acute and chronic tubulointerstitial lesions in repeat but not baseline kidney biopsies.Conclusion:Our results highlight the usefulness of per-protocol repeat biopsies as an integral part of the treatment evaluation, also in patients who have shown adequate clinical response. Glomerular lesions consistent with active renal disease portend LN relapses, while tubulointerstitial lesions consistent with active disease and chronic damage portent long-term renal function impairment.Disclosure of Interests:Ioannis Parodis: None declared, Christina Adamichou: None declared, Selda Aydin: None declared, Alvaro Gomez: None declared, Nathalie Demoulin: None declared, Julia Weinmann-Menke: None declared, Frederic Houssiau Grant/research support from: UCB, Consultant of: GSK, Farah Tamirou: None declared

We present a 35-year-old female patient who was started on rifampicin (900 mg orally once daily) and trimethoprim/sulfamethoxazole (TMP/SMX) (160/800 mg orally twice daily) after being diagnosed with brucellosis. Following defervescence and improvement in her general condition, fever recurred on the 12th day of treatment. A re-challenge drug test lead to causality assessment and treatment was switched to a combination of streptomycin (1 g intramuscularly) for 10 days and TMP/SMX (160/800 mg orally twice daily) for 4 weeks. Our patient is doing well after 12 months of follow-up.

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.

The spectrum of kidney damage associated with monoclonal gammopathy is wide, and notably encompasses diseases secondary to the abnormal precipitation or deposition of monoclonal immunoglobulins. Crystal(cryo)globulin-induced kidney disease is a rare but dramatic complication of monoclonal gammopathy, characterized by spontaneous crystallization of monoclonal immunoglobulins in the renal and systemic vasculature.

WOS: 000354124400016 PubMed ID: 25959163 Background: Hepatitis C virus (HCV) status cannot be reliably predicted in anti-HCV positive/HCV-RNA negative individuals who may either have recovered spontaneously or have a false-positive test due to antibody cross-reaction. Investigating T lymphocyte responses in individuals with different HCV status may help understand the cellular immune mechanisms underlying spontaneous recovery, treatment response, and chronicity. Objective: We aimed to determine whether anti-HCV positive, HCV-RNA negative individuals are truly spontaneous recoverers from acute HCV infection. Study design: We used enzyme-linked immunosorbent spot (ELISPOT) assay to compare HCV-specific lymphocyte response among anti-HCV positive/HCV-RNA negative individuals, patients with sustained virological response to interferon-gamma/ribavirin treatment, and patients with chronic HCV infection. Results: We found that 83% of anti-HCV positive/HCV-RNA negative individuals without a past medical history of acute icteric hepatitis had an HCV-specific T lymphocyte response in peripheral blood. Lymphocyte responses in these individuals were similar in magnitude to treatment responders unlike patients with chronic HCV whose virus-directed immunity was significantly suppressed. Conclusions: Detection of HCV-specific T lymphocyte responses using ELISPOT is a feasible method to ascertain past asymptomatic acute HCV infection. Office of Scientific Research Projects, Istanbul University [BYPS-1-26/31012007] This study is funded in part by the Office of Scientific Research Projects, Istanbul University (no: BYPS-1-26/31012007).

Central nervous system infection caused by Human Herpesvirus 6 (HHV-6) is well known in immunocompromised; however, data regarding immunocompetent patients is limited to case series. We describe a 29-year-old immunocompetent pregnant woman with meningoencephalitis due to HHV-6 and review current literature. HHV-6 should be kept in mind in patients with meningoencephalitis of unknown etiology.

Background Chronic renal impairment remains a feared complication of lupus nephritis (LN). Yet, little is known about mechanisms and markers of disease severity in the lupus kidney. Methods We performed high-throughput transcriptomic studies (Illumina HumanHT12 v4 Expression Beadchips) on archived (- 80 degrees) kidney biopsies from 32 SLE patients and 8 controls (pre-transplant donors). Unsupervized clustering and differential gene expression studies were performed using GeneSpring software. Pathway analyses were carried on using DAVID and GSEA. Clinical and biological data were retrieved from the patients9 medical records. Immunohistochemistry experiments (CD3, CD20, CD21) were performed on the same samples, and on an additional cohort of 37 SLE kidney biopsies. Syndecan-1 (SDC1) was used as a marker of renal tubular cell response to stress. Results Compared to controls, LN samples overexpressed transcripts involved in interferon signature, apoptosis, chemokines, antigen presentation, T and B cell activation. Unsupervized clustering studies isolated 14 SLE samples based on their gene expression features. These samples were characterized by a significantly lower estimated GFR at the time of biopsy (T0) (50.7 versus 97.4 ml/min/1.72m2), but also at follow-up (49.1 versus 85.8 ml/min/1.72m2) compared to the other SLE samples. Yet, apparent renal disease duration at T0, disease duration at last follow-up (median 91.5 versus 86 months), double-stranded DNA antibody titers at T0 and other relevant characteristics (histological scores, proteinuria, numbers of subsequent flares) were not different between both groups. From a transcriptomic point of view, these 14 samples were characterized by the overexpression of transcripts and pathways involved in adaptive immune responses: antigen presentation, T cell differentiation and B cell activation. Immunohistochemistry studies confirmed a significant association between the presence of CD3 and CD20 positive cells in the interstitial space and lower estimated GFR at baseline in the same, but also in an independent set of samples. The presence of CD3 and CD20 positive cells was also associated with lower SDC1 expression on renal tubular cells. Low SDC1 expression on renal tubular cells was strongly associated with impaired kidney function at baseline. Conclusions LN kidney biopsy samples from patients with lower estimated GFR are characterized by the overexpression of transcripts pointing to the activation of a local antigen-dependent immune response. Activation of “second wave” immune effectors in the LN kidney is a known feature of the disease, and impacts kidney function through alterations in the function of renal tubular cells. Acknowledgements The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115565, resources of which are composed of financial contribution from the European Union9s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies9 in kind contribution Disclosure of Interest None declared

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.

Background: Blood stream infections (BSIs) due to carbapenem-resistant Enterobacteriaceae (CRE) are associated with high hospital mortality rates and present a tremendous challenge to clinicians. The optimal treatment remains undefined. We aimed to investigate the risk factors for mortality and the correlation between different treatment modalities and outcomes. Methods: The clinical characteristics and treatment outcomes of a cohort of 36 patients with BSIs due to CRE were investigated and a retrospective nested case–control study of surviving and non-surviving patients was conducted. Results: Fifty percent of the cases were male and the mean patient age was 54.9 ± 15.8 years. Klebsiella pneumoniae was the etiological agent in 26 cases (72.2%), Escherichia coli in eight (22.2%), and Enterobacter aerogenes in two (5.5%). All strains were phenotypically positive for carbapenemase activity and all except two (one E. coli and one K. pneumoniae) yielded both blaOXA-48 carbapenemases and blaCTX-M-type extended-spectrum beta-lactamases (ESBLs) in PCR products. The 14-day, 28-day, and all-cause in-hospital mortality rates were 41.6%, 50%, and 58.3%, respectively. The median time to death was 8 days (range 2–52 days). No significant differences were observed between survivors and non-survivors in terms of baseline characteristics, comorbid conditions, etiologies, or sources of bacteremia, however hematological malignancies (p = 0.015) and prolonged neutropenia (p = 0.044) were more common in non-survivors. Microbiological eradication and clinical response within 7 days were two major determinants of 28-day attributable mortality (p = 0.001 and p = 0.001, adjusted r2 = 0.845). Colistin-based dual combinations, and preferably triple combinations, were associated with significantly better outcomes when compared to non-colistin-based regimens (p

Non-clear cell renal cell carcinoma accounts for about 20% of all kidney cancers. Tubulocystic carcinoma of the kidney (TCK) is a newly described entity with distinct molecular, genetic and clinical features. In 2013, it was one of five new renal tumors to be recognized by the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia. We describe here a case of TCK with a rare genetic signature, unusual metastases and limited response to an anti-vascular endothelial growth factor inhibitor in what we believe is the youngest patient on record to date.

We observed a 76-year-old man who presented “acute kidney-lung failure” 9 months after intravesical Bacillus Calmette-Guerin (BCG) adjuvant treatment for a T1 bladder cancer. He had inflammatory infiltration on chest radiography and required dialysis for acute renal failure. A percutaneous renal biopsy was performed and revealed tubulointerstitial nephritis with a moderate eosinophilic infiltrate without granulomatous lesion. After a few days, an open lung biopsy was also done due to respiratory deterioration. The anatomopathologic specimen demonstrated moderate fibrosis with lympho-neutrophilic infiltration and few aspecific granulomatous lesions without caseous necrosis. Sarcoidosis was suspected and high dose oral methylprednisolone was started. Three weeks later, Mycobacterium bovis was identified by Polymerase Chain Reaction on open lung biopsy. He responded well to steroids and tuberculostatic tri-therapy. After one month of immunosuppressive treatment, renal function was resolved and hemodialysis could be discontinued. Despite the frequent use of adjuvant BCG immunotherapy, systemic complications such as hepatitis, pneumonitis, spondylodiscitis or multiorgan failure are rare (

The soluble form of the interleukin 7 receptor (sIL-7R) is produced by fibroblasts after stimulation with proinflammatory cytokines. Increased sIL-7R serum and synovial fluid levels were recently demonstrated in patients with rheumatoid arthritis., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis characterized by abrupt onset of hypertension, thrombotic microangiopathy, and kidney injury. The mechanisms of the disease remain ill-defined, but a growing body of evidence suggests that activation of the complement system may be involved. Methods: Here, we report the case of a patient presenting with severe SRC and strong evidence of complement activation, both in serum and in the kidney, in the absence of genetic defect of the complement system. Results: Immunofluorescence studies on kidney biopsy showed significant deposits of C1q and C4d in the endothelium of renal arterioles, pointing toward activation of the classical pathway. Because of the dramatic clinical and histological severity, and the lack of response to early treatment with angiotensin-converting enzyme inhibitors, calcium channel blockers and plasma exchange, the patient was treated with the specific C5 blocker eculizumab. Contrarily to conventional treatment, eculizumab efficiently blocked C5b-9 deposition ex vivo and maintained hematological remission. Unfortunately, the patient died from heart failure a few weeks later. Postmortem examination of the heart showed diffuse patchy interstitial fibrosis, the typical lesion of systemic sclerosis-related cardiomyopathy, but normal coronary arteries and myocardial microvasculature. Conclusion: SRC may lead to complement system activation through the classical pathway. Early administration of C5 inhibitor eculizumab may have therapeutic potential in patients with life-threatening SRC refractory to conventional treatment using angiotensin-converting enzyme inhibitors., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Beside classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. MATERIAL AND METHODS Patients with refractory mCRC treated with regorafenib in our institution were reviewed. Severe treatment-related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P 3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity. RESULTS Among the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms and portal tract inflammation with porto-central bridging and fibrosis in the delayed presentation. None patients had CYP3A4 gene mutations. Similar polymorphisms in UGT1A9 gene promoter region (UGT1A9 variant -118T9>10 (rs3832043)) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan-based chemotherapy. CONCLUSION This is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of a close liver tests monitoring during regorafenib treatment. This article is protected by copyright. All rights reserved.

Summary: The most common manifestation of HIV in the kidney is HIV-associated nephropathy (HIVAN). In this report, we describe the first documented case of membranous glomerulonephritis in an HIV-positive individual in Turkey, the country with the lowest HIV prevalence in the region. The case occurred in an HIV-positive, hepatitis C (HCV)-negative, and hepatitis B (HBV)-negative Caucasian male, who presented with nephrotic-range proteinuria. The patient had a favorable response to HAART and an angiotensin-receptor blocker. Keywords: HIV, Nephropathy, Membranous glomerulonephritis

This study evaluated the presence of carbapenem hydrolysing β-lactamase genes and plasmid-mediated quinolone resistance (PMQR) determinants in 22 Klebsiella pneumoniae isolates collected from the Istanbul Medical Faculty, Turkey, which reduced the susceptibility or resistance to carbapenem. The VITEK® 2 system and E-tests were used to determine the minimum inhibitory concentrations needed to inhibit bacterial growth. Genes were screened by polymerase chain reaction, and gene transferability was evaluated by transconjugation. Strain clonality was investigated by pulsed-field gel electrophoresis (PFGE). All strains were OXA-48 β-lactamase producers and three (13.6%) were also positive for the aac(6′)-Ib-cr gene. Most of the strains harboured other b-lactamase (bla) genes such as blaTEM, blaSHV, blaCTX-M and blaVEB-1. The transconjugants mostly harboured blaOXA-48 and other β-lactamases separately. PFGE revealed eight pulsotypes among the isolates. The coexistence of blaOXA-48 and PMQR in K. pneumoniae isolates may present a significant threat to health, especially in the nosocomial setting.

BACKGROUND: To assess the safety and preliminary efficacy of concurrent radiotherapy, capecitabine, and cetuximab in the preoperative treatment of patients with rectal cancer. PATIENTS AND METHODS: Forty patients with rectal cancer (T3-T4, and/or N+, endorectal ultrasound) received preoperative radiotherapy (1.8 Gy, 5 days/week for 5 weeks, total dose 45 Gy, three-dimensional conformal technique) in combination with cetuximab [initial dose 400 mg/m(2) intravenous given 1 week before the beginning of radiation followed by 250 mg/m(2)/week for 5 weeks] and capecitabine for the duration of radiotherapy (650 mg/m(2) orally twice daily, first dose level; 825 mg/m(2) twice daily, second dose level). RESULTS: Four and six patients were treated at the first and second dose level of capecitabine, respectively. No dose-limiting toxicity occurred. Thirty additional patients were treated with capecitabine at 825 mg/m(2) twice daily. The most frequent grade 1/2 side-effects were acneiform rash (87%), diarrhea (65%), and fatigue (57%). Grade 3 diarrhea was found in 15%. Three grade 4 toxic effects were recorded: one myocardial infarction, one pulmonary embolism, and one pulmonary infection with sepsis. Two patients (5%) had a pathological complete response. CONCLUSIONS: Preoperative radiotherapy in combination with capecitabine and cetuximab is feasible with some patients achieving pathological downstaging.

BACKGROUND Aristolochic acids (AA) are nephrotoxic and carcinogenic. The aim of this study was to assess the long-term outcome of patients with AA nephropathy (AAN) after kidney transplantation. METHODS Observational study. Patients' characteristics, long-term surveillance and follow-up data, patient and graft survival, as well as outcomes with respect to rejection, cardiovascular complications, infections, and cancers with a focus on urothelial carcinomas, are reported. RESULTS Twenty patients transplanted for AAN were included. All were submitted to prophylactic bilateral ureteronephrectomy and annual surveillance of the bladder. Median duration of posttransplant follow-up was 12.5 (3-19) years. Time from diagnosis of AAN to renal replacement therapy was relatively short (1 [0-15] years). Immunosuppression consisted of a triple therapy in the majority of patients. Nineteen patients had upper urinary tract multifocal atypia. Eleven patients presented with urothelial carcinomas of the upper tract; 2 of them with additional bladder urothelial carcinomas. Of these 2 patients, one required radical cystectomy. One patient developed a hepatocarcinoma. Patient survival was 100% in AAN patients at 5, 10, and 15 years after transplantation. Graft survival at 5, 10, and 15 years was 95%, 83%, and 75%. CONCLUSIONS Despite a high prevalence of urothelial carcinoma and the risk of bladder carcinoma, the long-term patient and kidney graft survival is excellent in patients with AAN, provided that prophylactic bilateral ureteronephrectomy and lifelong surveillance of the bladder are performed.

Aim This report describes a case of kidney failure secondary to orlistat, a lipase inhibitor commonly used in the treatment of obesity. Case report An 80-year-old man with type 2 diabetes who was being treated with orlistat developed rapidly progressive kidney failure. Low-grade albuminuria argued against diabetic nephropathy. Renal biopsy showed tubulointerstitial nephritis associated with numerous calcium oxalate crystals. Enteric hyperoxaluria was attributed to the orlistat treatment. The latter was stopped and the patient received calcium supplements. Six months after orlistat withdrawal, oxaluria was normalized and kidney function stabilized. Conclusion Oxalate nephropathy may result from hyperoxaluria secondary to orlistat treatment. This suggests that kidney function and oxaluria be closely monitored in patients taking orlistat.