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Introduction: Kidney biopsies (KBs) are performed in patients with type 2 diabetes (T2D) to diagnose non-diabetic or hypertensive kidney disease (NDHKD) potentially requiring specific management compared to diabetic and or hypertensive nephropathy (absence of NDHKD). Indications for KB are based on the presence of atypical features compared to the typical course of diabetic nephropathy. In this study, we assessed the association of different patterns of atypical features, or KB indications, with NDHKD. Methods: Native KBs performed in patients with T2D were analyzed. Data were collected from the patients’ records. KB indications were determined according to the presence of different atypical features considered sequentially: (1) presence of any feature suggesting NDHKD which is not among the following ones, (2) recent onset of nephrotic syndrome, (3) low or rapidly declining estimated glomerular filtration rate (eGFR), (4) rapid increase in proteinuria, (5) short duration of diabetes, (6) presence of hematuria, or (7) normal retinal examination. Results: Among the 463 KBs analyzed, NDHKD was diagnosed in 40% of the total population and 54, 40, 24, and 7% of the KBs performed for indications 1–4 respectively. Conversely, no patient who underwent KB for indications 5–7 displayed NDHKD. Logistic regression analyses identified eGFRCKD-EPI >15 mL/min/1.73 m2, urinary protein-to-Cr ratio

To retrospectively characterize the molecular features of Non-Small Cell Lung Carcinomas (NSCLC) with peritoneal carcinomatosis (PC), clinicopathological data of 12 patients diagnosed with NSCLC and PC between 2007 and 2016 were collected. Immunohistochemistry and Next Generation Sequencing (NGS) were performed on cases with available material. PC was the initial presentation of NSCLC in 17% of the cases. Overall, patients with PC displayed a poor median survival of 12 weeks. Histology was adenocarcinoma in 11 cases. 37.5% of cases showed PD-L1 immunostaining positivity (50% cut-off). ALK and ROS1 immunostainings were negative. Using NGS, we identified 17 molecular alterations in 9 genes (TP53, KRAS, STK11, BRAF, EGFR, DDR2, ERBB4, SMAD4, CTNNB1) in 88.9% of adenocarcinomas. To the best of our knowledge, 5 of these variants are not referenced in the literature. In conclusion, PC might be the initial presentation of NSCLC. Molecular profiling of our cases did not find any effective targetable alteration, except from high PD-L1 expression.

Background and Aims Kidney Biopsies (KB) performed in patients with Type-2 diabetes (T2D) usually aim at differentiating diabetic nephropathy (DN) from other kidney diseases. However, KB could also help refining patients’ prognosis, both in terms of renal survival, and in terms of patient survival. In 2010, the Renal Pathology Society developed a pathological classification of DN, but the prognostic value of the described items , is still imperfectly documented. We aimed to assess the prognostic performances of these items to predict renal and patient survival. Method Native KBs with diabetic and/or hypertensive nephropathy (DN/HN) performed in patients with T2D in four French centers were analyzed and scored according to the classification developed by the Renal Pathology Society. Clinical and biological data was collected from the patients’ records. Survival analyses were performed for renal survival (time to first dialysis or preemptive transplantation) and death after dichotomization of continuous data). For each of the analyses, we first established a model comprising clinical data only. We then assessed the benefit of adding each of the pathological item to the clinical model. Finally, we performed a backward stepwise analysis to identify items predictive of renal and/or patient survival. Results We analyzed 165 biopsies with DN/HN from patients with T2D and with at least 12 months of follow-up (unless they reached an endpoint during the first year). Among them, 73 (44%) were male, 155 (94%) had hypertension, 53 (34%) hematuria, 22 (15%) had proliferative diabetic retinopathy (DR), 33 (23%) had non-proliferative DR, 90 (62%) had no DR (20 had missing data). Mean (SD) age was 63 (11), median [IQR] eGFRCKD-EPI was 29 [18;45] ml/min/1.73m², urinary protein-to-creatinine ratio was 0.38 [0.14;0.83] g/mmol, HbA1c was 7 [6.2;8.2] % and diabetes duration before KB was 10 [5;19] years. The median [IQR] follow-up was 33 months[18;57]. During the follow-up, 43 (26%) patients died and 69 (42%) required renal replacement therapy (RRT). The percentage of ischemic glomeruli, and presence of more than one area of arteriolar hyalinosis (ah=2), were predictive of renal survival and improved the predictive value of the model when added to clinical parameters. Presence of at least one convincing Kimmelstiel–Wilson lesion (nodular glomerulosclerosis or Class III DN) was predictive of death and similarly improved the predictive model (See figure). Conclusion Pathological findings on KB, as classified by the Renal Pathology Society, carry significant prognostic value in patients with T2D and DN/HN. Vascular lesions (presence of arteriolar hyalinosis and less than 7% of ischemic glomeruli) predicted the need for RRT, while nodular glomerulosclerosis was predictive of death.

Background The coronavirus disease 2019 (COVID-19) may be associated with kidney injury, which may impact patient's prognosis. Methods We report a multicentric retrospective case series of patients with COVID-19 who developed acute kidney injury (AKI) and/or proteinuria and underwent a kidney biopsy in Paris and its metropolitan area. Results Forty-seven patients (80.9% men) with COVID-19 who underwent a kidney biopsy between 8 March and 19 May 2020 were included. The median age was 63 years (interquartile range 52–69). Comorbidities included hypertension (66.0%), diabetes mellitus (27.7%), obesity (27.7%), history of chronic kidney disease (25.5%), cardiac diseases (38.6%) and respiratory diseases (27.3%). Initial symptoms were fever (85.1%), cough (63.8%), shortness of breath (55.3%) and diarrhoea (23.4%). Almost all patients developed AKI (97.9%) and 63.8% required renal replacement therapy. Kidney biopsy showed two main histopathological patterns, including acute tubular injury in 20 (42.6%) patients, and glomerular injury consisting of collapsing glomerulopathy (CG) and focal segmental glomerulosclerosis in 17 (36.2%) patients. Two (4.3%) patients had acute vascular nephropathy, while 8 (17%) had an alternative diagnosis most likely unrelated to COVID-19. Acute tubular injury occurred almost invariably in the setting of severe forms of COVID-19, whereas patients with glomerular injury had various profiles of COVID-19 severity and CG was only observed in patients harbouring a combination of APOL1 risk variants. At the last follow-up, 16 of the 30 patients who initially required dialysis were still on dialysis, and 9 had died. Conclusions This study describes the spectrum of kidney lesions in patients with COVID-19. While acute tubular injury is correlated with COVID-19 severity, the pattern of glomerular injury is intimately associated with the expression of APOL1 risk variants.

Rupture of splenic artery aneurysms (SAAs) is associated with a high mortality rate. The aim of this study was to identify the features of SAAs. Tissue sections from SAAs were compared to nonaneurysmal splenic arteries using various stains. The presence of intraluminal thrombus (ILT), vascular smooth muscle cells (VSMCs), cluster of differentiation (CD)-68+ phagocytes, myeloperoxidase+ neutrophils, CD3+, and CD20+ adaptive immune cells were studied using immunofluorescence microscopy. Analysis of SAAs revealed the presence of atherosclerotic lesions, calcifications, and ILT. Splenic artery aneurysms were characterized by a profound vascular remodeling with a dramatic loss of VSMCs, elastin degradation, adventitial fibrosis associated with enhanced apoptosis, and increased matrix metalloproteinase 9 expression. We observed an infiltration of immune cells comprising macrophages, neutrophils, T, and B cells. The T and B cells were found in the adventitial layer of SAAs, but their organization into tertiary lymphoid organs was halted. We failed to detect germinal centers even in the most organized T/B cell follicles and these lymphoid clusters lacked lymphoid stromal cells. This detailed histopathological characterization of the vascular remodeling during SAA showed that lymphoid neogenesis was incomplete, suggesting that critical mediators of their development must be missing.

Background and Aims Diabetic Nephropathy (DN) is usually a presumptive diagnosis based on clinical and biological evidences. However, Renal Biopsies (RB) may be performed when the suspicion of Non-Diabetic Renal Disease (NDRD) with potential specific treatment arises from atypical features mainly identified through studies focusing on the power of individual clinical and biological features to predict NDRD. We aimed to assess the actual value of RB indications (RBi) to discriminate NDRD from Type 2 Diabetes (T2D) Associated Renal Disease (T2D-ARD) such as DN and Hypertensive nephropathy which are frequently associated, seen in similar patients with high cardiovascular risk, lack for specific treatment and might be therefore be considered as “failure events” in the context of RB performed to diagnose NDRD with specific treatment. Method We conducted a retrospective multicenter study in four nephrology units and reviewed the charts of patients with T2D who underwent a first RB from 2006 to 2015. Clinical and biological characteristics, RBi and diagnoses were retrospectively collected from the patients’ medical charts. RBi were defined according to the sequence in Figure 1. As such, diabetic retinopathy may be absent in patients of all indication groups, conversely, patients in group 6 and 7 had stable proteinuria and renal function. Similarly, patients with monoclonal gammopathy were all included in group 1.We considered missing data regarding the absence/presence of Diabetic Retinopathy (DR) as meaningful, suggesting the data was unneeded to reach a decision of RBi. We performed univariate and multivariate logistic regression analyses to identify clinical or biological features associated with the diagnosis of NDRD. We also compared the number and percentage of actual NDRD diagnosed for each of the RBi. Results 464 first renal biopsies were performed in 464 patients during the study period. Two RB were excluded because the RBi could not be clearly identified through careful reviewing of the patients’ medical charts. Of the 462 remaining RB, 40% revealed NDRD. The most frequent were acute interstitial nephritis, IgA nephropathy and acute tubular necrosis (8.7%, 5.8% and 4.1% respectively). Patients with NDRD were more frequently >65yo (55 vs 44%), with serum creatinine (SCr) >250 µmol/l (52 vs 30%), hematuria (58 vs 36%), non-retrieved DR status (45 vs 17%), and less frequently with urinary-to-protein ratio (UPCR) >3g/g (33 vs 57%), HbA1c >7% (32 vs 50%) and duration of diabetes >5 years (52 vs 72%).Logistic regression analyses identified high SCr, UPCR, hematuria and low diabetes duration as predictive of NDRD. Surprisingly, missing RD status rather than absence of RD was predictive of NDRD. As expected NDRDs were frequent in patient with RBi 1 to 3 (53%, 40% and 21%), infrequent in patients with RBi 5 (7%) and totally absent from patients with RBi 6 and 7 despite their predictive value as regards with NDRD. Conclusion Our study confirms several well-known facts on the subject of renal biopsy in patients with T2D: 1) Renal biopsy is useful in selected patients with T2D and renal disease to diagnose NDRD with specific treatment. 2) Hematuria and short duration of diabetes are predictive of NDRD. On the other hand, our study suggests two novel and antidogmatic findings: 1) Assessing the presence of diabetic retinopathy is not required for RBi. 2) Hematuria is not indicative of NDRD in patients with otherwise typical diabetic kidney disease. Of course, our study is limited by its retrospective design precluding us of precisely defining what was considered rapid evolution of DFG or proteinuria emphasizing the need for prospective studies.

Acute kidney injury (AKI) is a major complication in patients with cancer, associated with significant morbidity and mortality. Only two cases of kidney lymphangitic carcinomatosis associated with AKI have been reported, in gastric and colorectal adenocarcinoma. Here, we report on a 53-year-old man with pancreatic adenocarcinoma who developed AKI as a result of kidney lymphangitic carcinomatosis. The patient rapidly became anuric and required haemodialysis. Kidney lymphangitic carcinomatosis should be considered as a cause of AKI in patients with cancer and may become a more frequent clinical finding as patients with metastatic carcinoma survive for longer.

Le diagnostic de nephropathie diabetique est generalement clinique. Une biopsie renale peut etre realisee en cas d’atypie afin d’eliminer une maladie renale non diabetique. Nous avons evalue l’opinion des nephrologues francophones par un questionnaire anonyme portant sur les criteres cliniques et biologiques — en particulier l’absence de retinopathie diabetique, la presence d’une hematurie, la diminution du debit de filtration glomerulaire ou l’elevation de la proteinurie — les amenant a retenir l’indication de biopsie renale chez des patients diabetiques de type 2 avec albuminurie>0,5g/jour ou equivalent. Cent quatre-vingt-huit personnes ont repondu au questionnaire, reparties entre internes (12 %), assistants (13 %), praticiens en hopital universitaire (26 %), en hopital general (24 %), en secteur associatif (10 %), en secteur prive (10 %), en exercice mixte (3 %) ou sans pratique clinique (2 %). L’elevation de la proteinurie etait un critere d’indication de biopsie renale pour 51 % des participants, le syndrome nephrotique pour 56 % des participants, l’absence de retinopathie diabetique pour 57 % des participants, la courte duree du diabete pour 65 % des participants, la progression rapide de l’insuffisance renale chronique pour 75 % des participants et l’hematurie pour 78 % des participants. Notre enquete revele donc une incertitude de la communaute nephrologique quant aux criteres d’indication de biopsie renale chez les patients diabetiques de type 2 ayant une proteinurie et la discordance des opinions vis-a-vis des recommandations et de la litterature, en particulier au regard de l’absence de retinopathie diabetique. Ces resultats soulignent la necessite d’une etude analysant les resultats de ces biopsies au regard de leurs indications.

International audience; Objectives: Adult immunoglobulin A vasculitis (IgAV) is an immune complex small vessel vasculitis. So far, the involvement of T cells in this pathology has been poorly studied. The aim of this study was to analyze T-cell homeostasis as well as cytokine and chemokine concentrations in the blood and tissues of IgAV patients. Methods: T cells, cytokine and chemokine concentrations were analyzed in peripheral blood using flow cyto-metry and multiplex assays. T-cell infiltrates in the kidney and the skin were characterized by im-munohistochemistry. This study prospectively included 44 adult patients with biopsy-proven IgAV and 24 age-and sex-matched healthy controls.Results: We observed reduced proportions of circulating CXCR5-and CXCR3-expressing memory CD4 T cells at diagnosis but normal values at remission. The plasma levels of Th1-related cytokines (IL-12, IL-27 and IFNγ) and of the TFH-related cytokine, IL-21, were paradoxically not reduced in patients. We observed increased plasma concentrations of the CXCR5 ligand, CXCL13, and of the CXCR3 ligands, CXCL10/11, suggesting a potential relocation of the corresponding T cells into inflamed tissues. We then confirmed the recruitment of CXCR3-expressing T cells into the skin and kidneys. In the skin, T-cell infiltrates mainly co-localized with damaged dermal small vessels. Finally, patients with the largest kidney T-cell infiltrates were also those with the highest proteinuria.Conclusion: Altogether, our results strongly suggest that, in IgAV patients, CXCL10/11 orchestrate the recruitment of CXCR3-expressing T cells in injured tissues, contributing to tissue damage and disease activity.

Primary cardiac synovial sarcoma is an extremely rare disease. Its prognosis is poor with a median survival time of 24 months, even when adequate and timely treatment is given. This case reports a 61-year-old woman presenting with primary cardiac synovial sarcoma with an 8-year survival time following surgical and adjuvant chemotherapy.

We describe the case of a 40 year-old woman admitted for dyspnea and severe asthenia. The transthoracic echocardiogram (TTE) showed a mass consistent with a left atrial myxoma, but the Fluorine-18-fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET-CT) study revealed intense metabolic activity (SUVmax=7.6) suggesting malignancy. However, pathology confirmed the diagnosis of a benign atrial myxoma

We read with great interest the European League Against Rheumatism/European Renal Association–European Dialysis and Transplant Association guidelines for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).1 We strongly support the recommendation of performing a renal biopsy whenever a renal involvement is suspected as the only organ-threatening or life-threatening manifestation. Indeed, we came across several cases of different diseases presenting as AAV which support this recommendation, as exemplified below. An 18-year-old woman self-presented to the emergency department (ED) with abdominal pain, diarrhoea, gross …

Lymph vessels play an important role in tumor progression. Pulmonary adenocarcinomas, accounting for half of non-small-cell lung carcinomas, compose a spectrum of histological types, exclusively or without a lepidic growth pattern (LGP) along preserved interalveolar septa. In that context, this study was designed to investigate the lymphatic vascular pattern associated with LGP and the concomitant invasive component of pulmonary adenocarcinomas. Using the D2-40 monoclonal antibody as a marker of lymphatic endothelial cells, the lymphatic vessel density (LVD) and vessel-area fraction (LVAF) were morphometrically analyzed in four adenocarcinomas in situ (AIS) and the LGP of eight invasive adenocarcinomas (LPIA), and compared with their invasive pattern (IPIA). LVD in AIS (2.1 ± 0.7 mm−2) and LPIA (2.4 ± 1 mm−2) were significantly lower than that in IPIA (14.9 ± 13.6 mm−2) ( p=0.001). Moreover, the lymphatic vascular pattern in LGP was similar to that of normal lung, with isolated small lymphatic vessels within the interalveolar septa. Our results showing the scarcity of lymphatics in LGP suggest an absence of septal lymphangiogenesis associated with the LGP pattern in lung adenocarcinomas, which could explain, at least partially, the better prognosis observed in tumors with exclusive or predominant lepidic spread compared with other subtypes.

RATIONALE Malakoplakia is a rare disease characterized by the presence of nongranulomatous macrophage infiltration. In most cases, it affects the urinary tract. Malakoplakia can cause acute kidney injury when it is localized in the kidneys. PATIENT CONCERNS Here, we report the case of a 65-year-old female patient with renal malakoplakia responsible for hypercalcemia. During her initial assessment, she was also diagnosed 25-OH vitamin D insufficiency, for which she was prescribed oral cholecalciferol. Three months later, she developed severe hypercalcemia with normal 25-OH vitamin D and parathyroid hormone levels and high 1,25-dihydroxyvitamin D levels. DIAGNOSES After a superimposed granulomatous disease was excluded, malakoplakia cells were suspected to be responsible for the abnormal 25-hydroxyvitamin D3 1-alpha-hydroxylase activity, which was confirmed by immunohistochemistry. INTERVENTIONS Cholecalciferol was stopped, the patient was rehydrated with intravenous physiological saline, and prednisone was initiated to decrease the enzyme activity. OUTCOMES Six months later, she displayed normal serum calcium, 25-OH vitamin D and 1,25-dihydroxyvitamin D levels. LESSONS This case illustrates that malakoplakia may exhibit ectopic 25-hydroxyvitamin D3 1-alpha-hydroxylase activity and cause severe hypercalcemia upon vitamin D supplementation. Therefore, such supplementation should not be given in malakoplakia patients without an actual deficiency and requires careful monitoring of serum calcium.

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Background & aims The contribution of liver biopsy for the diagnosis of presumed benign hepatocellular lesions lacking the diagnostic features of focal nodular hyperplasia (FNH) on magnetic resonance imaging (MRI) is unknown. We evaluated liver biopsy and MRI performances in this setting. Methods Magnetic resonance imaging and slides of liver biopsies performed for a presumed benign hepatocellular lesion (2006-2013) without the typical features of FNH on MRI were blindly reviewed (n = 45). Eighteen lesions were surgically removed and also analyzed. The final diagnosis was the diagnosis established after surgery or on the biopsy in the absence of surgery. Results The final diagnosis was FNH (n = 19), hepatocellular adenoma (HCA, n = 15), hepatocellular carcinoma (n = 3) and indefinite (n = 4). Four lesions corresponded to non hepatocellular lesions. FNH, HNF1A mutated and inflammatory HCA were diagnosed accurately on the biopsy in 95%, 67% and 100% of the cases respectively. Diagnostic performance of liver biopsy for HNF1A mutated HCA was lower because of the lack of non-tumoral tissue. Diagnosis based on morphological analysis was certain and correct in 27 cases. Immunostaining allowed a definite diagnosis in 12 additionnal cases. Radiological diagnosis was in agreement with the histological diagnosis in 75.6% of the cases, with a very high sensitivity (97%) and specificity (100%) for the diagnosis of HNF1A mutated HCA. Conclusions Liver biopsy has a good diagnostic performance particularly for FNH and inflammatory HCA, and sampling of non-lesional tissue is highly recommended. A biopsy does not seem necessary if H-HCA is diagnosed on MRI.

Dear Editor, We read with great interest the recent article of Wendum et al. [1] describing histological lesions observed in the liver of 13 adult patients with heterozygous MDR3/ABCB4 gene mutations. They performed multidrug resistance Pglycoprotein 3 (MDR3) immunostaining on formalin-fixed paraffin-embedded sections of 11 patients and reported that the staining had a diffuse and strong canalicular pattern in patients and controls, except in one case who disclosed a faint staining. This finding suggested a lack of sensitivity of this technique for the diagnosis of MDR3/ABCB4 heterozygous mutations. Since we previously suggested that MDR3 immunostaining on frozen liver sections could be useful for the diagnosis of unexplained anicteric cholestasis in adult patients [2], we would like to contribute by providing our experience of MDR3 immunostaining realized on frozen liver biopsy sections of a new series of adult patients with MDR3/ABCB4 mutations. Between April 2007 and March 2011, 32 adult patients with unexplained anicteric cholestasis had ABCB4 gene sequencing, using polymerase chain reaction amplification and DNA sequencing of exons 2 to 28 and all splice junctions. Among these 32 patients, ten carried six different ABCB4 mutations. These ten patients (six females, 17– 72 years of age) displayed various clinical characteristics: three fulfilled the criteria for low phospholipid-associated cholelithiasis syndrome [3]; one had an anteriority of intrahepatic cholestasis of pregnancy; and six had an unexplained anicteric cholestasis—two of them with associated elevated aminotransferase level. Histopathological analysis using Picrosirius red and hematoxylin–eosin-stained liver biopsy sections showed that nine patients had portal fibrosis (three F1, four F2, one F3, and one F4 according to Ishak fibrosis score); six of them displaying a jigsaw pattern of biliary-type fibrosis. Bile duct lesions corresponding to mild cholangitis could be observed in four patients. Ductopenia, defined as a loss of more than 50 % of bile ducts, was seen in two patients. Lastly, six cases showed a mild to moderate ductular reaction. The clinicopathological features are detailed in Table 1. Frozen liver biopsies were available for 14 patients (five cases and nine controls). Immunohistochemistry was performed on 4-μm frozen sections by using MDR3 monoclonal antibody (clone P3II-26) and MRP2 antibody (clone M2III-6) as a control to check tissue immune reactivity. As shown in Fig. 1, we observed a diffuse and intense canalicular staining with MDR3 antibody, in the available frozen liver biopsies of the five patients with heterozygous ABCB4 mutations and in the nine controls. Positive canalicular staining was also observed with MRP2 antibody, confirming the immunoreactivity of our samples. These results are in contradiction with our previous report [2] in which no or faint MDR3 immunostaining was observed in frozen liver biopsies from four patients with A. Sannier (*) :M. Tepper :M. Ziol Service d’Anatomie Pathologique, GHU Paris-Seine-Saint-Denis, Hopital Jean Verdier, AP-HP, Avenue du 14 Juillet, 93143 Bondy Cedex, France e-mail: aureliesannier@free.fr

Aims Neoadjuvant radiochemotherapy (RCT) followed by surgical resection is the treatment for locally advanced mid-rectal or low rectal cancer. The aim of this study was to evaluate postoperative histological prognostic factors in a series of surgical specimens after neoadjuvant RCT. Methods and results One hundred and thirteen patients were included. Macroscopic and microscopic examinations were performed according to CAP recommendations, with additional criteria such as tumour budding, the presence of calcifications, and response to neoadjuvant therapy assessed according to Modified Rectal Cancer Regression Grade (m-RCRG). The 3-year disease-free survival (DFS) was 67.6%. In univariate analysis, ypTN stage, tumour budding, circumferential margin, invaded margin and vascular and perineural invasion were prognostic factors. In multivariate analysis, the presence of calcifications (P = 0.04) and an involved circumferential margin (P = 0.03) were the only independent factors for worse DFS. mRCRG was not correlated with DFS. Among the 50 m-RCRG1 tumours, DFS was better in ypT0 patients than in other ypT stages (P = 0.003). Conclusions The presence of calcifications in the tumour bed is described for the first time as a prognostic factor in rectal cancer. The prognostic value of budding was demonstrated in this study after neoadjuvant RCT. ypT stage appears to be a more reliable predictor of oncological outcome than histological tumour regression grade, which needs to be standardized for better reproducibility.