Interstitial Mononuclear Cell Research Articles

Adamts1 and Cyst Expansion in Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by mutations in either the Pkd1 or Pkd2 genes leading to progressive cyst growth and often kidney failure. We have previously demonstrated that tubules can enlarge following loss of Pkd1 without an increase in tubular cell numbers, suggesting that tubular basement membrane remodeling is important for cystic dilation. RNA sequencing of Pkd1 null kidneys revealed increased expression of 17 metalloproteinases, of which A Disintegrin and Metalloproteinase with Thrombospondin Motif 1 (Adamts1) is the most highly expressed and upregulated. Mice were generated with inducible tubule-specific knockout of Adamts1 alone (AtsTKO), Pkd1 alone (PkdTKO), or both (P/ATKO) following doxycycline induction from 4-6 weeks age. Uninduced mice were used as controls. AtsTKO mice had no detectable phenotype through 12 weeks age. Upregulation of Adamts1 in PkdTKO kidneys correlated with a significant increase in the 70 kDa cleavage product of the V1 isoform of versican, which localized to the tubular basement membrane and adjacent interstitial mononuclear cells. Simultaneous deletion of both Adamts1 and Pkd1 (P/ATKO) reduced Adamts1 expression levels by >90%, prevented V1 versican cleavage, and reduced interstitial macrophage accumulation and activation. P/ATKO mice demonstrated reduced cystic enlargement, improved BUN and creatinine and better survival than did PkdTKO mice. Preventing Adamts1 upregulation following loss of tubular Pkd1 effectively reduced cyst growth and preserved kidney function.

A potential defensive role of TIM-3 on T lymphocytes in the inflammatory involvement of diabetic kidney disease.

The aberrant mobilization and activation of various T lymphocyte subpopulations play a pivotal role in the pathogenesis of diabetic kidney disease (DKD), yet the regulatory mechanisms underlying these processes remain poorly understood. Our study is premised on the hypothesis that the dysregulation of immune checkpoint molecules on T lymphocytes disrupts kidney homeostasis, instigates pathological inflammation, and promotes DKD progression. A total of 360 adult patients with DKD were recruited for this study. The expression of immune checkpoint molecules on T lymphocytes was assessed by flow cytometry for peripheral blood and immunofluorescence staining for kidney tissue. Single-cell sequencing (scRNA-seq) data from the kidneys of DKD mouse model were analyzed. Patients with DKD exhibited a reduction in the proportion of CD3+TIM-3+ T cells in circulation concurrent with the emergence of significant albuminuria and hematuria (p=0.008 and 0.02, respectively). Conversely, the incidence of infection during DKD progression correlated with an elevation of peripheral CD3+TIM-3+ T cells (p=0.01). Both univariate and multivariate logistic regression analysis revealed a significant inverse relationship between the proportion of peripheral CD3+TIM-3+ T cells and severe interstitial mononuclear infiltration (OR: 0.193, 95%CI: 0.040,0.926, p=0.04). Immunofluorescence assays demonstrated an increase of CD3+, TIM-3+ and CD3+TIM-3+ interstitial mononuclear cells in the kidneys of DKD patients as compared to patients diagnosed with minimal change disease (p=0.03, 0.02 and 0.002, respectively). ScRNA-seq analysis revealed decreased gene expression of TIM3 on T lymphocytes in DKD compared to control. And one of TIM-3's main ligands, Galectin-9 on immune cells showed a decreasing trend in gene expression as kidney damage worsened. Our study underscores the potential protective role of TIM-3 on T lymphocytes in attenuating the progression of DKD and suggests that monitoring circulating CD3+TIM3+ T cells may serve as a viable strategy for identifying DKD patients at heightened risk of disease progression.

Chicken egg lysozyme enhanced the growth performance, feed utilization, upregulated immune-related genes, and mitigated the impacts of Aeromonas hydrophila infection in Nile tilapia (Oreochromisniloticus)

Functional supplements, including lysozyme, are highly approved as immunostimulant and antibacterial agents with a high potential for use in aquaculture. In this regard, Nile tilapia was treated with lysozyme at 0, 0.5, 1, 1.5, and 3 g/kg for 60 days, then challenged with Aeromonas hydrophila. Fish were stocked in 15 glass aquaria (70 L each) with an equal initial weight of 10.72 ± 0.71 g per fish and 15 fish per aquarium. The regression analysis revealed that dietary lysozyme supplementation at 1.83–2 g/kg enhanced the growth performance, protein efficiency ratio, and protein productive value while reducing the feed conversion ratio of tilapia. Markedly, tilapia treated with lysozyme had a low mortality rate (30–50 %) compared to the control, which recorded a 70 % mortality rate after 15 days of challenge with A. hydrophila. The regression analysis also revealed that the highest lysozyme activity of tilapia-fed lysozyme for 60 days is achieved by 2.05 g/kg lysozyme. The expression of Nf-κb, IL-1β, and IL-8 genes is upregulated in tilapia-fed lysozyme at 0.5, 1, 1.5, and 3 g/kg for 60 days before and after A. hydrophila infection. The expression of GPX and CAT genes was higher in tilapia-fed lysozyme at 0.5, 1, 1.5, and 3 g/kg for 60 days before and after A. hydrophila infection. Before infection, the relative transcription of the lysozyme and C3 was upregulated in tilapia-fed lysozyme at 0.5, 1, 1.5, and 3 g/kg. However, lysozyme gene expression in tilapia treated with 0.5 g/kg lysozyme had no significant differences from those fed 0 g/kg lysozyme. After infection, the relative transcription of the lysozyme gene was upregulated in tilapia fed 1 and 1.5 g/kg, while tilapia fed 1 g/kg lysozyme had the highest C3 gene transcription. After infection, the hepatocytes in the livers of fish fed 0 g/kg lysozyme exhibited a noticeable fatty alteration, along with congestion, a light infiltration of inflammatory cells, and the start of necrosed cell regeneration. However, the livers of fish that received lysozyme were normal except for infiltrations of perivascular and interstitial mononuclear cells, depending on the supplementation dose. In conclusion, dietary lysozyme is recommended at 1.83–2.05 g/kg to gain high growth performance, immune response, and high resistance to A. hydrophila in Nile tilapia.

Hematological and Histopathological Study Effect of Molybdate and Sulfate Alone and in Combination Overloaded Intake on Copper Outcome in Mature Male Rats

The object of this study were to evaluate the effect of molybdate and sulfate overload alone or in combination overload intake on copper outcome with regard toxicopathological changes in mature male rats. Twenty eight adult male rats were housed and arbitrarily divided into four equal groups (seven rat/group) and treated as follows for 60 days: control received distilled water, groups T1 received sodium molybdate 50 mg/kg B.W and T2: given orally 500 mg/kg B.W of sodium sulfate and T3 group were given sodium molybdate and sodium sulfate in combination at half dose in comparison with T1 and T2 doses. The blood tests results, which included Red Blood Cell count, hemoglobin concentration and Packed Cell Volume % that conducted a after one month and at the end of the experiment showed a significant reductions in general but were more in T1 group followed by T2 group, while T3 group showed less decline than that recorded in each of T1 and T2 groups. These functional changes were accompanied by structural changes in the hepatic and renal tissues. Histopathological changes following molybdate (50 mg/kg B.W) exposure were manifested by extensive areas of necrosis, hemorrhage, and hyperplasia of bile ductules. Besides focal area of necrosis and suppurative granuloma observed in livers of rats received 500 mg/kg B.W of sodium sulfate, mild infiltrate of mononuclear cell within the hepatic parenchyma, suppurative granuloma and proliferation of kupffer’s cells with hyperplasia of bile ductules seen in liver of rats received combination of them at half dose. While section of kidney from T1 group showed marked fibrous thickening of the capsule, severe cortical hemosiderosis with infiltrate of plasma cell and neutrophils, While in T2 group showed atrophy of glomerular tuft, focal interstitial mononuclear cells infiltration with deposition of hyaline cast. The histological changes revealed that renal damage was also observed in T3 group but at a little degree, depending on the result of this study it can be concluded that molybdate and sulfate alone and in combination succeeded to induce copper deficiency with severe changes in hematological and histopathological parameters in rats.

Pathological lesions associated with Vibrio infection in Atlantic horse mackerel (Trachurus trachurus L., 1758) from the western coast of Tripoli, Libya.

Vibrios are aquatic bacteria causing Vibriosis in humans and aquatic animals. Vibriosis is a significant disease of cultured and wild fish. The present study aimed to address the impact of Vibrios on the health status of Trachurus trachurus inhabiting the coastal area of Tripoli. A total of 100 samples of (T. trachurus) were collected randomly from the Western Coast of Tripoli and Bab Al-Baher market, throughout the period from spring 2019 to summer 2019. All the sampled fish were examined externally and internally and lesions were recorded. Bacterial isolation from the liver and kidney was carried out using the appropriate culture media. Tissue samples were taken from the liver, kidney, and spleen in 10% neutral buffered formalin for a histopathology examination. The tissue sections were stained with hematoxylin and eosin to assess morphologically and Perl's Prussian blue for the demonstration of ferric iron. On average 69% of the infected fish exhibited at least one pathological lesion. Vibrios were recovered from 90% of the examined fish. The histopathological changes of the liver showed severe congestion of blood vessels (BVs), mononuclear cell infiltration surrounding a bile duct, granular degeneration and coagulative necrosis of hepatocytes in the centrilobular area, marked vacuolar degeneration of hepatocytes, activation of melano-macrophage centers (MMCs), multiple cysts of nematode in hepatic tissue (incidental finding). The histopathological alterations of the kidney showed severe congestion of BVs, vacuolar degeneration of the renal tubular epithelium, severe interstitial mononuclear cell infiltration, and marked activation of MMCs in the kidney. Moreover, congestion of BVs and marked activation of melano-macrophages (MMCs) were found in the spleen. The MMCs of most of the sampled tissues showed a strong positive reaction for ferric iron. The polluted aquatic environment by sewage at Tripoli Coast is an essential factor for triggering the pathogenicity and invasion of Vibrios to vulnerable Atlantic horse mackerel. Also, this study is a preliminary step to give a baseline for further future studies on epidemiology and control of Vibrio infection in Libyan fish.

Porcine dermatitis and nephropathy syndrome on natural infection of Porcine Circovirus Type-2 in pigs in Kerala, southern India

Porcine circovirus type-2 (PCV-2), is a widely studied pathogen in the swine population during the last decade. Even though, PCV-2 has many disease manifestations, the objective of the current study was to investigate the cutaneous and renal lesions in PCV-2 infected cases. Swine carcasses presented for post-mortem examination with a history of skin lesions, inappetance, dyspnoea and diarrhoea, during September 2021 to April 2022 from different parts of Kerala were utilised in this study. The samples were collected and screened with Polymerase chain reaction (PCR) after which, histological and immunohistochemical examination were performed. Three samples were found positive for PCV-2 out of 25 samples using PCR. Microscopically, skin revealed congestion, haemorrhages and infiltration of mononuclear infiltration cells and neutrophils in dermis and spongiosis in epidermis. Kidney revealed haemorrhages, congestion, tubular necrosis and degenerative alterations, interstitial mononuclear cell infiltration with occasional glomerulitis and vasculitis in the renal pelvis. Localisation of PCV-2 antigen was observed in renal tissue and lymph node with immunohistochemistry. Altogether, these findings were suggestive of porcine dermatitis and nephropathy syndrome (PDNS) in pigs. These results indicate the importance of including PCV-2 in the differential diagnosis of cutaneous lesions caused by bacterial and viral etiologies in pigs.

Esculetin alleviates murine lupus nephritis by inhibiting complement activation and enhancing Nrf2 signaling pathway

Ethnopharmacological relevanceEsculetin is a bioactive compound of medicinal herb Hydrangea paniculata, and has showed anti-oxidation and anti-inflammation bioactivities. Renal local oxidative stress and inflammation are import contributors for progression of lupus nephritis (LN). Aim of the studyIn the present study, the renal protective effect of esculetin against LN was evaluated using MRL/lpr mice. Materials and methodsMRL/lpr mice were orally administrated with esculetin (20 mg/kg and 40 mg/kg) from 10 to 20 weeks and then renal function and kidney pathology were analyzed. ResultsEsculetin significantly attenuated renal impairment in MRL/lpr mice by reducing blood urea nitrogen (BUN), serum creatinine (Scr) and albuminuria, and ameliorated the glomerular hypertrophy, tubular interstitial fibrosis and mononuclear cell infiltration into interstitium. mRNA microarray suggested that esculetin could significantly down-regulate complement cascade, inflammation and fibrosis pathway, and up-regulate Nrf2-related anti-oxidation genes. Most surprising finding in the current study was that esculetin could inhibit the complement activation both in classical and alternative pathway using in vitro hemolysis assay, further enzyme assay suggested that esculetin blocked the C3 convertase (C4b2a) to exert this inhibitory capability. Molecular docking predicted that esculetin had four conventional hydrogen bonds interacting with C4b2a, and CDOCKER energy is relatively lower. Luciferase reporter gene demonstrated that esculetin could activate Nrf2 signaling pathway, and further flow cytometry confirmed that anti-oxidation bioactivity of esculetin was dependent on Nrf2 activation. On the other hand, esculetin could inhibit NFκB nuclear translocation and TGFβ-smad3 profibrosis pathway. ConclusionEsculetin shows beneficial effect on LN progression, and it may be a good natural leading compound for design of chemical compounds to treat LN.

Postmortem pathological changes in extrapulmonary organs in SARS-CoV-2 rt-PCR-positive cases: a single-center experience.

BackgroundAlthough the lung is seen as the main target organ affected by SARS-CoV-2, other organs are also damaged.AimWe aimed to determine the extrapulmonary findings of autopsies performed on cases with positive results with postmortem polymerase chain reaction test.MethodsPathological changes in extrapulmonary organs were examined with light microscopy.ResultsHeart, liver, spleen, kidney, pancreas, and central nervous system samples of these cases were evaluated. About 80% of the cases were men, and 20% were women. In the examination of heart, 28 of the cases had scar, 14 had acute myocardial infarction, 6 had acute and previous myocardial infarction findings, 2 had myocarditis, and 4 had interstitial mononuclear inflammatory cell infiltration. In the examination of the liver, portal inflammation was observed in 84 of the cases, steatosis in 54, centrilobular necrosis in 9, and capillary endotheliitis in the portal area in 7 of them. In the evaluation of the kidney, 37 cases had chronic pyelonephritis, 36 had tubular damage, 15 had tubulointerstitial necrosis, 16 had subcapsular microhemorrhage, 10 had capillary endothelitis, and 9 had a microvascular fibrin trombosis in their glomerular capillaries. In the central nervous system, 8 cases had infarction and liquefaction, 56 had perivascular petechial hemorrhage, 54 had acute hypoxic ischemic change, 3 had parenchymal microhemorrhage, and 52 had capillary endotheliitis.ConclusionAutopsies play an important role in systematically examining the damage caused by the virus in all organs in order to elucidate the pathogenesis of SARS-CoV-2 infection and contribute to the clinical management of infected patients.

Exposure to High-Fat Style Diet Induced Renal and Liver Structural Changes, Lipid Accumulation and Inflammation in Intact and Ovariectomized Female Rats

PurposeWe hypothesized that low estrogen levels aggravate obesity-related complications. Diet-induced obesity can cause distinct pathologies, including impaired glucose tolerance, inflammation, and organ injury that leads to fatty liver and chronic kidney diseases. To test this hypothesis, ovariectomized (OVX) rats were fed a high-fat style diet (HFSD), and we examined structural changes and inflammatory response in the kidney and liver.MethodsSprague-Dawley female rats were ovariectomized or sham-operated and divided into four groups: sham-operated rats fed a normal diet (ND); ovariectomized rats fed a normal diet (OVX-ND); sham-operated rats fed a HFSD; ovariectomized rats fed a high-fat style diet (OVX-HFSD). Mean blood pressure and fasting blood glucose were measured on weeks 0 and 10. The rats were sacrificed 10 weeks after initiation of ND or HFSD, the kidney and liver were harvested for histological, immunohistochemical and immunofluorescence studies.ResultsHFSD-fed rats presented a significantly greater adiposity index compared to their ND counterparts. Liver index, fasting blood glucose and mean blood pressure was increased in OVX-HFSD rats compared to HFSD rats at study terminal. Histological and morphometric studies showed focal interstitial mononuclear cell infiltration in the kidney of HFSD rats with mesangial expansion being greater in the OVX-HFSD rats. Both HFSD fed groups showed increased expressions of renal inflammatory markers, namely TNF-alpha, IL-6 and MCP-1, and infiltrating M1 macrophages with some influence of ovarian hormonal status. HFSD-feeding also caused hepatocellular steatosis which was aggravated in ovariectomized rats fed the same diet. Furthermore, hepatocellular ballooning was observed only in the OVX-HFSD rats. Similarly, HFSD-fed rats showed increased expressions of the inflammatory markers and M1 macrophage infiltration in the liver; however, only IL-6 expression was magnified in the OVX-HFSD.ConclusionOur data suggest that some of the structural changes and inflammatory response in the kidney and liver of rats fed a HFSD are exacerbated by ovariectomy.

Amelioration of renal cortex histological alterations by aqueous garlic extract in gentamicin induced renal toxicity in albino rats: a histological and immunohistochemical study

ABSTRACT Background: Aminoglycosides, particularly gentamicin, endure crucial antibiotics in the armamentarium for severe Gram-negative bacterial infections through their significant risk for nephrotoxicity. Co-administration of several applicant nephroprotective agents has been investigated at the preclinical level. Garlic was proved to be an oxidative stress combatant with unique antioxidant potential. Aim of the work: To assess renal cortex structural changes due to gentamicin treatment and the role of the aqueous garlic extract (AGE) in ameliorating these changes. Material and methods: Thirty-two male albino rats were assigned into four equal groups. Group I (Control group) received 0.9% NaCl solution through oral gavage in the same volume as in AGE-treated group. Group II (AGE treated group) received AGE by oral gavage at 250 mg/kg/day. Group III (Gentamicin treated group) received Gentamicin at 80 mg/kg/day intraperitoneally. Group IV (Gentamicin and AGE cotreated group) received both gentamicin and AGE. The duration of the treatment was 21 days. Specimens of renal cortex of all groups were processed for light microscopic examination. Specimens were additionally prepared for electron microscopic examination. Morphometric study and statistical analysis were performed. Results: Examination of the renal cortex in the gentamicin treated rats showed both proximal and distal tubular necrosis, vacuolation, desquamation and interstitial mononuclear cell infiltration. Masson’s trichrome staining revealed intense deposition of collagen fibers. Strong positive immunoreaction for caspase-3 was observed. Ultrastructurally, the glomerulus showed thickened basement membrane, destructed endothelium. Proximal and distal convoluted tubular cells exhibited vacuolations, distorted mitochondria and nuclear chromatin condensation with loss of microvilli. AGE ameliorated these changes. Conclusion: Aqueous garlic extract ameliorates the histological changes caused by gentamicin in the rat renal cortex.

Artificial intelligence identifies inflammation and confirms fibroblast foci as prognostic tissue biomarkers in idiopathic pulmonary fibrosis

A large number of fibroblast foci (FF) predict mortality in idiopathic pulmonary fibrosis (IPF). Other prognostic histological markers have not been identified. Artificial intelligence (AI) offers a possibility to quantitate possible prognostic histological features in IPF. We aimed to test the use of AI in IPF lung tissue samples by quantitating FF, interstitial mononuclear inflammation, and intra-alveolar macrophages with a deep convolutional neural network (CNN). Lung tissue samples of 71 patients with IPF from the FinnishIPF registry were analyzed by an AI model developed in the Aiforia® platform. The model was trained to detect tissue, air spaces, FF, interstitial mononuclear inflammation, and intra-alveolar macrophages with 20 samples. For survival analysis, cut-point values for high and low values of histological parameters were determined with maximally selected rank statistics. Survival was analyzed using the Kaplan-Meier method. A large area of FF predicted poor prognosis in IPF (p=0.01). High numbers of interstitial mononuclear inflammatory cells and intra-alveolar macrophages were associated with prolonged survival (p=0.01 and p=0.01, respectively). Of lung function values, low diffusing capacity for carbon monoxide was connected to a high density of FF (p=0.03) and a high forced vital capacity of predicted was associated with a high intra-alveolar macrophage density (p=0.03). The deep CNN detected histological features that are difficult to quantitate manually. Interstitial mononuclear inflammation and intra-alveolar macrophages were novel prognostic histological biomarkers in IPF. Evaluating histological features with AI provides novel information on the prognostic estimation of IPF.

Dimethyl fumarate ameliorates cisplatin-induced renal tubulointerstitial lesions.

Dimethyl fumarate (DMF) has an antioxidant effect by activating the nuclear factor erythroid 2-related transcription factor 2 (Nrf2). Cisplatin (CIS) has nephrotoxicity as a frequently associated side effect that is mainly mediated by oxidative stress. In this study, we investigated whether the DMF-mediated antioxidative mechanism activated by Nrf2 can ameliorate CIS-induced renal tubulointerstitial lesions in rats. In Experiments 1 and 2, 25 five-week-old male Wistar rats were divided into five groups: control, CIS, and 3 CIS+DMF groups (300, 1,500, and 7,500 ppm in Experiment 1; 2,000, 4,000, and 6,000 ppm in Experiment 2). Rats were fed their respective DMF-containing diet for 5 weeks. CIS was injected 1 week after starting DMF administration, and the same volume of saline was injected into the control group. CIS-induced severe tubular injury, such as necrosis and degeneration in the outer segment of the outer medulla, was inhibited in the 7,500 ppm DMF group and ameliorated in all DMF groups in Experiment 2. Increased interstitial mononuclear cell infiltration and increased Sirius red-positive areas were also observed in CIS-administered groups, and these increases tended to be dose-dependently inhibited by DMF co-administration in Experiments 1 and 2. The numbers of α-smooth muscle actin (SMA)-positive myofibroblasts, CD68-positive macrophages, and CD3-positive lymphocytes observed in the peritubular area also increased with CIS administration, and these increases were dose-dependently inhibited by DMF co-administration. Moreover, renal cortical mRNA expression of Nrf2-related genes such as NQO1 increased in DMF groups. This investigation showed that DMF ameliorates CIS-induced renal tubular injury via NQO1-mediated antioxidant mechanisms and reduces the consequent tubulointerstitial fibrosis.

Anti-urolithiatic activity of Solanum nigrum hydroalcoholic extract in ethylene glycol-induced urolithiasis in rats

Background and objectives Urolithiasis is a growing public health problem. Asymptomatic kidney stones are kept under observation. The aim of this study was to explore the anti-urolithiatic activity of the hydroalcoholic extract of Solanum nigrum fruit in ethylene glycol-induced urolithiasis in rats. Materials and methods Urolithiasis was induced by oral administration of ammonium chloride 1% and ethylene glycol (0.75% v/v) in drinking water for 28 days. Hydroalcoholic extract of Solanum nigrum fruit (200 and 400 mg/kg) and cystone (750 mg/kg) were administered orally from the 15th day as a curative regimen. Results and conclusion Administration of ethylene glycol caused an elevation of serum creatinine, urea, calcium, and malondialdehyde and a reduction of magnesium and glutathione. In addition, renal content of tumor necrosis factor alpha was elevated and adiponectin renal content was reduced in urolithiatic control. Histopathological examination revealed tubular degeneration, dilatation, presence of calcium oxalate crystals in the lumen of renal tubules, and intense interstitial mononuclear cell infiltration in the lithiatic control group. Treatment with both doses of Solanum nigrum reversed all biochemical parameters and histopathological alterations. The results demonstrate that the hydroalcoholic extract of Solanum nigrum has potent anti-urolithiatic activity against calcium oxalate urolithiasis induced by ethylene glycol through tumor necrosis factor alpha inhibition and adiponectin stimulation as well as in maintaining balance between stone promoter (calcium) and inhibitor (magnesium).

The Immunoscore is a Superior Prognostic Tool in Stages II and III Colorectal Cancer and is Significantly Correlated with Programmed Death-Ligand 1 (PD-L1) Expression on Tumor-Infiltrating Mononuclear Cells.

In colorectal cancer (CRC), the indication for immune checkpoint inhibitors is determined by the microsatellite instability status of the tumors. However, an optimal biomarker for their indication has not been fully identified to date. This study aimed to establish the clinicopathologic importance of the Immunoscore (IS) in CRC and to clarify the relationships between the IS, programmed death-ligand 1 (PD-L1) expression, and tumor-associated macrophages. In 132 cases, CRC was diagnosed and surgically treated in our department from 2009 to 2010. Immunohistochemical staining using primary antibodies PD-L1, CD3, CD8, CD68, and CD163 was performed. The IS was determined according to the proposal of an international task force. Statistical analyses were performed to investigate the correlation between the IS, clinicopathologic variables, and expression of immune checkpoint molecules. The overall survival (OS) and relapse-free survival (RFS) in the high-IS group (I3-4) were significantly better than in the low-IS group (I0-2) (OS: P = 0.0420; RFS: P = 0.0226). The positivity rate for PD-L1 on tumor cells (tPD-L1) was only 0.8%, whereas that for PD-L1 on interstitial tumor-infiltrating mononuclear cells (iPD-L1) was 18.2%. The iPD-L1-positive group showed significantly better survival in terms of both OS and RFS than the iPD-L1-negative group (OS: P = 0.0278; RFS: P = 0.0253). The findings showed significant correlation between the IS and iPD-L1 expression (P < 0.0001). The study found that a high IS was a good indicator of a better prognosis and significantly correlated with iPD-L1 expression in CRC.

Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis.

BackgroundDysregulation of Fractalkine (CX3CL1) and its receptor CX3CR1 has been linked to the pathobiology of chronic inflammatory conditions. We explored CX3CL1 in systemic sclerosis (SSc) related progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in two different but complementary sources of biomaterial.MethodsWe collected lung tissue at the time of lung transplantation at UCLA from SSc-ILD patients (n = 12) and healthy donors (n = 12); and serum samples from the prospective Oslo University Hospital SSc cohort (n = 292) and healthy donors (n = 100). CX3CL1 was measured by ELISA. Cellular sources of CX3CL1/CX3CR1 in lung tissues were determined by immunohistochemistry and immunofluorescence. ILD progression and new onset PH endpoints were analysed.ResultsCX3CL1 concentrations were increased in SSc in lung tissue as well as in sera. In the UCLA cohort, CX3CL1 was highly correlated with DLCO. In the SSc-ILD lungs, CX3CL1 was identified in reactive type II pneumocytes and airway epithelial cells. CX3CR1 stained infiltrating interstitial mononuclear cells, especially plasma cells. In the Oslo cohort, CX3CL1 correlated with anti-Topoisomerase-I-antibody and lung fibrosis. CX3CL1 was associated with ILD progression in multivariable regression analysis but not PH.ConclusionCX3CL1 is associated with progressive SSc-ILD but not SSc-PH. The CX3CR1/CX3CL1-biological axis may be involved in recruiting antibody secreting plasma cells to SSc lungs, thereby contributing to the immune-mediated pathobiology of SSc-ILD.

Expression of CMIP in podocytes is restricted to specific classes of lupus nephritis.

Lupus glomerulopathies are classified into various histological patterns, which probably result from different pathophysiological origins. Podocyte injury can be demonstrated in lupus nephritis but its clinical relevance is far little appreciated and is often masked by proliferative lesions and inflammatory cell infiltrations. Two patterns of podocyte lesions may be considered, either occurring in the context of renal inflammation or reflecting podocyte dysfunction in non-proliferative and non-inflammatory glomerulopathies. This distinction remains elusive since no reliable biomarker discriminates between both entities. CMIP was recently found induced in some glomerular disease but its expression in different lupus nephritis classes has not been investigated. Twenty-four adult patients with lupus nephritis, including non-proliferative (n = 11) and proliferative (n = 13) glomerulopathies were analyzed. Clinical, biological and immunological data were compared with immunomorphological findings. We analyzed by quantitative and qualitative methods the expression of CMIP in different histological classes. We found CMIP abundance selectively increased in podocytes in class II and class V glomerulopathies, while in proliferative forms (class III and class IV), CMIP was rarely detected. CMIP was not expressed in cellular crescents, endothelial cells or mesangial cells. CMIP colocalized with some subsets of B and T cells within glomerular or interstitial mononuclear cell infiltrates but never with macrophages. Hematuria is rarely present in lupus glomerulopathies expressing CMIP. There was no correlation between classical immunological markers and CMIP expression. Thus, CMIP induction in lupus nephritis seems restricted to non-proliferative glomerulopathies and may define a specific pattern of podocyte injury.

ACUTE MYELOMONOCYTIC LEUKEMIA PRESENTING AS PULMONARY INFILTRATES SECONDARY TO LEUKEMIC INFILTRATION

SESSION TITLE: Lung Pathology 1 SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Malignant infiltration of pulmonary parenchyma is a rare complication of acute myeloid leukemia and commonly found on autopsy of patients without prior clinical pulmonary symptoms. We present a case of a 75-year-old female with acute myelomonocytic leukemia presenting as rapidly progressive respiratory failure with pulmonary leukemic infiltration. CASE PRESENTATION: The patient presented to her local hospital after 2 weeks of fevers, chest pain, dyspnea, and a non productive cough. CT angiogram of her chest revealed bilateral diffuse pulmonary infiltrates, loculated pleural effusions, and no evidence of pulmonary embolism. She underwent a left thoracentesis that yielded 13ml of an exudative effusion with following counts (RBCs 16 k/uL, WBCs 5.8 k/uL with 41% neutrophils, 8% lymphocytes, 6% monocytes, 43% macrophages & 2% mesothelial cells), as well as negative cultures and cytology. Due to progression of respiratory failure despite broad spectrum antimicrobials over the next 5 days, and new onset of atrial fibrillation, she was transferred to our hospital. Initial blood counts revealed abnormal peripheral monocytosis (AMC 1.8 k/uL, 32%) with a normal WBC count at 5.6 k/uL. Peripheral smear revealed premature monocytes. Her respiratory failure continued to progress requiring mechanical ventilation. She underwent exploratory thoracoscopy, lung wedge resection and intraoperative bronchoalveolar lavage. Lavage was significant for a WBC count of 400 per uL, 66% of which were monocytes. Lavage and pleural fluid cytologies were negative for malignant cells. Follow up blood counts showed progression of her monocytosis with appearance of promonocytes and peripheral blasts. Peripheral blood flow cytometry revealed 6% atypical myeloblasts and 45% atypical monocytic cells. Pleural and lung biopsies revealed an atypical interstitial mononuclear cell infiltrate with monocytic differentiation consistent with involvement by myeloid leukemia. Faced with refractory shock, multiorgan failure, and the most likely diagnosis of of acute leukemia, her family elected to transition to comfort measures and refused a bone marrow biopsy for diagnostic confirmation. She was palliatively extubated and passed away 4 days after her transfer. Autopsy was performed and confirmed acute myelomonocytic leukemia with leukemic infiltration of lungs, pleura, pericardium and spleen. DISCUSSION: Malignant infiltration of the lung is a rare manifestation of acute myeloid leukemia. We presented a case of progressive respiratory failure secondary to pulmonary and pleural involvement as an early presentation of acute myelomonocytic leukemia with a fatal outcome. CONCLUSIONS: Although uncommon, leukemic lung infiltration remains in the differential of acute pulmonary infiltrates in setting of blood dyscrasias suggestive of acute myeloid leukemia and can cause profound respiratory failure before a leukemia diagnosis is established. Reference #1: Wu Y-K, Huang Y-C, Huang S-F, Huang C-C, Tsai Y-H. Acute respiratory distress syndrome caused by leukemic infiltration of the lung. J Formos Med Assoc. 2008;107(5):419-423. Reference #2: Koh TT, Colby TV, Müller NL. Myeloid leukemias and lung involvement. Semin Respir Crit Care Med. 2005;26(5):514-519 Reference #3: Hildebrand FL, Rosenow EC, Habermann TM, Tazelaar HD. Pulmonary complications of leukemia. Chest. 1990;98(5):1233-1239 DISCLOSURES: No relevant relationships by Abdallah Abboud, source=Web Response No relevant relationships by Timothy Dwyer, source=Web Response No relevant relationships by Kathryn Gillen, source=Web Response No relevant relationships by Joel Mermis, source=Web Response No relevant relationships by Mitchell Tener, source=Web Response

Replacement of mycophenolate mofetil with a JAK inhibitor, AS2553627, in combination with low-dose tacrolimus, for renal allograft rejection in non-human primates

In renal transplant patients, using mycophenolate mofetil (MMF) with calcineurin inhibitors (CNIs; cyclosporine and tacrolimus [TAC]) has led to a significant improvement in graft survival. However, reducing or withholding MMF due to its gastrointestinal adverse events increases rejection risk. CNI-sparing strategies are important to avoid CNI-related nephrotoxicity in clinical settings. Here, we investigated AS2553627, a JAK inhibitor replacing MMF in combination with a sub-therapeutic dose of TAC to treat allograft rejection in a monkey model. AS2553627 inhibited proliferation of IL-2 stimulated T cells with little species difference between monkeys and humans. In MMF monotherapy, oral administration of 20 or 40 mg/kg/day prolonged graft survival with median survival times (MSTs) of 16.5 days and 33 days, respectively, whereas untreated animals showed MST of 6 days. In MMF/TAC (1 mg/kg/day, p.o.) combination therapy, pharmacokinetic analysis indicated that MMF 20 mg/kg/day achieved the clinical target AUC0-24h and prolonged renal allograft survival, with MST of 24 days. Oral administration of AS2553627 0.24 mg/kg/day in combination with TAC significantly prolonged renal allograft survival to MST of >90 days with low plasma creatinine levels. Histopathological analysis revealed that acute T cell-mediated rejection events such as vasculitis and interstitial mononuclear cell infiltration were significantly inhibited in AS2553627/TAC-treated allografts compared with MMF/TAC-treated allografts. All AS2553627/TAC-treated monkeys surviving >90 days exhibited less interstitial fibrosis/tubular atrophy than monkeys in the MMF/TAC group. These results suggest that AS2553627 replacing MMF is an attractive CNI-sparing strategy to prevent renal allograft rejection.

Secondary Oxalate Nephropathy: A Systematic Review

IntroductionLittle is known of the clinical outcomes of secondary oxalate nephropathy. To inform clinical practice, we performed a systematic review of case reports and case series to examine the clinical characteristics and outcomes of patients with secondary oxalate nephropathy.MethodsElectronic databases were searched for case reports and case series of individual cases or cohorts of patients with biopsy-proven oxalate nephropathy in native or transplanted kidneys from 1950 until January 2018.ResultsFifty-seven case reports and 10 case series met the inclusion criteria, totaling 108 patients. The case series were meta-analyzed. Mean age was 56.4 years old, 59% were men, and 15% were kidney transplant recipients. Fat malabsorption (88%) was the most commonly attributed cause of oxalate nephropathy, followed by excessive dietary oxalate consumption (20%). The mean baseline serum creatinine was 1.3 mg/dl and peaked at 4.6 mg/dl. Proteinuria, hematuria, and urinary crystals was reported in 69%, 32%, and 26% of patients, respectively. Mean 24-hour urinary oxalate excretion was 85.4 mg/d. In addition to universal oxalate crystal deposition in tubules and/or interstitium, kidney biopsy findings included acute tubular injury (71%), tubular damage and atrophy (69%), and interstitial mononuclear cell infiltration (72%); 55% of patients required dialysis. None had complete recovery, 42% had partial recovery, and 58% remained dialysis-dependent. Thirty-three percent of patients died.ConclusionSecondary oxalate nephropathy is a rare but potentially devastating condition. Renal replacement therapy is required in >50% of patients, and most patients remain dialysis-dependent. Studies are needed for effective preventive and treatment strategies in high-risk patients with hyperoxaluria-enabling conditions.

Pentoxifylline May Restore Kanamycin-Induced Renal Damage in Rats

Background: Kidney damage can be caused by many factors, such as using certain drugs in high doses or over the longterm. The use of one such group of drugs, aminoglycosides, which act as Gram-negative antibacterial therapeutic agents,can lead to nephrotoxicity. It has been hypothesized that aminoglycoside-induced nephrotoxicity might be prevented byusing pentoxifylline, which has antioxidant and anti-inflammatory effects and improves microcirculation. The objectiveof this present research was to determine the protective effects of pentoxifylline on kanamycin-induced kidney damage.Materials, Methods &amp; Results: Thirty-two male Wistar rats were divided into four groups as follows: control, pentoxifylline,kanamycin, and kanamycin + pentoxifylline. The control group received intraperitoneal (IP) injections of 0.5 mL normalsaline solution once a day (d) (SID) for 20 d; the pentoxifylline group received IP injections of 50 mg/kg pentoxifyllinetwice a day (BID) for 20 d, the kanamycin group received subcutaneous (SC) injections of 500 mg/kg kanamycin SID for20 d, and the kanamycin + pentoxifylline group received both SC injections of 500 mg/kg kanamycin SID and IP injectionsof 50 mg/kg pentoxifylline BID for 20 d. At the end of 20 d, blood samples were taken from the heart by cardiac punctureunder general anesthesia. After euthanizing the rats by cervical dislocation under anesthesia, the kidneys were immediatelyremoved, relative kidney weights were calculated, and routine pathologic evaluations were conducted. Hemogramparameters were measured using a blood cell count apparatus and serum biochemical parameters were measured usingan autoanalyzer. Kanamycin also caused (P &lt; 0.05) tubular degeneration and tubular dilatation. Although pentoxifyllinesignificantly reduced the level of kanamycin-induced tubular degeneration (P &lt; 0.05), it did not significantly reduce tubulardilatation. Increases in relative kidney weights (P &lt; 0.05) and in interstitial mononuclear cell (MNC) infiltrates wereobserved in the kanamycin and kanamycin + pentoxifylline groups compared to those in the control and pentoxifyllinegroups. Statistically significant changes were determined in the levels of some hemogram and biochemical parameterswithin reference ranges (P &lt; 0.05).Discussion: In this study, both tubular degeneration and dilatation were observed in the kanamycin group. Pentoxifyllineinhibited (P &lt; 0.05) kanamycin-induced tubular degeneration and appeared to also reduce tubular dilatation, although thisreduction was not significant. Tubular necrosis, epithelial edema of proximal tubules, tubular fibrosis, and perivascularinflammation might also be observed in aminoglycoside-induced nephrotoxicity. In current research, pentoxifylline preventedtubular damage induced by kanamycin, but did not inhibit infiltration by MNCs. Pentoxifylline also amelioratedamikacin- or gentamycin-induced histopathologic changes, especially those associated with tubular structures. The protectiveeffects of pentoxifylline on kanamycin-induced tubular nephrotoxicity in this research might be a result of its stimulatingthe production of prostaglandin, a vasodilator, and of its improving microcirculation. Although the anti-inflammatoryeffects of pentoxifylline have been reported, these did not inhibit kanamycin-induced infiltration by interstitial MNCs inthe present study. These results could indicate that the anti-inflammatory effects of pentoxifylline are not obvious and/orare dose dependent. Statistically significantly changes were determined in the levels of some hemogram and biochemicalparameters in reference ranges. However, these changes were within the reference ranges for rats. These results suggestedthat kanamycin-induced tubular degeneration and dilatation might be prevented by administering pentoxifylline.