Kidney

The reasons for the increased incidence of de novo anti-human leukocyte antibody (HLA) donor-specific antibodies (DSAs) observed after kidney allograft nephrectomy are not fully understood. One advocated mechanism suggests that at graft loss, DSAs are not detected in the serum because they are fixed on the nonfunctional transplant; removal of the kidney allows DSAs to then appear in the blood circulation. The aim of our study was to compare anti-HLA antibodies present in the serum and in the graft at the time of an allograft nephrectomy. Using solid-phase assays, anti-HLA antibodies were searched for in the sera of 17 kidney transplant patients undergoing allograft nephrectomy. No anti-HLA antibodies were detected in the graft if they were not also detected in the serum. Eleven of the 12 patients who had DSAs detected in their sera also had DSAs detected in the grafts. Epitopic analysis revealed that most anti-HLA antibodies detected in removed grafts were directed against the donor. In summary, our data show that all anti-HLA antibodies that were detected in grafts were also detected in the sera. These intragraft anti-HLA antibodies are mostly directed against the donor at an epitopic level but not always at an antigenic level.

Summary Background and objectives Within the last few years, anti–human leukocyte antigen detection assays have significantly improved. This study asked, using the Luminex single-antigen assay, whether an allograft nephrectomy allowed donor-specific alloantibodies to appear that were not previously detected in the serum when the failed kidney was still in place. Design, setting, participants, & measurements After losing the kidney allograft and stopping immunosuppressive therapy, the proportions of donor-specific alloantibodies and nondonor-specific alloantibodies were compared in patients who had (n=48; group I) and had not (n=21; group II) undergone an allograft nephrectomy. Allograft nephrectomies were performed at 150 days after kidney allograft loss, and the time between allograft nephrectomy and last follow-up was 538±347 days. Results At kidney allograft loss, donor-specific alloantibodies were detected in three group II patients (14.2%) and six group I patients (12.5%). At l...

Mutations in the photoreceptor membrane guanylyl cyclase RetGC-1 have been linked to autosomal dominant cone-rod dystrophy. Three mutations were identified that alter strictly conserved residues within the RetGC-1 dimerization domain, a region predicted to form an amphipathic ␣-helical coil. Here we report on a biochemical characterization of one of the mutations, a substitution of cysteine for arginine at residue 838. We generated this mutation in vitro and measured its catalytic activity and sensitivity to guanylyl cyclase activating protein 1 (GCAP-1) and GCAP-2. The R838C substitution has several effects. It reduces the overall catalytic ability of RetGC-1 and dramatically reduces stimulation by GCAP-2, although GCAP-2 still appears to interact with the protein. The R838C substitution also increases the apparent affinity of RetGC-1 for GCAP-1 and alters the Ca 2؉ sensitivity of the GCAP-1 response, allowing the mutant to be stimulated by GCAP-1 at higher Ca 2؉ concentrations than wild type. The diminished response to GCAP-2, which we propose is not likely the cause of cone-rod degeneration in these patients, is interesting mechanistically because it separates the ability to bind a specific GCAP from the ability to be stimulated by it, and it also discriminates between the mechanisms of activation of GCAP-1 vs. GCAP-2. We suggest that the gain-of-function effects of R838C on RetGC-1 stimulated by GCAP-1, which are dominant in vitro and may cause an abnormal increase in cGMP synthesis in dark-adapted photoreceptors, may be the cause of the cone-rod degeneration.

Metabotropic glutamate receptors (mGluRs) mediate a variety of responses to glutamate in the central nervous system. A primary role for group-III mGluRs is to inhibit neurotransmitter release from presynaptic terminals, but the molecular mechanisms that regulate presynaptic trafficking and activity of group-III mGluRs are not well understood. Here, we describe the interaction of mGluR7, a group-III mGluR and presynaptic autoreceptor, with the cytoskeletal protein, alpha tubulin. The mGluR7 carboxy terminal (CT) region was expressed as a GST fusion protein and incubated with rat brain extract to purify potential mGluR7-interacting proteins. These studies yielded a single prominent mGluR7 CT-associated protein of 55 kDa, which subsequent microsequencing analysis revealed to be alpha tubulin. Coimmunoprecipitation assays confirmed that full-length mGluR7 and alpha tubulin interact in rat brain as well as in BHK cells stably expressing mGluR7a, a splice variant of mGluR7. In addition, protein overlay experiments showed that the CT domain of mGluR7a binds specifically to purified tubulin and calmodulin, but not to bovine serum albumin. Further pull-down studies revealed that another splice variant mGluR7b also interacts with alpha tubulin, indicating that the binding region is not localized to the splice-variant regions of either mGluR7a (900-915) or mGluR7b (900-923). Indeed, deletion mutagenesis experiments revealed that the alpha tubulin-binding site is located within amino acids 873-892 of the mGluR7 CT domain, a region known to be important for regulation of mGluR7 trafficking. Interestingly, activation of mGluR7a in cells results in an immediate and significant decrease in alpha tubulin binding. These data suggest that the mGluR7/alpha tubulin interaction may provide a mechanism to control access of the CT domain to regulatory molecules, or alternatively, that this interaction may lead to morphological changes in the presynaptic membrane in response to receptor activation. Keywords carboxy terminal domain; mGluR7; protein-protein interaction; regulation; tubulin Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors (GPCRs) that are widely distributed throughout the central nervous system and modulate cell excitability and synaptic transmission. There are eight molecular subtypes of mGluRs that are divided

To coexist with complement, human tissues express membrane-integrated regulatory proteins that inhibit the activity of autologous complement on cell suoCaces. Certain of these complement regulatory proteins act as obligatory cofaaors for proteolytic inactivation of activated C4(C4b) by factor I. Extraembryonic tissues and in particular trophoblasts constitute an interface at risk from maternal complement during pregnancy. The present study examined syncytiotrophoblast plasma membrane (STM) cofactor activity for cleavage of immobilized methylamine-treated complement component C4 (C4ma), a C4b analog by factor L Membrane cofactor protein (MCP or CD46) provided most of the cofactor activity in STM preparations. Minor cofactor activity was derived from C4 binding protein that was firmly bound to STM. Cofactor activity for cleavage of C4ma at its two sites for factor I was enhanced at higher concentrations of STM and at lower concentrations cleavage at a C terminal site predominated. Soluble cofactor activity was present in STM preparations and was provided by 65 KDa, 55 KDa and 50 KDa soluble species of MCP that lacked amphiphilic properties. These results are consistent with a major role for MCP in regulation of C4 activity on the maternalfacing surfaces of extraembryonic tissues during human development. Soluble MCP may provide additional fluid phase complement regulatory activity in the maternotrophoblastic zone.

Many cell surface glycoconjugates are differentiation markers and are involved in cell-cell and intermolecular interactions in development, immunity and cancer. Membrane cofactor protein (MCP) comprises structurally related 65 and 55 kDa glycoproteins that bear O-and N-linked glycans. MCP prevents amplification of autologous complement action on human cells. Wc used immunoblotting with MCP-spccific monoclonal antibody TRA-2-10 to determine lectin-binding properties and glycosidase sensitivities of MCP in a study of cell-specific variation in glycosylation of this protein. The results showed that N-linked glycans on placental syncytiotrophoblast and cytotrophoblast, kidney and platclet MCP are similar in binding to concanavalin A and Lens culinaris lectins, but arc not bound by leucophytohemagglutinin. Leetin binding prior to and after neuraminidasc digestion indicates that MCP from these sources is highly sialylatcd. 65 kDa MCP was confirmed to contain more O-linked glycans than 55 kDa MCP. A fraction of platelet 65 kDa MCP is distinct, however, in bearing peripheral fucose residues. Syncytiotrophoblast is unique in containing a ! 10 kDa form of MCP in non-reducing SDS-PAGE that resembles 65 kDa MCP in glycosylation. Chorion laeve MCP in 4 of 8 preparations was unusually heterogeneous and differed from syncytiotrophoblast MCP after ncuraminidase digestion in the forms bound to peanut agglutinin and WGA. The results indicated for the first time, differences in O-linked glycosylation of MCP in chorion laeve cytotrophoblast relative to syncytiotrophoblast, platelet and kidney MCP. We conclude that structures of MCP glyeans can differ between trophoblasts and other cell types.

Cluster of Differentiation antigen 59 (CD59) is a glycosyl phosphatidylinositol-linked protein that protects cells from damage by lytic terminal complexes of complement. Soluble forms of CD59 in serum have been little investigated in disease states. In the present study, by using a sandwich ELISA, reactivities with antibodies to CD59 were compared for sera and plasma from normal individuals and those with renal, leukemia, heart, liver and lung diseases. In all of 44 renal patients, reactivities were up to threefold higher than those of normals and patients with other conditions. The soluble CD59-related antigen displayed epitopes recognized by an anti-CD59 rabbit antiserum and CD59 monoclonal antibodies MEM-43 and YTH 53.1. Failure to bind the hydrophobic matrix phenyl Sepharose suggested that the CD59-related antigen lacked a membrane-anchoring structure. Although the cellular origin of soluble CD59-related antigen is unknown, some effect common to different renal diseases can promote increased plasma levels of this antigen. In two individuals, monitored before and after renal transplantation, plasma levels of CD59-related antigen decreased towards normal after receipt of a kidney.

Forty-eight patients with chronic myelocytic leukemia, aged 11 to 47, were treated with high-dose cyclophosphamide and fractionated total body irradiation, followed by infusion of marrow from HLA-identical siblings. They were randomized to receive either methotrexate (MTX) (n = 23) or cyclosporine (CSP) (n = 25) as postgrafting prophylaxis for graft-v-host disease (GVHD). All patients had evidence of sustained hematopoietic engraftment. Seventeen of the 25 patients receiving CSP and 17 of the 23 patients receiving MTX are alive between one and almost four (median, 1.7) years, with an actuarial survival rate at three years of 62% and 66%, respectively (P = .60). Also, with respect to most other parameters studied, the two drugs were identical. The probability of acute GVHD was .42 and .46, respectively (P = .70), that of chronic GVHD, .50 and .63 (P = .44), and that of death from transplant-related causes, .30 and .24 (P = .51). There were no differences in the speed of granulocyte a...

Cissampelos sympodialis is a plant to northeastern Brazil region used by populace for treating diseases respiratory. Several studies have shown that the ethanol extract of the leaves have immunomodulatory and anti-inflammatory activities. The infusion is an ancient popular technique widely used in traditional medicine using as extracting means just hot water. This study aims to investigate the acute toxicological potential administering a dose of 2000mg/kg in Rattus norvegicus combined with in silico study of 117 alkaloids present in Cissampelos genre. In silico, 5 we can determine which molecules have a high toxicity (21, 8, 93, 32 and 88) and low toxicity (57, 77, 28, 25 and 67) and their percentage metabolizing liver. The toxicological evaluation in vivo showed that there was a decrease in water consumption in males only and feed intake in both sexes. However, these numbers were not statistically sufficient to change the weight gain of the animals. As for the biochemical paramete...

We have investigated the glycosphingolipids of pig kidney with a special interest in identifying compounds which may be involved in the rejection of tissue in xenotransplantation. Nine neutral glycosphingolipids have been characterized in porcine kidney and structurally characterized by a combination of techniques including 1H-NMR, permethylation analysis and thin-layer chromatography (TLC) immunostaining with carbohydrate sequence-specific monoclonal antibodies. The major components are members of the globo family and represent the human pk and P antigens. Three other compounds were found to contain a neolacto core structure; the major neolacto compound carries a nonreducing terminal epitope (Galcd-3Gal/?l-4GlcNAc) recognized by the naturally-occurring human antibody, anti-Gal, and a second neolacto compound carries the blood group A trisaccharide (GalNAcel-3(Fuccd-2)Gal). These results are discussed with respect to tissue transplantation.

Self financing Background: New oral anticoagulants like direct thrombin inhibitors are an attractive alternative to vitamin K antagonists as anticoagulation therapy and can be used in heparin-induced thrombocytopenia. They are convenient in low-risk surgery, as there is no need for bridging with heparins. Patients who need urgent major surgery are at similar risk as on warfarin therapy, which, however, is much higher than in elective procedures. Due to their elimination profiles, these drugs are generally contraindicated in patients with severe renal insufficiency. On the other hand, pancreas transplantation is associated with high risk of bleeding and substantial risk of graft thrombosis. There are no recommendations on anticoagulation therapy in high-risk patients on kidney-pancreas waiting lists who cannot be given heparins. Case Report: We describe a case of simultaneous pancreas-kidney transplantation in a patient with heparin-induced thrombocytopenia on dabigatran treatment. Conclusions: We conclude that, despite the high risk, pancreas transplantation in a patient with HIT can be safely done while on NOAC therapy, but an access to idarucizumab should be assured.

Touch spray-mass spectrometry (TS-MS) is an ambient ionization technique (ionization of unprocessed samples in the open air) that may find intraoperative applications in quickly identifying the disease state of cancerous tissues and in defining surgical margins. In this study, TS-MS was performed on fresh kidney tissue (~1-5 cm 3), within one hour of resection, from 21 human subjects afflicted by renal cell carcinoma (RCC). The preliminary diagnostic value of TS-MS data taken from freshly resected tissue was evaluated. Principal component analysis (PCA) of the negative ion mode (m/z 700-1000) data provided separation between RCC (16 samples) and healthy renal tissue (13 samples). Linear discriminant analysis (LDA) on the PCA compressed data estimated sensitivity (true positive rate) and specificity (true negative rate) of 98% and 95%, respectively, based on histopathological evaluation. The results indicate that TS-MS might provide rapid diagnostic information in spite of the complexity of unprocessed kidney tissue and the presence of interferences such as urine and blood. Desorption electrospray ionization imaging (DESI-MSI) in the negative ionization mode was performed on the tissue specimens after TS-MS analysis as a reference method. The DESI imaging experiments provided phospholipid profiles (m/z 700-1000) that also separated RCC and healthy tissue in the PCA space, with PCA-LDA sensitivity and specificity of 100% and 89%, respectively. The TS and DESI loading plots indicated that different ions contributed most to the separation of RCC from healthy renal tissue (m/z 794

Social media is being used more and more by businesses and CEOs to share information and interact with investors. Compared to other channels for disclosure, social media sites like Twitter allow for more timely disclosure to a larger audience (e.g., paper-and web-based). However, little academic research has been done to analyze the function of social networks in developing markets. There is still a lack of knowledge regarding how social media interactions between different parties may encourage greater transparency in various organizational structures and in nations where stakeholder interests are less secure. So, the objective of the study is to investigate the relationship between social networks and transparency. The sample is collected from the financial statements of 100 Egyptian-listed firms in EGX 100 as a secondary source of data. The data cover 9 years beginning from 2012 to 2020. The results indicate that social networks have a significant effect on financial transparency. So, by increasing the use of the firm's website, website traffic, and Facebook, financial transparency will increase. However, using Twitter may have a negative effect on financial transparency.

Key Points Post-HSCT hemoglobinuria was associated with graft type (BMT+Cord).Post-HSCT hemoglobinuria was associated with early (48–72 hours) post-HSCT AKI.Graft type (BMT+Cord) was associated with AKI among patients with hemoglobinuria. Background Information on risk factors of hemoglobinuria after hematopoietic stem-cell transplant (HSCT) and its association with AKI, mortality, and engraftment is limited. Methods We conducted a retrospective cohort study on all consecutive adults that underwent HSCT from January 6, 1999, to November 6, 2017. The study included 6039 patients that underwent bone marrow transplantation (BMT), umbilical cord blood, and peripheral blood stem-cell transplantation (PBSCT). Results Early post-HSCT, AKI occurred in 393 (7%) patients, and 52 (0.9%) patients had post-HSCT hemoglobinuria. Post-HSCT hemoglobinuria was associated with graft type (BMT+Cord), underlying disease (lymphoma, acute leukemia), and fludarabine-based conditioning regimen. Post-HSCT he...

Forty-seven patients with primary advanced (N = 37) or recurrent ovarian carcinoma (N = 10) completed a 12-month course of CAP chemotherapy or developed progressive disease while on therapy and were evaluated. All patients were treated between August 1, 1977 and August 1, 1982. Cyclophosphamide 400 mg/m2, Adriamycin (doxorubicin) 40 mg/m2, and cisplatin 60 mg/m2, were administered every 4 weeks intravenously. After 8 courses the cisplatin was stopped. The patients then received 500 mg/m2 of cyclophosphamide and 50 mg/m2 of Adriamycin. At the cumulative dose of 450 mg/m2, the Adriamycin was stopped and cyclophosphamide was given at 1 g/m2 alone until the patient had received a total of 12-13 courses from the initiation of the chemotherapy protocol. The cardiac, renal, and hematopoetic toxicity of the regimen was mild to moderate. The median survival of the entire study population was 32 months. The median survival of the patients with primary disease was 36 months. The median survival of patients with recurrent disease was 20 months. There was a significant difference in median survival based on size of the largest lesion prior to initiation of chemotherapy. There was no difference in median survival based on tumor grade or comparing Stage 111 to Stage IV tumors. The most important aspects of the study appeared to be the length of the median survival of the patients, the fact that all patients who were complete responders and who were considered to have no evidence of disease, have been documented by second look, and the success of secondary treatment after second-look procedures revealed persistent tumor. The authors additionally report the use of weight change as an indicator of tumor response, and the importance of the pelvic examination complimented by fine-needle aspiration in following the course of these patients.

Effects on renal development were studied using tobramycin (TBM) as a model compound. Pregnant Sprague‐Dawley rats were injected i.p. with TBM at 30 or 60 mg/kg body weight/day on gestational days (GD) 10–19. Kidneys from dams and conceptuses were examined on GD 20 and on postnatal day (PD) 9. The dosing regimen caused in dams moderate proximal tubular alterations and increased concentrations in serum creatinine. Fetal kidneys showed granularity and swelling of proximal tubule cells at the 30 mg/kg dose, poor glomerular differentiation at the 60 mg/kg dose, increased glomerular density at both doses, and no changes on macroscopic examination at either dose. In newborns were observed a moderate developmental delay and tubular lesions at the higher dose, and dose‐related increases of glomerular density and relative medullary area at both doses. All findings were more pronounced in males. A maturational disruption of the tubular structures possibly leading to increased glomerular densi...

1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches.

Hypoalbuminemia (HA) is frequently observed in systemic inflammatory diseases and in liver disease. However, the influence of HA on the pharmacokinetics and toxicity of compounds with high plasma albumin binding remained insufficiently studied. The 'lack-of-delivery-concept' postulates that HA leads to less carrier mediated uptake of albumin bound substances into hepatocytes and to less glomerular filtration; in contrast, the 'concept-of-higher-free-fraction' argues that increased concentrations of non-albumin bound compounds facilitate hepatocellular uptake and enhance glomerular filtration. To address this question, we performed intravital imaging on livers and kidneys of anesthetized mice to quantify the spatio-temporal tissue distribution of the mycotoxin ochratoxin A (OTA) based on its auto-fluorescence in albumin knockout and wild-type mice. HA strongly enhanced the uptake of OTA from the sinusoidal blood into hepatocytes, followed by faster secretion into bile canaliculi. These toxicokinetic changes were associated with increased hepatotoxicity in heterozygous albumin knockout mice for which serum albumin was reduced to a similar extent as in patients with severe hypoalbuminemia. HA also led to a shorter half-life of OTA in renal capillaries, increased glomerular filtration, and to enhanced uptake of OTA into tubular epithelial cells. In conclusion, the results favor the 'concept-of-higher-free-fraction' in HA; accordingly, HA causes an increased tissue uptake of compounds with high albumin binding and increased organ toxicity. It should be studied if this concept can be generalized to all compounds with high plasma albumin binding that are substrates of hepatocyte and renal tubular epithelial cell carriers.

Aim: The information about kidney diseases in the general population of Albania is scant and not well-documented. The aim of our analysis was to describe the trend of selected kidney diseases in Albania for the period 1990-2019. Methods: Our analysis was based on the estimates available from the Global Burden of Disease (GBD) studies, reported by the Institute for Health Metrics and Evaluation (IHME). For Albania, IHME uses the data mainly available from the National Institute of Statistics. Results: The age-standardized proportional mortality due to kidney dysfunction in Albania in 1990 was about 4.2% compared with 6.0% in 2019. There was evidence of a reduction in the past three decades in the mortality rate and burden of acute glomerulonephritis in the Albanian population. At a crude level, chronic kidney disease and its share attributable to hypertension exhibited a gradual increase from 1990 to 2019, whereas the age-standardized estimates were lower in 2019 than in 1990. Conclusion: Our analysis summarizes valuable information about the mortality rate and burden of kidney diseases in Albania, a post-communist country in Southeastern Europe characterized by a rapid and intensive process of political and socioeconomic transition. Similar to most of the countries worldwide, kidney diseases constitute a significant health challenge for the health care system in Albania.

Background and Aims The main mechanism of therapeutic action of mesenchymal stem cells (MSCs) could be resulted from their secretome content rather than their direct differentiation into damaged cells [1, 2]. Preconditioning of MSCs with different strategies like culturing in 3 dimensional (3D) culture scaffolds could improve their therapeutic potential [1]. Based on our previous study [1] in which the concentrations of total protein and specifically VEGF and IL-4 in conditioned mediums (CMs) collected from MSCs cultured in 3D culture conditions were increased compared to one of 2D, the aim of this study is comparative analysis of effects of CMs obtained from MSCs incubated under 2D and 3D culture conditions on kidney functions of rats with autoimmune type I diabetes (aT1D) induced with streptozocin (STZ). Method Isolation and characterization of the umbilical cord MSCs and the following analysis of concentrations of total protein and paracrine factors in the 2D-CMs and 3D-CMs were ...

Objectives: To explore the long-term outcomes in foetuses presenting with an enlarged bladder antenatally. Methods-Design: A retrospective cohort study was conducted over a 15-year period between 2003 and 2018. Setting and participants: Foetuses suspected to have enlarged bladders antenatally were included. Outcome measurements and statistical analysis: Analyses were done based on the trimester the enlarged bladder was detected, live births, terminations, surgical interventions, creatinine levels and bladder measurements post-delivery, and subsequent health outcomes. Results: From the 50 foetuses identifi ed prenatally, detections were as follows: fi rst trimester (9 cases), second trimester (30 cases), and third trimester (11 cases). There were 14 terminations (28%), 5 stillbirths (10%), and 31 live births (62%). Among the terminated and stillbirth/neonatal death cases, the most frequent diagnosis in males was PUV (57%). Two female foetuses were terminated due to lumbosacral spina bifi da and sacrococcygeal teratoma obstructing the ureters, respectively. In surviving males, PUV was predominant (48.3% of 29 males). In fi ve cases megacystis had resolved by birth, including one following in-utero surgery. Among the two female cases, one issue was resolved by birth, and the second had bilateral ureteroceles. Post-birth, surgical intervention was needed in 61% of males and 50% of females. The commonest surgery was ablation of posterior urethral valves. The median age for surgery was 1.5 months with a median follow-up of 4 years and the longest follow-up of fourteen years. Six children had no postnatal renal or urological follow-up. The mean peak creatinine level was 132, dropping to 47 in the latest measurement. Half of the patients with pathology evident at birth exhibited abnormal bladder function. There was one neonatal death. Three patients necessitated a kidney transplant due to chronic kidney disease. Conclusion: Foetuses diagnosed with an enlarged bladder in the second trimester most frequently had the posterior urethral valve as the underlying cause. For patients continuing the pregnancy, most had live births. About 1 in 10 posterior urethral valve survivors developed chronic kidney conditions, leading to a renal transplant.

Kidney supportive care (KSC) and conservative kidney management (CKM) are essential treatments for kidney failure (KF) but are nonexistent, poorly developed, and/or poorly integrated with kidney care across low-, middle-, and high-income countries. This article reviews the updated definitions and evidence for KSC and CKM and discusses who will most benefit from these treatments. Conservative kidney management involves highly individualized active treatment that comes with its own set of recommendations that focus predominantly on patient-specific goals and health-related quality of life. The recommendations for managing the complications of kidney failure and the symptoms of pain, restless legs, uremic pruritus, nausea and vomiting, poor sleep and fatigue, and breathlessness in people receiving CKM are reviewed. Additional considerations for delivering CKM in low resource settings are discussed.

Cytosolic and mitochondrial creatine kinases (CK), through the creatine kinase-phosphocreatine (CK/PCr) system, provide a temporal and spatial energy buffer to maintain cellular energy homeostasis. However, the effects of bacterial infections on the kidney remain poorly understood and are limited only to histopathological analyses. Thus, the aim of this study was to investigate the involvement of cytosolic and mitochondrial CK activities in renal energetic homeostasis in silver catfish experimentally infected with Aeromonas caviae. Cytosolic CK activity decreased in infected animals, while mitochondrial CK activity increased compared to uninfected animals. Moreover, the activity of the sodium-potassium pump (Na(+), K(+)-ATPase) decreased in infected animals compared to uninfected animals. Based on this evidence, it can be concluded that the inhibition of cytosolic CK activity by A. caviae causes an impairment on renal energy homeostasis through the depletion of adenosine triphosphat...

To study the role of Na+/H+exchanger isoform 2 (NHE2) and isoform 3 (NHE3) in sodium-fluid volume homeostasis and renal Na+conservation, mice with Nhe2( Nhe2−/−) and/or Nhe3( Nhe3−/−) null mutations were fed a Na+-restricted diet, and urinary Na+excretion, blood pressure, systemic acid-base and electrolyte status, and renal function were analyzed. Na+-restricted Nhe2−/−mice, on either a wild-type or Nhe3 heterozygous mutant ( Nhe3+/−) background, did not exhibit excess urinary Na+excretion. After 15 days of Na+restriction, blood pressure, fractional excretion of Na+, and the glomerular filtration rate (GFR) of Nhe2−/−Nhe3+/−mice were similar to those of Nhe2+/+and Nhe3+/−mice, and no metabolic disturbances were observed. Nhe3−/−mice maintained on a Na+-restricted diet for 3 days exhibited hyperkalemia, urinary salt wasting, acidosis, sharply reduced blood pressure and GFR, and evidence of hypovolemic shock. These results negate the hypothesis that NHE2 plays an important renal funct...

The apical Na+‐H+ exchanger NHE3 plays an important role in fluid reabsorption in the proximal tubule. However, whether its deletion alters the salt and water transport in the distal nephron remains unknown. To answer these questions, wild‐type (Nhe3+/+) and NHE3 null mice (Nhe3−/−) were placed in metabolic cages and their water balance and urine osmolality were examined. Nhe3−/− mice demonstrated a significant polydipsia (P < 0.03) and polyuria (P < 0.04), with a lower urine osmolality (P < 0.003) as compared to Nhe3+/+ mice. Northern hybridization and immunoblotting studies indicated that the mRNA expression and protein abundance of the collecting duct (CD) water channel AQP2 decreased by 52 % (P < 0.0003) and 73 % (P < 0.003) in the cortex, and by 53 % and 54 % (P < 0.002) in the inner medulla (IM) of Nhe3−/− vs. Nhe3+/+ mice. The expression of AQP2 in the outer medulla (OM) remained unchanged. Further, the mRNA expression and protein abundance of the medullary ...

The severe organ shortage in Israel has prompted many patients to undergo kidney transplantation abroad. In May 2008, the Israeli Knesset approved the Israel Transplant Law prohibiting organ trade and disallowing health insurers to reimburse the cost of illegal transplantation abroad. The aim of this study was to assess the initial effect of the law on kidney transplantations inside and outside the country. The number of kidney transplantations performed inside and outside Israel was compared between the 3-year periods before and after implementation of the transplant law (2006-2008 and 2009-2011). Further analysis compared the number of deceased-donor and live-donor transplantations performed in Israel during the same periods. The results showed that the number of transplants performed abroad dropped significantly, from a median of 143 per year during 2006-2008 to <45 per year during 2009-2011. There was a parallel increase in the number of kidney transplantations from living do...

The aim of this study is to demonstrate whether fullerenol C60 protects renal injury in sevofl urane-administered rats. METHOD: Rats (n: 24) were randomly divided into four groups: Control (Group C), Fullerenol C60 (Group F), Sevofl urane (Group S), Fullerenol C60-Sevofl urane (Group FS). Thirty minutes before the procedure, Fullerenol C60, 100 mg/kg, was administered intraperitoneally. Sevofl urane (2.3 %) was applied for 3 hours to rats in S and FS groups. Biochemical and histopathological parameters were analyzed in renal tissue samples. Kruskal-Wallis and Mann-Whitney U tests were used in statistical analyzes. RESULTS: Malondialdehyde (MDA) level and catalase (CAT) enzyme activity in Group S were signifi cantly higher than that in all other groups. Paraoxanase (PON) enzyme activity in Group S was signifi cantly lower than in Groups C and FS. The histopathological examination showed that vascular vacuolization and hypertrophy (VVH) and lymphocyte infi ltration (LI) were signifi cantly higher in the Group S compared to the Group C. CONCLUSION: Renal histopathology revealed that the administration of Fullerenol C60 prior to sevofl urane inhalation reduced oxidative stress and partially corrected the damage caused by anesthesia. We concluded that Fullerenol C60 has a renal protective effect in rats when administered before sevofl urane anesthesia (Tab. 2, Fig. 4, Ref. 40).

Tubuloglomerular feedback (TGF) and the myogenic mechanism combine in each nephron to regulate blood flow and glomerular filtration rate. Both mechanisms are nonlinear, generate self-sustained oscillations, and interact as their signals converge on arteriolar smooth muscle, forming a regulatory ensemble. Ensembles may synchronize. Smooth muscle cells in the ensemble depolarize periodically, generating electrical signals that propagate along the vascular network. We developed a mathematical model of a nephron-vascular network, with 16 versions of a single nephron model containing representations of both mechanisms in the regulatory ensemble, to examine the effects of network structure on nephron synchronization. Symmetry, as a property of a network, facilitates synchronization. Nephrons received blood from a symmetric electrically conductive vascular tree. Symmetry was created by using identical nephron models at each of the 16 sites and symmetry breaking by varying nephron length. T...

A close relationship between angiotensin II (ANG II) and the renal dopaminergic system (RDS) has been reported. Our aim was to study whether renal dopamine and ANG II can interact to modify renal sodium handling and then to elucidate the related mechanism. Anesthetized male Sprague-Dawley rats were used in experiments. ANG II, exogenous dopamine, and decynium-22 (or D-22, an isocyanine that specifically blocks electrogenic organic cation transporters, OCTs), were infused in vivo for 120 min. We analyzed renal and hemodynamic parameters, renal Na + , K +-ATPase levels, OCT activity, and urinary dopamine concentrations. We also evaluated the expression of D 1 receptor, electroneutral organic cation transporters (OCTNs), and OCTs. ANG II decreased renal excretion of sodium in the presence of exogenous dopamine, increased Na + , K +-ATPase activity, and decreased the urinary dopamine concentration. D-22 treatment exacerbated the ANG II-mediated decrease in renal excretion of sodium and dopamine urine excretion but did not modify ANG II stimulation of Na + , K +-ATPase activity. The infusion of ANG II did not affect the expression of D 1 receptor, OCTs, or OCTNs. However, the activity of OCTs was diminished by the presence of ANG II. Although ANG II did not alter the expression of D 1 receptor, OCTs, and OCTNs in renal tissues, it modified the activity of OCTs and thereby decreased the urinary dopamine concentration, showing a novel mechanism by which ANG II decreases dopamine transport and its availability in the tubular lumen to stimulate D 1 receptor. This study demonstrates a relationship between ANG II and dopamine, where both agents counteract their effects on sodium excretion.

In the kidney, a high salt intake favors oxidative stress and hypoxia and causes the development of fibrosis. Both atrial natriuretic peptide (ANP) and hypoxia inducible factor (HIF-1α) exert cytoprotective effects. We tested the hypothesis that renal expression of ANP and HIF-1αis involved in a mechanism responding to the oxidative stress produced in the kidneys of rats chronically fed a high sodium diet. Sprague-Dawley rats were fed with a normal salt (0.4% NaCl) (NS) or a high salt (8% NaCl) (HS) diet for 3 weeks, with or without the administration of tempol (T), an inhibitor of oxidative stress, in the drinking water. We measured the mean arterial pressure (MAP), glomerular filtration rate (GFR), and urinary sodium excretion (UVNa). We evaluated the expression of ANP, HIF-1α, and transforming growth factor (TGF-β1) in renal tissues by western blot and immunohistochemistry. The animals fed a high salt diet showed increased MAP andUVNalevels and enhanced renal immunostaining of AN...

Polychlorinated biphenyls (PCBs) exist as persistent organic pollutants in numerous river systems in the United States. Unfortunately, some of these rivers are sites of active Atlantic salmon restoration programs, and polychlorinated biphenyls have been implicated as ancillary factors contributing to failed salmon restoration. Here, we investigate the immediate and chronic effects of intermediate duration aqueous PCB exposure (1 or 10 g L −1 Aroclor 1254) on the mitogen-stimulated lymphoproliferative response of Atlantic salmon anterior kidney leukocytes (AKLs). A short-term study was designed to examine immunomodulation in Atlantic salmon smolts immediately following 21 days of aqueous exposure, while a long-term study evaluated chronic impacts in the mitogen response in parr 15 months post-exposure as larvae. The proliferative response of AKLs to the mitogens concanavalin A (CON A), phytohemaglutinnin-P (PHA-P), pokeweed mitogen (PWM), and lipopolysaccharide were used as an indice of immunomodulation. The proliferative response to the T-cell mitogens CON A and PHA-P was significantly increased in the 10 g L −1 group (n = 10; P = 0.043 and 0.002, respectively) immediately following exposure of smolts. Additionally, The PHA-P response was significantly increased in the 1 g L −1 exposure group (n = 10, P = 0.036). In fish treated as larvae and tested 15 months later, the PHA-P sensitive populations exhibited elevated proliferation in the 1 and 10 g L −1 groups (n = 12, P < 0.04) relative to the vehicle control while the PWM response was significantly increased (n = 12, P = 0.036) only in the 10 g L −1 treated groups. These results demonstrate an immunomodulatory effect of PCBs on T-cell mitogen sensitive populations of lymphocytes in Atlantic salmon as well as long-term immunomodulation in PHA-P and PWM sensitive populations.

Histiocytic sarcoma is the most frequent hematopoietic tumor in rats. We report here a histiocytic sarcoma infiltrating the liver, the spleen and the pancreas from a Wistar rat. In the liver, the tumor was associated with oval cell and bile duct hyperplasia. The cells looked like neoplastic histocytic cells described in this species but with some particularities (e.g. lack of multinucleated giant cells). At immunohistochemistry, neoplastic cells in the liver were vimentine positive but lysozyme and CD68 negative. In the kidney, lysozyme-positive cytoplasmic droplets were observed. We describe here an atypical case of histiocytic sarcoma in the rat and we compare the nature of these neoplastic cells to other species.

To characterize in vivo the translational control elements present in the 5&#39; nontranslated region (5&#39;NTR) of hepatitis A virus (HAV) RNA, we created an HAV-permissive monkey kidney cell line (BT7-H) that stably expresses T7 RNA polymerase and carries out cytoplasmic transcription of uncapped RNA from transfected DNA containing the T7 promoter. The presence of an internal ribosomal entry site (IRES) within the 5&#39;NTR of HAV was confirmed by using BT7-H cells transcribing bicistronic RNAs in which the 5&#39;NTR was placed within the intercistronic space, controlling translation of a downstream reporter protein (bacterial chloramphenicol acetyltransferase). However, translation directed by the 5&#39;NTR in these bicistronic transcripts and in monocistronic T7 transcripts in which the HAV 5&#39;NTR was placed upstream of the chloramphenicol acetyltransferase coding sequence was very inefficient compared with the translation of monocistronic transcripts containing either the I...

Chronic kidney diseaQueryse (CKD) is associated with oxidative stress which can interrupt the nitric oxide (NO)/soluble guanylyl cyclase (sGC) signaling and decrease cyclic guanosine monophosphate (cGMP) production. Low cGMP concentrations can cause kidney damage and progression of CKD. The novel sGC activator runcaciguat targets the oxidized and heme-free form of sGC, restoring cGMP production under oxidative stress. The purpose of this study is to investigate if runcaciguat could provide an effective treatment for CKD. Runcaciguat was used for the treatment not only in rat CKD models with different etiologies and comorbidities, namely of hypertensive rats, the renin transgenic (RenTG) rat, and angiotensinsupplemented (ANG-SD) rat, but also in rats with diabetic and metabolic CKD, the Zucker diabetic fatty (ZDF) rat. The treatment duration was 2 to 42 weeks and runcaciguat was applied orally in doses from 1 to 10 mg/kg/bid. In these different rat CKD models, runcaciguat significantly reduced proteinuria (urinary protein to creatinine ratio; uPCR). These effects were also significant at doses which did not or only moderately decrease systemic blood pressure. Moreover, runcaciguat significantly decreased kidney injury biomarkers and attenuated morphological kidney damages. In RenTG rats, runcaciguat improved survival rates and markers of heart injury. These data demonstrate that the sGC activator runcaciguat exhibits cardio-renal protection at doses which did not reduce blood pressure and was effective in hypertensive as well as diabetic and metabolic CKD models. These data, therefore, suggest that runcaciguat, with its specific mode of action, represents an efficient treatment approach for CKD and associated CV diseases.

Chronic kidney disease (CKD) progression is associated with persisting oxidative stress, which impairs the NO-sGC-cGMP signaling cascade through the formation of oxidized and heme-free apo-sGC that cannot be activated by NO. Runcaciguat (BAY 1101042) is a novel, potent, and selective sGC activator that binds and activates oxidized and heme-free sGC and thereby restores NO-sGC-cGMP signaling under oxidative stress. Therefore, runcaciguat might represent a very effective treatment option for CKD/DKD. The potential kidney-protective effects of runcaciguat were investigated in ZSF1 rats as a model of CKD/DKD, characterized by hypertension, hyperglycemia, obesity, and insulin resistance. ZSF1 rats were treated daily orally for up to 12 weeks with runcaciguat (1, 3, 10 mg/kg/bid) or placebo. The study endpoints were proteinuria, kidney histopathology, plasma, urinary biomarkers of kidney damage, and gene expression profiling to gain information about relevant pathways affected by runcacig...

Chronic kidney diseaQueryse (CKD) is associated with oxidative stress which can interrupt the nitric oxide (NO)/soluble guanylyl cyclase (sGC) signaling and decrease cyclic guanosine monophosphate (cGMP) production. Low cGMP concentrations can cause kidney damage and progression of CKD. The novel sGC activator runcaciguat targets the oxidized and heme-free form of sGC, restoring cGMP production under oxidative stress. The purpose of this study is to investigate if runcaciguat could provide an effective treatment for CKD. Runcaciguat was used for the treatment not only in rat CKD models with different etiologies and comorbidities, namely of hypertensive rats, the renin transgenic (RenTG) rat, and angiotensin-supplemented (ANG-SD) rat, but also in rats with diabetic and metabolic CKD, the Zucker diabetic fatty (ZDF) rat. The treatment duration was 2 to 42 weeks and runcaciguat was applied orally in doses from 1 to 10 mg/kg/bid. In these different rat CKD models, runcaciguat significan...

Background and PurposeGeneration of cGMP via NO‐sensitive soluble guanylyl cyclase (sGC) has been implicated in the regulation of renal functions. Chronic kidney disease (CKD) is associated with decreased NO bioavailability, increased oxidative stress and oxidation of sGC to its haem‐free form, apo‐sGC. Apo‐sGC cannot be activated by NO, resulting in impaired cGMP signalling that is associated with chronic kidney disease progression. We hypothesised that sGC activators, which activate apo‐sGC independently of NO, increase renal cGMP production under conditions of oxidative stress, thereby improving renal blood flow (RBF) and kidney function.Experimental ApproachTwo novel sGC activators, runcaciguat and BAY‐543, were tested on murine kidney. We measured cGMP levels in real time in kidney slices of cGMP sensor mice, vasodilation of pre‐constricted glomerular arterioles and RBF in isolated perfused kidneys. Experiments were performed at baseline conditions, under L‐NAME‐induced NO defi...

For another article on a related topic see page 681. Purpose: DLP® hyperspectral imaging is a technology that can be used to construct a highly sensitive, noninvasive, real-time tissue hemoglobin saturation map. This almost video rate technology may be a tool to monitor renal perfusion/ oxygenation during hilar occlusion and kidney recovery. We describe our initial experience using hyperspectral imaging to assess renal hemoglobin saturation parameters during open partial nephrectomy for renal cortical tumors in humans. Materials and Methods: Hyperspectral images were collected intraoperatively during open partial nephrectomy. The kidney was actively illuminated using a hyperspectral imaging camera with visible light consisting of a chemometrically predetermined spectrum (520 to 645 nm) for hemoglobin. Spectroscopic reflectance images were captured by a focal plane array, which were digitally processed to visualize the percent of oxyhemoglobin at each image pixel. Results: Hyperspectral imaging was done in 21 patients with a mean age of 56 years who were undergoing partial nephrectomy. Mean clamp time was 37.0 minutes. Median baseline percent of oxyhemoglobin in all patients was 74.6%. Hyperspectral imaging revealed a median 20.0% decrease from normalized preocclusion baseline at a median 10.3 minutes of hilar occlusion, where it plateaued for the duration of kidney ischemia. Upon reperfusion the percent of oxyhemoglobin returned to baseline at a median of 5.8 minutes. Conclusions: Hyperspectral imaging is a real-time noninvasive method to assess renal oxyhemoglobin saturation intraoperatively throughout the kidney. A nadir percent of oxyhemoglobin is attained within 10 minutes of hilar occlusion. This knowledge may allow future surgical or pharmacological interventions that titrate or minimize ischemic injury in real time.

Recombinant human brain-derived neurotrophic factor (rhBDNF) and neurotrophin 3 (rhNT-3), two recently cloned molecules closely related to nerve growth factor (NGF), were produced from human cDNA expressed in human embryonic kidney cells. The recombinant proteins were tested in cultures of dissociated fetal rat brain cells containing basal forebrain cholinergic neurons. rhBDNF stimulated the differentiation of the cholinergic neurons, similar to NGF, which is well established as a neurotrophic factor for these cells. However, rhBDNF was particularly effective during the first few days in vitro, whereas the stimulatory action of rhNGF was more pronounced later in the development of the cultures. This finding indicates the existence of different time periods of responsiveness of the cholinergic neurons to BDNF and NGF. To assess the selectivity of the effect of rhBDNF on cholinergic neurons, its actions were tested in cultures of ventral mesencephalon containing dopaminergic cells. In...