Search

Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE). All current treatment regimens include oral steroids, which are associated with severe adverse events and long-term damage. We have piloted a steroid-avoiding protocol (rituxilup) for the treatment of biopsy-proven active International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III, IV, or class V LN.We report the findings from the first 50 consecutive patients, treated with 2 doses of rituximab (1 g) and methyl prednisolone (500 mg) on days 1 and 15, and maintenance treatment of mycophenolate mofetil. Patients on maintenance steroids or with life-threatening SLE or requiring dialysis were excluded. Renal remission was defined as serum creatinine no greater than 15% above baseline; complete biochemical remission (CR) was defined as urine protein : creatinine ratio (PCR)50 mg/mmol or partial remission (PR) if PCR50 mg/mmol but non-nephrotic and50% reduction.A total of 45 (90%) patients achieved CR or PR by a median time of 37 weeks (range 4-200). Overall, 72% (n=36) achieved CR (median time 36 weeks (11-58)) and a further 18% (n=9) achieved persistent PR (median time 32 weeks (19-58)). By 52 weeks, CR and PR had been achieved in 52% (n=26) and 34% (n=17) respectively. In all, 12 relapses occurred in 11 patients, at a median time of 65.1 weeks (20-112) from remission. A total of 6/50 patients had systemic flares. Of the 45 responders, only 2 required2 weeks of oral steroids. Adverse events were infrequent; 18% were admitted, 10% for an infective episode.The rituxilup cohort demonstrates that oral steroids can be safely avoided in the treatment of LN. If findings are confirmed, it could mark a step change in the approach to the treatment of LN.

'C3 glomerulopathy' is a recent disease classification comprising several rare types of glomerulonephritis (GN), including dense deposit disease (DDD), C3 glomerulonephritis (C3GN) and CFHR5 nephropathy. These disorders share the key histological feature of isolated complement C3 deposits in the glomerulus. A common aetiology involving dysregulation of the alternative pathway (AP) of complement has been elucidated in the past decade, with genetic defects and/or autoantibodies able to be identified in a proportion of patients. We review the clinical and histological features of C3 glomerulopathy, relating these to underlying molecular mechanisms. The role of uncontrolled C3 activation in pathogenesis is emphasized, with important lessons from animal models. Methods, advantages and limitations of gene testing in the assessment of individuals or families with C3 glomerulopathy are discussed. While no therapy has yet been shown consistently effective, clinical evaluation of agents targeting specific components of the complement system is ongoing. However, limits to current knowledge regarding the natural history and the appropriate timing and duration of proposed therapies need to be addressed.

In renal transplant patients with de novo donor-specific antibodies (dnDSA) we studied the value of microcirculation inflammation (MI; defined by the addition of glomerulitis (g) and peritubular capillaritis (ptc) scores) to assess long-term graft survival in a retrospective cohort study. Out of all transplant patients with standard immunological risk (n = 638), 79 (12.4%) developed dnDSA and 58/79 (73%) had an indication biopsy at or after dnDSA development. Based on the MI score on that indication biopsy patients were categorized, MI0 (n = 26), MI1 + 2 (n = 21) and MI ≥ 3 (n = 11). The MI groups did not differ significantly pretransplantation, whereas posttransplantation higher MI scores developed more anti-HLA class I + II DSA (p = 0.011), showed more TCMR (p

Item does not contain fulltext The Oxford Classification of IgA nephropathy does not account for glomerular crescents. However, studies that reported no independent predictive role of crescents on renal outcomes excluded individuals with severe renal insufficiency. In a large IgA nephropathy cohort pooled from four retrospective studies, we addressed crescents as a predictor of renal outcomes and determined whether the fraction of crescent-containing glomeruli associates with survival from either a >/=50% decline in eGFR or ESRD (combined event) adjusting for covariates used in the original Oxford study. The 3096 subjects studied had an initial mean+/-SD eGFR of 78+/-29 ml/min per 1.73 m2 and median (interquartile range) proteinuria of 1.2 (0.7-2.3) g/d, and 36% of subjects had cellular or fibrocellular crescents. Overall, crescents predicted a higher risk of a combined event, although this remained significant only in patients not receiving immunosuppression. Having crescents in at least one sixth or one fourth of glomeruli associated with a hazard ratio (95% confidence interval) for a combined event of 1.63 (1.10 to 2.43) or 2.29 (1.35 to 3.91), respectively, in all individuals. Furthermore, having crescents in at least one fourth of glomeruli independently associated with a combined event in patients receiving and not receiving immunosuppression. We propose adding the following crescent scores to the Oxford Classification: C0 (no crescents); C1 (crescents in less than one fourth of glomeruli), identifying patients at increased risk of poor outcome without immunosuppression; and C2 (crescents in over one fourth of glomeruli), identifying patients at even greater risk of progression, even with immunosuppression.

FcγRIIb is the sole inhibitory FcR for IgG in humans and mice, where it is involved in the negative regulation of Ab production and cellular activation. FcγRIIb-deficient mice show exacerbated disease following the induction of nephrotoxic nephritis (NTN). In this study, we determined the cellular origin of the FcγRIIb-knockout phenotype by inducing NTN in mice with a deficiency of FcγRIIb on either B cells alone (FcγRIIBfl/fl/CD19Cre+) or myeloid cells (FcγRIIBfl/fl/CEBPαCre+). Deletion of FcγRIIb from B cells did not increase susceptibility to NTN, compared with wild-type (WT) mice, despite higher Ab titers in the FcγRIIBfl/fl/CD19Cre+ mice compared with the WT littermate controls. In contrast, mice lacking FcγRIIb on myeloid cells had exacerbated disease as measured by increased glomerular thrombosis, glomerular crescents, albuminuria, serum urea, and glomerular neutrophil infiltration when compared with WT littermate controls. The role for FcγRIIb expression on radioresistant intrinsic renal cells in the protection from NTN was then investigated using bone marrow chimeric mice. FcγRIIb−/− mice transplanted with FcγRIIb−/− bone marrow were more susceptible to NTN than WT mice transplanted with FcγRIIb−/− bone marrow, indicating that the presence of WT intrinsic renal cells protects from NTN. These results demonstrate that FcγRIIb on myeloid cells plays a major role in protection from NTN, and therefore, augmentation of FcγRIIb on these cells could be a therapeutic target in human Ab-mediated glomerulonephritis. Where there was a lack of FcγRIIb on circulating myeloid cells, expression of FcγRIIb on intrinsic renal cells provided an additional level of protection from Ab-mediated glomerulonephritis.

A novel mechanism in genetically determined P2RX7 levels in macrophages regulates Nlrp3-inflammasome activation and susceptibility to crescentic glomerulonephritis. P2RX7, a mediator of IL-1β and IL-18 processing and release, is a ligand-gated cation channel that is expressed by macrophages. In experimental Crgn, P2RX7 deficiency attenuates renal injury, but the underlying mechanism is unknown. Here, we show that P2RX7 levels and the expression of several genes belonging to the Nlrp3-inflammasome pathway are up-regulated in the macrophages of the WKY rat, a strain uniquely susceptible to macrophage-dependent NTN. Importantly, following P2RX7 activation, WKY BMDMs produce markedly increased levels of active caspase-1, IL-1β, and IL-18 when compared with the NTN-resistant LEW rat BMDMs. P2RX7 and active IL-1β, IL-18, and caspase-1 protein levels were markedly increased in the WKY nephritic glomeruli 4 days following induction of NTN, and the use of a P2RX7 antagonist reduced the levels of secreted active IL-1β. Interestingly, the post-translational control of P2RX7-mediated inflammasome activation is under the genetic regulation of two previously identified Crgn quantitative trait loci in the BMDMs and nephritic glomeruli of the WKY rat. In conclusion, we propose a novel mechanism, whereby genetically determined P2RX7 levels in macrophages regulate Nlrp3-inflammasome activation and susceptibility to Crgn.

Background: There are no prospective randomized controlled trials describing the outcome of acute interstitial nephritis (AIN) treated with steroids, and retrospective studies are limited. Methods: We identified adult patients with a diagnosis of AIN without glomerular pathology over a 14-year period. Treated patients all received oral prednisolone and three also recieved IV methylprednisolone. Data were collected retrospectively on estimated glomerular filtration rate (eGFR), change in eGFR from time of biopsy, dependence on renal replacement therapy (RRT) and mortality, and outcomes were analysed according to the treatment prescribed. Results: A total of 187 eligible patients with AIN were identified and 158 were treated with steroids. There was no difference in median eGFR or dependence on RRT at the time of biopsy. Steroid-treated patients had significantly higher eGFR at all time points post-biopsy up to 24 months, when median eGFR was 43 mL/min in the steroid-treated group and 24 mL/min in the untreated group (P = 0.01). Fewer patients in the steroid-treated group were dialysis dependent by 6 months (3.2% versus 20.6%, P = 0.0022) and 24 months (5.1% versus 24.1%, P = 0.0019). Conclusions: This large retrospective study suggests a benefit of steroids in treatment of AIN with greater improvement in eGFR and fewer patients progressing to end-stage renal disease.

Crescentic glomerulonephritis (CGN), which frequently results in acute and chronic kidney disease, is characterized by and dependent on glomerular infiltration by macrophages. The mannose receptor (MR) is a pattern recognition receptor implicated in the uptake of endogenous and microbial ligands by macrophages, mesangial cells (MCs), and selected endothelial cells. It is upregulated on alternatively activated macrophages (i.e., macrophages associated with tissue repair and humoral immunity) and involved in antigen presentation to T cells. We used the mouse model of nephrotoxic nephritis to investigate the role of MR in CGN. Our results demonstrate what we believe to be a novel role for MR in the promotion of CGN that is independent of adaptive immune responses. MR-deficient (Mr-/-) mice were protected from CGN despite generating humoral and T cell responses similar to those of WT mice, but they demonstrated diminished macrophage and MC Fc receptor-mediated (FcR-mediated) functions, including phagocytosis and Fc-mediated oxygen burst activity. Mr-/- MCs demonstrated augmented apoptosis compared with WT cells, and this was associated with diminished Akt phosphorylation. Macrophage interaction with apoptotic MCs induced a noninflammatory phenotype that was more marked in Mr-/- macrophages than in WT macrophages. Our results demonstrate that MR augments Fc-mediated function and promotes MC survival. We suggest that targeting MR may provide an alternative therapeutic approach in CGN while minimizing the impact on adaptive immune responses, which are affected by conventional immunosuppressive approaches.

Objectives. The aim was to investigate whether the signalling lymphocyte activation molecule (SLAM) signalling pathways contribute to LN and whether SLAM receptors could be valuable biomarkers of disease activity. Methods. Peripheral blood mononuclear cells from 30National Research Ethics Service SLE patients with biopsy-proven LN were analysed by flow cytometry. Clinical measures of disease activity were assessed. The expression of the SLAM family receptors on T-cell subpopulations [CD4, CD8 and double negative (DN) T cells] was measured and compared between lupus patients with active renal disease and those in remission. Results. The frequency of CD8 T cells expressing SLAMF3, SLAMF5 and SLAMF7 was significantly lower in LN patients who were in remission. In contrast, these subsets were similar in patients with active renal disease and in healthy individuals. Patients with active nephritis had an increased percentage of circulating monocytes, consistent with a potential role played by these cells in glomerular inflammation. Changes in the frequency of DN T cells positive for SLAMF2, SLAMF4 and SLAMF7 were observed in lupus patients irrespective of the disease activity. We detected alterations in the cellular expression of the SLAM family receptors, but these changes were less obvious and did not reveal any specific pattern. The percentage of DN T cells expressing SLAMF6 could predict the clinical response to B-cell depletion in patients with LN. Conclusion. Our study demonstrates altered expression of the SLAM family receptors in SLE T lymphocytes. This is consistent with the importance of the SLAM-associated pathways in lupus pathogenesis.

Renal pathologists and nephrologists met on February 20, 2015 to establish an etiology/pathogenesis-based system for classification and diagnosis of GN, with a major aim of standardizing the kidney biopsy report of GN. On the basis of etiology/pathogenesis, GN is classified into the following five pathogenic types, each with specific disease entities: immune-complex GN, pauci-immune GN, antiglomerular basement membrane GN, monoclonal Ig GN, and C3 glomerulopathy. The pathogenesis-based classification forms the basis of the kidney biopsy report. To standardize the report, the diagnosis consists of a primary diagnosis and a secondary diagnosis. The primary diagnosis should include the disease entity/pathogenic type (if disease entity is not known) followed in order by pattern of injury (mixed patterns may be present); score/grade/class for disease entities, such as IgA nephropathy, lupus nephritis, and ANCA GN; and additional features as detailed herein. A pattern diagnosis as the sole primary diagnosis is not recommended. Secondary diagnoses should be reported separately and include coexisting lesions that do not form the primary diagnosis. Guidelines for the report format, light microscopy, immunofluorescence microscopy, electron microscopy, and ancillary studies are also provided. In summary, this consensus report emphasizes a pathogenesis-based classification of GN and provides guidelines for the standardized reporting of GN.

BACKGROUND AND OBJECTIVES: For many women pregnancy is the first contact with health services, thus providing an opportunity to identify renal disease. This study compares causes and long-term renal outcomes of biopsy-proven renal disease identified during pregnancy or within 1 year postpartum, with nonpregnant women.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Native renal biopsies (1997-2012), in women of childbearing age (16 to RESULTS: One hundred and seventy-three pregnancy-related biopsies (19 antenatal, 154 postpregnancy) were identified and matched with 1000 controls. FSGS was more common in pregnancy-related biopsies (32.4%) than controls (9.7%) (PCONCLUSIONS: Pregnancy is an opportunity to detect kidney disease. FSGS is more common in women who have been pregnant than in controls, and disease identified in pregnancy or within 1 year postpartum is more likely to show a subsequent decline in renal function. Further work is required to determine whether pregnancy initiates, exacerbates, or reveals renal disease.

Background: Immunoglobulin M (IgM) nephropathy is an idiopathic glomerulonephritis characterized by diffuse mesangial deposition of IgM. IgM nephropathy has been a controversial diagnosis since it was first reported, and there are few data identifying specific pathological features that predict the risk of progression of renal disease. Methods: We identified 57 cases of IgM nephropathy among 3220 adults undergoing renal biopsy at our institution. Biopsies had to satisfy the following three criteria to meet the definition of IgM nephropathy in this study: (i) dominant mesangial staining for IgM, (ii) mesangial deposits on electron microscopy (EM) and (iii) exclusion of systemic disease. Results: The median age was 42 years and 24 patients were male. Thirty-nine per cent of patients presented with the nephrotic syndrome, 49% presented with non-nephrotic proteinuria and 39% had eGFR

Summary What is known and Objective: Rifampicin (RIF) shows wide variability in its pharmacokinetics. The purpose of this study was to develop and validate a population pharmacokinetic model to characterize the inter- and intra-individual variability in pharmacokinetic parameters of RIF in Mexican patients. Methods: Ninety-four patients receiving antituberculosis therapy participated in this prospective study. Plasma concentration-time data were described using a one-compartment model with lag time, absorption and first-order elimination. The potential influence of demographic and clinical characteristics of the patients, and the pharmaceutical formulation (A, B, C and D) on the pharmacokinetics parameters, was evaluated by non-linear mixed-effect modelling (nonmem). Seventy-seven additional patients participated in the validation of the model. Results and Discussion: The final population pharmacokinetic model obtained was as follows: apparent clearance CL/F = 8·17 L/h (1·40 as high for males), apparent distribution volume Vd/F = 50·1 L (1·29 as high for males), absorption rate constant KaA = 0·391/h, KaB,C,D = 2·70/h, relative bioavailability FA = 0·468, FB,C,D = 1, lag time in the absorption phase Tlag = 0·264 h. The final model improved the precision on the parameter estimates (CL/F, Vd/F and Ka by 31·9%, 16·7% and 92·9%, respectively). The residual variability was 27·3%. What is new and Conclusion: Gender was associated with changes in CL/F and Vd/F whereas the pharmaceutical formulation was associated with changes in F and altered the Ka. The validation data set showed that the model could be used in clinical practice for Bayesian dose adjustment of RIF in TB patients.

BACKGROUND Chronic antibody-mediated rejection is an important cause of late graft failure. Developing an early marker of the disease may allow diagnosis and treatment before irreversible graft damage has occurred. The aim of this study was to assess whether, on electron microscopy examination, peritubular capillary (PTC) basement membrane multilayering precedes and predicts the development of transplant glomerulopathy (TG). METHODS We used a vintage matched case-control method. Sixteen case-control pairs were created among all renal transplant patients from October 2005. Cases were patients who developed TG, and controls were patients with a late (>36 months) posttransplant (indication or surveillance) biopsy without TG. Electron microscopy was carried out on a biopsy taken earlier in the posttransplantation period for both cases and controls. RESULTS For every additional PTC of 25 examined with three or more layers in the early biopsy, the risk of having TG in the later biopsy was increased by 1.4-fold (95% confidence interval, 1.1-1.9; P=0.015). For every PTC of 25 with five or more layers, the risk was increased by 1.6-fold (95% confidence interval, 1.0-2.7; P=0.063). Thus, the risk of future TG increased substantially with every additional PTC of 25 showing multilayering in the early biopsy. CONCLUSIONS Peritubular capillary basement membrane multilayering on electron microscopy is a useful marker of early chronic antibody-mediated damage, and information can be obtained by assessing PTC with three to four layers of basement membrane in addition to those with five or more layers. This finding must be validated in a prospective study.

The association between systemic lupus erythematosus (SLE) and cardiovascular events is well established in epidemiologic studies. In particular, results have shown a substantial increase in angina and myocardial infarction in patients with SLE (1). Imaging studies have shown an increased prevalence of carotid plaque and coronary calcification in patients with SLE, suggesting that there is an accelerated burden of atherosclerosis in these patients (2, 3). Given the inflammatory nature of atherosclerosis, the acceleration of disease in the presence of SLE is perhaps not surprising. However, the exact underlying mechanisms involved are still poorly defined. Studies utilizing murine models of atherosclerosis in combination with a lupus-like disease have been reported (4–8). Accelerated atherosclerosis has been described in apolipoprotein E (ApoE)–deficient mice with either the gld or lpr mutation (4, 6, 8), and in bone marrow chimeras of gld mice transplanted into low-density lipoprotein (LDL) receptor–deficient (Ldlr−/−) mice (gld→Ldlr−/−) (7). Radiation chimeras using the triple-congenic lupus mouse strain B6.Sle1.2.3 transplanted into Ldlr−/− mice (Sle1.2.3→Ldlr−/−) also showed increased atherosclerosis, which was thought to be due to systemic activation of B and T cells (5). As immune complex (IC) formation is a feature of SLE, it seems logical to suppose that accelerated atherosclerosis in SLE could be attributed to increased IC deposition within the arterial walls, with subsequent activation of complement. However, there is no experimental evidence to support this hypothesis. Hypocomplementemia has been linked to defective clearance of apoptotic cells (9), which is considered to be a key pathogenetic mechanism in the development of both lupus and atherosclerosis (4). Acceleration of murine atherosclerosis attributed to accumulation of apoptotic cells within atherosclerotic lesions has been described in the context of deficiency of complement C1q (10), Mer receptor tyrosine kinase (11, 12), and lactadherin (13). A lupus-like phenotype associated with defective uptake of apoptotic cells has also been demonstrated in these mice (9, 14, 15). Even though all these findings indicate that synergistic mechanisms may operate in both conditions, whether the same pathways lead to an accelerated development of atherosclerosis and increased renal damage remains to be elucidated. Herein we describe a novel mouse model of lupus and atherosclerosis (Sle16.Ldlr−/−) generated by crossing Ldlr−/− mice with the congenic line Sle16 (16). The Sle16 line carries, on chromosome 1, an interval originating in the 129 mouse strain, and these mice develop autoantibodies and mild renal inflammation with IC deposition without proteinuria (16). We observed that both nephritis and atherosclerosis were accelerated in the Sle16.Ldlr−/− mice, suggesting that synergistic interactions take place between systemic immune dysregulation and dyslipidemia. Importantly, our data indicate that distinct complement-related mechanisms operate in the kidney when compared to the arterial walls.

Since 1990, walleyes Sander vitreus in Lake Erie have been tagged annually with jaw tags to better understand the population dynamics and ecological characteristics of individual spawning populations. Although the data collected from this tagging program have been used for a variety of management purposes (e.g., estimating migration patterns, stock intermixing, and mortality rates), there has been only cursory examination of the shedding and reporting rates associated with the program. We used double tagging and high-reward tagging experiments to estimate tag shedding and reporting rates for jaw-tagged walleyes in Lake Erie. Double tagging of walleyes with jaw and passive integrated transponder (PIT) tags suggested that the tagging method and tagging agency contributed to the observed variability in both immediate (within 21 d of tagging) retention and chronic jaw tag shedding rates. Agency-specific model-averaged estimates of immediate tag retention ranged from 95% to 99%. For chronic shedding, ...

The role of the complement system in renal disease has long been recognized, but there have been major advances in our understanding of its role over the past decade. Complement plays a critical role not only in host's defense against infection and preventing damage to "self" tissues but also mediates tissue injury, both in the glomerulus and tubulointerstitium. Although injury may originate in the glomerulus, resulting proteinuria and complement activation within the tubular lumen may lead to tubulointerstitial damage and progressive renal disease. Recent advances in our understanding of the mechanisms by which complement mediates renal injury have led to the development of promising strategies with which complement may be targeted to prevent renal injury and its associated complications.

Background: Fc receptor-mediated macrophage activation is a major cause of glomerular damage in crescentic glomerulonephritis. Results: We investigated the role of a novel rat Fc receptor, Fcgr3-rs, in human and rat macrophage activation. Conclusion: We showed that this receptor prevents the cell signaling of its paralogue (Fcgr3). Significance: These results provide a novel way to inhibit Fc receptor-mediated cell activation in macrophages., Crescentic glomerulonephritis (Crgn) is a complex disease where the initial insult is often the glomerular deposition of antibodies against intrinsic or deposited antigens in the glomerulus. The role of Fc receptors in the induction and progression of Crgn is increasingly recognized, and our previous studies have shown that copy number variation in Fcgr3 partially explains the genetic susceptibility of the Wistar-Kyoto (WKY) rat to nephrotoxic nephritis, a rat model of Crgn. The Fcgr3-related sequence (Fcgr3-rs) is a novel rat-specific Fc receptor with a cytoplasmic domain 6 amino acids longer than its paralogue, Fcgr3. The Fcgr3-rs gene is deleted from the WKY rat genome, and this deletion is associated with enhanced macrophage activity in this strain. Here, we investigated the mechanism by which the deletion of Fcgr3-rs in the WKY strain leads to increased macrophage activation. By lentivirus-mediated gene delivery, we generated stably transduced U937 cells expressing either Fcgr3-rs or Fcgr3. In these cells, which lack endogenous Fcgr3 receptors, we show that Fcgr3-rs interacts with the common Fc-γ chain but that Fc receptor-mediated phagocytosis and signaling are defective. Furthermore, in primary macrophages, expression of Fcgr3-rs inhibits Fc receptor-mediated functions, because WKY bone marrow-derived macrophages transduced with Fcgr3-rs had significantly reduced phagocytic activity. This inhibitory effect on phagocytosis was mediated by the novel cytoplasmic domain of Fcgr3-rs. These results suggest that Fcgr3-rs may act to inhibit Fcgr3-mediated signaling and phagocytosis and could be considered as a novel mechanism in the modulation of Fc receptor-mediated cell activation in autoimmune diseases.

As the cultural and A linguistic diversity of U.S. schoolchildren grows and as federal legislation mandates greater accountability in school districts, states are feeling a sense of urgency to support successful outcomes for English learners. Over 5 million students are learning English in America's public schools, accounting for more than 10% of the K-12 population. That's an increase of over 50% in the last decade alone. This demographic change has been matched by changes in national policy. Before No Child Left Behind, states set their own accountability policies. Now, they must demonstrate that English learners are making progress in English and achieving challenging academic content standards. When the Elementary and Secondary Education Act (ESEA) is reauthorized, it will likely continue the trend of establishing and meeting explicit expectations for this growing population. Assuring that English learners succeed has proven to be much more challenging than most educators assumed. The challenge appears to be rooted in what it means to "learn English" in school. Academically successful English learners do not simply learn to manage their everyday lives in English-speaking contexts; rather, they learn to negotiate multiple academic environments, make sense of complex content, articulate their understanding of that content in academic forms, and assess their own growing understanding. That is, they learn to use "academic languages." Education research describes the language demands English learners face in American schools in terms of the linguistic and literacy skills associated with core academic subject areas (Anstrom et al., 2010). These skills involve more than specialized, content-specific vocabulary. Proficient use of English in science class, for example, involves the ability to communicate scientifically. That is, English used in science classrooms draws on vocabulary, grammar, and discourse unique to science. For example, scientists seek to be objective. They often use the passive voice in their writing and speaking. For example, rather than stating what a plant root or leaf does (active voice), a biology teacher is more likely to describe a general process through which water and nutrients are absorbed by root systems and are transported to leaves where carbohydrates and sugars are produced (passive voice). Why? Because the passive voice suggests distance or objectivity. Similarly, each academic discipline uses specialized vocabulary, grammatical structures, and discourse features. All students must learn to speak, write, and think in these specialized ways, but the journey for English learners is longer and more difficult. In this article, we share findings about the journey to English proficiency for English learners and offer insights on how to establish clear expectations for English learners and their schools. We address the relationship between academic language and academic content proficiency, the rate at which English learners acquire academic English, and the time needed for English learners to become English proficient. Specifically, we focus on two questions: * What does it mean to be "English proficient?" * How long does it take English learners to reach this status? There isn't enough good research in this area to give clear answers to those who teach English learners, but some studies provide valuable insights. Also helpful are discoveries from the World-Class Instructional Design and Assessment Consortium (WIDA), a 27-state alliance that shares English language proficiency standards and assessments, and engages in research and professional development. Federal policy The English that teachers speak with students in the classroom is different from the English spoken on the playground, in the mall, or at home. English used in informal settings has less complex grammatical forms, few uses of technical vocabulary, frequent use of slang and idioms, frequent cultural and contextual references, and a much more personal sense. …

Background. Experimental autoimmune glomerulonephritis (EAG) can be induced in Wistar–Kyoto (WKY) rats by immunization with the recombinant NC1 domain of the alpha 3 chain of type IV collagen [a3(IV)NC1]. EAG is characterized by circulating and deposited anti-a3(IV)NC1 antibodies, accompanied by focal necrotizing glomerulonephritis with crescent formation. Programmed death-1 (PD-1) receptor is preferentially expressed on activated T cells and binds two known ligands present on antigen presenting cells, PDL-1 and PDL-2. Engagement of PD-1 by its ligands results in a negative regulatory effect, with inhibition of downstream cellular signalling events and diminished cellular proliferation. Methods. In order to investigate the role of the PD-1/PDL-1 co-inhibitory pathway in development of EAG, the in vivo effects of a stimulating PDL-1/Fc fusion protein were examined after the onset of disease. Results. Stimulation of PD-1 led to a significant reduction in albuminuria, serum urea, serum creatinine, crescent formation and tubular damage compared with controls. There was also a reduction in numbers of glomerular macrophages, CD41 T cells, CD81 T cells and PD11 cells compared with controls. No reduction was observed in levels of circulating or deposited antibodies. Conclusions. These results demonstrate that PDL-1/Fc fusion protein is effective in treatment of glomerulonephritis and confirm the importance of the PD-1/PDL-1 T-cell coinhibitory pathway in development of EAG. Strategies designed to stimulate this pathway may provide a novel approach to treatment of human glomerulonephritis.

One of the mandates of the No Child Left Behind Act is that states show adequate yearly progress in their English language learners’ (ELLs) acquisition of English language proficiency. States are required to assess ELLs’ English language proficiency annually in four language domains (listening, reading, writing, and speaking) to measure their progress; they are also required to report on a composite comprehension measure. Often the clearest way to effectively monitor students’ progress is to measure assessment results across grades on the same scale. In measurement terms, scores from tests across all grade levels can be put on the same scale using vertical scaling. In addition, to help stakeholders understand and interpret the results, these scale scores are often interpreted in terms of proficiency levels. In this article, we use the vertical scaling of WIDA ACCESS for ELLs®, a large-scale K-12 Academic English Language Proficiency assessment to illustrate measurement and practical issues involved in this technique. We first give background on the need for vertical scaling. We then assess the literature on vertical scaling and describe the procedures used for WIDA ACCESS for ELLs® to vertically scale test scores and interpret the results in terms of the WIDA ACCESS for ELLs® Proficiency Scale. Next we review several studies that have been conducted to gauge the effectiveness of that scaling. We end the paper with a discussion of the broad issues that arise from vertical scaling.

There is an intimate association between complement dysregulation and glomerular pathology. Here we summarise the recent progress.C3 glomerulopathy has been introduced as a term that encompasses glomerular pathology characterised by isolated C3 deposition. The prototypic example of C3 glomerulopathy is dense deposit disease (DDD). Characterisation of a mutant C3 molecule in familial DDD has reinforced the concept that this condition results from systemic C3 dysregulation. Complement factor H-related 5 (CFHR5) nephropathy is the most recently described C3 glomerulopathy. Its characterisation supports a biological role for CFHR5 on complement regulation within the kidney. Atypical haemolytic uraemic syndrome (aHUS) is strongly associated with genetic defects in complement regulation. Animal model data indicate that the critical step in the development of renal thrombotic microangiopathy in this syndrome is activation of complement C5. Importantly, there are now many reports of the successful use of a monoclonal anti-C5 antibody therapy (eculizumab) in this syndrome and clinical trials are in progress. Intriguingly, animal model data have demonstrated a critical role for C5 activation in pauci-immune glomerulonephritis.C5 inhibition appears to be effective therapy for aHUS. An important unresolved question is the role of C5 inhibition in C3 glomerulopathies.

Total deficiency of complement factor H (CFH) is associated with dense deposit disease (DDD) and atypical haemolytic uraemic syndrome (aHUS). CFH is the major regulator of the alternative pathway of complement activation and its complete deficiency results in uncontrolled C3 activation through this pathway and secondary C3 deficiency. Plasma infusion, as a source of CFH, has been used with variable success to treat renal disease associated with CFH deficiency. However, the risks of volume and protein overload limit this therapeutic approach. In this study, we investigated the efficacy of a purified human CFH (hCFH) preparation in Cfh-gene knockout mice. These mice spontaneously develop both secondary plasma C3 deficiency and renal abnormality characterised by massive deposition of C3 along the glomerular basement membrane. The renal lesion is analogous to human dense deposit disease. Treatment of knockout mice with hCFH resulted in rapid normalization of plasma C3 levels and resolution of the glomerular basement membrane C3 deposition. Long-term assessment of mice with hCFH was not possible because of the development of an immune response against hCFH. Hence, we suggest that hCFH can be an effective alternative therapy to plasma infusions in patients with renal disease associated with CFH deficiency.

Several distinct pathological patterns of glomerular inflammation are associated with abnormal regulation of the complement system, specifically, with dysregulation of the alternative pathway of the complement system. However, these conditions share the pathological finding of complement C3 (C3) deposited within the glomerulus in the absence of substantial immunoglobulin. This finding has alerted us and others to the possible presence of genetic and acquired complement dysregulation in individual patients. This article summarizes our current understanding of the relationship between dysregulation of the complement system and glomerular inflammation. Here, we suggest that glomerular pathologies that are characterized by the isolated deposition of C3 could usefully be classified by the term C3 glomerulopathy. In our view, this classification would alert the pathologist and nephrologist to the importance of screening for acquired and genetic abnormalities in complement regulation. In the future, it could help to identify individuals who might benefit from therapeutic inhibition of the complement system.

The 129-derived Sle16 is a susceptibility locus for systemic autoimmunity when present on the C57BL/6 (B6) background. Genetic analysis of a (129×B6)F2 cross identified a region from the B6 chromosome 3 (Sle18) with positive linkage to antinuclear Abs. In this study, we have generated a B6 congenic strain harboring the 129 allele of Sle18 and intercrossed this line with the lupus-prone B6.129-Sle16 strain. The presence of the 129-Sle18 allele in the B6.129-Sle16Sle18 double congenic mice suppressed the development of Sle16-mediated autoantibody production and ameliorated the renal pathology. The 129-Sle18 locus rectified the B cell abnormalities detected in the B6.129-Sle16 mice, such as the reduction in the percentage of marginal zone B and B1a cells and the increased number of germinal centers. The B6.129-Sle16Sle18 spleens still displayed an increased percentage of activated T and B cells. However, in the B6.129-Sle16Sle18 strain the percentage of naive T cells was equivalent to that in B6.129-Sle18 and B6 mice and these cells showed a reduced proliferative response to anti-CD3 stimulation compared with B6.129-Sle16 T cells. There was a significant increase in the percentage of CD4+FoxP3+regulatory T cells in all congenic strains. These cells had normal regulatory function when tested in vitro. Thus, 129-Sle18 represents a novel, non-MHC lupus-suppressor locus probably operating as a functional modifier of B cells that, in combination with other factors, leads to lupus resistance. Further characterization of this locus will help to uncover the immune mechanism(s) conferring protection against lupus.

Factor H is an important regulator of complement activation in plasma and on cell surfaces in both humans and mice. If FH function is compromised, inappropriate complement activation on self-surfaces can have disastrous effects as seen in the kidney diseases atypical haemolytic uremic syndrome (aHUS) and C3 glomerulopathy. As FH constructs have been proposed to be used in treatment for these diseases, we studied the distribution of exogenous FH fragments in mice. Full-length mFH, mFH1-5 and mFH18-20 fragments were radiolabelled, and their distribution was examined in WT, FH-/- and FH-/- C3-/- mice in vivo. Whole body scintigraphy revealed accumulation of radioactivity in the abdominal part of the mice, but also to the thyroid gland and urinary bladder. At organ level in WT mice, some full-length FH accumulated in internal organs, but most of it remained in the circulation. Both of the mFH fragments accumulated in the kidneys and were excreted in urine. For mFH1-5, urinary secretion is the likely cause for the accumulation. Concentration of mFH18-20 to kidneys was slower, and at tissue level, mFH18-20 was localized at the proximal tubuli in WT and FH-/- C3-/- mice. No C3-independent binding to glomeruli was detected. In conclusion, these results show that glomerular glycosaminoglycans and sialic acids alone do not collect FH in kidneys. Deposition of C3 fragments is also needed, which implies that in aHUS, the problem is in simultaneous recognition of C3 fragments and glycosaminoglycans or sialic acids by FH, not just the inability of FH to recognize glomerular endothelium as such.

Antibody-mediated glomerulonephritis, including that resulting from immune complexes, is an important cause of renal failure and is in need of more specific and effective treatment. Binding of antibody or immune complexes to Fc receptors activates intracellular signal transduction pathways, including spleen tyrosine kinase (Syk), leading to the production of inflammatory cytokines. We examined the effect of R788 (fostamatinib disodium), an oral prodrug of the selective Syk inhibitor R406, in nephrotoxic nephritis in Wistar-Kyoto rats. Treatment with R788 reduced proteinuria, tissue injury, glomerular macrophage and CD8+ cell numbers, and renal monocyte chemoattractant protein-1 (MCP-1) and IL-1beta, even when we started treatment after the onset of glomerulonephritis. When we administered R788 from days 4 to 10, glomerular crescents reduced by 100% (P < 0.01) compared with the vehicle group. When we administered R788 treatment from days 7 to 14, established glomerular crescents reversed (reduced by 21%, P < 0.001), and renal function was better than the vehicle group (P < 0.001). In vitro, R406 downregulated MCP-1 production from mesangial cells and macrophages stimulated with aggregated IgG. These results suggest that Syk is an important therapeutic target for the treatment of glomerulonephritis.

CASE PRESENTATION A 42-year-old Indo-Asian woman presented to her local emergency department with a 1-week history of joint pains, fatigue, and episodic macroscopic hematuria. She was prescribed oral cephalexin and analgesia for a presumed urinary tract infection. Subsequently, she developed a skin rash, leg edema, and recurrent epistaxis, prompting withdrawal of her antibiotics. Her condition failed to improve over the ensuing week, and on return to the emergency department, she was found to have developed progressive edema, hematuria, and proteinuria on urine dipstick testing. Blood tests showed a rise in the serum creatinine over 1 week from 114 to 240 μmol/l. The patient was transferred to our renal unit for further investigation and management.

Maturation schedules, key determinants of fish stocks' harvest potential and population dynamics, are influenced by both plastic and adaptive processes. Various indices are used to describe maturation schedules, and these have differential advantages for discriminating between plastic and adaptive processes. However, potential sampling-related biases associated with different maturation indices have not been fully evaluated. We analyzed three maturation indices for walleyes Sander vitreus in Lake Erie; Saginaw Bay, Lake Huron; and Oneida Lake, New York: age and length at 50% maturity, midpoint of age-specific maturity ogives (age-specific length at which probability of maturity = 0.50), and midpoints of probabilistic maturation reaction norms (PMRNs; age-specific length at which probability of maturing in the following year = 0.50). We then compared estimated maturation indices to evaluate sensitivity of different maturation indices to sampling-induced biases and to assess the relative importance...

We report the case of a 59-year-old woman who presented with a persistent papular and nodular cutaneous eruption and new-onset asthma, with normal renal function but persistent haematuria and proteinuria. Investigations revealed eosinophilia, both antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibodies on serological testing (double-positive vasculitis), and a focal necrotizing glomerulonephritis on renal biopsy. Histological examination of a skin biopsy showed a dense neutrophilic infiltrate with focal fibrinoid necrosis and few eosinophils. The clinical and pathological features suggested a double-positive vasculitis/Churg-Strauss overlap syndrome presenting with a predominantly neutrophilic dermatosis. Specific cutaneous features in patients with double-positive vasculitis have not been documented previously. The patient has responded extremely well to immunosuppressive treatment and her disease is currently in remission.

Familial lecithin:cholesterol acyltransferase deficiency (FLD) is a monogenic autosomal recessive condition, affecting cholesterol esterification and leads to progressive renal impairment and end-stage renal failure, probably due to the abnormal lipoprotein (X) (Lp(X)). We report a case of FLD, whom we treated with a combination of nicotinic acid 1.5g nocte and fenofibrate M/R 160mg od and report changes in lipid profile and Lp(X), after six weeks and serum creatinine and urine albumin/creatinine ratio after 12 months. We assessed the cardiovascular risk using electron beam computed tomography. At baseline total cholesterol was 6.61mmol/L; HDL cholesterol 0.57mmol/L; Lp(X) cholesterol 3.24mmol/L; triglyceride 4.13mmol/L; apolipoprotein A1 46mg/dL; and apolipoprotein B 53mg/dL. After six weeks of treatment his total cholesterol was 4.16; HDL cholesterol 0.52; Lp(X) cholesterol 1.73mmol/L; triglyceride 1.80mmol/L; apolipoprotein A1 36mg/dL; and apolipoprotein B 50mg/dL. Baseline serum creatinine was 106micromol/L and urine albumin/creatinine ratio was 127.3mg/mmol and after 12 months was 101micromol/L and 31.5mg/mmol respectively. His coronary artery calcification score was zero. We have shown, we believe for the first time, that combination lipid modifying therapy in FLD leads to a reduction in Lp(X) concentration and an associated reduction in urine albumin excretion at 12 months.

Dense deposit disease (DDD) is strongly associated with the uncontrolled activation of the complement alternative pathway. Factor H (CFH)-deficient (Cfh(-/-)) mice spontaneously develop C3 deposition along the glomerular basement membrane (GBM) with subsequent development of glomerulonephritis with features of DDD, a lesion dependent on C3 activation. In order to understand the role of CFH in preventing renal damage associated with the dysregulation of the alternative pathway we administered purified mouse CFH (mCFH) to Cfh(-/-) mice. 24h following the administration of mCFH we observed an increase in plasma C3 levels with presence of intact C3 in circulation showing that mCFH restored control of C3 activation in fluid phase. mCFH resulted in the reduction of iC3b deposition along the GBM. The exogenous mCFH was readily detectable in plasma but critically not in association with C3 along the GBM. Thus, the reduction in GBM C3 was dependent on the ability of mCFH to regulate C3 activation in plasma. Western blot analysis of glomeruli from Cfh(-/-) mice demonstrated the presence of iC3b. Our data show that the C3 along the GBM in Cfh(-/-) mice is the C3 fragment iC3b and that this is derived from plasma C3 activation. The implication is that successful therapy of DDD is likely to be achieved by therapies that inhibit C3 turnover in plasma.

To provide a review and discussion of histological prognostic indicators in immunoglobulin A (IgA) nephropathy (IgAN).A variety of histological parameters and classifications have been used to attempt to predict prognosis in patients with IgAN. Grading systems used thus far do not consistently provide a useful adjunct to clinical prognostic parameters. This may be due to the variety of grading systems used, to inconsistent patient recruitment processes, and to the use of actuarial renal survival as an end point. This has led to the development of a new IgAN classification proposal by the International IgA Nephropathy Network in conjunction with the Renal Pathological Society. Additional potential markers of disease progression currently under investigation include glomerular parameters such as number and size, markers of podocyte function and of complement activation, inflammatory infiltrates and mediators of tubulointerstitial fibrosis.There is a need for an internationally accepted, reproducible and clinically meaningful pathological classification of IgAN. Such a classification is currently being developed. By using only reproducible, single parameters and validating them on a large group of cases from all over the world, it is hoped that a useful clinically predictive tool will be developed.

Dendritic cells (DCs) are known to produce C1q, the initiator of the classical complement pathway. We demonstrate that murine DCs deficient in C1q (C1qa−/−) are poorer than wild-type (WT) DCs at eliciting the proliferation and Th1 differentiation of antigen-specific T cells. These defects result from decreased production of IL-12p70 by C1qa−/− DCs and impaired expression of costimulatory molecules CD80 and CD86 in response to CD40 ligation. The defective production of IL-12p70 and the reduced expression of CD80 and CD86 by C1qa−/− DCs were specifically mediated via CD40 ligation, as normal levels of IL-12p70 and CD80/86 were observed after ligation of Toll-like receptors (TLRs) on C1qa−/− DCs. CD40 ligation on C1qa−/− DCs, but not TLR ligation, results in decreased phosphorylation of p38 and ERK1/2 kinases. A strong colocalization of CD40 and C1q was observed by confocal microscopy upon CD40 ligation (but not TLR ligation) on DCs. Furthermore, human DCs from 2 C1q-deficient patients were found to have impaired IL-12p70 production in response to CD40L stimulation. Our novel data suggest that C1q augments the production of IL-12p70 by mouse and human DCs after CD40 triggering and plays important roles in sustaining the maturation of DCs and guiding the activation of T cells.

Synthetic diets prepared by Ralston Purina, and commercial pet foods were fed to brown shrimp (Penaeus aztecus) in replicated, 30-day feeding trials under controlled environmental conditions. A number of Ralston Purina diets were evaluated for palatability. Postlarval hatchery-raised shrimp and larger stock obtained from the bays were used. Individual lengths and weights of those animals stocked and harvested were used to statistically develop averages from which growth rate, survival, food conversion, and condition index were calculated. Growth rates were found to be related to the size of shrimp, feeding rate, protein content and available metabolizable energy. Survival was found to be related to food availability, disease, and the diet fed. Food conversion was related to the diet requirements of the shrimp and the feeding rate. The condition index was not related to diet and was descriptive of the intermolt stage of the individuals only. As postlarvae, brown shrimp were able to utilize a 45% protein diet effectively when fed at 10% of body weight per day. Development into juveniles changed the relative importance of protein and metabolizable energy in the diet with an accompanying reduction in the food conversion. The growth rates measured in these tests were about half of those measured in the natural habitat and in ponds with supplemental feeding.

BACKGROUND ABO incompatible (ABOi) live-donor renal transplantation is a successful and accepted form of treatment for patients with renal failure. Although there is significant controversy as to how antiblood group antibodies should be removed and their resynthesis prevented, subsequent immunosuppressive regimes have all involved steroids. We and other groups have successfully used steroid sparing regimes for conventional ABO compatible transplantation and this study describes the use of our steroid sparing protocol in ABOi transplantation. METHODS We have transplanted 10 ABOi patients using 1 week of steroids (prednisolone 1 mg/kg for 4 days, 0.5 mg/kg for 3 days and then stopped), tacrolimus and mycophenolate mofetil. Steroids were reintroduced in the event of rejection. RESULTS Patient- and allograft-survival 1 year posttransplantation is 100%. Three patients experienced antibody-mediated rejection within 2 weeks of transplantation, which was successfully reversed. There has been no late rejection. Allograft function was similar to our live-donor ABO compatible transplant patients receiving a similar steroid sparing regime (12-month mean creatinine 131+/-15 micromol/L vs. 138+/-48 micromol/L; mean CrCl 63.2+/-22 mL/min vs. 56.7+/-20 mL/min). CONCLUSIONS This study shows that ABOi live-donor transplantation can be successfully accomplished using a steroid-sparing protocol.

Objective: Various studies have shown that bone marrow stem cells can rescue mice from acute renal tubular damage under a conditioning advantage (irradiation or cisplatin treatment) favouring donor cell engraftment and regeneration; however, it is not known whether bone marrow cells (BMCs) can contribute to repair of acute tubular damage in the absence of a selection pressure for the donor cells. The aim of this study was to examine this possibility. Materials and methods: Ten‐week‐old female mice were assigned into control non‐irradiated animals having only vehicle treatment, HgCl(2)‐treated non‐irradiated mice, HgCl(2)‐treated non‐irradiated mice infused with male BMCs 1 day after HgCl(2), and vehicle‐treated mice with male BMCs. Tritiated thymidine was given 1 h before animal killing. Results: Donor BMCs could not alleviate non‐irradiated mice from acute tubular damage caused by HgCl(2), deduced by no reduction in serum urea nitrogen combined with negligible cell engraftment. However, donor BMCs could home to the bone marrow and spleen and display proliferative activity. This is the first report to show that despite no preparative myeloablation of recipients, engrafted donor BMCs can synthesize DNA in the bone marrow and spleen. Conclusions: Exogenous BMCs do not rescue non‐irradiated mice from acute renal tubular damage caused by HgCl(2), despite establishment of chimerism and cell proliferation in bone marrow and spleen.

Objective: Our previous studies have demonstrated that endogenous bone marrow cells (BMCs) contribute to renal tubular regeneration after acute tubular injury. The aim of this study was to examine which fraction of BMCs, haematopoietic lineage marrow cells (HLMCs) or mesenchymal stem cells (MSCs), are effective. Materials and methods: Six‐week‐old female mice were lethally irradiated and were transplanted with female enhanced green fluorescent protein‐positive (GFP(+)), plastic non‐adherent marrow cells (as a source of HLMCs) plus cloned cultured male GFP(−) MSCs. Four weeks later, they were assigned into two groups: control mice with vehicle treatment and mice treated with HgCl(2). Tritiated thymidine was given 1 h before animal killing which occurred at intervals over 2 weeks. Kidney sections were stained for a tubular epithelial marker, cell origin indicated by GFP immunohistochemistry or Y chromosome in situ hybridization; periodic acid‐Schiff staining was performed, and samples were subjected to autoradiography. One thousand consecutive renal tubular epithelial cells per mouse, in S phase, were scored as either female (indigenous) GFP(+) (HLMC‐derived) or male (MSC‐derived). Results: Haematopoietic lineage marrow cells and MSCs stably engrafted into bone marrow and spleen, but only HLMC‐derived cells, not MSCs, were found in the renal tubules and were able to undergo DNA synthesis after acute renal injury. A few MSCs were detected in the renal interstitium, but their importance needs to be further explored. Conclusion: Haematopoietic lineage marrow cells, but not cloned cultured MSCs, can play a role not only in normal wear‐and‐tear turnover of renal tubular cells, but also in repair after tubular injury.

Systemic lupus erythematosus (SLE) is an autoimmune disease that displays highly variable clinical features. The serologic hallmark of SLE is the production of autoantibodies directed against a wide spectrum of self antigens, especially nuclear components, such as DNA. Several lines of evidence indicate that both in humans and in animal models, SLE susceptibility is inherited as a multifactorial genetic trait (1). To identify the genetic components of SLE, linkage analyses have been performed in spontaneous lupus–prone mice, and these studies have led to the identification of several genomic intervals (2). Interestingly, a great proportion of the intervals detected are strain-specific, confirming the genetic complexity of the disease and indicating the presence of extensive heterogeneity in the genes that contribute to the pathogenesis of SLE. However, 1 interval, located on the distal region of chromosome 1 in the mouse and on its orthologous region in humans, has shown strong linkage in several human and murine studies (3,4). One of the best characterized loci in this region is Sle1b, which was identified via linkage analysis of the lupus-prone NZM2410 mouse model (5). This locus, when expressed on the C57BL/6 genetic background (B6.Sle1b), can induce a relatively benign autoimmune disease characterized by loss of tolerance to nuclear antigens, an increase in the proportion of activated T cells and B cells, and mild splenomegaly. These features seem to be linked to a specific haplotype of the signaling lymphocytic activation molecule (SLAM)/CD2 family of genes, indicating that these genes might mediate the autoimmune phenotype associated with the Sle1b locus (6,7). However, in the same chromosome 1 region, there are several other candidate genes, such as Apcs, Fcgr2, Cd55, Pdcd1, and Ro antigen. All of these genes were inactivated in 129-derived embryonic stem cells, and the knockout models displayed a variable degree of autoimmunity (8–12). However, the interpretation of the autoimmune phenotype (13) observed in these gene-targeted models has recently been questioned (14). Studies by our group and others (8,15–17) have shown that hybrid strains between 129 and C57BL/6 (B6) mice, commonly used in the generation of gene-targeted mice, are spontaneously predisposed to the development of humoral autoimmunity, with low levels of renal disease. Genome-wide linkage studies conducted on the 129 × B6 hybrid mice identified a strong association between a 129-derived segment on chromosome 1, now named Sle16, and the expression of autoantibodies (14,18). The autoimmune effect of this locus has recently been defined further by the study of B6 subcongenic strains carrying 129 fragments of different lengths (14,19). The analysis of these lines revealed that a 129 interval between 87.9 cM and 100 cM (D1Mit15 and D1Mit115) was sufficient to induce the autoimmune phenotype, and the congenic line carrying this fragment, named B6.129chr1b, was selected for the present study. It is noteworthy that the B6.129chr1b congenic mice mirror the combination of genes created when a gene in this region is targeted on 129 embryonic stem cells and then backcrossed onto the B6 genetic background. Immunoglobulin-transgenic models have been instrumental in understanding B cell regulation, revealing several key mechanisms including receptor editing, deletion, anergy, and ignorance (20–24). Chen et al (25) generated an anti-DNA–knockin model in which the rearranged variable heavy chain (VH) gene of an anti-DNA antibody (VH3H9) was inserted at the Igh locus. This allowed the transgenic locus to undergo normal editing, isotype switching, and somatic mutation. A variety of light chains can combine with the VH3H9 to yield anti-DNA antibodies (26), but only a few light chains are able to “silence” VH3H9 so that it no longer binds to DNA. By virtue of this characteristic, the mice expressing only the VH3H9 chain (VH3H9R mice) can generate anti-DNA specificities. When the VH3H9R mice were crossed with the knockin transgenic light chain Vκ8 mice (27), the antibody generated in the double-transgenic mice (VH3H9R/Vκ8R mice) (28) bound only single-stranded DNA (ssDNA) and not double-stranded DNA (dsDNA) (27). Previous studies with the VH3H9R mice showed that autoreactive transgenic B cells accumulated in the splenic marginal zone and were regulated by anergy in the presence of a nonautoimmune background, such as BALB/c (25,29) and B6 (30,31), but were activated in a model of chronic graft-versus-host disease (30). Similarly, the VH3H9R/Vκ8R-knockin transgenic B cells were regulated by anergy in nonautoimmune disease–prone BALB/c mice, while in autoimmune disease–prone MRL/Mp.lpr/lpr animals, transgenic B cells escaped tolerance induction and underwent class switching and affinity maturation (32). To determine whether the Sle16 locus could influence the selection of self-reactive B cells, we bred the B6.129chr1b mice with the VH3H9R.B6 mice and the VH3H9R/Vκ8R.B6 mice and monitored the regulation and activation of anti-DNA–transgenic B cells over a period of 10 months. A similar analysis was also performed with mice deficient in serum amyloid P component (B6. Apcs−/−), chosen as an example of an autoimmune mouse strain with a targeted deletion of 1 of the candidate genes located within the 129chr1b region. The analysis of these mice showed that hemizygosity of the Sle16 locus was sufficient to impair B cell anergy and to induce class switching and epitope spreading. The immunologic alterations were more pronounced in mice that were homozygous for the Sle16 locus and were similar in the B6. Apcs−/− mice, indicating that the lack of serum amyloid P component had no additional effect on the loss of B cell tolerance.

The role of embryonal or adult stem cells, in particular bone marrow (BM)-derived stem cells, in regenerating the kidney after injury has been the subject of intensive investigation. BM-derived stem cells have been shown to give rise to small numbers of most renal cell types, including tubular cells, mesangial cells, podocytes, vascular cells and interstitial cells. However, the role this infrequent display of BM cell plasticity plays in organ regeneration is less certain. Injections of BM-derived cells do improve renal function in many animal models of renal disease. Current opinion attributes this renoprotective effect mainly to paracrine factors supporting regeneration by local renal cells and to immunomodulatory effects, rather than to transdifferentiation of BM cells into renal cells. Several groups have identified native renal stem cell populations, although their role in renal regeneration has not yet been well defined.

The patient is a 45-yr-old Caucasian man with no significant past medical history, who in December 2006 developed arthralgias affecting both shoulders and hips and subsequently noticed shortness of breath with a cough, and a lower limb rash. These symptoms did not improve with diclofenac or with a course of antibiotic therapy prescribed by his general practitioner. The patient presented to his local hospital when he developed hemoptysis, epistaxis, and sinusitis, as well as a worsening of his shortness of breath, rash. and arthralgias. He had lost 3.5 kg in weight during the course of his illness. He was on no medication except for diclofenac, prescribed in the previous month, and a course of amoxicillin. His family history included rheumatoid arthritis and lung cancer in two family members, both of whom were heavy smokers. He was originally from Ireland but had been living in the United Kingdom for the previous 25 yr. He had a partner and three children and was an ex-smoker. At the local hospital, examination was unremarkable except for a lower limb vasculitic rash. Initial blood tests (Table 1) revealed significant renal impairment with a serum creatinine of 345 μmol/L (normal range 50 to 110 μmol/L) and an acute inflammatory response with a C-reactive protein (CRP) of 204 mg/dl and a serum albumin of 31 g/L. He was treated with antibiotics for a presumed chest infection and with intravenous fluids. On the sixth day of admission, creatinine had increased to 563 μmol/L and he was acidotic with serum bicarbonate 18 mmol/L, at which point he was admitted to the intensive care unit for hemofiltration. Hemoglobin had fallen to 9 from 12 g/L on admission. Further investigations revealed an antineutrophil cytoplasm antibody (ANCA) by immunofluorescence and an anti-PR3 antibody concentration of 728 IU/ml (normal range 0 to 19 …

C1q-deficient mice have been shown to develop a lupus-like disease and to display an impaired clearance of apoptotic cells that are enriched in lupus autoantigens. However, the role of C1q in the regulation of autoreactive B cells remains debatable. To explore this we crossed MRL/Mp C1q-deficient mice with knock-in transgenic (Tg) mice expressing an anti-ssDNA antibody (VH3H9R and VH3H9R/VLkappa8R). Analysis of the VH3H9R mice showed that in the absence of C1q higher titres of Tg-derived IgM and IgG3 anti-ssDNA antibodies were detectable. In contrast, in the VH3H9R/VLkappa8R C1q-deficient animals no increase in Tg antibody levels was observed. In both models the lack of C1q induced a marked reduction of marginal zone B cells and this was paralleled by a significant increase in the percentage of plasmocytes. Thus, one could postulate that in the absence of C1q the failure to clear efficiently dying cells provides an additional stimulus to the autoreactive Tg B cells resulting in their emigration from the marginal zone B cell compartment with subsequent increase in plasmocytes. However, the lack of C1q led to an increased production of Tg IgM and IgG3 antibodies only in VH3H9R mice indicating that additional genetic susceptibility factors are required to break self-tolerance.

Acute renal failure resulting from hypoperfusion and hypoxia is a significant clinical problem. Hypoxia activates the heterodimeric transcription factor hypoxia inducible factor (HIF), leading to changes in gene expression that promote tissue adaptation and survival. To determine whether HIF may protect the kidney from ischemia-reperfusion injury, we subjected hif1a(+/-) and hif2a(+/-) mice to renal ischemia-reperfusion injury. Injury was substantially more severe in hif(+/-) than in littermate controls, consistent with a protective role for HIF. Because wild-type mice exhibited submaximal HIF accumulation in response to no-flow ischemia, we tested compounds that might augment the protective HIF response following ischemia-reperfusion in these animals. We found that l-mimosine and dimethyloxalylglycine, two small molecules that activate HIF by inhibiting HIF hydroxylases, protected mouse kidneys from ischemia-reperfusion injury. Therefore, pharmacological activation of HIF may offer an effective strategy to protect the kidney from ischemic injury.

Alport syndrome (AS) is a hereditary glomerulopathy caused by a mutation in type IV collagen genes, which disrupts glomerular basement membrane, leading to progressive glomerulosclerosis and end-stage renal failure. There is at present no cure for AS, and cell-based therapies offer promise to improve renal function. In this study, we found that human first trimester fetal chorionic stem cells (CSC) are able to migrate to glomeruli and differentiate down the podocyte lineage in vitro and in vivo. When transplanted into 7-week-old Alport 129Sv-Col4α3(tm1Dec)/J (-/-) mice, a single intraperitoneal injection of CSC significantly lowered blood urea and urine proteinuria levels over the ensuing 2 weeks. In addition, nearly two-thirds of transplanted -/- mice maintained their weight above the 80% welfare threshold, with both males and females weighing more than age-matched nontransplanted -/- mice. This was associated with less renal cortical fibrosis and interstitial inflammation compared to nontransplanted mice as shown by reduction in murine CD4, CD68, and CD45.2 cells. Transplanted CSC homed to glomeruli, where they expressed CR1, VEGFA, SYNAPTOPODIN, CD2AP, and PODOCIN at the RNA level and produced PODOCIN, CD2AP, and COLIVα3 proteins in nontransplanted -/- mice, indicating that CSC have adopted a podocyte phenotype. Together, these data indicate that CSC may be used to delay progression of renal pathology by a combination of anti-inflammatory effects and replacement of the defective resident podocytes.

Severe peritubular capillary basement membrane multilayering (PTCBML) is part of the Banff definition of chronic antibody-mediated rejection. We retrospectively investigated whether assessment of the mean number of layers of basement membrane (BM) around peritubular capillaries (PTC) can be used in a cohort of patients with de novo donor-specific antibodies (dnDSA) as an early marker to predict long-term antibody-mediated injury. This is a retrospective cohort study with 151 electron microscopy samples from 54 patients with dnDSA, assessed at around 1 year after transplantation, for a mean number of BM layers around PTC and in serial biopsies. Graft survival and time to transplant glomerulopathy (TG) development were estimated in survival analyses. We found that a mean PTCBML count greater than 2.5 layers assessed in a sample of 25 PTCs around 1 year after transplantation is indicative of the development of TG in patients with dnDSA (P = 0.001). In addition, in patients with serial biopsies available for electron microscopy analysis, we could distinguish 2 groups: patients with a mean PTCBML count of 2.5 or less on all biopsies, and patients who developed greater than 2.5 layers at any time after transplantation. The latter group reflected dnDSA patients at risk for TG development (P < 0.001). In patients with dnDSA, PTCBML score added significantly to the sensitivity and specificity of prediction of TG compared with microcirculation injury score alone. Our results highlight the potential value of assessing the mean number of BM in PTC for early prediction of progression to chronic antibody-mediated injury

Floodplain land use is currently of concern. Agri-environmental policy favours grass over arable agriculture, while urban development is deemed unsuitable. The role of meadowland requires evaluation because it exhibits a potential to deliver environmental goods beyond flood detention and habitat creation; it has the potential to take up particular elements and trap sediment. This is particularly important where there is eutrophication of water from agriculture and wastewater and also physical degradation of the channel and floodplain. In this study, carbon (C), nitrogen and phosphorus (P) status and sediment deposition at typical locations on a southern English floodplain were investigated. It is concluded that C sequestration could be significant and there is sediment trapping during times of flood but further P accumulation in the topsoil of grazing land is limited. It is concluded that nutrient loading of the river from sewage effluent and from agriculture is best prevented at source.

Patterns in abundance, growth, and condition of lake whitefish (Coregonus clupeaformis) from Lake Erie were compared with those from Lake Ontario. Discontinuous assessment data were available from 1972 to 2003 for each lake to describe abundance, growth, and condition, while a seasonally intensive field program was undertaken in 2003 to describe diet, energy density, and gonadosomatic index (GSI). Through time, abundance declined more in Lake Ontario than in Lake Erie. Length-at-age (growth) and condition both declined significantly in Lake Ontario but did not change in Lake Erie. Diet analysis revealed chironomids, dreissenid mussels and sphaeriids made up the bulk of lake whitefish diet in Lake Erie. Diet in Lake Ontario exhibited more seasonal variability with amphipods and gastropods comprising the bulk of the spring and fall diets, and dreissenid mussels dominating summer diets. Lake whitefish energy density (J/g wet mass) was significantly higher in Lake Erie than in Lake Ontario, increasin...

The Wistar-Kyoto (WKY) rat shows marked susceptibility to crescentic glomerulonephritis. In the model of nephrotoxic nephritis (NTN) that is induced by a small dose of nephrotoxic globulin, WKY rats developed crescents in 80 +/- 2% of glomeruli at day 10, whereas no crescents were seen in Lewis rats. This was associated with marked increase in monocyte chemoattractant protein-1 synthesis in WKY glomeruli. It was posited whether susceptibility depended on circulating cells or intrinsic renal cells. Bone marrow (BM) isografts from WKY to WKY or Lewis to Lewis did not affect susceptibility to NTN. When BM was transferred from WKY to Lewis rats, crescents developed in 35 +/- 9% of glomeruli 10 d after induction of NTN, indicating that susceptibility could be transferred by BM cells. However, crescents were also seen in WKY rats that were given Lewis marrow. For assessment of the contribution of intrinsic renal cells, kidneys from WKY or Lewis rats were transplanted into F1 animals. In NTN, the ratio of crescents in the transplanted kidney to the native kidney was significantly higher for WKY-to-F1 than for Lewis-to-F1 transplants, demonstrating that the kidney itself also influences susceptibility. Mesangial cell responses were then examined in the two strains. Mesangial cells that were derived from WKY rats synthesized significantly more monocyte chemoattractant protein-1 basally and after stimulation with heat-aggregated rabbit IgG or TNF-alpha. These results show that susceptibility to NTN in the WKY rat depends on both circulating and intrinsic renal cells and that there are genetic differences between the strains in mesangial responses to inflammatory stimuli.

Lake Erie walleyes Sander vitreus support important fisheries and have been managed as one stock, although preliminary tag return and genetic analyses suggest the presence of multiple stocks that migrate among basins within Lake Erie and into other portions of the Great Lakes. We examined temporal and spatial movement and abundance patterns of walleye stocks in the three basins of Lake Erie and in Lake St. Clair with the use of tag return and sport and commercial catch-per-unit effort (CPUE) data from 1990 to 2001. Based on summer tag returns, western basin walleyes migrated to the central and eastern basins of Lake Erie and to Lake St. Clair and southern Lake Huron, while fish in the central and eastern basins of Lake Erie and in Lake St. Clair were primarily caught within the basins where they were tagged. Seasonal changes in sport and commercial effort and CPUE in Lake Erie confirmed the walleye movements suggested by tag return data. Walleyes tagged in the western basin but recaptured in the ...