Complement Activation and Progression of Chronic Kidney Disease

Proteinuria is a strong predictor of progression in chronic kidney disease. Complement proteins are a major constituent of the urine of proteinuric patients. Complement is activated in the tubular lumen through the alternative pathway, and complement activation products are deposited on the apical surface of tubular epithelial cells. Recent animal studies have suggested that complement activation in the tubular compartment plays an important role in proteinuria-associated tubulointerstitial injury. Complement deficiency, depletion or inhibition all reduce the tubular cell damage and interstitial fibrosis that develops in proteinuric animals. In particular, inhibition of anaphylatoxin receptors protects the kidneys from proteinuria-associated damage. In this review, we discuss the evidence for a role of complement activation in the progression of chronic kidney disease

Synergy between type 1 fimbriae expression and C3 opsonisation increases internalisation of E. coli by human tubular epithelial cells

<p>Abstract</p> <p>Background</p> <p>Bacterial infection of the urinary tract is a common clinical problem with <it>E. coli </it>being the most common urinary pathogen. Bacterial uptake into epithelial cells is increasingly recognised as an important feature of infection. Bacterial virulence factors, especially fimbrial adhesins, have been conclusively shown to promote host cell invasion. Our recent study reported that C3 opsonisation markedly increases the ability of <it>E. coli </it>strain J96 to internalise into human proximal tubular epithelial cells via CD46, a complement regulatory protein expressed on host cell membrane. In this study, we further assessed whether C3-dependent internalisation by human tubular epithelial cells is a general feature of uropathogenic <it>E. coli </it>and investigated features of the bacterial phenotype that may account for any heterogeneity.</p> <p>Results</p> <p>In 31 clinical isolates of <it>E. coli </it>tested, C3-dependent internalisation was evident in 10 isolates. Type 1 fimbriae mediated-binding is essential for C3-dependent internalisation as shown by phenotypic association, type 1 fimbrial blockade with soluble ligand (mannose) and by assessment of a type 1 fimbrial mutant.</p> <p>Conclusion</p> <p>we propose that efficient internalisation of uropathogenic <it>E. coli </it>by the human urinary tract depends on co-operation between type 1 fimbriae-mediated adhesion and C3 receptor -ligand interaction.</p

Computerized clinical decision support for the early recognition and management of acute kidney injury: a qualitative evaluation of end-user experience

Background - Although the efficacy of computerized clinical decision support (CCDS) for acute kidney injury (AKI) remains unclear, the wider literature includes examples of limited acceptability and equivocal benefit. Our single-centre study aimed to identify factors promoting or inhibiting use of in-patient AKI CCDS. Methods - Targeting medical users, CCDS triggered with a serum creatinine rise of ≥25 μmol/L/day and linked to guidance and test ordering. User experience was evaluated through retrospective interviews, conducted and analysed according to Normalization Process Theory. Initial pilot ward experience allowed tool refinement. Assessments continued following CCDS activation across all adult, non-critical care wards. Results - Thematic saturation was achieved with 24 interviews. The alert was accepted as a potentially useful prompt to early clinical re-assessment by many trainees. Senior staff were more sceptical, tending to view it as a hindrance. ‘Pop-ups’ and mandated engagement before alert dismissal were universally unpopular due to workflow disruption. Users were driven to close out of the alert as soon as possible to review historical creatinines and to continue with the intended workflow. Conclusions - Our study revealed themes similar to those previously described in non-AKI settings. Systems intruding on workflow, particularly involving complex interactions, may be unsustainable even if there has been a positive impact on care. The optimal balance between intrusion and clinical benefit of AKI CCDS requires further evaluation

CCL2 nitration is a negative regulator of chemokine-mediated inflammation.

Chemokines promote leukocyte recruitment during inflammation. The oxidative burst is an important effector mechanism, this leads to the generation of reactive nitrogen species (RNS), including peroxynitrite (ONOO). The current study was performed to determine the potential for nitration to alter the chemical and biological properties of the prototypical CC chemokine, CCL2. Immunofluorescence was performed to assess the presence of RNS in kidney biopsies. Co-localisation was observed between RNS-modified tyrosine residues and the chemokine CCL2 in diseased kidneys. Nitration reduced the potential of CCL2 to stimulate monocyte migration in diffusion gradient chemotaxis assays (p < 0.05). This was consistent with a trend towards reduced affinity of the nitrated chemokine for its cognate receptor CCR2b. The nitrated chemokine was unable to induce transendothelial monocyte migration in vitro and failed to promote leukocyte recruitment when added to murine air pouches (p < 0.05). This could potentially be attributed to reduced glycosaminoglycan binding ability, as surface plasmon resonance spectroscopy showed that nitration reduced heparan sulphate binding by CCL2. Importantly, intravenous administration of nitrated CCL2 also inhibited the normal recruitment of leukocytes to murine air pouches filled with unmodified CCL2. Together these data suggest that nitration of CCL2 during inflammation provides a mechanism to limit and resolve acute inflammation

Acute kidney injury electronic alerts: mixed methods Normalization Process Theory evaluation of their implementation into secondary care in England

Objective Around one in five emergency hospital admissions are affected by acute kidney injury (AKI). To address poor quality of care in relation to AKI, electronic alerts (e-alerts) are mandated across primary and secondary care in England and Wales. Evidence of the benefit of AKI e-alerts remains conflicting, with at least some uncertainty explained by poor or unclear implementation. The objective of this study was to identify factors relating to implementation, using Normalization Process Theory (NPT), which promote or inhibit use of AKI e-alerts in secondary care. Design Mixed methods combining qualitative (observations, semi-structured interviews) and quantitative (survey) methods. Setting and participants Three secondary care hospitals in North East England, representing two distinct AKI e-alerting systems. Observations (>44 hours) were conducted in Emergency Assessment Units (EAUs). Semi-structured interviews were conducted with clinicians (n=29) from EAUs, Vascular or General Surgery, or Care of the Elderly. Qualitative data were supplemented by NoMAD surveys (n=101). Analysis Qualitative data were analysed using the NPT framework, with quantitative data analysed descriptively and using Chi Square and Wilcoxon Signed Ranks Test for differences in current and future normalization. Results Participants reported familiarity with the AKI e-alerts but that the e-alerts would become more normalized in the future (p<0.001). No single NPT mechanism led to current (un)successful implementation of the e-alerts, but analysis of the underlying sub-constructs identified several mechanisms indicative of successful normalization (internalization, legitimation) or unsuccessful normalization (initiation, differentiation, skill set workability, systematization). Conclusions Clinicians recognised the value and importance of AKI e-alerts in their practice, though this was not sufficient for the e-alerts to be routinely engaged with by clinicians. To further normalize the use of AKI e-alerts, there is a need for tailored training on use of the e-alerts and routine feedback to clinicians on the impact that e-alerts have on patient outcomes

Complement factor I deficiency: a potentially treatable cause of fulminant cerebral inflammation

Objective To raise awareness of complement factor I (CFI) deficiency as a potentially treatable cause of severe cerebral inflammation. Methods Case report with neuroradiology, neuropathology, and functional data describing the mutation with review of literature. Results We present a case of acute, fulminant, destructive cerebral edema in a previously well 11-year-old, demonstrating massive activation of complement pathways on neuropathology and compound heterozygote status for 2 pathogenic mutations in CFI which result in normal levels but completely abrogate function. Conclusions Our case adds to a very small number of extant reports of this phenomenon associated with a spectrum of inflammatory histopathologies including hemorrhagic leukoencephalopathy and clinical presentations resembling severe acute disseminated encephalomyelitis. CFI deficiency can result in uncontrolled activation of the complement pathways in the brain resulting in devastating cerebral inflammation. The deficit is latent, but the catastrophic dysregulation of the complement system may be the result of a C3 acute phase response. Diagnoses to date have been retrospective. Diagnosis requires a high index of suspicion and clinician awareness of the limitations of first-line clinical tests of complement activity and activation. Simple measurement of circulating CFI levels, as here, may fail to diagnose functional deficiency with absent CFI activity. These diagnostic challenges may mean that the CFI deficiency is being systematically under-recognized as a cause of fulminant cerebral inflammation. Complement inhibitory therapies (such as eculizumab) offer new potential treatment, underlining the importance of prompt recognition, and real-time whole exome sequencing may play an important future role

Comparison of the outcome of kidney transplantation after pulsatile or continuous ex vivo hypothermic machine perfusion of kidneys donated after cardiac death: analysis of kidney pairs

Background Hypothermic machine perfusion is used to improve renal perfusion and reduce the rate of early and late graft dysfunction. It has been used in our unit since 2001. It has two modes of flow: continuous or pulsatile. The aim of this study is to compare the modes of perfusion in terms of perfusion-related parameters, graft survival and estimated glomerular filtration rate. Methods All donation after cardiac death kidneys between 2002 and 2014 were reviewed. Sixty-four pairs of kidneys were identified of which one kidney underwent pulsatile and the other continuous perfusion. Machine parameters including resistance and perfusion flow index levels at 0, 1, 2, 3, 4 hours were recorded and glutathione S-transferase measured in perfusate. Delayed graft function frequency, estimated glomerular filtration rate from the 1st week of transplantation until 5th year and graft survival rates were determined. Results Machine parameters were similar at all time points. Delayed graft function frequency, estimated glomerular filtration rates and graft survival were equivalent irrespective of perfusion mode. Conclusion Pulsatile perfusion may be regarded as more physiological. However, we could not identify differences in short or long term outcomes following transplantation of kidneys from the same donor that had been perfused under pulsatile or continuous conditions

Outcomes of patients with atypical haemolytic uraemic syndrome with native and transplanted kidneys treated with eculizumab: a pooled post hoc analysis

Atypical hemolytic uremic syndrome (aHUS) often leads to end-stage renal disease (ESRD) and kidney transplantation; graft loss rates are high due to disease recurrence. A post hoc analysis of four prospective clinical trials in aHUS was performed to evaluate eculizumab, a terminal complement inhibitor, in patients with native or transplanted kidneys. The trials included 26-week treatment and extension periods. Dialysis, transplant, and graft loss were evaluated. Study endpoints included complete thrombotic microangiopathy (TMA) response, TMA event-free status, hematologic and renal parameters, and adverse events. Of 100 patients, 74 had native kidneys and 26 in the transplant subgroup had a collective history of 38 grafts. No patients lost grafts and only one with preexisting ESRD received a transplant on treatment. Efficacy endpoints were achieved similarly in both subgroups. After 26 weeks, mean absolute estimated glomerular filtration rate increased from baseline to 61 and 37 mL/min/1.73 m2 in native (n=71; P<0.0001) and transplanted kidney (n=25; P=0.0092) subgroups. Two patients (one/subgroup) developed meningococcal infections; both recovered, one continued therapy. Eculizumab was well tolerated. Eculizumab improved hematologic and renal outcomes in both subgroups. In patients with histories of multiple graft losses, eculizumab protected kidney function. (ClinicalTrials. gov numbers : NCT00844545, NCT00844844, NCT00838513, NCT00844428, NCT01193348, and NCT01194973) This article is protected by copyright. All rights reserved

A urinary microRNA panel that is an early predictive biomarker of delayed graft function following kidney transplant

Predicting immediate and subsequent graft function is important in clinical decision-making around kidney transplantation, but is difficult using available approaches. Here we have evaluated urinary microRNAs as biomarkers in this context. Profiling of 377 microRNAs in the first urine passed post-transplantation identified 6 microRNAs, confirmed to be upregulated by RT-qPCR in an expanded cohort (miR-9, -10a, -21, -29a, -221, and -429, n = 33, P < 0.05 for each). Receiver operating characteristic analysis showed Area Under the Curve 0.94 for this panel. To establish whether this early signal was sustained, miR-21 was measured daily for 5 days post-transplant, and was consistently elevated in those developing Delayed Graft Function (n = 165 samples from 33 patients, p < 0.05). The biomarker panel was then evaluated in an independent cohort, sampled at varying times in the first week post-transplantation in a separate transplant center. When considered individually, all miRs in the panel showed a trend to increase or a significant increase in those developing delayed Graft Function (miR-9: P = 0.068, mIR-10a: P = 0.397, miR-21: P = 0.003, miR-29a: P = 0.019, miR-221: P = 0.1, and miR-429: P = 0.013, n = 47) with Area Under the Curve 0.75 for the panel. In conclusion, combined measurement of six microRNAs had predictive value for delayed graft function following kidney transplantation. Introductio