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Objective Nonadherence to medication is present in at least 50% of patients with apparent treatment-resistant hypertension. We examined the factors associated with nonadherence as detected by a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based urine antihypertensive drug assay. Methods All urine antihypertensive test results, carried out for uncontrolled hypertension (BP persistently >140/90 mmHg) between January 2015 and December 2016 at a single toxicology laboratory were analysed. Drugs detected were compared with the antihypertensive drugs prescribed. Patients were classified as adherent (all drugs detected), partially nonadherent (at least one prescribed drug detected) or completely nonadherent (no drugs detected). Demographic and clinical parameters were compared between the adherent and nonadherent groups. Binary logistic regression analysis was performed to determine association between nonadherence and demographic and clinical factors. Results Data on 300 patients from nine hypertension centres across the United Kingdom were analysed. The median age was 59 years, 47% women, 71% Caucasian, median clinic BP was 176/95 mmHg and the median number of antihypertensive drugs prescribed was four. One hundred and sixty-six (55%) were nonadherent to prescribed medication with 20% of these being completely nonadherent. Nonadherence to antihypertensive medication was independently associated with younger age, female sex, number of antihypertensive drugs prescribed, total number of all medications prescribed (total pill burden) and prescription of a calcium channel blocker. Conclusion This LC-MS/MS urine analysis-based study suggests the majority of patients with apparent treatment-resistant hypertension are nonadherent to prescribed treatment. Factors that are associated with nonadherence, particularly pill burden, should be taken into account while treating these patients.

Buttonhole cannulation, or buttonhole needling, is one of several methods of vascular access for dialysis patients. While this is a well-established technique, practices continue to vary across the UK. Catherine Fielding, Pat Cain, Paula Debling et al outline the new clinical practice recommendations that were introduced to help standardise and improve this vascular access technique.

Human Endogenous Retroviruses (HERVs) have been implicated in autoimmune and other diseases. Molecular mimicry has been postulated as a potential mechanism of autoimmunity. Exogenous viruses have also been reported to be associated with the same diseases, as have genetic and environmental factors. If molecular mimicry were to be shown to be an initiating mechanism of some autoimmune diseases, then therapeutic options of blocking antibodies and peptides might be of benefit in halting diseases at the outset. Bioinformatic and molecular modelling techniques have been employed to investigate molecular mimicry and the evidence for the association of HERVs and autoimmunity is reviewed. The most convincing evidence for molecular mimicry is in rheumatoid arthritis, where HERV K-10 shares amino acid sequences with IgG1Fc, a target for rheumatoid factor. Systemic lupus erythematosus is an example of a condition associated with several autoantibodies, and several endogenous and exogenous viruses have been reported to be associated with the disease. The lack of a clear link between one virus and this condition, and the spectrum of clinical manifestations, suggests that genetic, environmental and the inflammatory response to a virus or viruses might also be major factors in the pathogenesis of lupus and other autoimmune conditions. Where there are strong associations between a virus and an autoimmune condition, such as in hepatitis C and cryoglobulinaemia, the use of bioinformatics and molecular modelling can also be utilized to help to understand the role of molecular mimicry in how HERVs might trigger disease.

Genetic and environmental factors appear to contribute to the pathogenesis of systemic lupus erythematosus (SLE). Viral infections have been reported to be associated with the disease. A number of exogenous viruses have been linked to the pathogenesis of SLE, of which Epstein-Barr virus (EBV) has the most evidence of an aetiological candidate. In addition, human endogenous retroviruses (HERV), HRES-1, ERV-3, HERV-E 4-1, HERV-K10 and HERV-K18 have also been implicated in SLE. HERVs are incorporated into human DNA, and thus can be inherited. HERVs may trigger an autoimmune reaction through molecular mimicry, since homology of amino acid sequences between HERV proteins and SLE autoantigens has been demonstrated. These viruses can also be influenced by oestrogen, DNA hypomethylation, and ultraviolet light (UVB) exposure which have been shown to enhance HERV activation or expression. Viral infection, or other environmental factors, could induce defective apoptosis, resulting in loss of immune tolerance. Further studies in SLE and other autoimmune diseases are needed to elucidate the contribution of both exogenous and endogenous viruses in the development of autoimmunity. If key peptide sequences could be identified as molecular mimics between viruses and autoantigens, then this might offer the possibility of the development of blocking peptides or antibodies as therapeutic agents in SLE and other autoimmune conditions.

Autoimmune rheumatic diseases, such as RA and SLE, are caused by genetic, hormonal and environmental factors. Human Endogenous Retroviruses (HERVs) may be triggers of autoimmune rheumatic disease. HERVs are fossil viruses that began to be integrated into the human genome some 30-40 million years ago and now make up 8% of the genome. Evidence suggests HERVs may cause RA and SLE, among other rheumatic diseases. The key mechanisms by which HERVS are postulated to cause disease include molecular mimicry and immune dysregulation. Identification of HERVs in RA and SLE could lead to novel treatments for these chronic conditions. This review summarises the evidence for HERVs as contributors to autoimmune rheumatic disease and the clinical implications and mechanisms of pathogenesis are discussed.

Summary Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections within the human genome. These molecular fossils draw parallels with present-day exogenous retroviruses and have been linked previously with immunopathology within rheumatoid arthritis (RA). Mechanisms of pathogenesis for HERV-K in RA such as molecular mimicry were investigated. To clarify a role for HERVs in RA, potential autoantigens implicated in autoimmunity were scanned for sequence identity with retroviral epitopes. Short retroviral peptides modelling shared epitopes were synthesized, to survey anti-serum of RA patients and disease controls. A novel real-time polymerase chain reaction (PCR) assay was also developed to quantify accurately levels of HERV-K (HML-2) gag expression, relative to normalized housekeeping gene expression. Both serological and molecular assays showed significant increases in HERV-K (HML-2) gag activity in RA patients, compared to disease controls. The real-time PCR assay identified significant up-regulation in HERV-K mRNA levels in RA patients compared to inflammatory and healthy controls. Exogenous viral protein expression and proinflammatory cytokines were also shown to exert modulatory effects over HERV-K (HML-2) transcription. From our data, it can be concluded that RA patients exhibited significantly elevated levels of HERV-K (HML-2) gag activity compared to controls. Additional factors influencing HERV activity within the synovium were also identified. The significant variation in RA patients, both serologically and transcriptionally, may be an indication that RA is an umbrella term for a number of separate disease entities, of which particular HERV polymorphisms may play a role in development.

Background. The early identification of kidney allografts at risk of later dysfunction has implications for clinical practice. Donor quality scoring systems (preoperative) and measures of early allograft function (first week postoperative) have previously shown practical utility. This study aimed to determine the optimal parameter(s) (preoperative and postoperative) with greatest predictive power for the development of subsequent allograft dysfunction. Methods. Consecutive deceased donor renal transplants (n=217) were studied. In each, the following measures were assessed: Preoperative donor quality scores: expanded criteria donor status; Deceased Donor Score (Nyberg et al., Am J Transplant 2003;3:715); Donor Risk Score (Schold et al., Am J Transplant 2005; 5(4 pt 1): 757); and delayed graft function (DGF) Nomogram (Irish et al., J Am Soc Nephrol 2003; 14:2967). Postoperative early function measures: dialysis requirement and duration; extended DGF definition (Boom et al., Kidney Int 2000; 58:859); creatinine at day 5 and day 7; creatinine reduction ratios at day 2 and day 7; and urine output posttransplantation. Primary outcome measures were creatinine at 12 months and the development of chronic kidney disease stage 4T. Results. Of donor scoring systems, Donor Risk Score was best associated with subsequent allograft function. Of early function measures: the extended definition of DGF, creatinine at day 5, and dialysis duration showed greatest predictive power in the patient population overall, those not requiring postoperative dialysis, and those requiring dialysis, respectively. No scores or early function measures were associated with change in creatinine between 6 and 12 months. Conclusions. This study validates and identifies the optimal early predictive parameter available for kidney transplant recipients, with implications for refining early postoperative management and potential utility in organ allocation policy.

Objective.Human endogenous retrovirus (HERV)-K10 has been implicated in the etiology and pathogenesis of rheumatoid arthritis (RA). A secondary immune response to this virus might suggest an antigen-driven response in patients. The Gag region of HERV-K10 could provide a key epitope important for immunological reactivity. We investigated the presence of IgG antibodies to this region and assessed its significance in RA.Methods.We determined an antigenic peptide on the matrix segment of HERV-K10 and developed an ELISA system to detect IgG antibodies in patients with RA and controls. The presence of antibodies to the matrix peptide (denoted as MAG1: RIGKELKQAGRKGNI) was correlated with patient details.Results.On screening patients’ serum, we found a significantly higher mean IgG antibody response to MAG1 in 30 patients with RA as compared to 23 patients with inflammatory bowel disease (p = 0.003), 29 patients with osteoarthritis (p = 0.001), and 43 healthy individuals (p = 0.002). Reactivity was not observed to a control peptide possessing a nonhomologous amino acid sequence. On evaluating clinical details with serological activity, no correlation with disease duration (p = 0.128), sex (p = 0.768), or rheumatoid factor status (p = 0.576) was found.Conclusion.A significantly elevated IgG antibody response to an HERV-K10 Gag matrix peptide was observed in patients with RA, suggesting that the exposure of HERV-K10 may cause a secondary, antigenic driven immune response in RA.

Epitope mapping allowed the location of antigenic determinants on a protein macromolecule to be identified. In particular, pepscan techniques that utilize a series of overlapping peptides, help detect key amino acid residues that are important in antibody recognition and binding. In a previous study, we employed 15-mer peptides spanning the entire length of IgG1Fc to ascertain successfully the target epitopes of isotypic/allotypic monoclonal reagents. As an extension to this work we have used these peptides to evaluate the location of epitope targets of five IgM rheumatoid factor antibodies (RFAbs). Overall, 2 antibodies, RFAb TS2 and TS1, detected a similar epitope within the CH3 domain (360-KNQVSLTCLVKGFYP-374), whilst 1 (RFAb SJ1) recognised an epitope in the CH2 domain (294-EQYNSTYRVVSVLTV-308). In contrast, 2 RFAbs, PRSJ2 and PRTS1 detected four and five epitopes respectively within the Fc region. RFAb PRSJ2 recognised epitopes detected by RFAB TS2 and TS1 but also further epitopes in the CH2 domain (256-TPEVTCVVVDVSHED-270) and CH3 domain (418-QQGNVFSCSVMHEAL-432). Similarly, RFAb PRTS1 detected all four epitopes plus a fifth in the CH3 domain (382-ESNGQPENNYKTTPP-396). In essence there was a consensus of target epitopes identified by these rheumatoid factor antibodies. Interestingly, two epitopes (256–270, CH2 domain and 360–374, CH3 domain) were novel in that they had not been identified in previous pepscan studies. The other epitopes recognised, either overlapped or were immediately adjacent to previous epitopes detected by poly/monoclonal rheumatoid factor antibodies. Molecular modelling (PCImdad) of IgG1Fc showed that all five epitopes were exposed and surface accessible for antibody interaction. In addition, a bioinformatics analysis of the Fc region using ExPASy was employed to identify key antigenic determinants. This ‘in silico’ approach may provide a means of determining key regions without the need to develop overlapping peptides spanning the entire length of a macromolecule.

The introduction of recombinant human erythro-poietin (epoetin) transformed the management ofanaemia for the vast majority of dialysis patients.The immediate benefit of transfusion-independencewas a lower risk of contracting blood-borne infectionsand iron overload. The raised haematocrit ledto improvements in quality of life, which in turn hasbeen associated with improved long term survival [1,2].For the first decade or so, various brands orformulations of epoetin were available, includingepoetin alfa (Epogen, Procrit in the US; Eprex,Erypro in Europe). A second-generation erythropoieticagent (darbepoetin alfa) was developed by incorporat-ing an additional two glycosylation chains to theerythropoietin molecule, resulting in a product with alonger half-life and a consequent reduced dosingfrequency [3].Since 1998, there has been a rapid increase in theincidence of epoetin therapy-associated pure red cellaplasia (PRCA), largely associated with the Eprexbrand of epoetin, but described with the Epogen andNeoRecormon brands of epoetin. In 2002, Casadevallet al. [4] described a new complication of epoetintherapy, that of PRCA associated with anti-erythropoietin antibodies.To date, however, no cases of anti-erythropoietinmediated PRCA has been described with darbepoetinalfa, and indeed it has been suggested that theadditional glycosylation may cause this molecule tobe more resistant to antibody generation than epoetin.We describe what we believe to be the first case ofantibody-mediated PRCA associated with the admin-istration of darbepoetin alfa alone.

SUMMARYHuman endogenous retroviruses (HERVs) are a significant component of a wider family of retroelements that constitute part of the human genome. These viruses, perhaps representative of previous exogenous retroviral infection, have been integrated and passed through successive generations within the germ line. The retention of HERVs and isolated elements, such as long-terminal repeats, could have the potential to harm. In this review we describe HERVs within the context of the family of known transposable elements and survey these viruses in terms of superantigens and molecular mimics. It is entirely possible that these mechanisms provide the potential for undesired immune responses.