Thomas Cairns

Mycophenolic acid 12-h trough level monitoring in renal transplantation: association with acute rejection and toxicity.

Studies of renal transplantation utilizing trough plasma level monitoring of mycophenolic acid (MPA) have shown inconsistent associations with toxicity and rejection.

Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

In both atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) complement plays a primary role in disease pathogenesis. Herein we report the outcome of a 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference where key issues in the management of these 2 diseases were considered by a global panel of experts. Areas addressed included renal pathology, clinical phenotype and assessment, genetic drivers of disease, acquired drivers of disease, and treatment strategies. In order to help guide clinicians who are caring for such patients, recommendations for best treatment strategies were discussed at length, providing the evidence base underpinning current treatment options. Knowledge gaps were identified and a prioritized research agenda was proposed to resolve outstanding controversial issues.

Polymorphism in the human anti-pig natural antibody repertoire: Implications for antigen-specific immunoadsorption

BACKGROUNDnAnti-Galalpha1-3Gal antibodies cause hyperacute rejection (HAR) in pig-to-primate xenotransplantation. Long-term graft survival has not been achieved despite abrogation of HAR using transgenic pigs. IgG and IgM anti-Galalpha1-3Gal also play a role in the events following abrogation of HAR. Characterizing these antibodies and developing a system for their removal is therefore crucial to future success in xenotransplantation.nnnMETHODS AND RESULTSnWe have developed a neoglycoprotein enzyme-linked immunosorbent assay to probe the precise antigenic requirements for the binding of anti-Galalpha1-3Gal and have analyzed 77 normal sera. Sixty-six percent of individuals have IgG that recognizes the Galalpha1-3Gal di-, tri-, and pentasaccharides (D, T, and P, respectively), termed DTP phenotype. The frequency of other phenotypes was - -P, 13%; -TP, 12%; D-P, 8%; and DT-, 1%. The IgG subclasses found were IgG2 (95%), IgG3 (34%), IgG1 (31%), and IgG4 (17%). IgM in 91% of individuals recognized all three antigens. Further antibody heterogeneity was demonstrated when immunoadsorbents derived from Galalpha1-3Galbeta1-4GlcNAcbeta1-3Galbeta1-4Glc (PENTA) were tested. Galalpha1-3Galbeta1-4Glc (TRI 6) or PENTA agarose were effective for IgG removal in all individuals. For IgM removal, two deoxy derivatives were completely successful in 73% of individuals. Combining the Galalpha1-3Gal (DI) and TRI 6 agarose produced an adsorbent that completely removed anti-Galalpha1-3Gal IgG and IgM in all individuals tested.nnnCONCLUSIONSnAlthough the polymorphism in the anti-Galalpha1-3Gal repertoire, which we have demonstrated, represents a major obstacle to the development of an effective immunoadsorbent, the combination of DI and TRI 6 agarose appears sufficient for pig-to-human xenotransplantation.

Outcome of patients with preformed donor-specific antibodies following alemtuzumab induction and tacrolimus monotherapy.

It has been shown that low‐level preformed donor‐specific antibodies (DSAbs) detected by luminex beads in the setting of a negative CDC and flow cytometry crossmatch (CDC/FCXM) are associated with inferior allograft outcomes. The relevance of preformed DSAbs in patients receiving alemtuzumab induction and tacrolimus monotherapy has not been studied. Four hundred and eighty renal transplant recipients with a negative CDC/FCXM had their pretransplant sera retrospectively screened for DSAbs. 45/480 (9.4%) of patients were found to have preformed DSAbs. Females and patients receiving regrafts were more likely to have a DSAb (p = 0.008 and p < 0.0001, respectively). Patients with DSAbs had inferior allograft survival (p = 0.047), increased incidence of antibody‐mediated rejection (p < 0.0001) and inferior allograft function at 6 months posttransplant (p = 0.017). Patients with HLA class I DSAb (alone or in combination with a Class II DSAb) with high mean fluorescence intensities (MFIs) were at highest risk. We conclude that patients with preformed DSAb are at high risk of adverse outcomes when receiving a minimal immunosuppressive regime incorporating alemtuzumab induction. Patients found to have a preformed DSAb despite a negative crossmatch might benefit from augmented immunosuppression.

Eculizumab as rescue therapy in severe resistant lupus nephritis

ities ( = 0.48, P = 0.04). There are MSUS studies reporting early changes or baseline PDUS predicting a variety of RA outcome measures. We cite two studies that use baseline PDUS to predict other 1 year outcomes. Ellegaard et al. [7] demonstrated that MSUS colour fraction quantification of the wrist in 109 RA patients starting a TNF inhibitor predicted which patients would remain on therapy in 1 year (P = 0.02). Kamishima et al. [8] evaluated 29 RA patients starting i.v. tocilizumab and performed MSUS at baseline, 2 and 5 months. The authors reported that the quantitative PDUS may be predictive of structural damage progression at 1 year. There are limitations to our study. This is a small openlabel study, and we performed post hoc analyses to determine whether baseline PDUS can predict the 12 month response to therapy. As a result of the limited sample size, we were unable to perform multivariate regression models with more than two variables. Yet, in this small cohort, we were able to demonstrate a significant difference between patients with baseline PDUS >5 and <5. In conclusion, we found that those patients with severe disease activity had a wide range of baseline PDUS and that patients with high baseline PDUS had a more robust response to therapy. Perhaps high PDUS may identify patients with an RA phenotype more amenable to biologic intervention. In addition, patients with low baseline PDUS and high DAS28/CDAI may have other factors (comorbidities, obesity, OA, fibromyalgia, etc.) besides RA disease activity that resulted in their high scores. We posit that PDUS rather than DAS28 identifies those patients with modifiable disease activity. Thus, PDUS assessment may aid in treatment decisions concerning whether escalation or switching therapy is needed in RA patients with multiple co-morbidities. Additional studies are required to validate these findings.

Inhibition of the pig to human xenograft reaction, using soluble Gal alpha 1-3Gal and Gal alpha 1-3Gal beta 1-4GlcNAc.

Natural anti-carbohydrate antibodies are central to hyperacute rejection in ABO-incompatible allotransplantation and in discordant xenotransplantation. ABO-incompatible rejection has been inhibited successfully using intravenous soluble carbohydrates as antibody inhibitors. The approach has been less successful previously in pig to primate xenotransplantation, where the necessary concentrations of a partial inhibitor (Gal alpha 1-6Glc) proved highly toxic. In this study, we have identified more effective inhibitors of the dominant human anti-pig antibodies that bind to the pentasaccharide Gal alpha 1-3Gal beta 1-4GlcNAc beta 1-3Gal beta 1-4Glc beta 1-. The inhibitors are the terminal disaccharide (Gal alpha 1-3Gal) and terminal trisaccharide (Gal alpha 1-3Gal beta 1-4GlcNAc) of the target pentasaccharide. Twelve sera (3 from each ABO blood group) were tested in 3 different assays: lymphocytotoxic, lymphocyte flow cytometry, and solid-phase antigen ELISA. Fifty percent to 75% inhibition of human IgG and IgM was achieved using the disaccharide and trisaccharide inhibitors in the range of 10-50 mM. Disaccharide (70 mM) was used to inhibit hyperacute thrombosis in pig kidneys perfused for 40 min with heparinized human AB whole blood. The disaccharide completely inhibited red cell occlusion of glomerular but not of intertubular capillaries, although there was residual platelet thrombus in glomeruli. Disaccharide and trisaccharide can, therefore, be used in concentrations shown for other carbohydrate inhibitors to be nontoxic, for inhibition of hyperacute pig-to-human xenograft rejection. The inhibition is incomplete, however, and other antigen specificities and other rejection mechanisms are likely to be involved.

Translumbar central venous catheters for long-term haemodialysis

BACKGROUNDnVascular access for haemodialysis is achieved by tunnelled central venous catheter (CVC) in at least 23% of prevalent patients in the UK, Canada and the USA. Use of CVCs is associated with an increased incidence of venous stenosis that can progressively limit future vascular access routes. Lack of conventional venous access routes mandates the use of alternative strategies such as the translumbar approach.nnnMETHODSnWe retrospectively analysed patients at our centre requiring translumbar inferior vena caval CVCs (TesioCath) for haemodialysis in the period 1999-2008. Written and electronic records capturing dialysis adequacy and complications, hospital admissions and laboratory data were examined.nnnRESULTSnThirty-nine pairs of translumbar CVCs were inserted in 26 patients with 15 864 catheter days follow-up, mean patient age 61.9 +/- 12.1 years, 31% diabetic, 15% with ischaemic heart disease. All insertions were successful. Insertion of one CVC was associated with a self-limiting retroperitoneal haematoma. No patients died of a catheter-related cause or through lack of vascular access. Cumulative assisted primary catheter site patency was 81% at 6 months and 73% at 1 year (median 18.5 months). Good dialysis adequacy was achieved throughout (mean single-pool Kt/V 1.5 +/- 0.4). The incidence of access-related infection was 2.84/1000 catheter days (exit site infection rate 2.02/1000 catheter days; catheter-related bacteraemia rate 0.82/1000 catheter days). Catheter dysfunction (need for thrombolytic infusion or catheter change) led to 0.88 admissions per 1000 catheter days.nnnCONCLUSIONnTranslumbar inferior vena caval CVCs can offer relatively safe and effective long-term haemodialysis access in patients with no other options.

Demonstration of IgM antibodies of high affinity within the anti-Galalpha1-3Gal antibody repertoire.

BACKGROUNDnHuman anti-Galalpha1-3Gal IgG and IgM xenoantibodies can distinguish between very similar epitopes with a high degree of selectivity.nnnMETHODSnAnti-Galalpha1-3Gal antibodies were affinity isolated using two separate Galalpha1-3Gal-based immunoadsorbents, Galalpha1-3Gal itself and Galalpha1-3Galbeta1-4Glc. IgG and IgM were separated using a protein G column. Antibody purity was achieved by serial adsorption/elutions from the columns. By this means, different antibody fractions were prepared that contained either IgG or IgM, reactive with either Galalpha1-3Gal, Galalpha1-3Galbeta1-4Glc, or both. The dissociation equilibrium constants (Kd) of these antibodies were then measured using an IAsys biosensor.nnnRESULTS AND CONCLUSIONSnSera from two individuals were used and Kd values for one IgG (fraction 1A) and two IgM (fractions 1B and 2A) fractions were obtained. The Kd for the IgG was 4.85 x 10(-7) M (fraction 1A). For IgM, the Kd values were higher at 7.8x10(-10) M (fraction 1B) and 1.07x10(-10) M (fraction 2A). Natural anti-pig antibodies include high affinity IgM that continue to be produced without class switch. The B cell mechanism behind this is not known. It may be possible to exploit this mechanism in future xenotransplantation strategies.

Ten-year patient survival on maintenance haemodialysis: association with treatment time and dialysis dose.

BACKGROUNDnAnalyses of national registry-based datasets have demonstrated the association of longer haemodialysis treatment times with lowered mortality risk.nnnMETHODSnWe performed a prospective cohort study of 451 incident haemodialysis patients and examined the effect of targeting higher dialysis dose with extended treatment time, on 10-year patient outcomes.nnnRESULTSnMean treatment time (TT) was 233 ± 22.8 minutes (median 235, range 180-296). Overall patient survival was 95% at 1 year, 75% at 3 years, 56% at 5 years and 25% at 10 years. Increasing TT was associated with incremental 10-year patient survival (TT >/=241 minutes 39.7%, TT 226-240 minutes 19.6% and TT </=225 minutes 14.7%; p<0.001). Single pool Kt/V and TT were strong independent predictors of patient survival in Cox multivariate analysis (p<0.0001). At 10 years, each 0.1-unit increase in spKt/V and 20-minute increase in TT were associated with a 20% and 32% decrease in the relative risk of death, respectively. Survival benefits of higher dialysis dose and longer TT were cumulative, with highest survival exhibited by patients achieving both Kt/V >1.6 and TT >/=241 minutes, and lowest survival exhibited by patients receiving Kt/V <1.2 and TT </=225 minutes.nnnCONCLUSIONnExtended treatment times are associated with higher patient survival irrespective of dialysis dose. Further study of extended treatment time and effect on patient outcomes is needed.

Ofatumumab for B cell depletion therapy in ANCA-associated vasculitis: a single-centre case series

Objectives. B cell depletion is an effective treatment strategy in ANCA-associated vasculitis (AAV). Ofatumumab is a fully humanized anti-CD20 mAb that has shown efficacy in the treatment of haematological malignancy and RA. The use of ofatumumab in the treatment of AAV has not previously been reported. Methods. This study was based on a case series of eight patients who received ofatumumab, in conjunction with low-dose CYC and oral steroids, in the treatment of AAV. Results. Eight patients received ofatumumab: seven for remission induction in active disease (three relapsing; four with new disease) and one for remission maintenance. B cell depletion was achieved in all patients by 1 month, and was sustained for at least 6 months. All patients with active disease achieved clinical remission (BVAS of zero, or BVAS ⩽5 if all scores due to persistent urinary abnormalities in the presence of stable or improving renal function) by 3 months. This was associated with a rapid fall in ANCA titres, reduced inflammatory responses and improvements in renal function. At 12 months, three patients had repopulated B cells associated with the recurrence of circulating ANCAs, although no patients experienced major clinical relapse in the first 24 months. No unexpected side effects were observed. Conclusion. Treatment with ofatumumab resulted in similar serological and clinical responses to those seen in previous cohorts treated at our centre with a comparable CS, CYC and rituximab-based regimen. Ofatumumab should be considered an alternative B cell depleting agent in patients who are intolerant of, or unresponsive to, rituximab.