Genetically distinct subsets within ANCA-associated vasculitis.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. METHODS: A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. RESULTS: We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding α(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P=6.2×10(-89), P=5.6×10(-12,) and P=2.6×10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P=2.1×10(-8)). CONCLUSIONS: This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.).

Impact of donor mismatches at individual HLA-A, -B, -C, -DR, and -DQ loci on the development of HLA-specific antibodies in patients listed for repeat renal transplantation.

We have analyzed the relationship between donor mismatches at each HLA locus and development of HLA locus-specific antibodies in patients listed for repeat transplantation. HLA antibody screening was undertaken using single-antigen beads in 131 kidney transplant recipients returning to the transplant waiting list following first graft failure. The number of HLA mismatches and the calculated reaction frequency of antibody reactivity against 10,000 consecutive deceased organ donors were determined for each HLA locus. Two-thirds of patients awaiting repeat transplantation were sensitized (calculated reaction frequency over 15%) and half were highly sensitized (calculated reaction frequency of 85% and greater). Antibody levels peaked after re-listing for repeat transplantation, were independent of graft nephrectomy and were associated with length of time on the waiting list (odds ratio 8.4) and with maintenance on dual immunosuppression (odds ratio 0.2). Sensitization was independently associated with increasing number of donor HLA mismatches (odds ratio 1.4). All mismatched HLA loci contributed to the development of HLA locus-specific antibodies (HLA-A: odds ratio 3.2, HLA-B: odds ratio 3.4, HLA-C: odds ratio 2.5, HLA-DRB1: odds ratio 3.5, HLA-DRB3/4/5: odds ratio 3.9, and HLA-DQ: odds ratio 3.0 (all significant)). Thus, the risk of allosensitization following failure of a first renal transplant increases incrementally with the number of mismatches at all HLA loci assessed. Maintenance of re-listed patients on dual immunosuppression was associated with a reduced risk of sensitization.

The effect of rituximab therapy on immunoglobulin levels in patients with multisystem autoimmune disease.

BACKGROUND: Rituximab is a B cell depleting anti-CD20 monoclonal antibody. CD20 is not expressed on mature plasma cells and accordingly rituximab does not have immediate effects on immunoglobulin levels. However, after rituximab some patients develop hypogammaglobulinaemia. METHODS: We performed a single centre retrospective review of 177 patients with multisystem autoimmune disease receiving rituximab between 2002 and 2010. The incidence, severity and complications of hypogammaglobulinaemia were investigated. RESULTS: Median rituximab dose was 6 g (1-20.2) and total follow-up was 8012 patient-months. At first rituximab, the proportion of patients with IgG <6 g/L was 13% and remained stable at 17% at 24 months and 14% at 60 months. Following rituximab, 61/177 patients (34%) had IgG <6 g/L for at least three consecutive months, of whom 7/177 (4%) had IgG <3 g/L. Low immunoglobulin levels were associated with higher glucocorticoid doses during follow up and there was a trend for median IgG levels to fall after ≥ 6 g rituximab. 45/115 (39%) with IgG ≥ 6 g/L versus 26/62 (42%) with IgG <6 g/L experienced severe infections (p=0.750). 6/177 patients (3%) received intravenous immunoglobulin replacement therapy, all with IgG <5 g/L and recurrent infection. CONCLUSIONS: In multi-system autoimmune disease, prior cyclophosphamide exposure and glucocorticoid therapy but not cumulative rituximab dose was associated with an increased incidence of hypogammaglobulinaemia. Severe infections were common but were not associated with immunoglobulin levels. Repeat dose rituximab therapy appears safe with judicious monitoring.

Association of calcium, phosphate and parathyroid hormone with renal allograft function: a retrospective cohort study.

BACKGROUND: Significant variations in postoperative levels of parathyroid hormone (PTH), calcium and phosphate exist after renal transplantation, but whether they affect allograft function is unknown. We investigated the association between early post-transplant levels of PTH, calcium and phosphate and graft function. METHODS: We performed a single-centre cohort study of renal transplant recipients from Addenbrooke's Hospital, Cambridge, between April 1997 and March 2007, evaluating the association between plasma calcium, phosphate and PTH 1 month after transplantation and change in epidermal growth factor receptor (eGFR) in the first 12 months after transplantation (estimated using the Modification of Diet in Renal Disease Study equation). Differences in eGFR between 26 and 52 weeks after transplantation were computed using mixed effects linear regression models for repeated measures of eGFR, while adjusting for sociodemographic and biochemical variables. RESULTS: Three hundred and forty-three patients were eligible for study. The mean age (standard deviation) at transplant was 43 years (13 years). Between 30 and 90 days after transplantation, the median (25th-75th percentile) eGFR was 33 (26-50) ml/min/1.73 m(2), the mean calcium level was 2.4 (0.17) mmol/l and the mean phosphate level was 0.78 (0.23) mmol/l. There was a significant interaction between calcium and phosphate levels (p = 0.006). In patients with low levels of phosphate, higher levels of calcium were associated with declining eGFR over time. However, in patients with a high phosphate level, higher calcium was associated with improved eGFR. CONCLUSIONS: Higher serum calcium in patients with low serum phosphate after transplantation is associated with a decline in graft function during the first year after transplantation. Disorders of mineral metabolism after transplant may represent an important therapeutic target to preserve allograft function.

The accuracy of diagnostic coding for acute kidney injury in England - a single centre study.

BACKGROUND: Acute kidney injury (AKI) is an independent risk factor for mortality and is responsible for a significant burden of healthcare expenditure, so accurate measurement of its incidence is important. Administrative coding data has been used for assessing AKI incidence, and shows an increasing proportion of hospital bed days attributable to AKI. However, the accuracy of coding for AKI and changes in coding over time have not been studied in England. METHODS: We studied a random sample of admissions from 2005 and 2010 where ICD-10 code N17 (acute renal failure) was recorded in the administrative coding data at one acute NHS Foundation Trust in England. Using the medical notes and computerised records we examined the demographic and clinical details of these admissions. RESULTS: Against a 6.3% (95% CI 4.8-7.9%) increase in all non-elective admissions, we found a 64% increase in acute renal failure admissions (95% CI 41%-92%, p < 0.001) in 2010 compared to 2005. Median age was 78 years (IQR 72-87), 11-25% had a relevant pre-admission co-morbidity and 64% (55-73%) were taking drugs known to be associated with AKI. Over both years, 95% (91-99%) of cases examined met the Kidney Disease: Improving Global Outcomes criteria for AKI. CONCLUSIONS: Patients with hospital admissions where AKI has been coded are elderly with multiple co-morbidities. Our results demonstrate a high positive predictive value of coding data for a clinical diagnosis of AKI, with no suggestion of marked changes in coding of AKI between 2005 and 2010.

Using machine learning to model older adult inpatient trajectories from electronic health records data.

Electronic Health Records (EHR) data can provide novel insights into inpatient trajectories. Blood tests and vital signs from de-identified patients' hospital admission episodes (AE) were represented as multivariate time-series (MVTS) to train unsupervised Hidden Markov Models (HMM) and represent each AE day as one of 17 states. All HMM states were clinically interpreted based on their patterns of MVTS variables and relationships with clinical information. Visualization differentiated patients progressing toward stable 'discharge-like' states versus those remaining at risk of inpatient mortality (IM). Chi-square tests confirmed these relationships (two states associated with IM; 12 states with ≥1 diagnosis). Logistic Regression and Random Forest (RF) models trained with MVTS data rather than states had higher prediction performances of IM, but results were comparable (best RF model AUC-ROC: MVTS data = 0.85; HMM states = 0.79). ML models extracted clinically interpretable signals from hospital data. The potential of ML to develop decision-support tools for EHR systems warrants investigation.

Switching of anti-TNF-α agents in Behçet's disease.

OBJECTIVES: Recent reports suggest efficacy of anti-tumour necrosis factor-alpha (TNF-α) therapy in Behçet's disease. However, the switching of anti-TNF-α agents for treatment failure remains unexplored. Our aims were to describe the efficacy and safety of a second anti-TNF-α agent in Behçet's disease patients after failure of a first agent. METHODS: In this retrospective case series, 34 Behçet's disease patients receiving anti-TNF-α agents, 19 of whom switched to a second anti-TNF-α agent, were identified. We assessed the response to anti-TNF-α agents, the duration of anti-TNF-α therapy, the reasons for withdrawal, adverse events, the Behçet's Disease Current Activity Form (BDCAF), C-reactive protein (CRP), ESR and concomitant therapies at the onset of the first and second anti-TNF-α therapies, and after 6, 12 and 24 months. RESULTS: Clinical improvements were seen in 26/34 (76%) after the first and 18/19 (95%) after the second anti-TNF-α agent. Continuation rates at 24 months were 14.4% after the first and 22.3% after the second anti-TNF-α agent. The most frequent reason for discontinuation was secondary failure in both groups (12 after the first anti-TNF-α agent and 8 after the second). Adverse events leading to treatment withdrawal were seen in 10 after the first anti-TNF-α agent and three after the second. CONCLUSIONS: [corrected] The second anti-TNF-α agent in Behçet's disease demonstrated similar efficacy to that seen with the first agent without new safety concerns, supporting switching to a second anti-TNF-α agent. However, long-term continuation rates for anti-TNF-α therapy were low after both the first and second agents.

Novel expression signatures identified by transcriptional analysis of separated leucocyte subsets in systemic lupus erythematosus and vasculitis.

OBJECTIVE: To optimise a strategy for identifying gene expression signatures differentiating systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody-associated vasculitis that provide insight into disease pathogenesis and identify biomarkers. METHODS: 44 vasculitis patients, 13 SLE patients and 25 age and sex-matched controls were enrolled. CD4 and CD8 T cells, B cells, monocytes and neutrophils were isolated from each patient and, together with unseparated peripheral blood mononuclear cells (PBMC), were hybridised to spotted oligonucleotide microarrays. RESULTS: Using expression data obtained from purified cells a substantial number of differentially expressed genes were identified that were not detectable in the analysis of PBMC. Analysis of purified T cells identified a SLE-associated, CD4 T-cell signature consistent with type 1 interferon signalling driving the generation and survival of tissue homing T cells and thereby contributing to disease pathogenesis. Moreover, hierarchical clustering using expression data from purified monocytes provided significantly improved discrimination between the patient groups than that obtained using PBMC data, presumably because the differentially expressed genes reflect genuine differences in processes underlying disease pathogenesis. CONCLUSION: Analysis of leucocyte subsets enabled the identification of gene signatures of both pathogenic relevance and with better disease discrimination than those identified in PBMC. This approach thus provides substantial advantages in the search for diagnostic and prognostic biomarkers in autoimmune disease.

Long-term efficacy and safety of rituximab in refractory and relapsing systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus is a relapsing autoimmune disease. Conventional therapy increases the risk of infection and malignancies; furthermore, a minority of patients suffer from refractory disease. B-cell depletion with the chimeric +AFw-anti-CD20 monoclonal antibody, rituximab, is an alternative therapy for relapsing and refractory systemic lupus erythematosus. We sought to assess the long-term efficacy and safety of rituximab in this patient subgroup. METHODS: Thirty-one sequential patients with relapsing or refractory systemic lupus erythematosus, 11 of whom had active lupus nephritis, received rituximab [either 375 mg/m(2)/week × 4 (n = 16) or 1000 mg × 2 (n = 15)]. The median follow-up was 30 months. RESULTS: Thirty of 31 (97%) patients had depleted peripheral B cells. Twenty-seven of 31 (87%) patients achieved remission (17 complete, 10 partial). Renal response occurred in 10/11 patients (4 complete, 6 partial) with active glomerulonephritis. Clinical improvement was reflected by reductions of disease activity, proteinuria and daily prednisolone dose. Eighteen of 27 (67%) patients relapsed after a median of 11 months. Relapses occurred on or after the return of circulating B cells in 10 but in the absence of B-cell return in 8. Re-treatment with rituximab was effective. Infusion reactions were common (18/31; 58%), and infections occurred in 8/31 (26%) patients. CONCLUSIONS: Rituximab had a high rate of efficacy in relapsing or refractory systemic lupus erythematosus with or without renal involvement. Although relapse was common, it responded to re-treatment. The contribution of rituximab to infection risk was uncertain in view of the complex disease course and concomitant therapy of the patients studied.

Complement abnormalities in acquired lipodystrophy revisited.

CONTEXT: Lipodystrophy is a heterogeneous condition characterized by an inherited or acquired deficiency in the number of adipocytes required for the storage of energy as triglycerides. Acquired lipodystrophy is frequently associated with other autoimmune disorders. One well-studied form is characterized by the selective loss of upper body fat in association with activation of the alternative complement pathway by C3 nephritic factor, low complement factor C3, and mesangiocapillary glomerulonephritis. OBJECTIVE: We now describe an immunologically distinct form of acquired generalized lipodystrophy, with evidence of activation of the classical complement pathway (low C4) and autoimmune hepatitis. Patients and Research Design: Three unrelated patients with acquired lipodystrophy and low complement C4 levels are described. In vitro analysis of the complement pathway was undertaken to determine the reason for the low C4 complement levels. Biopsies were obtained from liver, bone marrow, and adipose tissue for histological analysis. RESULTS: All three patients manifested near-total lipodystrophy, chronic hepatitis with autoimmune features, and low C4 complement levels. Additional autoimmune diseases, including severe hemolytic anemia, autoimmune thyroid disease, and polyneuropathy, were variably present. Detailed studies of complement pathways suggested constitutive classical pathway activation. CONCLUSIONS: Although the previously described syndrome, which typically results in a cephalad pattern of partial lipodystrophy, results from activation of the alternative complement pathway, this form, in which lipodystrophy is generalized, is associated with activation of the classical pathway. Future therapeutic approaches to these disorders may benefit from being tailored to their distinct immunopathogenesis.

Microarray analysis of human leucocyte subsets: the advantages of positive selection and rapid purification.

BACKGROUND: For expression profiling to have a practical impact in the management of immune-related disease it is essential that it can be applied to peripheral blood cells. Early studies have used total peripheral blood mononuclear cells, and as a consequence the majority of the disease-related signatures identified have simply reflected differences in the relative abundance of individual cell types between patients and controls. To identify cell-specific changes in transcription it would be necessary to profile purified leucocyte subsets. RESULTS: We have used sequential rounds of positive selection to isolate CD4 and CD8 T cells, CD19 B cells, CD14 monocytes and CD16 neutrophils for microarray analysis from a single blood sample. We compared gene expression in cells isolated in parallel using either positive or negative selection and demonstrate that there are no significant consistent changes due to positive selection, and that the far inferior results obtained by negative selection are largely due to reduced purity. Finally, we demonstrate that storing cells prior to separation leads to profound changes in expression, predominantly in cells of the myeloid lineage. CONCLUSION: Leukocyte subsets should be prepared for microarray analysis by rapid positive selection.

Comparison of the Phenotype and Outcome of Granulomatosis with Polyangiitis Between UK and Japanese Cohorts.

OBJECTIVE: There are differences in the frequencies of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis subgroups between different geographic regions, and we have reported differences in the phenotype of microscopic polyangiitis between Europe and Japan. In this retrospective observational study, we compared phenotypes and outcomes of granulomatosis with polyangiitis (GPA) between the United Kingdom and Japan. METHODS: We identified 128 UK and 82 Japanese patients with GPA diagnosed between 2000 and 2012. We evaluated baseline characteristics including ANCA status and organ involvement, treatment, patient and renal survival, and time to first relapse. RESULTS: Median age at onset was higher in Japan than in the UK (62.2 yrs vs 57.5 yrs, p < 0.01). The proportion of patients with proteinase 3 (PR3)-ANCA was lower in Japan than in the UK (61.0% vs 85.2%, p < 0.01), while the proportion of myeloperoxidase-ANCA was higher in Japan than the UK (34.1% vs 8.6%, p < 0.01). Serum creatinine at diagnosis was lower in Japan than the UK (68.1 µmol/l vs 101.0 µmol/l, p < 0.01). Respiratory involvement was more frequent in Japan than the UK (69.5% vs 40.6%, p < 0.01). In both countries, most patients received both glucocorticoids and cyclophosphamide. At 60 months the cumulative survival rates were 87.6% and 94.3% in Japan and the UK, respectively (p = 0.03). At 60 months the cumulative relapse rates were 37.1% and 68.1% in Japan and the UK, respectively (p < 0.01). CONCLUSION: Japanese patients with GPA were older at disease onset, with less PR3-ANCA positivity, milder renal dysfunction, and more frequent respiratory involvement than UK patients. The relapse-free survival rate was higher in Japan than the United Kingdom.

Alemtuzumab as Remission Induction Therapy in Behçet Disease: A 20-year Experience.

OBJECTIVE: To study the efficacy and safety of anti-CD52 antibody (alemtuzumab) in the treatment of refractory and relapsing Behçet disease (BD). METHODS: Thirty-two patients (22 women) with BD received 60 courses of alemtuzumab between 1994 and 2013. Three-dose regimens were used: 134 mg in 21 courses (Group 1), 95 mg in 18 courses (Group 2), and 60 mg in 21 courses (Group 3). Immunosuppressive drugs were stopped at the time of alemtuzumab, and prednisolone was reduced according to clinical response. Treatment response was assessed by clinical status, inflammatory activity, prednisolone dose, and the need for subsequent immunosuppressive drugs and disease relapse. RESULTS: After the first alemtuzumab course, 27 of 32 patients (84%) achieved partial or complete remission (CR). Fifty of 60 courses (83%) resulted in remission (66% CR) without differences in remission rates between dosing regimens. Profound lymphocyte depletion occurred after all courses. Relapse-free survival rates were 83.6% at 6 months and 52.8% at 12 months, and were higher among Group 1 patients (Group 1: 100% and 77.8%, Group 2: 81.3% and 37.5%, and Group 3: 65.0% and 37.1%, p < 0.001). Mild to moderate infusion reactions occurred after 16 courses (27%). Eight patients (25%) developed symptomatic thyroid disease. CONCLUSION: Alemtuzumab led to remission in the majority of patients with difficult-to-treat BD. Relapse was common and may be associated with lower dosing. Adverse events included infusion reactions and new autoimmunity. Achieving complete lymphocyte depletion did not affect the remission rate or duration.

Heparin-induced hyperkalemia after cardiac surgery.

Surgeons are increasingly faced with patients suffering from complicated pathology in multiple organ systems, to which multiple therapeutic agents with complex adverse effects are often prescribed. We face a daily challenge in maintaining an up-to-date knowledge of these complications. Heparin is widely used in surgical practice, yet our awareness of its adverse effects, other than bleeding and thrombocytopenia, remains poor. We will present an example of heparin-induced hyperkalemia following administration for cardiopulmonary bypass and intraaortic balloon pump prophylaxis. This is a rare but serious complication of heparin therapy, not usually reported in the context of a cardiac surgical patient. We will also discuss the renal physiology leading to hyperkalemia and the options available for its management.

Randomized trial of enteric-coated mycophenolate sodium versus mycophenolate mofetil in multi-system autoimmune disease.

BACKGROUND: The use of mycophenolate mofetil (MMF) in autoimmune disease is often limited by adverse effects. In this single-centre, open label, parallel design study, we investigated whether enteric-coated mycophenolate sodium (MS) is better tolerated and therefore more efficacious than MMF in primary systemic vasculitis (PSV) and systemic lupus erythematosus (SLE). METHODS: Forty patients with vasculitis or systemic lupus erythematosus (SLE) due to commence MMF for active disease or remission maintenance were randomized to receive either 1440 mg/day MS or 2000 mg/day MMF (18 PSV, 2 SLE per group) in addition to corticosteroids. Random allocation was performed by minimization for age, diagnosis and renal function using a computer algorithm. Twenty-five were treated for active disease (5 first-line therapy, 20 salvage therapy) and 15 for remission maintenance. The composite primary end point was treatment failure and/or drug intolerance over 12 months. Treatment failure was defined as failure to achieve remission by 6 months or disease relapse and treatment intolerance was defined as inability to tolerate and maintain the target dose of MS or MMF within 12 months. RESULTS: Forty patients were included in the analyses. MS was associated with a lower primary end point rate [hazard ratio (HR) 0.37; 95% CI 0.17-0.80; P = 0.012] (11/20, 55% patients) compared with MMF (17/20, 85% patients). Treatment failure alone was less common in the MS group (HR 0.28; 95% CI 0.095-0.82; P = 0.020), although drug intolerance did not differ between groups (HR 0.53; 95% CI 0.20-1.42; P = 0.21). Despite randomization, patients in the MMF group may have had a higher baseline risk for treatment failure; more MMF patients had refractory disease and granulomatosis with polyangiitis (Wegener's). A glomerular filtration rate (GFR) ≤40 mL/min was associated with intolerance. Serious adverse events were common (55% MMF and 45% MS patients). CONCLUSIONS: No differences in treatment tolerance were observed between the MS and MMF groups. Despite similar treatment intolerance, MS was associated with improved efficacy in PSV and SLE compared with MMF. However, baseline group imbalances in factors potentially affecting remission and relapse may have influenced the results. Treatment intolerance was common and strongly associated with low GFR. Further treatment trials are warranted to investigate the effect of GFR on mycophenolic acid pharmacokinetics and clinical outcomes (ISRCTN83027184; EUDRACT 2005-002207-16; Funding Novartis UK).

Comparison of phenotype and outcome in microscopic polyangiitis between Europe and Japan.

OBJECTIVE: There are differences between Europe and Japan in the incidence and antineutrophil cytoplasmic antibody (ANCA) serotype of patients with microscopic polyangiitis (MPA). However, differences in phenotype or outcome have not been explored. We aimed to identify differences in phenotype and outcome of MPA between Europe and Japan. METHODS: Sequential cohorts of patients with MPA and renal limited vasculitis were collected from European and Japanese centers (n = 147 and n = 312, respectively). Trial databases from the European Vasculitis Society and the Japanese patients with Myeloperoxidase (MPO)-ANCA-Associated Vasculitis (JMAAV) trial were studied (n = 254 and n = 48, respectively). We evaluated baseline characteristics including ANCA status and organ involvement, treatment, survival, and renal survival. Differences in survival and renal survival were studied using multivariate analysis. RESULTS: The non-trial cohorts showed patients with MPA in Japan had a higher age at onset, more frequent MPO-ANCA positivity, lower serum creatinine, and more frequent interstitial pneumonitis than those in Europe (all p < 0.01). Comparisons between the trial databases demonstrated similar results. Cumulative patient survival and renal survival rates were not different between Europe and Japan (p = 0.71 and p = 0.38, respectively). Multivariate analysis identified age at onset, serum creatinine, gastrointestinal, and respiratory involvement as factors with higher risk of death. For endstage renal failure, serum creatinine and use of plasma exchange were identified as factors with higher risk, and immunosuppressant use as lower risk factors. CONCLUSION: Phenotypes in patients with MPA were different between Europe and Japan. However, the outcomes of patient survival and renal survival were similar.

ACE inhibitor and angiotensin receptor-II antagonist prescribing and hospital admissions with acute kidney injury: a longitudinal ecological study.

BACKGROUND: ACE Inhibitors (ACE-I) and Angiotensin-Receptor Antagonists (ARAs) are commonly prescribed but can cause acute kidney injury (AKI) during intercurrent illness. Rates of hospitalization with AKI are increasing. We aimed to determine whether hospital AKI admission rates are associated with increased ACE-I/ARA prescribing. METHODS AND FINDINGS: English NHS prescribing data for ACE-I/ARA prescriptions were matched at the level of the general practice to numbers of hospital admissions with a primary diagnosis of AKI. Numbers of prescriptions were weighted for the demographic characteristics of general practices by expressing prescribing as rates where the denominator is Age, Sex, and Temporary Resident Originated Prescribing Units (ASTRO-PUs). We performed a mixed-effect Poisson regression to model the number of admissions for AKI occurring in each practice for each of 4 years from 1/4/2007. From 2007/8-2010/11, crude AKI admission rates increased from 0.38 to 0.57 per 1000 patients (51.6% increase), and national annual ACE-I/ARA prescribing rates increased by 0.032 from 0.202 to 0.234 (15.8% increase). There was strong evidence (p<0.001) that increases in practice-level prescribing of ACE-I/ARA over the study period were associated with an increase in AKI admission rates. The increase in prescribing seen in a typical practice corresponded to an increase in admissions of approximately 5.1% (rate ratio = 1.051 for a 0.03 per ASTRO-PU increase in annual prescribing rate, 95%CI 1.047-1.055). Using the regression model we predict that 1,636 (95%CI 1,540-1,780) AKI admissions would have been avoided if prescribing rates were at the 2007/8 level, equivalent to 14.8% of the total increase in AKI admissions. CONCLUSION: In this ecological analysis, up to 15% of the increase in AKI admissions in England over a 4-year time period is potentially attributable to increased prescribing of ACE-I and ARAs. However, these findings are limited by the lack of patient level data such as indication for prescribing and patient characteristics.

A comprehensive study of clinical, biochemical, radiological, vascular, cardiac, and sleep parameters in an unselected cohort of patients with acromegaly undergoing presurgical somatostatin receptor ligand therapy.

CONTEXT: Attainment of safe GH and IGF-1 levels is a central goal of acromegaly management. OBJECTIVE: The aim of this study was to determine the extent to which reductions in GH and IGF-1 concentrations correlate with amelioration of radiological, metabolic, vascular, cardiac, and respiratory sequelae in a single unselected patient cohort. STUDY DESIGN: This was a prospective, within-subject comparison in 30 patients with newly diagnosed acromegaly (15 women and 15 men: mean age, 54.3 years; range, 23-78 years) before and after 24 weeks of lanreotide Autogel (ATG) therapy. RESULTS: Reductions in GH and IGF-1 concentrations and tumor volume were observed in all but 2 patients (median changes [Δ]: GH, -6.88 µg/L [interquartile range -16.78 to -3.32, P = .000001]; IGF-1, -1.95 × upper limit of normal [-3.06 to -1.12, P = .000002]; and pituitary tumor volume, -256 mm(3) [-558 to -72.5, P = .0002]). However, apnea/hypopnea index scores showed highly variable responses (P = .11), which were independent of ΔGH or ΔIGF-1, but moderately correlated with Δweight (R(2) = 0.42, P = .0001). Although systolic (P = .33) and diastolic (P = .76) blood pressure were unchanged, improvements in arterial stiffness (aortic pulse wave velocity, -0.4 m/s [-1.2 to +0.2, P = .046]) and endothelial function (flow mediated dilatation, +1.73% [-0.32 to +6.19, P = .0013]) were observed. Left ventricular mass index regressed in men (-11.8 g/cm(2) [-26.6 to -1.75], P = .019) but not in women (P = .98). Vascular and cardiac changes were independent of ΔGH or ΔIGF-1 and also showed considerable interindividual variation. Metabolic parameters were largely unchanged. CONCLUSIONS: Presurgical ATG therapy lowers GH and IGF-1 concentrations, induces tumor shrinkage, and ameliorates/reverses cardiac, vascular, and sleep complications in many patients with acromegaly. However, responses vary considerably between individuals, and attainment of biochemical control cannot be assumed to equate to universal complication control.

Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types.

The likelihood for immunological rejection of Human Leukocyte Antigens (HLA)-mismatched induced pluripotent stem cells (iPSCs) limits their therapeutic potential. Here we show how a tissue bank from 150 selected homozygous HLA-typed volunteers could match 93% of the UK population with a minimal requirement for immunosuppression. Our model provides a practical approach for using existing HLA-typed samples to generate an iPSC stem cell bank that circumvents prospective typing of a large number of individuals.