We performed fine-mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine-mapping implicated rs10830963 as driving T2D association. We confirmed that this T2D-risk allele increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D-risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

Background and aimsCoronary artery disease (CAD) risk is associated with non-coding genetic variants at the phosphatase and actin regulating protein 1(PHACTR1) gene locus. The PHACTR1 gene encodes an actin-binding protein with phosphatase regulating activity. The mechanism whereby PHACTR1 influences CAD risk is unknown. We hypothesized that PHACTR1 would be expressed in human cell types relevant to CAD and regulated by atherogenic or genetic factors.Methods and resultsUsing immunohistochemistry, we demonstrate that PHACTR1 protein is expressed strongly in human atherosclerotic plaque macrophages, lipid-laden foam cells, adventitial lymphocytes and endothelial cells. Using a combination of genomic analysis and molecular techniques, we demonstrate that PHACTR1 is expressed as multiple previously uncharacterized transcripts in macrophages, foam cells, lymphocytes and endothelial cells. Immunoblotting confirmed a total absence of PHACTR1 in vascular smooth muscle cells. Real-time quantitative PCR showed that PHACTR1 is regulated by atherogenic and inflammatory stimuli. In aortic endothelial cells, oxLDL and TNF-alpha both upregulated an intermediate length transcript. A short transcript expressed only in immune cells was upregulated in macrophages by oxidized low-density lipoprotein, and oxidized phospholipids but suppressed by lipopolysaccharide or TNF-alpha. In primary human macrophages, we identified a novel expression quantitative trait locus (eQTL) specific for this short transcript, whereby the risk allele at CAD risk SNP rs9349379 is associated with reduced PHACTR1 expression, similar to the effect of an inflammatory stimulus.ConclusionsOur data demonstrate that PHACTR1 is a key atherosclerosis candidate gene since it is regulated by atherogenic stimuli in macrophages and endothelial cells and we identify an effect of the genetic risk variant on PHACTR1 expression in macrophages that is similar to that of an inflammatory stimulus.

Elderly patients form the most rapidly expanding group of hemodialysis (HD) patients in Europe and the United States. There are initiatives to promote an increase in arteriovenous fistula (AVF) formation. There are concerns that elderly patients may have lower rates of surgical vascular access compared with younger patients due to risks of higher co-morbidities, surgical complications, and higher AVF nonuse rates. The aim of this study was to compare access-related survival and morbidity for dialysis catheters and AVFs and to evaluate the AVF nonuse rate in an elderly population. We have performed a retrospective analysis of access survival and morbidity in patients > or = 70 years of age, either on maintenance HD or predialysis with preemptive formation of surgical access. One hundred and forty-six patients had permanent HD access created during the 18-month study period, from 1 January 2006 to June 2007. There were 89 male and 57 female patients in whom 78 AVFs and 137 tunneled venous catheters were inserted. There was a significantly greater loss of vascular access due to infection in the catheter group compared with the AVF group (P<0.016). Access survival was also significantly prolonged in the AVF group (446 days, 95% confidence interval 405-487) compared with the catheter group (276 days, 95% confidence interval 240-313), P=0.001. The rate of nonuse of AVFs was low (16%). We conclude that an AVF is the preferred form of vascular access in elderly HD patients.

Hypertension secondary to hydronephrosis is not commonly reported in the medical literature. Tubuloglomerular feedback and the renin-angiotensin-aldosterone axis are thought to mediate this process. We describe a patient presenting with acute kidney injury and bilateral hydronephrosis secondary to pelvic malignancy in which peripheral venous renin and aldosterone were elevated. Her blood pressure improved rapidly following insertion of bilateral nephrostomies. The speed of resolution of hypertension following relief of obstruction suggests that humorally mediated vasoconstriction can play an important role in the mechanism by which hydronephrosis causes hypertension. We also discuss other causes of renal parenchymal compression that may lead to the development of hypertension.

Background Dialysis patients and immunosuppressed renal patients are at increased risk of COVID-19 and were excluded from vaccine trials. We conducted a prospective multicentre study to assess SARS-CoV-2 vaccine antibody responses in dialysis patients and renal transplant recipients, and patients receiving immunosuppression for autoimmune disease. Methods Patients were recruited from three UK centres (ethics:20/EM/0180) and compared to healthy controls (ethics:17/EE/0025). SARS-CoV-2 IgG antibodies to spike protein were measured using a multiplex Luminex assay, after first and second doses of Pfizer BioNTech BNT162b2(Pfizer) or Oxford-AstraZeneca ChAdOx1nCoV-19(AZ) vaccine. Results Six hundred ninety-two patients were included (260 dialysis, 209 transplant, 223 autoimmune disease (prior rituximab 128(57%)) and 144 healthy controls. 299(43%) patients received Pfizer vaccine and 379(55%) received AZ. Following two vaccine doses, positive responses occurred in 96% dialysis, 52% transplant, 70% autoimmune patients and 100% of healthy controls. In dialysis patients, higher antibody responses were observed with the Pfizer vaccination. Predictors of poor antibody response were triple immunosuppression (adjusted odds ratio [aOR]0.016;95%CI0.002–0.13;p < 0.001) and mycophenolate mofetil (MMF) (aOR0.2;95%CI 0.1–0.42;p < 0.001) in transplant patients; rituximab within 12 months in autoimmune patients (aOR0.29;95%CI 0.008–0.096;p < 0.001) and patients receiving immunosuppression with eGFR 15-29 ml/min (aOR0.031;95%CI 0.11–0.84;p = 0.021). Lower antibody responses were associated with a higher chance of a breakthrough infection. Conclusions Amongst dialysis, kidney transplant and autoimmune populations SARS-CoV-2 vaccine antibody responses are reduced compared to healthy controls. A reduced response to vaccination was associated with rituximab, MMF, triple immunosuppression CKD stage 4. Vaccine responses increased after the second dose, suggesting low-responder groups should be prioritised for repeated vaccination. Greater antibody responses were observed with the mRNA Pfizer vaccine compared to adenovirus AZ vaccine in dialysis patients suggesting that Pfizer SARS-CoV-2 vaccine should be the preferred vaccine choice in this sub-group.

BackgroundDialysis patients and immunosuppressed renal patients are at increased risk of COVID-19 and were excluded from vaccine trials. We conducted a prospective multicentre study to assess SARS-CoV-2 vaccine antibody responses in dialysis patients and renal transplant recipients, and patients receiving immunosuppression for autoimmune disease. Methods Patients were recruited from three UK centres (ethics:20/EM/0180) and compared to healthy controls (ethics:17/EE/0025). SARS-CoV-2 IgG antibodies to spike protein were measured using a multiplex Luminex assay, after first and second doses of Pfizer BioNTech BNT162b2(Pfizer) or Oxford-AstraZeneca ChAdOx1nCoV-19(AZ) vaccine.Results692 patients were included (260 dialysis, 209 transplant, 223 autoimmune disease (prior rituximab 128(57%)) and 144 healthy controls. 299(43%) patients received Pfizer vaccine and 379(55%) received AZ. Following two vaccine doses, positive responses occurred in 96% dialysis, 52% transplant, 70% autoimmune patients and 100% of healthy controls. In dialysis patients, higher antibody responses were observed with the Pfizer vaccination. Predictors of poor antibody response were triple immunosuppression (adjusted odds ratio [aOR]0.016;95%CI0.002-0.13;p<0.001) and mycophenolate mofetil (MMF) (aOR0.2;95%CI 0.1-0.42;p<0.001) in transplant patients; rituximab within 12 months in autoimmune patients (aOR0.29;95%CI 0.008–0.096;p<0.001) and patients receiving immunosuppression with eGFR 15-29ml/min (aOR0.031;95%CI 0.11–0.84;p=0.021). ConclusionsAmongst dialysis, kidney transplant and autoimmune populations SARS-CoV-2 vaccine antibody responses are reduced compared to healthy controls. A reduced response to vaccination was associated with rituximab, MMF, triple immunosuppression CKD stage 4. Vaccine responses increased after the second dose, suggesting low-responder groups should be prioritised for repeated vaccination. Greater antibody responses were observed with the mRNA Pfizer vaccine compared to adenovirus AZ vaccine in dialysis patients suggesting that Pfizer SARS-CoV-2 vaccine should be the preferred vaccine choice in this sub-group.

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Background and Aims There is high quality evidence that favours the use of arteriovenous fistulas (AVFs) over central venous catheters (CVCs) for haemodialysis access, based on the association with lowest mortality and fewest complications [1]. However, less is known regarding patient and nurse preferences concerning access choices and the drivers underlying these preferences. One previous study [2] identified physical concerns regarding fistulas as the predominant barrier preventing patients with a CVC from switching to an AVF. Here we provide an expansion on these barriers, alongside novel exploration of nursing opinion on access choice. Methods Data was collected through individually administered patient surveys across 4 regional dialysis sites in East Anglia (n = 380), and anonymised online survey requests to nursing staff at the sites. Deductive and inductive strategies were employed for analysis of the qualitative data. The aim of the thematic analysis of the data was to determine the preferred access modality of patients and nurses, and the drivers for the preferences. Results 63% (n = 238) of patients responded to the questionnaire. Patient responses fell into one of four categories; drivers toward, or barriers against AVFs or CVCs. The largest of these categories was the barriers for AVFs, within which four main themes were identified: ‘Fear’, ‘difficult AVF surgery’, ‘patient preference for lines’ or ‘patients awaiting AVF surgery or transplant’. A smaller theme of ‘insufficient information’ regarding access choice was also identified. ‘Fear’ was the largest theme, within which five subthemes were identified: fear of needles, pain, bleeding, fistula appearance, or fear of complications heard from other patients on the dialysis unit. ‘Difficult AVF surgery’ encompassed two subthemes; those who have had previous failed traumatic attempts or those whose current vascular architecture was not amenable to fistula surgery. The other three categories received far fewer responses. The AVF driver category focussed on fistulas being preferred medically with reduced infection risk, whilst drivers for lines included it being ‘comfortable’ and patients saying that the line works for them. The one comment in the CVC barrier category cited difficulties experienced with lines like blockages and infections. 13 responses were received from dialysis nurses. All respondents were aware of the medical preference for patients to have a fistula, and the reasons why. Nurses themselves also preferred their patients to have fistulas, referencing the same reasons. However, most nurses thought patients preferred CVCs, and were able to cite the same reasons as the patients themselves. Lastly, nurses reported that they convey the benefits and risks of different access types correctly when asked by patients at the dialysis units. Conclusion These findings highlight that, whilst doctors and nurses focus on long-term health benefits of AVF when discussing vascular access choices, patients are focussed on the immediate potential risks of an AVF. We hypothesise that, whilst dialysing, patients share stories of fistula-related complications that drive short-term fear of AVFs, with such impact that the messages conveyed by health professionals are often negated. This difference in agendas is essential to acknowledge. The relationship between clinician, nurse and patient in the haemodialysis setting is unique given its longevity, frequency of contact, and holistic nature. Implementing a strategy to bridge this agenda gap could strengthen this relationship and provide a basis for optimum, evidence-based treatment. We therefore suggest the use of positive patient AVF experiences, delivered via peer education sessions, as a tool to introduce drivers for, and uptake of, AVF for dialysis patients in the future.