Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney.

AIMS: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. METHODS AND RESULTS: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. CONCLUSION: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.

Social deprivation modifies the association between incident foot ulceration and mortality in type 1 and type 2 diabetes: a longitudinal study of a primary-care cohort.

AIMS/HYPOTHESIS: The aim of this study was to determine whether social deprivation in the presence of diabetes is an independent predictor of developing a foot ulcer and separately of mortality. METHODS: This was a primary-care-based retrospective analysis of 13,955 adults with type 1 (n = 1370) or type 2 (n = 12,585) diabetes after a median follow-up of 10.5 years. Demographic characteristics, indices of social deprivation and clinical variables were assessed at baseline. The primary outcomes were new foot ulceration (in those without a previous history of foot ulcers) and all-cause mortality. Cox proportional hazard models were used to describe the associations among foot ulceration, social deprivation and mortality. RESULTS: The mean age of the population was 69.4 (range: 16-89) years. The incidence of foot ulceration was greater in individuals with type 2 (8.6%) compared with type 1 diabetes (4.8%). Occurrence was similar by sex, but increased with age and deprivation index. Individuals in the highest quintile of deprivation were 77% more likely to develop a foot ulcer compared with those in the lowest quintile (OR 1.77 [95% CI 1.45, 2.14], p < 0.0001). Overall, 2946 (21.1%) deaths were recorded. Compared with individuals without a foot ulcer, the development of a foot ulcer was associated with a higher age- and sex-adjusted mortality rate (25.9% vs 14.0%), and a 72% (HR 1.72 [95% CI 1.56, 1.90], p < 0.001) increased risk of mortality in those with type 2 diabetes. Risk of death increased by 14% per quintile of deprivation in a univariable analysis (HR 1.14 [95% CI 1.10, 1.17]). In multivariable Cox regression analyses, there was a 48% increased risk of mortality in individuals with a foot ulcer (HR 1.48 [95% CI 1.33, 1.66]) independent of the Townsend index score (HR 1.13 [95% CI 1.10, 1.17], per quintile), baseline age, sex, diabetes type, smoking status, hypertension, statin use, ß-blocker use, metformin use, HbA1c levels and insulin use. CONCLUSIONS/INTERPRETATION: This study confirms the high mortality rate in individuals with diabetes-related foot ulcers. In addition, socioeconomic disadvantage was found to be an independent effect modifier, contributing to an increased burden of mortality in people with diabetes who develop foot ulceration. In light of this, and as diabetes service configurations are orientated for the next 5-10 years, modelling of foot ulceration risk needs to take socioeconomic disadvantage into account.

Pain relief for outpatient hysteroscopy.

BACKGROUND: Hysteroscopy is increasingly performed in an outpatient setting. Pain is the primary reason for abandonment of procedure or incomplete assessment. There is no consensus upon routine use of analgesia during hysteroscopy. OBJECTIVES: To assess the effectiveness and safety of pharmacological interventions for pain relief in women undergoing outpatient hysteroscopy, compared with placebo, no treatment or other pharmacological therapies. SEARCH METHODS: In September 2016 we searched the Cochrane Gynaecology and Fertility (CGF) Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers (ClinicalTrials.gov and WHO ICTRP), together with reference checking and contact with study authors and experts. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing use of pharmacological interventions with other pharmacological interventions and pharmacological interventions versus placebo or no treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcome was mean pain score. MAIN RESULTS: We included 32 RCTS (3304 participants), of which only 19 reported data suitable for analysis. Most studies were at unclear or high risk of bias in most of the domains assessed. The evidence was low or very low quality, mainly due to risk of bias and imprecision. Baseline pain scores were relatively low in all groups. Analgesic versus placebo or no treatment Local anaesthetics Local anaesthetics reduced mean pain scores during the procedure [(SMD) -0.29, 95% CI -0.39 to -0.19, 10 RCTs, 1496 women, I2 = 80%, low-quality evidence)] and within 30 minutes (SMD 0.50, 95% CI -0.67 to -0.33, 5 RCTs, 545 women, I2 = 43%, low-quality evidence). This translates to a difference of up to 7 mm on a 0-10 cm visual analogue scale (VAS) during the procedure and up to 13 mm within 30 minutes, which is unlikely to be clinically meaningful. There was no clear evidence of a difference between the groups in mean pain scores after > 30 minutes (SMD -0.11, 95% CI -0.30 to 0.07, 4 RCTs, 450 women, I2 = 0%, low-quality evidence), or in rates of vasovagal reactions (OR 0.70, 95% CI 0.43 to 1.13, 8 RCTs, 1309 women, I2 = 66%, very low-quality evidence). There was insufficient evidence to determine whether there was a difference in rates of non-pelvic pain (OR 1.76, 95% CI 0.53 to 5.80, 1 RCT, 99 women, very low-quality evidence). Nonsteroidal anti-inflammatory drugs (NSAIDs) There was insufficient evidence to determine whether there was a difference between the groups in mean pain scores during the procedure (SMD -0.18, 95% CI -0.35 to 0.00, 3 RCTs, 521 women, I2 = 81%, low-quality evidence). Pain scores were lower in the NSAIDs group within 30 minutes (SMD -0.25, 95% CI -0.46 to -0.04, 2 RCTs, 340 women, I2=29%, low-quality evidence) and at over 30 minutes (SMD -0.27, 95% CI -0.49 to -0.05, 2 RCTs, 321 women, I2 = 78%, low-quality evidence). This equates to maximum differences of under 7.5 mm on a 0-10 cm scale, which are unlikely to be clinically significant. One RCT (181 women) reported adverse events: there was insufficient evidence to determine whether there was a difference between the groups in vasovagal reactions (OR 0.76, 95% CI 0.20 to 2.94, very low-quality evidence). For other reported adverse events (non pelvic pain and allergic reactions) evidence was lacking. Opioids One RCT utilised sublingual buprenorphine and one utilised oral tramadol. Data on pain scores during the procedure were unsuitable for pooling due to inconsistency. Tramadol was associated with a benefit of up to 22 mm on a 0-10 cm scale (SMD -0.76, 95% CI -1.10 to -0.42, 1 RCT, 140 women). However, the effect estimate for this outcome for sublingual opioids did not support a benefit from the intervention (SMD 0.08, 95% CI -0.22 to 0.39, 164 women). Compared with placebo, the pain score within 30 minutes of the procedure was reduced in the tramadol group, with a difference of up to 17mm on a 0-10cm scale (SMD -0.57, 95% CI -0.91 to -0.23 , 1 RCT, 140 women, low-quality evidence. There was no clear evidence of a difference between the tramadol and placebo groups at over 30 minutes (SMD -0.17, 95% CI -0.51 to 0.16, 1 RCT, 140 women, low-quality evidence). Nausea and vomiting occurred in 39% of the buprenorphine group, and in none of the placebo group (OR 107.55, 95% CI 6.44 to 1796.46) Analgesic versus any other analgesic Some comparisons did not report pain scores at all time frames of interest, and none reported data on adverse events. One RCT (84 women) compared local intracervical anaesthesia versus combined intracervical and paracervical anaesthesia. Pain scores were higher in the group with local intracervical anaesthesia during the procedure (SMD 4.27, 95% CI 3.49 to 5.06, very low-quality evidence), within 30 minutes (SMD 1.55, 95% CI 1.06 to 2.05, very low-quality evidence) and at more than 30 minutes (SMD 3.47, 95% CI 2.78 to 4.15, very low-quality evidence). This translates to a possible benefit in the combined group of up to 12 mm on a 0-10 cm scale during the procedure. Benefits at longer follow-up were smaller. One RCT compared antispasmodic + NSAID versus local paracervical anaesthesia. Pain scores were lower in the NSAID group than in the local anaesthesia group (during procedure: SMD -1.40, 95% CI -1.90 to -0.91; >30 minutes after procedure: SMD -0.87, 95% CI -1.33 to -0.41; 80 women, very low-quality evidence). This suggests a possible benefit of during the procedure of up to 23 mm on a 0-10 VAS scale and up to 11 mm >30 minutes after the procedure. Other comparisons included local intracervical anaesthesia versus combined intracervical, paracervical and topical anaesthesia, and opioid versus NSAIDs. Findings were inconclusive. AUTHORS' CONCLUSIONS: There was no consistent good-quality evidence of a clinically meaningful difference in safety or effectiveness between different types of pain relief compared with each other or with placebo or no treatment in women undergoing outpatient hysteroscopy.

Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets.

Genetic mechanisms of blood pressure (BP) regulation remain poorly defined. Using kidney-specific epigenomic annotations and 3D genome information we generated and validated gene expression prediction models for the purpose of transcriptome-wide association studies in 700 human kidneys. We identified 889 kidney genes associated with BP of which 399 were prioritised as contributors to BP regulation. Imputation of kidney proteome and microRNAome uncovered 97 renal proteins and 11 miRNAs associated with BP. Integration with plasma proteomics and metabolomics illuminated circulating levels of myo-inositol, 4-guanidinobutanoate and angiotensinogen as downstream effectors of several kidney BP genes (SLC5A11, AGMAT, AGT, respectively). We showed that genetically determined reduction in renal expression may mimic the effects of rare loss-of-function variants on kidney mRNA/protein and lead to an increase in BP (e.g., ENPEP). We demonstrated a strong correlation (r = 0.81) in expression of protein-coding genes between cells harvested from urine and the kidney highlighting a diagnostic potential of urinary cell transcriptomics. We uncovered adenylyl cyclase activators as a repurposing opportunity for hypertension and illustrated examples of BP-elevating effects of anticancer drugs (e.g. tubulin polymerisation inhibitors). Collectively, our studies provide new biological insights into genetic regulation of BP with potential to drive clinical translation in hypertension.

Contributions of obesity to kidney health and disease: insights from Mendelian randomization and the human kidney transcriptomics.

AIMS: Obesity and kidney diseases are common complex disorders with an increasing clinical and economic impact on healthcare around the globe. Our objective was to examine if modifiable anthropometric obesity indices show putatively causal association with kidney health and disease and highlight biological mechanisms of potential relevance to the association between obesity and the kidney. METHODS AND RESULTS: We performed observational, one-sample, two-sample Mendelian randomization (MR) and multivariable MR studies in ∼300 000 participants of white-British ancestry from UK Biobank and participants of predominantly European ancestry from genome-wide association studies. The MR analyses revealed that increasing values of genetically predicted body mass index and waist circumference were causally associated with biochemical indices of renal function, kidney health index (a composite renal outcome derived from blood biochemistry, urine analysis, and International Classification of Disease-based kidney disease diagnoses), and both acute and chronic kidney diseases of different aetiologies including hypertensive renal disease and diabetic nephropathy. Approximately 13-16% and 21-26% of the potentially causal effect of obesity indices on kidney health were mediated by blood pressure and type 2 diabetes, respectively. A total of 61 pathways mapping primarily onto transcriptional/translational regulation, innate and adaptive immunity, and extracellular matrix and metabolism were associated with obesity measures in gene set enrichment analysis in up to 467 kidney transcriptomes. CONCLUSIONS: Our data show that a putatively causal association of obesity with renal health is largely independent of blood pressure and type 2 diabetes and uncover the signatures of obesity on the transcriptome of human kidney.

Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.

The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.

Optimal timing for faecal tagging in same day CT colonography for patients with failed colonoscopy.

AIM: Same day CT colonography (CTC) for incomplete colonoscopy should be considered to avoid the need for further bowel preparation. Oral administration of contrast is essential for optimal colonic analysis of the CTC. Our aim was to determine the optimal time for giving contrast to people who underwent same day CTC after failed colonoscopy. METHODS: Data was extracted from the Trust database to identify the number of CTC referrals following failed or incomplete colonoscopy within the last 5 years, and the reason for their referral. Patients were then excluded if they had not received faecal tagging, which included all patients prior to 2013. Two experienced radiologists independently reviewed the CTCs to determine the level of faecal tagging, and this was correlated with the estimated length of time between the administration of the contrast agent and the CTC examination. RESULTS: 110 patients were identified within the 5 year period who had undergone same day CTC following failed colonoscopy. Reasons for the referral included incomplete colonoscopy (most common indication), contraindication to colonoscopy, poor colonoscopic view, refusal for colonoscopy and data unavailable. 60 patients had received faecal tagging, and two experienced radiologists independently reviewed these CTCs to determine the level of faecal tagging from the caecum to the rectum (complete bowel coverage). CONCLUSION: Our study suggests that contrast should be given approximately 256.4 ± 24.4 (4.27 h) minutes before same day CTC, but this time could be reduced where the left side of the colon had been successfully evaluated by colonoscopy. Further studies with multicentre collaborations are required.

Endothelium-derived extracellular vesicles promote splenic monocyte mobilization in myocardial infarction.

Transcriptionally activated monocytes are recruited to the heart after acute myocardial infarction (AMI). After AMI in mice and humans, the number of extracellular vesicles (EVs) increased acutely. In humans, EV number correlated closely with the extent of myocardial injury. We hypothesized that EVs mediate splenic monocyte mobilization and program transcription following AMI. Some plasma EVs bear endothelial cell (EC) integrins, and both proinflammatory stimulation of ECs and AMI significantly increased VCAM-1-positive EV release. Injected EC-EVs localized to the spleen and interacted with, and mobilized, splenic monocytes in otherwise naive, healthy animals. Analysis of human plasma EV-associated miRNA showed 12 markedly enriched miRNAs after AMI; functional enrichment analyses identified 1,869 putative mRNA targets, which regulate relevant cellular functions (e.g., proliferation and cell movement). Furthermore, gene ontology termed positive chemotaxis as the most enriched pathway for the miRNA-mRNA targets. Among the identified EV miRNAs, EC-associated miRNA-126-3p and -5p were highly regulated after AMI. miRNA-126-3p and -5p regulate cell adhesion- and chemotaxis-associated genes, including the negative regulator of cell motility, plexin-B2. EC-EV exposure significantly downregulated plexin-B2 mRNA in monocytes and upregulated motility integrin ITGB2. These findings identify EVs as a possible novel signaling pathway by linking ischemic myocardium with monocyte mobilization and transcriptional activation following AMI.