A Study of the Upper Gastrointestinal Complications of Renal Transplantation

The purpose of the work contained in this thesis is to investigate the aetiology of upper gastrointestinal disease in renal transplant recipients. It has been recognised for almost thirty years that transplant recipients suffer from a high prevalence of peptic ulceration and a high incidence of the complications of peptic ulceration. The aetiology of this problem remains unclear despite many studies which have attempted to define a cause. These studies have concentrated primarily on the role of gastric acid secretion and the contribution of factors such as hypercalcaemia hypergastrinaemia and corticosteroids. Some increase in gastric acid secretion has indeed been demonstrated although these differences have not been consistent and are not markedly different from the pattern of gastric acid secretion in patients on haemodialysis. Similarly the importance of corticosteroids remains unclear. In this thesis the specific aetiological factors studied were Helicobacter pylori, Cytomegalovirus and Herpes Simplex virus. Helicobacter pylori has been the cause of much interest in the field of peptic ulceration over the past eight years and its role in the aetiology of peptic ulceration and gastritis is a source of continuing debate, although the organism has not been previously investigated in transplant recipients. Cytomegalovirus has been implicated in case reports and uncontrolled series as a cause of peptic ulceration in transplant recipients. However the prevalence of the virus in the gastrointestinal tract of normal individuals is unknown and, because of this, its role as a pathogen in transplant recipients is still to be defined. Lastly Herpes simplex has been suggested as a cause of peptic ulceration in the general population although this is based on indirect evidence and there are no reports of the isolation of the virus from peptic ulcers. Herpes simplex has been identified in association with oesophagitis in both immunocompetent and immunosuppressed individuals but has not been reported in the gastroduodenal mucosa except on rare occassions. The study described in this thesis was performed on an unselected group of renal transplant recipients and on control tissue from non transplant patients. The study group underwent upper gastrointestinal endoscopy at between two and four months after transplantation. All endoscopic abnormalities were documented, and biopsy material was obtained from the gastroduodenal mucosa and stored for subsequent laboratory analysis. The biopsy material was examined histologically to assess the degree of gastritis and duodenitis and to detect the presence of Helicobacter pylori. The presence of Cytomegalovirus and Herpes Simplex was determined by immunohistochemistry. T lymphocyte subpopulations were assessed in the gastroduodenal mucosa of transplant recipients and control patients by immunohistochemistry in an attempt to elucidate the local immunological response to infection particularly with Helicobacter pylori. Symptomatic dyspepsia was identified in 60% of the study group. Peptic ulceration was present in 12% and a striking feature was the high prevalence of mucosal inflammatory lesions without ulceration. Duodenitis was identified in 48% and gastritis in 30%. In total 72% of the study group had one or more abnormality of the upper GI tract. Helicobacter pylori was identified in 48% and was strongly associated with gastritis, with gastric ulceration and with symptomatic dyspepsia. There was a tendency for Helicobacter infection to be associated with a higher serum urea and creatinine and with a higher prednisolone dose although these differences did not achieve statistical significance. Infection with Helicobacter pylori was independent of age and time elapsed since transplantation. Cytomegalovirus was identified in 48% of the study group, but was only present in 11% of the biopsies from the control group. Infection was significantly associated with duodenitis, but no association could be found with other pathological processes or with symptomatic dyspepsia. Cytomegalovirus was not related to renal function or immunosuppression and was independent of age and time elapsed since transplantation. Herpes simplex could not be identified in any of the biopsy material from either the study group or the control group and could not implicated in any disease process in the upper gastrointestinal tract. Analysis of mucosal T lymphocyte subsets revealed a tendency towards an increase in the the Leu2 subset associated with Helicobacter pylori infection, but this did not achieve statistical significance

Informed consent in refractive surgery: in-person vs telemedicine approach.

Purpose:The aim of this study was to compare the quality of consent process in refractive surgery between patients who had a preoperative consent discussion with the surgeon using a telemedicine approach and those who had a face-to-face discussion. Methods:Patients treated between January and December 2017 (8,184 laser vision correction [LVC] and 3,754 refractive lens exchange [RLE] patients) that attended day 1 and 1-month postoperative visit were retrospectively reviewed. Preoperative consent preparation included a consultation with an optometrist, observation of an educational video, and written information. Patients then selected either a face-to-face appointment with their surgeon (in-clinic group) or a telemedicine appointment (remote group) for their consent discussion, according to their preference. Patient experience questionnaire and clinical data were included in a multivariate model to explore factors associated with consent quality. Results:Prior to surgery, 80.1% of LVC and 47.9% of RLE patients selected remote consent. Of all LVC patients, 97.5% of in-clinic and 98.3% of remote patients responded that they were adequately consented for surgery (P=0.04). Similar percentages in the RLE group were 97.6% for in-clinic and 97.9% for remote patients (P=0.47). In a multivariate model, the major predictor of patient's satisfaction with the consent process was postoperative satisfaction with visual acuity, responsible for 80.4% of variance explained by the model. Other significant contributors were postoperative visual phenomena and dry eyes, difficulty with night driving, close-up and distance vision, postoperative uncorrected distance visual acuity, change in corrected distance visual acuity, and satisfaction with the surgeon's approach. The type of consent (remote or in-clinic) had no impact on patient's perception of consent quality in the regression model. Conclusion:The majority of patients opted for telemedicine-assisted consent. Those who chose it were equally satisfied as those who had a face-to-face meeting with their surgeon. Dissatisfaction with surgical outcome was the major factor affecting patient's perception of consent quality, regardless of the method of their consent

Monovision LASIK in emmetropic presbyopic patients.

BackgroundTo evaluate the efficacy and patient satisfaction of laser in situ keratomileusis (LASIK) monovision correction in presbyopic emmetropic patients.MethodsA retrospective review of 294 patients who underwent LASIK for monovision was conducted. All patients had preoperative uncorrected distance visual acuity in each eye of 20/25 or better in both eyes and underwent primary LASIK treatment in one eye with a near target; 82 patients underwent surgery in the distant eye for hypermetropia. Patients completed a patient-reported-outcome questionnaire at their one-month postoperative visit. Analysis was performed on a per patient basis with a logistic regression model.ResultsPatients achieved a postoperative mean spherical equivalent of -0.05 diopters (D) in the distant eye and -1.92 D in the near eye. Prior to surgery, 64.7% (n=178) of patients reported they were satisfied or very satisfied with their vision; postoperatively, this increased to 85.4% (n=251). The greatest predictor of dissatisfaction after surgery was severe patient-reported visual phenomena (glare, halos, starbursts, ghosting) (odds ratio 1.18, P=0.001).ConclusionsLASIK monovision for presbyopic patients with low refractive error and good preoperative uncorrected distance visual acuity is both safe and effective with high patient satisfaction. Patients who were dissatisfied in the postoperative period tended to be those with postoperative visual symptoms

Coronary CT Angiography and 5-Year Risk of Myocardial Infarction.

BACKGROUND: Although coronary computed tomographic angiography (CTA) improves diagnostic certainty in the assessment of patients with stable chest pain, its effect on 5-year clinical outcomes is unknown. METHODS: In an open-label, multicenter, parallel-group trial, we randomly assigned 4146 patients with stable chest pain who had been referred to a cardiology clinic for evaluation to standard care plus CTA (2073 patients) or to standard care alone (2073 patients). Investigations, treatments, and clinical outcomes were assessed over 3 to 7 years of follow-up. The primary end point was death from coronary heart disease or nonfatal myocardial infarction at 5 years. RESULTS: The median duration of follow-up was 4.8 years, which yielded 20,254 patient-years of follow-up. The 5-year rate of the primary end point was lower in the CTA group than in the standard-care group (2.3% [48 patients] vs. 3.9% [81 patients]; hazard ratio, 0.59; 95% confidence interval [CI], 0.41 to 0.84; P=0.004). Although the rates of invasive coronary angiography and coronary revascularization were higher in the CTA group than in the standard-care group in the first few months of follow-up, overall rates were similar at 5 years: invasive coronary angiography was performed in 491 patients in the CTA group and in 502 patients in the standard-care group (hazard ratio, 1.00; 95% CI, 0.88 to 1.13), and coronary revascularization was performed in 279 patients in the CTA group and in 267 in the standard-care group (hazard ratio, 1.07; 95% CI, 0.91 to 1.27). However, more preventive therapies were initiated in patients in the CTA group (odds ratio, 1.40; 95% CI, 1.19 to 1.65), as were more antianginal therapies (odds ratio, 1.27; 95% CI, 1.05 to 1.54). There were no significant between-group differences in the rates of cardiovascular or noncardiovascular deaths or deaths from any cause. CONCLUSIONS: In this trial, the use of CTA in addition to standard care in patients with stable chest pain resulted in a significantly lower rate of death from coronary heart disease or nonfatal myocardial infarction at 5 years than standard care alone, without resulting in a significantly higher rate of coronary angiography or coronary revascularization. (Funded by the Scottish Government Chief Scientist Office and others; SCOT-HEART ClinicalTrials.gov number, NCT01149590 .)

Identifying cell enriched miRNAs in kidney injury and repair

Small noncoding RNAs, miRNAs (miRNAs), are emerging as important modulators in the pathogenesis of kidney disease, with potential as biomarkers of kidney disease onset, progression, or therapeutic efficacy. Bulk tissue small RNA-sequencing (sRNA-Seq) and microarrays are widely used to identify dysregulated miRNA expression but are limited by the lack of precision regarding the cellular origin of the miRNA. In this study, we performed cell-specific sRNA-Seq on tubular cells, endothelial cells, PDGFR-β+ cells, and macrophages isolated from injured and repairing kidneys in the murine reversible unilateral ureteric obstruction model. We devised an unbiased bioinformatics pipeline to define the miRNA enrichment within these cell populations, constructing a miRNA catalog of injury and repair. Our analysis revealed that a significant proportion of cell-specific miRNAs in healthy animals were no longer specific following injury. We then applied this knowledge of the relative cell specificity of miRNAs to deconvolute bulk miRNA expression profiles in the renal cortex in murine models and human kidney disease. Finally, we used our data-driven approach to rationally select macrophage-enriched miR-16-5p and miR-18a-5p and demonstrate that they are promising urinary biomarkers of acute kidney injury in renal transplant recipients

Kidney single-cell atlas reveals myeloid heterogeneity in progression and regression of kidney disease

BACKGROUND: Little is known about the roles of myeloid cell subsets in kidney injury and in the limited ability of the organ to repair itself. Characterizing these cells based only on surface markers using flow cytometry might not provide a full phenotypic picture. Defining these cells at the single-cell, transcriptomic level could reveal myeloid heterogeneity in the progression and regression of kidney disease. METHODS: Integrated droplet– and plate-based single-cell RNA sequencing were used in the murine, reversible, unilateral ureteric obstruction model to dissect the transcriptomic landscape at the single-cell level during renal injury and the resolution of fibrosis. Paired blood exchange tracked the fate of monocytes recruited to the injured kidney. RESULTS: A single-cell atlas of the kidney generated using transcriptomics revealed marked changes in the proportion and gene expression of renal cell types during injury and repair. Conventional flow cytometry markers would not have identified the 12 myeloid cell subsets. Monocytes recruited to the kidney early after injury rapidly adopt a proinflammatory, profibrotic phenotype that expresses Arg1, before transitioning to become Ccr2(+) macrophages that accumulate in late injury. Conversely, a novel Mmp12(+) macrophage subset acts during repair. CONCLUSIONS: Complementary technologies identified novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease

Kidney single-cell atlas reveals myeloid heterogeneity in progression and regression of kidney disease

Background Little is known about the roles of myeloid cell subsets in kidney injury and in the limited ability of the organ to repair itself. Characterizing these cells based only on surface markers using flow cytometry might not provide a full phenotypic picture. Defining these cells at the single-cell, transcriptomic level could reveal myeloid heterogeneity in the progression and regression of kidney disease. Methods Integrated droplet– and plate-based single-cell RNA sequencing were used in the murine, reversible, unilateral ureteric obstruction model to dissect the transcriptomic landscape at the single-cell level during renal injury and the resolution of fibrosis. Paired blood exchange tracked the fate of monocytes recruited to the injured kidney. Results A single-cell atlas of the kidney generated using transcriptomics revealed marked changes in the proportion and gene expression of renal cell types during injury and repair. Conventional flow cytometry markers would not have identified the 12 myeloid cell subsets. Monocytes recruited to the kidney early after injury rapidly adopt a proinflammatory, profibrotic phenotype that expresses Arg1, before transitioning to become Ccr21 macrophages that accumulate in late injury. Conversely, a novel Mmp121 macrophage subset acts during repair. Conclusions Complementary technologies identified novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.