Chronic kidney disease (CKD) is associated with increased cardiovascular risk in comparison with the general population. This can be observed even in the early stages of CKD, and rises in proportion to the degree of renal impairment. Not only is cardiovascular disease (CVD) more prevalent in CKD, but its nature differs too, with an excess of morbidity and mortality associated with congestive cardiac failure, arrhythmia and sudden death, as well as the accelerated atherosclerosis which is also observed. Conventional cardiovascular risk factors such as hypertension, dyslipidaemia, obesity, glycaemia and smoking, are highly prevalent amongst patients with CKD, although in many of these examples the interaction between risk factor and disease differs from that which exists in normal renal function. Nevertheless, the extent of CVD cannot be fully explained by these conventional risk factors, and non-conventional factors specific to CKD are now recognised to contribute to the burden of CVD.
Oxidative stress is a state characterised by excessive production of reactive oxygen species (ROS) and other radical species, a reduction in the capacity of antioxidant systems, and disturbance in normal redox homeostasis with depletion of protective vascular signalling molecules such as nitric oxide (NO). This results in oxidative damage to macromolecules such as lipids, proteins and DNA which can alter their functionality. Moreover, many enzymes are sensitive to redox regulation such that oxidative modification to cysteine thiol groups results in activation of signalling cascades which result in adverse cardiovascular effects such as vascular and endothelial dysfunction.
Endothelial dysfunction and oxidative stress are present in association with many conventional cardiovascular risk factors, and can be observed even prior to the development of overt, clinical, vascular pathology, suggesting that these phenomena represent the earliest stages of CVD.
In the presence of CKD, there is increased ROS production due to upregulated NADPH oxidase (NOX), increase in a circulating asymmetric dimethylarginine (ADMA), uncoupling of endothelial nitric oxide synthase (eNOS) as well as other mechanisms. There is also depletion in exogenous antioxidants such as ascorbic acid and tocopherol, and a reduction in activity of endogenous antioxidant systems regulated by the master gene regulator Nrf-2. In previous studies, circulating markers of oxidative stress have been shown to be increased
in CKD, together with a reduction in endothelial function in a stepwise fashion relating to the severity of renal impairment. Not only is CVD linked to oxidative stress, but the progression of CKD itself is also in part dependent on redox sensitive mechanisms. For example, administration of the ROS scavenger tempol attenuates renal injury and reduces renal fibrosis seen on biopsy in a mouse model of CKD, whilst conversely, supplementation with the NOS inhibitor L-NAME causes proteinuria and renal impairment. Previous human studies examining the effect of antioxidant administration on vascular and renal function have been conflicting however. The work contained in this thesis therefore examines the effect of antioxidant administration on vascular and endothelial function in CKD.
Firstly, 30 patients with CKD stages 3 – 5, and 20 matched hypertensive controls were recruited. Participants with CKD had lower ascorbic acid, higher TAP and ADMA, together with higher augmentation index and pulse wave velocity. There was no difference in baseline flow mediated dilatation (FMD) between groups. Intravenous ascorbic acid increased TAP and O2-, and reduced central BP and augmentation index in both groups, and lowered ADMA in the CKD group only. No effect on FMD was observed.
The effects of ascorbic acid on kidney function was then investigated, however this was hindered by the inherent drawbacks of existing methods of non-invasively measuring kidney function. Arterial spin labelling MRI is an emerging imaging technique which allows measurement of renal perfusion without administration of an exogenous contrast agent. The technique relies upon application of an inversion pulse to blood within the vasculature proximal to the kidneys, which magnetically labels protons allowing measurement upon transit to the kidney. At the outset of this project local experience using ASL MRI was limited and there ensued a prolonged pre-clinical phase of testing with the aim of optimising imaging strategy. A study was then designed to investigate the repeatability of ASL MRI in a group of 12 healthy volunteers with normal renal function. The measured T1 longitudinal relaxation times and ASL MRI perfusion values were in keeping with those found in the literature; T1 time was 1376 ms in the cortex and 1491 ms in the whole kidney ROI, whilst perfusion was 321 mL/min/100g in the cortex, and 228 mL/min/100g in the whole kidney ROI. There was good reproducibility demonstrated on Bland Altman analysis, with a CVws was 9.2% for cortical perfusion and 7.1% for whole kidney perfusion.
Subsequently, in a study of 17 patients with CKD and 24 healthy volunteers, the effects of ascorbic acid on renal perfusion was investigated. Although no change in renal perfusion was found following ascorbic acid, it was found that ASL MRI demonstrated significant differences between those with normal renal function and participants with CKD stages 3 – 5, with increased cortical and whole kidney T1, and reduced cortical and whole kidney perfusion. Interestingly, absolute perfusion showed a weak but significant correlation with progression of kidney disease over the preceding year.
Ascorbic acid was therefore shown to have a significant effect on vascular biology both in CKD and in those with normal renal function, and to reduce ADMA only in patients with CKD. ASL MRI has shown promise as a non-invasive investigation of renal function and as a biomarker to identify individuals at high risk of progressive renal impairment.
Abstract Renal artery stenosis manifests as poorly-controlled hypertension, impaired renal function or pulmonary oedema, therefore the success of treatment is dependent on indication. This study aims to determine the outcomes of patients undergoing renal artery stenting (RASt) based on therapeutic aim compared to criteria used in the largest randomised trial. Retrospective case-note review of patients undergoing RASt between 2008–2021 ( n = 74). The cohort was stratified by indication for intervention (renal dysfunction, hypertension, pulmonary oedema) and criteria employed in the CORAL trial, with outcomes and adverse consequences reported. Intervention for hypertension achieved significant reduction in systolic blood pressure and antihypertensive agents at 1 year (median 43 mmHg, 1 drug), without detrimental impact on renal function. Intervention for renal dysfunction reduced serum creatinine by a median 124 μmol/L, sustained after 6 months. Intervention for pulmonary oedema was universally successful with significant reduction in SBP and serum creatinine sustained at 1 year. Patients who would have been excluded from the CORAL trial achieved greater reduction in serum creatinine than patients meeting the inclusion criteria, with equivalent blood pressure reduction. There were 2 procedure-related mortalities and 5 procedural complications requiring further intervention. 5 patients had reduction in renal function following intervention and 7 failed to achieve the intended therapeutic benefit. Renal artery stenting is effective in treating the indication for which it has been performed. Previous trials may have underestimated the clinical benefits by analysis of a heterogenous population undergoing a procedure rather than considering the indication, and excluding patients who would maximally benefit.
Sodium zirconium cyclosilicate (SZC) reduces serum potassium in patients with chronic hyperkalaemia in clinical trials, but its role in the emergency treatment of hyperkalaemia is unproven. We hypothesized that SZC use for emergent hyperkalaemia would be associated with a reduction in rates of emergency interventions for hyperkalaemia.
Proton pump inhibitors (PPIs) are associated with acute tubulointerstitial nephritis and there are reports associating their use with the development of chronic kidney disease (CKD).To determine if PPI use is associated with major adverse renal events (MARE) in patients with CKD.Observational cohort study comprising patients with CKD attending secondary care renal clinics from 1 January 2006 until 31 December 2016.We collated baseline clinical, socio-demographic and biochemical data at start of PPI (PPI group) or study inception (control group). MARE was considered a composite of doubling of creatinine or end-stage renal disease. Association between PPI exposure and progression to MARE was assessed by cause-specific hazards competing risk survival analysis.There were 3824 patients with CKD included in the analyses of whom 1195 were prescribed a PPI. The PPI group was younger (64.8 vs. 67.0 years, P < 0.001), with lower estimated glomerular filtration rate (eGFR) (30 vs. 35 ml/min, P < 0.001) and more proteinuria (64 vs. 48 mg/mmol, P < 0.001). PPI use was associated with progression to MARE on multivariable adjustment (hazard ratio 1.13 [95% confidence interval 1.02-1.25], P = 0.021). Other factors significantly associated with progression to MARE were higher systolic blood pressure, lower eGFR, greater proteinuria, congestive cardiac failure and diabetes. Hypomagnesaemia was more common in the PPI group (39.5 vs. 18.9%, P < 0.001).PPI use was associated with progression to MARE, but not death in patients with CKD after adjusting for factors known to predict declining renal function, including lower eGFR, proteinuria and comorbidities. A prospective cohort study is required to validate these findings.
Mapping of left ventricular (LV) native T1 is a promising non-invasive, non-contrast imaging biomarker. Native myocardial T1 times are prolonged in patients requiring dialysis, but there are concerns that the dialysis process and fluctuating fluid status may confound results in this population. We aimed to assess the changes in cardiac parameters on 3T cardiovascular magnetic resonance (CMR) before and after haemodialysis, with a specific focus on native T1 mapping. This is a single centre, prospective observational study in which maintenance haemodialysis patients underwent CMR before and after dialysis (both scans within 24 h). Weight measurement, bio-impedance body composition monitoring, haemodialysis details and fluid intake were recorded. CMR protocol included cine imaging and mapping native T1 and T2. Twenty-six participants (16 male, 65 ± 9 years) were included in the analysis. The median net ultrafiltration volume on dialysis was 2.3 L (IQR 1.8, 2.5), resulting in a median weight reduction at post-dialysis scan of 1.35 kg (IQR 1.0, 1.9), with a median reduction in over-hydration (as measured by bioimpedance) of 0.75 L (IQR 0.5, 1.4). Significant reductions were observed in LV end-diastolic volume (− 25 ml, p = 0.002), LV stroke volume (− 13 ml, p = 0.007), global T1 (21 ms, p = 0.02), global T2 (− 1.2 ms, p = 0.02) following dialysis. There was no change in LV mass (p = 0.35), LV ejection fraction (p = 0.13) or global longitudinal strain (p = 0.22). On linear regression there was no association between baseline over-hydration (as defined by bioimpedance) and global native T1 or global T2, nor was there an association between the change in over-hydration and the change in these parameters. Acute changes in cardiac volumes and myocardial native T1 are detectable on 3T CMR following haemodialysis with fluid removal. The reduction in global T1 suggests that the abnormal native T1 observed in patients on haemodialysis is not entirely due to myocardial fibrosis.
Premature cardiovascular (CV) death is the commonest cause of death in renal transplant recipients. Abnormalities of left ventricular (LV) structure (collectively termed uremic cardiomyopathy) and left atrial (LA) dilation, a marker of fluid status and diastolic function, are risk factors for reduced survival in patients with end stage renal disease (ESRD). In the present analysis, we studied the impact of pre-transplant LA and LV abnormalities on survival after successful renal transplantation (RT).One hundred nineteen renal transplant recipients (first transplant, deceased donors) underwent cardiovascular MRI (CMR) as part of CV screening prior to inclusion on the waiting list. Data regarding transplant function and patient survival after transplantation were collected.Median post-transplant follow-up was 4.3 years (interquartile range (IQR) 1.9, 6.2). During the post-transplant period, 13 patients returned to dialysis after graft failure and 23 patients died with a functioning graft. Survival analyses, censoring for patients returning to dialysis, showed that pre-transplant LV hypertrophy and elevated LA volume were significantly associated with reduced survival after transplantation. Multivariate Cox regression analyses demonstrated that longer waiting time, poorer transplant function, presence of LV hypertrophy and higher LA volume on screening CMR and female sex were independent predictors of death in patients with a functioning transplant.Presence of LVH and higher LA volume are significant, independent predictors of death in patients who are wait-listed and proceed with renal transplantation.
Purpose of review Recent advances in the world of glomerular diseases have largely focussed on remission induction with immune modulating therapy. It is well recognised that even with the best available treatments, patients with glomerular diseases may have an increased risk of progressive renal and cardiovascular disease. Recent findings The arrival of large trials looking at the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with chronic kidney disease (CKD) and diabetes or not has shifted the entire focus of current management and the shift needs to go further. This review summarises the background to these landmark trials and provides practical guidance for implementation of the results in a general nephrology clinic. In sub-group analyses of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) clinical trial, SGLT2i improved renal outcomes in patients with immunoglobulin A (IgA) nephropathy highlighting the potential for this drug class in glomerular disease. We also discuss where the gaps in evidence are and where future trials in glomerular diseases, be they primary or secondary, should be focussed. Summary The renal community has never before had evidence of this strength upon which to base recommendations for patients with CKD and we should be grasping it with both hands.
Abstract Background and Aims PatientView (https://patientview.org) is a web-based health record available throughout the United Kingdom which allows patients to review blood results and clinical communication from renal services. PatientView registration may differ across demographic groups and may be associated with improved clinical end points. We investigated the demographic factors associated with PatientView registration, and the association with incidence of severe hyperkalaemia. Method A retrospective analysis was performed of a prospectively-acquired database of adults with chronic kidney disease (CKD) stages 3 – 5 in a single Scottish health board attending 2006–2017. Individual start date was point of first clinic attendance; end date was date of death, commencement of renal replacement therapy or point of data extraction. Covariates included age, sex, biochemistry, socioeconomic status and co-morbidity. The Scottish Index of Multiple Deprivation (SIMD) was used as a measure of socioeconomic status, where quintile 1 is most deprived. A survival analysis of time to severe hyperkalaemia (>6.5mmol/L) was performed with PatientView registration as a time dependent covariate. Results Of 9935 patients, 967 (9.7%) were registered users of PatientView. The PatientView group had lower age in years (54.7 [42.7-65.6] vs 71.5 [62.1-78.4], p<0.001), estimated glomerular filtration rate (eGFR) (27.1 [18.6-38.8] vs 38.5 [28.3-51.8] ml/min/1.73m2, p<0.001), and higher SIMD (indicating lower levels of deprivation) (23 vs 13% in least deprived quintile, 25 vs 37% in most deprived quintile, p<0.001); fewer patients were female in the PatientView group (46 vs 51%, p<0.001). PatientView users had lower body mass index (29.1±7.6 vs 29.8±7.3 kg/m2, p<0.001), and lower prevalence of diabetes (28 vs 33%, p<0.001), heart failure (5 vs 7%, p<0.001), myocardial infarction (13 vs 22%, p<0.001) and stroke (3 vs 6%, p<0.001). On Cox regression, PatientView was associated with reduced risk of hyperkalaemia (HR 0.43, 95% CI 0.32,0.58) after adjustment for baseline eGFR, baseline serum potassium, SIMD, sex, diabetes and heart failure. Conclusion PatientView use is more prevalent amongst male, middle-aged patients with higher socioeconomic status. Registration with PatientView is associated with reduced likelihood of adverse clinical events including hyperkalaemia. Limitations include lack of ethnicity data, retrospective design and drug therapy. PatientView usage may associate with concordance to a low potassium diet, reflecting general health literacy. However, it is plausible that a causal relationship exists between Patientview usage and hyperkalaemia, by facilitating feedback on, and engagement with, lifestyle changes encouraged by healthcare providers. Whilst there remains a lack of PatientView registration in certain demographic groups, these should be targeted via quality improvement initiatives to enhance renal outcomes in underserved groups.
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