Khai Ping Ng

Atrial Fibrillation in CKD: Balancing the Risks and Benefits of Anticoagulation

Chronic kidney disease (CKD) and atrial fibrillation are common conditions that often coexist and are associated with increased risk of stroke. Despite the wealth of evidence for optimal management of atrial fibrillation in the general population, the role of anticoagulation with warfarin in individuals with CKD with atrial fibrillation is far less well defined. Current recommendations for anticoagulation in patients treated with dialysis and those with an earlier stage of CKD are based on clinical trials in the general atrial fibrillation population that have largely excluded individuals with CKD. Observational studies of anticoagulation in dialysis patients have produced conflicting results, mainly because of increased risk of bleeding. This, together with warfarins potential adverse effects on ectopic/vascular calcification and progression of CKD, may result in negating the benefits associated with anticoagulation in the general population. With the recent emergence of novel oral anticoagulants, there is an urgent need for a better understanding of the complex inter-relationship among CKD, atrial fibrillation, stroke, and bleeding risk. This knowledge is paramount to optimize the potential benefits of treatment and minimize the potential harms in this very high-risk and growing population.

The natural history of, and risk factors for, progressive Chronic Kidney Disease (CKD): the Renal Impairment in Secondary care (RIISC) study; rationale and protocol

BackgroundChronic kidney disease (CKD) affects up to 16% of the adult population and is associated with significant morbidity and mortality. People at highest risk from progressive CKD are defined by a sustained decline in estimated glomerular filtration rate (eGFR) and/or the presence of significant albuminuria/proteinuria and/or more advanced CKD. Accurate mapping of the bio-clinical determinants of this group will enable improved risk stratification and direct the development of better targeted management for people with CKD.Methods/DesignThe Renal Impairment In Secondary Care study is a prospective, observational cohort study, patients with CKD 4 and 5 or CKD 3 and either accelerated progression and/or proteinuria who are managed in secondary care are eligible to participate. Participants undergo a detailed bio-clinical assessment that includes measures of vascular health, periodontal health, quality of life and socio-economic status, clinical assessment and collection of samples for biomarker analysis. The assessments take place at baseline, and at six, 18, 36, 60 and 120 months; the outcomes of interest include cardiovascular events, progression to end stage kidney disease and death.DiscussionThe determinants of progression of chronic kidney disease are not fully understood though there are a number of proposed risk factors for progression (both traditional and novel). This study will provide a detailed bio-clinical phenotype of patients with high-risk chronic kidney disease (high risk of both progression and cardiovascular events) and will repeatedly assess them over a prolonged follow up period. Recruitment commenced in Autumn 2010 and will provide many outputs that will add to the evidence base for progressive chronic kidney disease.

Allopurinol is an independent determinant of improved arterial stiffness in chronic kidney disease: a cross-sectional study.

Background Arterial stiffness is increased in patients with CKD and is a powerful predictor of cardiovascular morbidity and mortality. Use of the xanthine oxidase inhibitor allopurinol has been shown to improve endothelial function, reduce left ventricular hypertrophy and possibly improve cardiovascular outcome. We explored the relationship between use of allopurinol and arterial stiffness in patients with chronic kidney disease (CKD). Methods Cross-sectional observational study of 422 patients with CKD with evidence of, or at high risk of, renal disease progression. Arterial stiffness was determined by carotid-femoral pulse wave velocity (PWV). Results The mean age was 63±16 years, median estimated glomerular filtration rate was 25 (interquartile range: 19–31) ml/min/1.73 m2 and mean PWV was 10.2±2.4 m/s. Seventy-seven patients (18%) were receiving regular allopurinol, 61% at a dose of 100 mg/day (range: 50–400 mg/day). Patients receiving allopurinol had significantly lower peripheral pulse pressure, central pulse pressure, central systolic blood pressure, serum uric acid level tissue advanced glycation end product levels but comparable high-sensitivity C-reactive protein levels. Use of allopurinol was associated with lower PWV. After adjusting for age, gender, ethnicity, tissue advanced glycation end product level, peripheral pulse pressure, smoking pack years, presence of diabetes mellitus and use of angiotensin converting enzyme inhibitor or angiotensin II receptor blocker, the use of allopurinol remained a significant independent determinant of PWV (mean difference: −0.63 m/s; 95% CI, −0.09 to −1.17 m/s, p = 0.02). Conclusion In patients with CKD, use of allopurinol is independently associated with lower arterial stiffness. This study provides further justification for a large definitive randomised controlled trial examining the therapeutic potential of allopurinol to reduce cardiovascular risk in people with CKD.

Central pulse pressure in patients with chronic kidney disease and in renal transplant recipients.

Patients with chronic kidney disease (CKD) and renal transplant recipients (RTR) have increased cardiovascular risk. The value of measuring central pulse pressure (cPP) over brachial pulse pressure (pPP) is not known. Central PP was measured in 597 patients (364 CKD:233 RTR). In multivariate analysis, age and female gender positively correlated with cPP; heart rate and estimated glomerular filtration rate negatively correlated with cPP. Associations for age, heart rate and gender persisted after additional adjustment for pPP and aortic wave reflection. This model accounted for 91% of the variability in cPP, with pPP alone accounting for 74%. Results were similar when both patient groups were analysed separately. A subset of patients with CKD had aortic pulse wave velocity (PWV) and left ventricular mass index (LVMI) measured. There were no differences in the univariate correlations between PWV (r=0.368 vs 0.315; P=0.4) or LVMI (r=0.125 vs 0.163; P=0.7); nor in the multivariate models created for PWV (P=0.1) or LVMI (P=0.1) when either cPP or pPP were used. This study demonstrates that in these patients most of the variability in cPP can be explained by pPP. Additionally, cPP does not appear to provide additional information beyond pPP in determining PWV and LVMI.

Health-Related Quality of Life Impacts Mortality but Not Progression to End-Stage Renal Disease in Pre-Dialysis Chronic Kidney Disease: A Prospective Observational Study

Background Chronic kidney disease (CKD) is associated with reduced health-related quality of life (HRQL). However, the relationship between pre-dialysis CKD, HRQL and clinical outcomes, including mortality and progression to end-stage renal disease (ESRD) is unclear. Methods All 745 participants recruited into the Renal Impairment In Secondary Care study to end March 2014 were included. Demographic, clinical and laboratory data were collected at baseline including an assessment of HRQL using the Euroqol EQ-5D-3L. Health states were converted into an EQ-5Dindex score using a set of weighted preferences specific to the UK population. Multivariable Cox proportional hazards regression and competing risk analyses were undertaken to evaluate the association of HRQL with progression to ESRD or all-cause mortality. Regression analyses were then performed to identify variables associated with the significant HRQL components. Results Median eGFR was 25.8 ml/min/1.73 m2 (IQR 19.6–33.7ml/min) and median ACR was 33 mg/mmol (IQR 6.6–130.3 mg/mmol). Five hundred and fifty five participants (75.7%) reported problems with one or more EQ-5D domains. When adjusted for age, gender, comorbidity, eGFR and ACR, both reported problems with self-care [hazard ratio 2.542, 95% confidence interval 1.222–5.286, p = 0.013] and reduced EQ-5Dindex score [hazard ratio 0.283, 95% confidence interval 0.099–0.810, p = 0.019] were significantly associated with an increase in all-cause mortality. Similar findings were observed for competing risk analyses. Reduced HRQL was not a risk factor for progression to ESRD in multivariable analyses. Conclusions Impaired HRQL is common in the pre-dialysis CKD population. Reduced HRQL, as demonstrated by problems with self-care or a lower EQ-5Dindex score, is associated with a higher risk for death but not ESRD. Multiple factors influence these aspects of HRQL but renal function, as measured by eGFR and ACR, are not among them.

Cardiovascular actions of mineralocorticoid receptor antagonists in patients with chronic kidney disease: A systematic review and meta-analysis of randomized trials.

Introduction: The safety and actions of mineralocorticoid receptor antagonists on surrogate markers of cardiovascular disease as well as major patient level cardiovascular end-points in patients with chronic kidney disease are unclear. Methods: MEDLINE, EMBASE, Trip Database, Cochrane Central Register of Controlled Trials, Cochrane Renal Group specialized register, Current Controlled Trials and clinicaltrials.gov were searched for relevant trials. Results: Twenty-nine trials (1581 patients) were included. Overall, mineralocorticoid receptor antagonists lowered both systolic and diastolic blood pressure (–5.24, 95% confidence interval (CI) –8.65, −1.82 mmHg; p=0.003 and −1.96, 95% CI −3.22, –0.69 mmHg; p=0.002 respectively). There were insufficient data to perform a meta-analysis of other cardiovascular effects. However, a systematic review of the studies included suggested a consistent improvement in surrogate markers of cardiovascular disease. Overall, the use of mineralocorticoid receptor antagonists was associated with an increased serum potassium (0.23, 95% CI 0.13, 0.33 mmol/l; p<0.0001) and higher risk ratio (1.76, 95% CI 1.20, 2.57; p=0.001) of hyperkalemia. Data on long-term cardiovascular outcomes and mortality were not available in any of the trials. Conclusions: The long-term effects of mineralocorticoid receptor antagonists on cardiovascular events, mortality and safety need to be established.

Serum tryptase concentration and progression to end-stage renal disease.

Mast cell activation can lead to nonclassical activation of the Renin–Angiotensin–Aldosterone System. However, the relevance of this to human chronic kidney disease is unknown. We assessed the association between serum tryptase, a product of mast cell activation, and progression to end‐stage renal disease or mortality in patients with advanced chronic kidney disease. We stratified patients by use of angiotensin‐converting enzyme inhibitors/angiotensin receptor II blockers (ACEi/ARB).

Results and lessons from the spironolactone to prevent cardiovascular events in early stage chronic kidney disease (STOP-CKD) randomised controlled trial

Objectives To determine whether low-dose spironolactone can safely lower arterial stiffness in patients with chronic kidney disease stage 3 in the primary care setting. Design A multicentre, prospective, randomised, placebo-controlled, double-blinded study. Setting 11 primary care centres in South Birmingham, England. Participants Adult patients with stage 3 chronic kidney disease. Main exclusion criteria were diagnosis of diabetes mellitus, chronic heart failure, atrial fibrillation, severe hypertension, systolic blood pressure <120 mm Hg or baseline serum potassium ≥5 mmol/L. Intervention Eligible participants were randomised to receive either spironolactone 25 mg once daily, or matching placebo for an intended period of 40 weeks. Outcome measures The primary end point was the change in arterial stiffness as measured by pulse wave velocity. Secondary outcome measures included the rate of hyperkalaemia, deterioration of renal function, barriers to participation and expected recruitment rates to a potential future hard end point study. Results From the 11 practices serving a population of 112 462, there were 1598 (1.4%) patients identified as being eligible and were invited to participate. Of these, 134 (8.4%) attended the screening visit of which only 16 (1.0%) were eligible for randomisation. The main reasons for exclusion were low systolic blood pressure (<120 mm Hg: 40 patients) and high estimated glomerular filtration rate (≥60 mL/min/1.73 m2: 38 patients). The trial was considered unfeasible and was terminated early. Conclusions We highlight some of the challenges in undertaking research in primary care including patient participation in trials. This study not only challenged our preconceptions, but also provided important learning for future research in this large and important group of patients. Trial registration number ISRCTN80658312.