Kathryn K. Stevens

Association of Left Atrial Volume With Mortality Among ESRD Patients With Left Ventricular Hypertrophy Referred for Kidney Transplantation

Background Left ventricular hypertrophy (LVH) is common in patients with end-stage renal disease (ESRD) and an independent risk factor for premature cardiovascular death. Left atrial volume (LAV), measured using echocardiography, predicts death in patients with ESRD. Cardiovascular magnetic resonance (CMR) imaging is a volume-independent method of accurately assessing cardiac structure and function in patients with ESRD. Study Design Single-center prospective observational study to assess the determinants of all-cause mortality, particularly LAV, in a cohort of ESRD patients with LVH, defined using CMR imaging. Setting & Participants 201 consecutive ESRD patients with LVH (72.1% men; mean age, 51.6 ± 11.7 years) who had undergone pretransplant cardiovascular assessment were identified using CMR imaging between 2002-2008. LVH was defined as left ventricular mass index >84.1 g/m2 (men) or >74.6 g/m2 (women) based on published normal left ventricle dimensions for CMR imaging. Maximal LAV was calculated using the biplane area-length method at the end of left ventricle systole and corrected for body surface area. Predictors CMR abnormalities, including LAV. Outcome All-cause mortality. Results 54 patients died (11 after transplant) during a median follow-up of 3.62 years. Median LAV was 30.4 mL/m2 (interquartile range, 26.2-58.1). Patients were grouped into high (median or higher) or low (less than median) LAV. There were no significant differences in heart rate and mitral valve Doppler early to late atrial peak velocity ratio. Increased LAV was associated with higher mortality. Kaplan-Meier survival analysis showed poorer survival in patients with higher LAV (log rank P = 0.01). High LAV and left ventricular systolic dysfunction conferred similar risk and were independent predictors of death using multivariate analysis. Limitations Only patients undergoing pretransplant cardiac assessment are included. Limited assessment of left ventricular diastolic function. Conclusions Higher LAV and left ventricular systolic dysfunction are independent predictors of death in ESRD patients with LVH.

Risk Factors of Ischemic Stroke and Subsequent Outcome in Patients Receiving Hemodialysis

Background and Purpose— End-stage renal disease (ESRD) requiring hemodialysis carries up to a 10-fold greater risk of stroke than normal renal function. Knowledge on risk factors and management strategies derived from the general population may not be applicable to those with ESRD. We studied a large ESRD population to identify risk factors and outcomes for stroke. Methods— All adult patients receiving hemodialysis for ESRD from January 1, 2007, to December 31, 2012, were extracted from the electronic patient record. Variables associated with stroke were identified by survival analysis; demographic, clinical, imaging, and dialysis-related variables were assessed, and case-fatality was determined. Follow-up was until December 31, 2013. Results— A total of 1382 patients were identified (mean age, 60.5 years; 58.5% men). The prevalence of atrial fibrillation was 21.2%, and 59.4% were incident hemodialysis patients. One hundred and sixty patients (11.6%) experienced a stroke during 3471 patient-years of follow-up (95% ischemic). Stroke incidence was 41.5/1000 patient-years in prevalent and 50.1/1000 patient-years in incident hemodialysis patients. Factors associated with stroke on regression analysis were prior stroke, diabetes mellitus, and age at starting renal replacement therapy. Atrial fibrillation was not significantly associated with stroke, and warfarin did not affect stroke risk in warfarin-treated patients. Fatality was 18.8% at 7 days, 26.9% at 28 days, and 56.3% at 365 days after stroke. Conclusions— Incidence of stroke is high in patients with ESRD on hemodialysis with high case-fatality. Incident hemodialysis patients had the highest stroke incidence. Many, but not all, important risk factors commonly associated with stroke in the general population were not associated with stroke in patients receiving hemodialysis.

Fibroblast Growth Factor 23 Predicts Left Ventricular Mass and Induces Cell Adhesion Molecule Formation

Elevated FGF-23 is a predictor of mortality and is associated with LVH in CKD. It may be a biomarker or a direct toxin. We assessed the relationship between FGF-23 and LVH in CKD using CMRI. In vitro we studied the effect of phosphate, FGF-23, and Klotho on E-selectin and VCAM production in HUVECs. FGF-23 concentration correlates negatively with eGFR and positively with LVMI. FGF-23 was an independent predictor of LVH in CKD. E-selectin and VCAM production was elevated in HUVECs cultured in high phosphate with FGF-23 or Klotho. This effect was attenuated in cells exposed to both FGF-23 and Klotho. FGF-23 is an independent predictor of LVH as measured by CMRI. We show preliminary data which supports that FGF-23 is toxic resulting in activation of the vascular endothelium. We do not prove causality with elevated FGF-23 and LVH. Further research should ascertain if lowering levels of FGF-23 translates to improved clinical outcomes.

SHARP: a stab in the right direction in chronic kidney disease

Patients with chronic kidney disease have an increased risk of premature cardiovascular disease, but the routine exclusion of patients with chronic kidney disease from cardiovascular or other interventional studies means that we have limited information on which to base treatment decisions and guidelines. Thus the results in The Lancet of the Study of Heart and Renal Protection (SHARP), which have been eagerly awaited by the renal community, are pertinent to everyone who treats patients with chronic kidney disease. Post-hoc analyses of cardiovascular intervention trials suggest that patients with low estimated glomerular fi ltration rate could benefi t from statin therapy. However, these patients had primary cardiovascular disease with coincidental mild chronic kidney disease, rather than primary renal disease. In patients receiving haemodialysis, two trials (AURORA and 4D) showed no benefi t from statins on a composite cardiovascular endpoint, and a similar study in renal transplant recipients showed a statistically non-signifi cant benefi t of statins (ALERT). In chronic kidney disease, as in chronic heart failure, the conventional relation between serum cholesterol and cardiovascular events is absent, sudden cardiac death (due to presumed arrhythmia or heart failure) prevails over non-fatal myocardial infarction, and extensive comorbidity heightens the risk of non-cardiac mortality. Consequently, indicative of the uncertain benefi ts and higher risk of drug-related adverse events, the uptake of statins is low in chronic kidney disease, for both primary and secondary prevention. SHARP included 9270 patients with chronic kidney disease, randomly assigned to receive simvastatin 20 mg daily plus ezetimibe 10 mg daily, or placebo, and followed up for a median of 4·9 years. 3023 participants were dialysis-dependent and 6247 were dialysisindependent, with varying severity of chronic kidney disease. The investigators used simvastatin plus ezetimibe to maximise lipid lowering and minimise side-eff ects. The primary endpoint was major atherosclerotic events, including death due to coronary disease, myocardial infarction, non-haemorrhagic stroke, or the need for revascularisation. The endpoint was refi ned during the study to exclude non-coronary cardiac death and haemorrhagic stroke, in view of emerging data. Despite adherence rates of only two-thirds, common in trials in chronic kidney disease, allocation to simvastatin plus ezetimibe was associated with an average 0·85 mmol/L reduction in LDL cholesterol and a 17% reduction in major atherosclerotic events (rate ratio 0·83, 95% CI 0·74–0·94, p=0·0021). The largest contribution to the primary endpoint was reduction in coronary revascularisation. Reassuringly, no diff erence in adverse outcomes was identifi ed (specifi cally cancer and myopathy) but, disappointingly, no survival benefi t or evidence of a renal protective eff ect was recorded, with more than 2000 of the patients who were dialysis-independent progressing to end-stage renal disease during the trial. Nonetheless, there is a clear message from SHARP: lipid lowering has signifi cant benefi ts in chronic kidney disease, specifi cally the prevention of atherosclerotic events. Why did SHARP succeed when previous trials in end-stage renal disease have failed? By comparison with AURORA and 4D, SHARP was larger, with a more specifi c coronary endpoint, and was weighted towards patients with less advanced chronic kidney disease, in whom the pathophysiology of cardiovascular disease is likely to be more akin to that in the general population. However, by the end of SHARP, most patients had end-stage renal disease (de novo or at baseline), and in the overall population lipid lowering was eff ective. No statistical evidence of heterogeneity between the dialysis-dependent and dialysis-independent subgroups was reported, although analysis of the Published Online June 9, 2011 DOI:10.1016/S01406736(11)60822-2

Deleterious effects of phosphate on vascular and endothelial function via disruption to the nitric oxide pathway

Abstract Background Hyperphosphataemia is an independent risk factor for accelerated cardiovascular disease in chronic kidney disease (CKD), although the mechanism for this is poorly understood. We investigated the effects of sustained exposure to a high-phosphate environment on endothelial function in cellular and preclinical models, as well as in human subjects. Methods Resistance vessels from rats and humans (± CKD) were incubated in a normal (1.18 mM) or high (2.5 mM) phosphate concentration solution and cells were cultured in normal- (0.5 mM) or high-phosphate (3 mM) concentration media. A single-blind crossover study was performed in healthy volunteers, receiving phosphate supplements or a phosphate binder (lanthanum), and endothelial function measured was by flow-mediated dilatation. Results Endothelium-dependent vasodilatation was impaired when resistance vessels were exposed to high phosphate; this could be reversed in the presence of a phosphodiesterase-5-inhibitor. Vessels from patients with CKD relaxed normally when incubated in normal-phosphate conditions, suggesting that the detrimental effects of phosphate may be reversible. Exposure to high-phosphate disrupted the whole nitric oxide pathway with reduced nitric oxide and cyclic guanosine monophosphate production and total and phospho endothelial nitric oxide synthase expression. In humans, endothelial function was reduced by chronic phosphate loading independent of serum phosphate, but was associated with higher urinary phosphate excretion and serum fibroblast growth factor 23. Conclusions These directly detrimental effects of phosphate, independent of other factors in the uraemic environment, may explain the increased cardiovascular risk associated with phosphate in CKD.

Predictors of sustained arteriovenous access use for haemodialysis.

Background: Guidelines encourage early arteriovenous (AV) fistula (AVF) planning for haemodialysis (HD). The aim of this study was to estimate the likelihood of sustained AV access use taking into account age, sex, comorbidity, anatomical site of first AVF and, for pre-dialysis patients, eGFR and proteinuria. Methods: 1,092 patients attending our centre who had AVF as their first AV access procedure between January 1, 2000 and August 23, 2012 were identified from the electronic patient record. The primary end-point was time to first sustained AV access use, defined as use of any AV access for a minimum of 30 consecutive HD sessions. Results: 52.9% (n = 578) of the patients ultimately achieved sustained AV access use. The main reasons for AV access non-use were AVF failure to mature and death. The 3-year Kaplan-Meier probability of sustained AV access use was 68.8% for those not on renal replacement therapy (RRT) (n = 688) and 74.2% for those already on RRT (n = 404) at the time of first AVF. By multivariate analysis in patients not on RRT, male sex (HR 2.22; p < 0.001), uPCR (HR 1.03; p = 0.03) and eGFR (hazard ratio, HR 0.85; p < 0.001) were independent predictors of AV access use. In patients already on RRT, age (HR 0.98; p < 0.001) and peripheral vascular disease (HR 0.48; p = 0.02) were independent predictors of AV access use. Conclusion: Our data suggest that refinement of the current guideline for timing of AV access creation in planning RRT is justified to take into account individual factors that contribute to the likelihood of technical success and clinical need.

Non-Contrast Renal Magnetic Resonance Imaging to Assess Perfusion and Corticomedullary Differentiation in Health and Chronic Kidney Disease

Aims: Arterial spin labelling (ASL) MRI measures perfusion without administration of contrast agent. While ASL has been validated in animals and healthy volunteers (HVs), application to chronic kidney disease (CKD) has been limited. We investigated the utility of ASL MRI in patients with CKD. Methods: We studied renal perfusion in 24 HVs and 17 patients with CKD (age 22-77 years, 40% male) using ASL MRI at 3.0T. Kidney function was determined using estimated glomerular filtration rate (eGFR). T1 relaxation time was measured using modified look-locker inversion and flow-sensitive alternating inversion recovery true-fast imaging and steady precession was performed to measure cortical and whole kidney perfusion. Results: T1 was higher in CKD within cortex and whole kidney, and there was association between T1 time and eGFR. No association was seen between kidney size and volume and either T1, or ASL perfusion. Perfusion was lower in CKD in cortex (136 ± 37 vs. 279 ± 69 ml/min/100 g; p < 0.001) and whole kidney (146 ± 24 vs. 221 ± 38 ml/min/100 g; p < 0.001). There was significant, negative, association between T1 longitudinal relaxation time and ASL perfusion in both the cortex (r = -0.75, p < 0.001) and whole kidney (r = -0.50, p < 0.001). There was correlation between eGFR and both cortical (r = 0.73, p < 0.01) and whole kidney (r = 0.69, p < 0.01) perfusion. Conclusions: Significant differences in renal structure and function were demonstrated using ASL MRI. T1 may be representative of structural changes associated with CKD; however, further investigation is required into the pathological correlates of reduced ASL perfusion and increased T1 time in CKD.

Risk factors and outcome of Stroke in renal transplant recipients

Stroke incidence is high in end‐stage renal disease, and risk factors differ between the dialysis and general populations. However, risk factors and outcomes following renal transplantation remain unclear. We analyzed all adult patients with a functioning renal transplant from 01/01/2007 to 12/31/2012. Data were extracted from the electronic patient record. Variables associated with stroke were identified by survival analyses; demographic, clinical, and imaging and laboratory variables were assessed and case fatality determined. Follow‐up was until 05/12/2013. A total of 956 patients were identified (median age 40.1 years, 59.9% male). Atrial fibrillation (AF) prevalence was 9.2%, and 38.2% received a transplant during follow‐up. A total of 26 (2.7%) experienced a stroke during 4409 patient‐years of follow‐up (84.6% ischemic). Stroke incidence was 5.96/1000 patient‐years. Factors associated with stroke on regression analysis were prior stroke, diabetes, age, systolic hypertension, and hemoglobin. Atrial fibrillation was associated with time to stroke (P<0.001). Warfarin did not associate with ischemic stroke risk in those with AF. Fatality was 19.2% at 7, 23.1% at 28, and 42.3% at 365 days after stroke. Patients with a functioning renal transplant have a high stroke incidence and case fatality. Unlike those on hemodialysis, risk factors are similar to the general population. We did not demonstrate benefit from warfarin use in those with AF.

Effect of left atrial and ventricular abnormalities on renal transplant recipient outcome—a single-center study

BackgroundPremature 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).MethodsOne 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.ResultsMedian 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.ConclusionsPresence of LVH and higher LA volume are significant, independent predictors of death in patients who are wait-listed and proceed with renal transplantation.

Phosphate as a cardiovascular risk factor: effects on vascular and endothelial function

BACKGROUND Hyperphosphataemia is a risk factor for accelerated cardiovascular disease in chronic kidney disease. The mechanism is poorly understood; it is unclear whether phosphate has direct effects or effects mediated via calcification or FGF23. We investigated direct effects of phosphate on endothelial function using myography to study rat and human blood vessels. In addition we assessed the effects of phosphate loading on endothelial function in a clinical study. METHODS Resistance vessels from patients with (n=12) and without (n=13) chronic kidney disease were incubated in normal or high phosphate. Vasoconstrictor and vasorelaxation responses were measured. Concentration-response curves were constructed and comparisons made. Identical experiments were performed in rat mesenteric vessels with and without phosphodiesterase type 5 inhibitor. A cross-over study was done in 19 healthy volunteers receiving phosphate supplements or binders and endothelial function measured by flow mediated dilatation (FMD). Primary outcome was percent change in FMD from baseline. FINDINGS Nine to 13 vessels were used in each group. Endothelium-dependent vasodilatation was impaired in high compared with normal phosphate in rat (mean maximum vasodilatation 64% [SE 9] vs 95 [1], p<0·001) and human vessels with (25·3 [11·1] vs 75·7 [13·6], p<0·001) and without chronic kidney disease (42·9 [12] vs 79·4 [8·2], p=0·003). In rat vessels, these effects were reversed by a phosphodiesterase type 5 inhibitor. In vivo in volunteers, endothelial function was reduced by phosphate loading (median maximum vasodilatation 3·38% [IQR 2·57-5·26] vs 8·4 [6·2-11·6], p<0·001); this effect was independent of serum phosphate concentration but associated with urinary phosphate excretion and serum FGF23 concentrations. INTERPRETATION Prolonged exposure to phosphate is associated with endothelial dysfunction, a direct effect of phosphate, which might contribute to cardiovascular risk in chronic kidney disease. In a high phosphate environment, endothelial and vascular dysfunction is evident in blood vessels and in man exposed to prolonged oral phosphate loading. These effects might be mediated by disruption of the NO pathway. FUNDING British Heart Foundation, Darlindas Charity for Renal Research.