The ViKTORIES trial: A randomized, double-blind, placebo-controlled trial of vitamin K supplementation to improve vascular health in kidney transplant recipients.

Premature cardiovascular disease and death with a functioning graft are leading causes of death and graft loss, respectively, in kidney transplant recipients (KTRs). Vascular stiffness and calcification are markers of cardiovascular disease that are prevalent in KTR and associated with subclinical vitamin K deficiency. We performed a single-center, phase II, parallel-group, randomized, double-blind, placebo-controlled trial (ISRCTN22012044) to test whether vitamin K supplementation reduced vascular stiffness (MRI-based aortic distensibility) or calcification (coronary artery calcium score on computed tomography) in KTR over 1 year of treatment. The primary outcome was between-group difference in vascular stiffness (ascending aortic distensibility). KTRs were recruited between September 2017 and June 2018, and randomized 1:1 to vitamin K (menadiol diphosphate 5 mg; n = 45) or placebo (n = 45) thrice weekly. Baseline demographics, clinical history, and immunosuppression regimens were similar between groups. There was no impact of vitamin K on vascular stiffness (treatment effect -0.23 [95% CI -0.75 to 0.29] × 10-3  mmHg-1 ; p = .377), vascular calcification (treatment effect -141 [95% CI - 320 to 38] units; p = .124), nor any other outcome measure. In this heterogeneous cohort of prevalent KTR, vitamin K supplementation did not reduce vascular stiffness or calcification over 1 year. Improving vascular health in KTR is likely to require a multifaceted approach.

Myocardial changes on 3T cardiovascular magnetic resonance imaging in response to haemodialysis with fluid removal.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Vitamin K Supplementation to Improve Vascular Stiffness in CKD: The K4Kidneys Randomized Controlled Trial.

BACKGROUND: Vascular calcification, a risk factor for cardiovascular disease, is common among patients with CKD and is an independent contributor to increased vascular stiffness and vascular risk in this patient group. Vitamin K is a cofactor for proteins involved in prevention of vascular calcification. Whether or not vitamin K supplementation could improve arterial stiffness in patients with CKD is unknown. METHODS: To determine if vitamin K supplementation might improve arterial stiffness in patients in CKD, we conducted a parallel-group, double-blind, randomized trial in participants aged 18 or older with CKD stage 3b or 4 (eGFR 15-45 ml/min per 1.73 m2). We randomly assigned participants to receive 400 µg oral vitamin K2 or matching placebo once daily for a year. The primary outcome was the adjusted between-group difference in carotid-femoral pulse wave velocity at 12 months. Secondary outcomes included augmentation index, abdominal aortic calcification, BP, physical function, and blood markers of mineral metabolism and vascular health. We also updated a recently published meta-analysis of trials to include the findings of this study. RESULTS: We included 159 randomized participants in the modified intention-to-treat analysis, with 80 allocated to receive vitamin K and 79 to receive placebo. Mean age was 66 years, 62 (39%) were female, and 87 (55%) had CKD stage 4. We found no differences in pulse wave velocity at 12 months, augmentation index at 12 months, BP, B-type natriuretic peptide, or physical function. The updated meta-analysis showed no effect of vitamin K supplementation on vascular stiffness or vascular calcification measures. CONCLUSIONS: Vitamin K2 supplementation did not improve vascular stiffness or other measures of vascular health in this trial involving individuals with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Vitamin K therapy to improve vascular health in patients with chronic kidney disease, ISRCTN21444964 (www.isrctn.com).

Research cardiac magnetic resonance imaging in end stage renal disease - incidence, significance and implications of unexpected incidental findings.

OBJECTIVES: Left ventricular mass (LVM) at cardiac magnetic resonance imaging (CMR) is a frequent end point in clinical trials in nephrology. Trial participants with end stage renal disease (ESRD) may have a greater frequency of incidental findings (IF). We retrospectively investigated prevalence of IF in previous research CMR and reviewed their subsequent impact on participants. METHODS: Between 2002 and 2006, 161 ESRD patients underwent CMR in a transplant assessment study. Images were used to assess LV mass and function. In the current study a radiologist reviewed the scans for IF. Review of patient records determined the subsequent clinical significance of IF. RESULTS: There were 150 IF in 95 study participants. Eighty-four (56 %) were new diagnoses. One hundred and two were non-cardiac. Fifteen were suspicious of malignancy. There was a clinically significant IF for 14.9 % of the participants. In six cases earlier identification of an IF may have improved quality of life or survival. CONCLUSIONS: Without radiology support clinically important IF may be missed on CMR. Patients undergoing CMR in trials should be counselled about the frequency and implications of IF. Patients with ESRD have a higher prevalence of IF than reported in other populations. Nephrology studies require mechanisms for radiologist reporting and strategies for dealing with IF. KEY POINTS: • Incidental findings on research cardiac magnetic resonance imaging can have significant consequences. • We considered incidental findings in historical renal cardiac resonance imaging clinical trials. • Incidental findings are common and important in the chronic kidney disease population. • Without radiology support, clinically significant incidental findings may be missed on imaging. • Study protocols, approvals and consent processes should take account of possible findings.

Native T1 mapping: inter-study, inter-observer and inter-center reproducibility in hemodialysis patients.

BACKGROUND: Native T1 mapping is a cardiovascular magnetic resonance (CMR) technique that associates with markers of fibrosis and strain in hemodialysis patients. The reproducibility of T1 mapping in hemodialysis patients, prone to changes in fluid status, is unknown. Accurate quantification of myocardial fibrosis in this population has prognostic potential. METHODS: Using 3 Tesla CMR, we report the results of 1) the inter-study, inter-observer and intra-observer reproducibility of native T1 mapping in 10 hemodialysis patients; 2) inter-study reproducibility of left ventricular (LV) structure and function in 10 hemodialysis patients; 3) the agreement of native T1 map and native T1 phantom analyses between two centres in 20 hemodialysis patients; 4) the effect of changes in markers of fluid status on native T1 values in 10 hemodialysis patients. RESULTS: Inter-study, inter-observer and intra-observer variability of native T1 mapping were excellent with co-efficients of variation (CoV) of 0.7, 0.3 and 0.4% respectively. Inter-study CoV for LV structure and function were: LV mass = 1%; ejection fraction = 1.1%; LV end-diastolic volume = 5.2%; LV end-systolic volume = 5.6%. Inter-centre variability of analysis techniques were excellent with CoV for basal and mid-native T1 slices between 0.8-1.2%. Phantom analyses showed comparable native T1 times between centres, despite different scanners and acquisition sequences (centre 1: 1192.7 ± 7.5 ms, centre 2: 1205.5 ± 5 ms). For the 10 patients who underwent inter-study testing, change in body weight (Δweight) between scans correlated with change in LV end-diastolic volume (ΔLVEDV) (r = 0.682;P = 0.03) representing altered fluid status between scans. There were no correlations between change in native T1 between scans (ΔT1) and ΔLVEDV or Δweight (P > 0.6). Linear regression confirmed ΔT1 was unaffected by ΔLVEDV or Δweight (P > 0.59). CONCLUSIONS: Myocardial native T1 is reproducible in HD patients and unaffected by changes in fluid status at the levels we observed. Native T1 mapping is a potential imaging biomarker for myocardial fibrosis in patients with end-stage renal disease.

Defining myocardial tissue abnormalities in end-stage renal failure with cardiac magnetic resonance imaging using native T1 mapping.

Noninvasive quantification of myocardial fibrosis in end-stage renal disease is challenging. Gadolinium contrast agents previously used for cardiac magnetic resonance imaging (MRI) are contraindicated because of an association with nephrogenic systemic fibrosis. In other populations, increased myocardial native T1 times on cardiac MRI have been shown to be a surrogate marker of myocardial fibrosis. We applied this method to 33 incident hemodialysis patients and 28 age- and sex-matched healthy volunteers who underwent MRI at 3.0T. Native T1 relaxation times and feature tracking-derived global longitudinal strain as potential markers of fibrosis were compared and associated with cardiac biomarkers. Left ventricular mass indices were higher in the hemodialysis than the control group. Global, Septal and midseptal T1 times were all significantly higher in the hemodialysis group (global T1 hemodialysis 1171 ± 27 ms vs. 1154 ± 32 ms; septal T1 hemodialysis 1184 ± 29 ms vs. 1163 ± 30 ms; and midseptal T1 hemodialysis 1184 ± 34 ms vs. 1161 ± 29 ms). In the hemodialysis group, T1 times correlated with left ventricular mass indices. Septal T1 times correlated with troponin and electrocardiogram-corrected QT interval. The peak global longitudinal strain was significantly reduced in the hemodialysis group (hemodialysis -17.7±5.3% vs. -21.8±6.2%). For hemodialysis patients, the peak global longitudinal strain significantly correlated with left ventricular mass indices (R = 0.426), and a trend was seen for correlation with galectin-3, a biomarker of cardiac fibrosis. Thus, cardiac tissue properties of hemodialysis patients consistent with myocardial fibrosis can be determined noninvasively and associated with multiple structural and functional abnormalities.

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.

Kidney biopsy findings in primary Sjögren syndrome.

BACKGROUND: Renal involvement is rare in primary Sjögren syndrome (PSS). In this study, we examined renal biopsy findings in patients with PSS and correlated them with their clinical and renal findings. METHODS: Twenty-five patients with PSS who underwent renal biopsies from two renal units in Scotland between 1978 and 2013 were identified from renal biopsy database. We examined the renal morphologic, clinical and renal findings at the time of renal biopsy, renal and patient outcomes. RESULTS: The diagnosis of PSS preceded renal biopsy in 18/25 patients. In this group, the median duration of the disease was 5.5 years. Significant proteinuria, combined microscopic haematuria and proteinuria and reduced renal excretory function were found in 76, 56 and 84% of patients, respectively. The 3-year actuarial patient survival was significantly lower in patients with glomerulonephritis as compared with tubulointerstitial nephritis (66 versus 100%, P = 0.02). There was no difference in 3-year actuarial renal survival between these two groups (92 versus 92%, P = 1.0). CONCLUSIONS: Renal biopsy is rare in PSS and often reveals diverse pathological findings. Glomerulonephritis, as compared with tubulointerstitial nephritis, is associated with higher early mortality. Further studies are needed to evaluate the utility of renal biopsy and its impact on disease management.

Cystatin C- and Creatinine-based Estimated GFR Differences: Prevalence and Predictors in the UK Biobank.

Rationale & Objective: Large differences between estimated glomerular filtration rate (eGFR) based on cystatin C (eGFRcys) and creatinine (eGFRcr) occur commonly. A comprehensive evaluation of factors that contribute to these differences is needed to guide the interpretation of discrepant eGFR values. Study Design: Cohort study. Setting & Participants: 468,969 participants in the UK Biobank. Exposures: Candidate sociodemographic, lifestyle factors, comorbidities, medication usage, and physical and laboratory predictors. Outcomes: eGFRdiff, defined as eGFRcys minus eGFRcr, categorized into 3 levels: lower eGFRcys (eGFRdiff, less than -15 mL/min/1.73 m2), concordant eGFRcys and eGFRcr (eGFRdiff, -15 to < 15 mL/min/1.73 m2), and lower eGFRcr (eGFRdiff, ≥15 mL/min/1.73 m2). Analytical Approach: Multinomial logistic regression models were constructed to identify predictors of lower eGFRcys or lower eGFRcr. We developed 2 prediction models comprising 375,175 participants: (1) a clinical model using clinically available variables and (2) an enriched model additionally including lifestyle variables. The models were internally validated in an additional 93,794 participants. Results: Mean ± standard deviation of eGFRcys was 88 ± 16 mL/min/1.73 m2, and eGFRcr was 95 ± 13 mL/min/1.73 m2; 25% and 5% of participants were in the lower eGFRcys and lower eGFRcr groups, respectively. In the multivariable enriched model, strong predictors of lower eGFRcys were older age, male sex, South Asian ethnicity, current smoker (vs never smoker), history of thyroid dysfunction, chronic inflammatory disease, steroid use, higher waist circumference and body fat, and urinary albumin-creatinine ratio >300 mg/g. Odds ratio estimates for these predictors were largely inverse of those in the lower eGFRcr group. The model's area under the curve was 0.75 in the validation set, with good calibration (1.00). Limitations: Limited generalizability. Conclusions: This study highlights the multitude of demographic, lifestyle, and health characteristics that are associated with large eGFRdiff. The clinical model may identify individuals who are likely to have discrepant eGFR values and thus should be prioritized for cystatin C testing.

Estimated glomerular filtration rate (eGFR) based on cystatin C and creatinine may differ substantially within an individual. Although most clinicians are aware that creatinine is influenced by muscle mass, there are additional numerous lifestyle and health characteristics that may affect serum concentrations of either biomarker. Our analyses of 468,969 individuals in the UK Biobank identified independent predictors of large differences between eGFR based on cystatin C and eGFR based on creatinine, which may inform the interpretation of discrepant eGFR values within an individual. We developed models that may be implemented at a population level to help health systems identify individuals who are likely to have large differences between eGFR based on cystatin C and eGFR based on creatinine and thus should be prioritized for cystatin C testing.

Survey of trainee attitudes to preparation for and participation in the FCEM examination.

INTRODUCTION AND AIMS: In the UK, specialist trainees in emergency medicine are required to pass the Fellowship of the College of Emergency Medicine (FCEM). This examination assesses clinical knowledge, attitudes and skills, management principles, critical appraisal, and the ability to search medical literature and synthesise information. The aims of this study were to ascertain what resources trainees felt were most valuable in preparation for the FCEM and to obtain trainee feedback on the running of the FCEM. METHODS: A questionnaire was developed in conjunction with the TSC into nine parts covering all aspects of preparation for and experience of sitting the FCEM. Email addresses of those trainees who had sat the FCEM examination in 2006 and 2007 were provided by the CEM and questionnaires were sent electronically to recipients. Responses were collated and analysed using Microsoft Excel. RESULTS: There was a response rate of 42% (86/203), of whom about three-quarters felt well prepared for the FCEM. The most highly valued resources for exam preparation were practice questions, private study and small group work. A yearly mock FCEM examination was felt to be important by those who had such access and local trainer involvement in exam preparation was perceived significant for success. CONCLUSIONS: Training programmes should make sure that facilities and expertise are available at a local level to allow trainees to have access to everything that is considered important in order to pass the FCEM.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios: associations with mortality in a haemodialysis cohort.

Background: Lymphocyte ratios reflect inflammation and have been associated with adverse outcomes in a range of diseases. We sought to determine any association between neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) and mortality in a haemodialysis cohort, including a coronavirus disease 2019 (COVID-19) infection subpopulation. Methods: A retrospective analysis was performed of adults commencing hospital haemodialysis in the West of Scotland during 2010-21. NLR and PLR were calculated from routine samples around haemodialysis initiation. Kaplan-Meier and Cox proportional hazards analyses were used to assess mortality associations. Results: In 1720 haemodialysis patients over a median of 21.9 (interquartile range 9.1-42.9) months, there were 840 all-cause deaths. NLR but not PLR was associated with all-cause mortality after multivariable adjustment [adjusted hazard ratio (aHR) for in participants with baseline NLR in quartile 4 (NLR ≥8.23) versus quartile 1 (NLR <3.12) 1.63, 95% confidence interval (CI) 1.32-2.00]. The association was stronger for cardiovascular death (NLR quartile 4 versus 1 aHR 3.06, 95% CI 1.53-6.09) than for non-cardiovascular death (NLR quartile 4 versus 1 aHR 1.85, 95% CI 1.34-2.56). In the COVID-19 subpopulation, both NLR and PLR at haemodialysis initiation were associated with risk of COVID-19-related death after adjustment for age and sex (NLR: aHR 4.69, 95% CI 1.48-14.92 and PLR: aHR 3.40, 95% CI 1.02-11.36; for highest vs lowest quartiles). Conclusions: NLR is strongly associated with mortality in haemodialysis patients while the association between PLR and adverse outcomes is weaker. NLR is an inexpensive, readily available biomarker with potential utility in risk stratification of haemodialysis patients.

Differential Associations of Cystatin C Versus Creatinine-Based Kidney Function With Risks of Cardiovascular Event and Mortality Among South Asian Individuals in the UK Biobank.

Background South Asian individuals have increased cardiovascular disease and mortality risks. Reliance on creatinine- rather than cystatin C-based estimated glomerular filtration rate (eGFRcys) may underestimate the cardiovascular disease risk associated with chronic kidney disease. Methods and Results Among 7738 South Asian UK BioBank participants without prevalent heart failure (HF) or atherosclerotic cardiovascular disease, we investigated associations of 4 eGFRcys and creatinine-based estimated glomerular filtration rate categories (<45, 45-59, 60-89, and ≥90 mL/min per 1.73 m2) with risks of all-cause mortality, incident HF, and incident atherosclerotic cardiovascular disease. The mean age was 53±8 years; 4085 (53%) were women. Compared with creatinine, cystatin C identified triple the number of participants with estimated glomerular filtration <45 (n=35 versus n=113) and 6 times the number with estimated glomerular filtration 45 to 59 (n=80 versus n=481). After multivariable adjustment, the eGFRcys 45 to 59 category was associated with higher risks of mortality (hazard ratio [HR], 2.38 [95% CI, 1.55-3.65]) and incident HF (sub-HR [sHR], 1.87 [95% CI, 1.09-3.22]) versus the eGFRcys ≥90 category; the creatinine-based estimated glomerular filtration rate 45 to 59 category had no significant associations with outcomes. Of the 7623 participants with creatinine-based estimated glomerular filtration rate ≥60, 498 (6.5%) were reclassified into eGFRcys <60 categories. Participants who were reclassified as having eGFRcys <45 had higher risks of mortality (HR, 4.88 [95% CI, 2.56-9.31]), incident HF (sHR, 4.96 [95% CI, 2.21-11.16]), and incident atherosclerotic cardiovascular disease (sHR, 2.29 [95% CI, 1.14-4.61]) versus those with eGFRcys ≥90; those reclassified as having eGFRcys 45 to 59 had double the mortality risk (HR, 2.25 [95% CI, 1.45-3.51]). Conclusions Among South Asian individuals, cystatin C identified a high-risk chronic kidney disease population that was not detected by creatinine and enhanced estimated glomerular filtration rate-based risk stratification for mortality, incident HF, and incident atherosclerotic cardiovascular disease.

Potential impact of NICE guidelines on referrals from primary care to nephrology: a primary care database and prospective research study.

BACKGROUND: National Institute for Health and Care Excellence 2021 guidelines on chronic kidney disease (CKD) recommend the use of the Kidney Failure Risk Equation (KFRE), which includes measurement of albuminuria. The equation to calculate estimated glomerular filtration rate (eGFR) has also been updated. AIM: To investigate the impact of the use of KFRE and the updated eGFR equation on CKD diagnosis (eGFR <60 mL/min/1.73 m2) in primary care and potential referrals to nephrology. DESIGN AND SETTING: Primary care database (Secure Anonymised Information Linkage Databank [SAIL]) and prospective cohort study (UK Biobank) using data available between 2013 and 2020. METHOD: CKD diagnosis rates were assessed when using the updated eGFR equation. Among people with eGFR 30-59 mL/min/1.73 m2 the following groups were identified: those with annual albuminuria testing and those who met nephrology referral criteria because of: a) accelerated eGFR decline or significant albuminuria; b) eGFR decline <30 mL/ min/1.73 m2 only; and c) KFRE >5% only. Analyses were stratified by ethnicity in UK Biobank. RESULTS: Using the updated eGFR equation resulted in a 1.2-fold fall in new CKD diagnoses in the predominantly White population in SAIL, whereas CKD prevalence rose by 1.9-fold among Black participants in UK Biobank. Rates of albuminuria testing have been consistently below 30% since 2015. In 2019, using KFRE >5% identified 182/61 721 (0.3%) patients at high risk of CKD progression before their eGFR declined and 361/61 721 (0.6%) low-risk patients who were no longer eligible for referral. Ethnic groups 'Asian' and 'other' had disproportionately raised KFREs. CONCLUSION: Application of KFRE criteria in primary care will lead to referral of more patients at elevated risk of kidney failure (particularly among minority ethnic groups) and fewer low-risk patients. Albuminuria testing needs to be expanded to enable wider KFRE implementation.

Sex differences in associations between creatinine and cystatin C-based kidney function measures with stroke and major bleeding.

PURPOSE: We sought to explore whether adding kidney function biomarkers based on creatinine (eGFRCr), cystatin C (eGFRCys) or a combination of the two (eGFRCr-Cys) could improve risk stratification for stroke and major bleeding, and whether there were sex differences in any additive value of kidney function biomarkers. METHOD: We included participants from the UK Biobank who had not had a previous ischaemic or haemorrhagic stroke or major bleeding episode, and who had kidney function measures available at baseline. Cause-specific Cox proportional hazards models tested associations between eGFRCr, eGFRCys and eGFRCr-Cys (mL/min/1.73 m2) with ischaemic and haemorrhagic stroke, major bleeding (gastrointestinal or intracranial, including haemorrhagic stroke) and all-cause mortality. FINDINGS: Among 452,879 eligible participants, 246,244 (54.4%) were women. Over 11.5 (IQR 10.8-12.2) years, there were 3706 ischaemic strokes, 795 haemorrhagic strokes, 26,025 major bleeding events and 28,851 deaths. eGFRCys was more strongly associated with ischaemic stroke than eGFRCr: an effect that was more pronounced in women (men - HR: 1.16, 95% CI: 1.12-1.19; female to male comparison - HR: 1.11, 95% CI: 1.05-1.16, per 10 mL/min/1.73 m2 decline in eGFRCys). This interaction effect was also demonstrated for eGFRCr-Cys, but not eGFRCr. eGFRCys and eGFRCr-Cys were more strongly associated with major bleeding and all-cause mortality than eGFRCr in both men and women. Event numbers were small for haemorrhagic stroke. DISCUSSION: To a greater degree than is seen in men, eGFRCr underestimates risk of ischaemic stroke and major bleeding in women compared to eGFRCys. The difference between measures is likely explained by non-GFR biology of creatinine and cystatin C. CONCLUSION: Enhanced measurement of cystatin C may improve risk stratification for ischaemic stroke and major bleeding and clinical treatment decisions in a general population setting, particularly for women.

Left ventricular dysfunction with preserved ejection fraction: the most common left ventricular disorder in chronic kidney disease patients.

Chronic kidney disease (CKD) is a risk factor for premature cardiovascular disease. As kidney function declines, the presence of left ventricular abnormalities increases such that by the time kidney replacement therapy is required with dialysis or kidney transplantation, more than two-thirds of patients have left ventricular hypertrophy. Historically, much research in nephrology has focussed on the structural and functional aspects of cardiac disease in CKD, particularly using echocardiography to describe these abnormalities. There is a need to translate knowledge around these imaging findings to clinical outcomes such as unplanned hospital admission with heart failure and premature cardiovascular death. Left ventricular hypertrophy and cardiac fibrosis, which are common in CKD, predispose to the clinical syndrome of heart failure with preserved left ventricular ejection fraction (HFpEF). There is a bidirectional relationship between CKD and HFpEF, whereby CKD is a risk factor for HFpEF and CKD impacts outcomes for patients with HFpEF. There have been major improvements in outcomes for patients with heart failure and reduced left ventricular ejection fraction as a result of several large randomized controlled trials. Finding therapy for HFpEF has been more elusive, although recent data suggest that sodium-glucose cotransporter 2 inhibition offers a novel evidence-based class of therapy that improves outcomes in HFpEF. These observations have emerged as this class of drugs has also become the standard of care for many patients with proteinuric CKD, suggesting that there is now hope for addressing the combination of HFpEF and CKD in parallel. In this review we summarize the epidemiology, pathophysiology, diagnostic strategies and treatment of HFpEF with a focus on patients with CKD.

Assessment of Cystatin C Level for Risk Stratification in Adults With Chronic Kidney Disease.

Importance: Kidney function is usually estimated from serum creatinine level, whereas an alternative glomerular filtration marker (cystatin C level) associates more closely with future risk of cardiovascular disease (CVD) and mortality. Objectives: To evaluate whether testing concordance between estimated glomerular filtration rates based on cystatin C (eGFRcys) and creatinine (eGFRcr) levels would improve risk stratification for future outcomes and whether estimations differ by age. Design, Setting, and Participants: A prospective population-based cohort study (UK Biobank), with participants recruited between 2006-2010 with median follow-up of 11.5 (IQR, 10.8-12.2) years; data were collected until August 31, 2020. Participants had eGFRcr greater than or equal to 45 mL/min/1.73 m2, albuminuria (albumin <30 mg/g), and no preexisting CVD or kidney failure. Exposures: Chronic kidney disease status was categorized by concordance between eGFRcr and eGFRcys across the threshold for hronic kidney disease (CKD) diagnosis (60 mL/min/1.73 m2). Main Outcomes and Measures: Ten-year probabilities of CVD, mortality, and kidney failure were assessed according to CKD status. Multivariable-adjusted Cox proportional hazards models tested associations between CVD and mortality. Area under the receiving operating curve tested discrimination of eGFRcr and eGFRcys for CVD and mortality. The Net Reclassification Index assessed the usefulness of eGFRcr and eGFRcys for CVD risk stratification. Analyses were stratified by older (age 65-73 years) and younger (age <65 years) age. Results: There were 428 402 participants: median age was 57 (IQR, 50-63) years and 237 173 (55.4%) were women. Among 76 629 older participants, there were 9335 deaths and 5205 CVD events. Among 351 773 younger participants, there were 14 776 deaths and 9328 CVD events. The 10-year probability of kidney failure was less than 0.1%. Regardless of the eGFRcr, the 10-year probabilities of CVD and mortality were low when eGFRcys was greater than or equal to 60 mL/min/1.73 m2; conversely, with eGFRcys less than 60 mL/min/1.73 m2, 10-year risks were nearly doubled in older adults and more than doubled in younger adults. Use of eGFRcys better discriminated CVD and mortality risk than eGFRcr. Across a 7.5% 10-year risk threshold for CVD, eGFRcys improved case Net Reclassification Index by 0.7% (95% CI, 0.6%-0.8%) in older people and 0.7% (95% CI, 0.7%-0.8%) in younger people; eGFRcr did not add to CVD risk estimation. Conclusions and Relevance: The findings of this study suggest that eGFRcr 45 to 59 mL/min/1.73 m2 includes a proportion of individuals at low risk and fails to capture a substantial proportion of individuals at high-risk for CVD and mortality. The eGFRcys appears to be more sensitive and specific for CVD and mortality risks in mild CKD.

Acute intermittent renal replacement therapy in a rural Scottish intensive care unit - a review of patient and renal outcomes.

In this study we report 5-year outcomes for patients who received intermittent haemodiafiltration for Acute Kidney Injury (AKI) between 2010 and 2014 in a small Scottish Intensive Care Unit (ICU). Dialysis independence and mortality at ICU discharge, 30 and 90 days, one and five years were determined. There were 1496 admissions to ICU during the study period. 12% of patient admissions required Renal Replacement Therapy (RRT). 56.3% of patients survived to ICU discharge and all were RRT independent at ICU discharge. 30 day, 90 day, 1 year and 5 year survival was 52.3%, 50.6%, 46.6% and 30.7% respectively. By 5 years, 2 patients had developed end stage kidney disease.

Relapse of treated anti-GBM disease following hair dye use.

An 18-year-old woman was treated for acute kidney injury (AKI) secondary to antiglomerular basement membrane (GBM) disease with prednisolone, cyclophosphamide and plasma exchange. She also had epistaxis at initial presentation with no other organ involvement and achieved good recovery of her kidney function. Two weeks after completing induction treatment, she re-presented with further AKI and pulmonary haemorrhage. She was recommenced on plasma exchange and steroids and was given rituximab. She recovered from her illness with significant improvement to her kidney function. The cause of her relapse was thought to be possibly due to the use of hair dye. This case highlights the importance of acknowledging potential environmental exposures to prevent relapses of disease. We were also able to demonstrate a case of successful treatment of anti-GBM disease with rituximab.

Global longitudinal strain by feature-tracking cardiovascular magnetic resonance imaging predicts mortality in patients with end-stage kidney disease.

BACKGROUND: Patients with end-stage kidney disease (ESKD) are at increased risk of premature death, with cardiovascular disease being the predominant cause of death. We hypothesized that left ventricular global longitudinal strain (LV-GLS) measured by feature-tracking cardiovascular magnetic resonance imaging (CMRI) would be associated with all-cause mortality in patients with ESKD. METHODS: A pooled analysis of CMRI studies in patients with ESKD acquired within a single centre between 2002 and 2016 was carried out. CMR parameters including LV ejection fraction (LVEF), LV mass index, left atrial emptying fraction (LAEF) and LV-GLS were measured. We tested independent associations of CMR parameters with survival using a multivariable Cox model. RESULTS: Among 215 patients (mean age 54 years, 62% male), mortality was 53% over a median follow-up of 5 years. The median LVEF was 64.7% [interquartile range (IQR) 58.5-70.0] and the median LV-GLS was -15.3% (IQR -17.24 to -13.6). While 90% of patients had preserved LVEF (>50%), 58% of this group had abnormal LV-GLS (>-16%). On multivariable Cox regression, age {hazard ratio [HR] 1.04 [95% confidence interval (CI) 1.02-1.05]}, future renal transplant [HR 0.29 (95% CI 0.17-0.47)], LAEF [HR 0.98 (95% CI 0.96-1.00)] and LV-GLS [HR 1.08 (95% CI 1.01-1.16)] were independently associated with mortality. CONCLUSIONS: In this cohort of patients with ESKD, LV-GLS on feature-tracking CMRI and LAEF was associated with all-cause mortality, independent of baseline clinical variables and future renal transplantation. This effect was present even when >90% of the cohort had normal LVEF. Using LV-GLS instead of LVEF to diagnose cardiac dysfunction in patients with ESKD could result in a major advance in our understanding of cardiovascular disease in ESKD.