Impaired Kidney Function, Cerebral Small Vessel Disease and Cognitive Disorders: The Framingham Heart Study.

BACKGROUND AND HYPOTHESIS: It remains unclear if the relation of chronic kidney disease (CKD) with cognitive dysfunction is independent of blood pressure (BP). We evaluated kidney function in relation to premorbid BP measurements, cerebral small vessel disease (CSVD) and incident mild cognitive impairment (MCI) and dementia in Framingham Offspring Cohort participants. METHODS: We included Framingham Offspring participants free of dementia, attending an examination during midlife (exam cycle 6, baseline) for ascertainment of kidney function status, with brain MRI late in life (exam cycles 7-9), cognitive outcome data and available interim hypertension and blood pressure assessments. We related CKD (estimated glomerular filtration rate < 60 ml/min/1.73m2) and albuminuria (urine albumin-to-creatinine ratio ≥ 30 mg/g) to CSVD markers and cognitive outcomes using multivariable regression analyses. RESULTS: Among 2604 participants (mean age 67.4 ± 9.2, 64% women, 7% had CKD and 9% albuminuria), albuminuria was independently associated with covert infarcts (adjusted OR, 1.55 [1.00-2.38]; P = 0.049) and incident MCI and dementia (adjusted HR, 1.68 [1.18-2.41]; P = 0.005 and 1.71, [1.11-2.64]; P = 0.015, respectively). CKD was not associated with CSVD markers but was associated with higher risk of incident dementia (HR, 1.53 [1.02-2.29]; P = 0.041), While albuminuria was predictive of the Alzheimer's disease subtype (Adjusted HR = 1.68, [1.03-2.74]; P = 0.04), CKD was predictive of vascular dementia (Adjusted HR, 2.78, [1.16-6.68]; P = 0.023). CONCLUSIONS: Kidney disease was associated with CSVD and cognitive disorders in asymptomatic community dwelling participants. The relation was independent of premorbid BP, suggesting that the link between kidney and brain disease may involve additional mechanisms beyond blood pressure related injury.

Capacity for the management of kidney failure in the International Society of Nephrology Western Europe region: report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA).

Western Europe boasts advanced health care systems, robust kidney care guidelines, and a well-established health care workforce. Despite this, significant disparities in kidney replacement therapy incidence, prevalence, and transplant access exist. This paper presents the third International Society of Nephrology Global Kidney Health Atlas's findings on kidney care availability, accessibility, affordability, and quality in 22 Western European countries, representing 99% of the region's population. The known chronic kidney disease (CKD) prevalence across Western Europe averages 10.6%, slightly above the global median. Cardiovascular diseases account for a substantial portion of CKD-related deaths. Kidney failure incidence varies. Government health expenditure differs; however, most countries offer government-funded acute kidney injury, dialysis, and kidney transplantation care. Hemodialysis and peritoneal dialysis are universally available, with variations in the number of dialysis centers. Kidney transplantation is available in all countries (except for 3 microstates), with variable transplant center prevalence. Conservative kidney management (CKM) is increasingly accessible. The region's kidney care workforce is substantial, exceeding global averages; however, workforce shortages are reported. Barriers to optimal kidney care include limited workforce capacity, lack of surveillance mechanisms, and suboptimal integration into national noncommunicable disease (NCD) strategies. Policy recognition of CKD as a health priority varies across countries. Although Western Europe exhibits strong kidney care infrastructure, opportunities for improvement exist, particularly in CKD prevention, surveillance, awareness, and policy implementation. Efforts to improve CKD care should include automated detection, educational support, and enhanced workflows. Based on these findings, health care professionals, stakeholders, and policymakers are called to act to enhance kidney care across the region.

Kidney Function, Albuminuria, and Risk of Incident Atrial Fibrillation: A Systematic Review and Meta-Analysis.

RATIONALE & OBJECTIVE: Atrial fibrillation (AF) and chronic kidney disease (CKD) often coexist. However, it is not known whether CKD is an independent risk factor for incident AF. Therefore, we evaluated the association between markers of CKD-estimated glomerular filtration rate (eGFR) and albuminuria-and incident AF. STUDY DESIGN: Systematic review and meta-analysis of cohort studies and randomized controlled trials. SETTING & STUDY POPULATIONS: Participants with measurement of eGFR and/or albuminuria who were not receiving dialysis. SELECTION CRITERIA FOR STUDIES: Cohort studies and randomized controlled trials were included that reported incident AF risk in adults according to eGFR and/or albuminuria. ANALYTICAL APPROACH: Age- or multivariate-adjusted risk ratios (RRs) for incident AF were extracted from cohort studies, and RRs for each trial were derived from event data. RRs for incident AF were pooled using random-effects models. RESULTS: 38 studies involving 28,470,249 participants with 530,041 incident AF cases were included. Adjusted risk of incident AF was greater among participants with lower eGFR than those with higher eGFR (eGFR<60 vs≥60mL/min/1.73m2: RR, 1.43; 95% CI, 1.30-1.57; and eGFR<90 vs≥90mL/min/1.73m2: RR, 1.42; 95% CI, 1.26-1.60). Adjusted incident AF risk was greater among participants with albuminuria (any albuminuria vs no albuminuria: RR, 1.43; 95% CI, 1.25-1.63; and moderately to severely increased albuminuria vs normal to mildly increased albuminuria: RR, 1.64; 95% CI, 1.31-2.06). Subgroup analyses showed an exposure-dependent association between CKD and incident AF, with the risk increasing progressively at lower eGFR and higher albuminuria categories. LIMITATIONS: Lack of patient-level data, interaction between eGFR and albuminuria could not be evaluated, possible ascertainment bias due to variation in the methods of AF detection. CONCLUSIONS: Lower eGFR and greater albuminuria were independently associated with increased risk of incident AF. CKD should be regarded as an independent risk factor for incident AF. PLAIN-LANGUAGE SUMMARY: Irregular heartbeat, or atrial fibrillation (AF), is the commonest abnormal heart rhythm. AF occurs commonly in people with chronic kidney disease (CKD), and CKD is also common in people with AF. However, CKD in not widely recognized as a risk factor for new-onset or incident AF. In this research, we combined data on more than 28 million participants in 38 studies to determine whether CKD itself increases the chances of incident AF. We found that both commonly used markers of kidney disease (estimated glomerular filtration rate and albuminuria, ie, protein in the urine) were independently associated with a greater risk of incident AF. This finding suggests that CKD should be recognized as an independent risk factor for incident AF.

Interplay Between Chronic Kidney Disease, Hypertension, and Stroke: Insights From a Multivariable Mendelian Randomization Analysis.

BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) increases the risk of stroke, but the extent through which this association is mediated by hypertension is unknown. We leveraged large-scale genetic data to explore causal relationships between CKD, hypertension, and cerebrovascular disease phenotypes. METHODS: We used data from genome-wide association studies of European ancestry to identify genetic proxies for kidney function (CKD diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]), systolic blood pressure (SBP), and cerebrovascular disease (ischemic stroke and its subtypes and intracerebral hemorrhage). We then conducted univariable, multivariable, and mediation Mendelian randomization (MR) analyses to investigate the effect of kidney function on stroke risk and the proportion of this effect mediated through hypertension. RESULTS: Univariable MR revealed associations between genetically determined lower eGFR and risk of all stroke (odds ratio [OR] per 1-log decrement in eGFR, 1.77; 95% CI 1.31-2.40; p < 0.001), ischemic stroke (OR 1.81; 95% CI 1.31-2.51; p < 0.001), and most strongly with large artery stroke (LAS) (OR 3.00; 95% CI 1.33-6.75; p = 0.008). These associations remained significant in the multivariable MR analysis, controlling for SBP (OR 1.98; 95% CI 1.39-2.82; p < 0.001 for all stroke; OR 2.16; 95% CI 1.48-3.17; p < 0.001 for ischemic stroke; OR 4.35; 95% CI 1.84-10.27; p = 0.001 for LAS), with only a small proportion of the total effects mediated by SBP (6.5% [0.7%-16.8%], 6.6% [0.8%-18.3%], and 7.2% [0.5%-24.8%], respectively). Total, direct and indirect effect estimates were similar across a number of sensitivity analyses (weighted median, MR-Egger regression). DISCUSSION: Our results demonstrate an independent causal effect of impaired kidney function, as assessed by decreased eGFR, on stroke risk, particularly LAS, even when controlled for SBP. Targeted prevention of kidney disease could lower atherosclerotic stroke risk independent of hypertension.

Development and Validation of a Predictive Risk Algorithm for Bleeding in Individuals on Long-term Hemodialysis: An International Prospective Cohort Study (BLEED-HD).

Background: Individuals with kidney disease are at a high risk of bleeding and as such tools that identify those at highest risk may aid mitigation strategies. Objective: We set out to develop and validate a prediction equation (BLEED-HD) to identify patients on maintenance hemodialysis at high risk of bleeding. Design: International prospective cohort study (development); retrospective cohort study (validation). Settings: Development: 15 countries (Dialysis Outcomes and Practice Patterns Study [DOPPS] phase 2-6 from 2002 to 2018); Validation: Ontario, Canada. Patients: Development: 53 147 patients; Validation: 19 318 patients. Measurements: Hospitalization for a bleeding event. Methods: Cox proportional hazards models. Results: Among the DOPPS cohort (mean age, 63.7 years; female, 39.7%), a bleeding event occurred in 2773 patients (5.2%, event rate 32 per 1000 person-years), with a median follow-up of 1.6 (interquartile range [IQR], 0.9-2.1) years. BLEED-HD included 6 variables: age, sex, country, previous gastrointestinal bleeding, prosthetic heart valve, and vitamin K antagonist use. The observed 3-year probability of bleeding by deciles of risk ranged from 2.2% to 10.8%. Model discrimination was low to moderate (c-statistic = 0.65) with excellent calibration (Brier score range = 0.036-0.095). Discrimination and calibration of BLEED-HD were similar in an external validation of 19 318 patients from Ontario, Canada. Compared to existing bleeding scores, BLEED-HD demonstrated better discrimination and calibration (c-statistic: HEMORRHAGE = 0.59, HAS-BLED = 0.59, and ATRIA = 0.57, c-stat difference, net reclassification index [NRI], and integrated discrimination index [IDI] all P value <.0001). Limitations: Dialysis procedure anticoagulation was not available; validation cohort was considerably older than the development cohort. Conclusion: In patients on maintenance hemodialysis, BLEED-HD is a simple risk equation that may be more applicable than existing risk tools in predicting the risk of bleeding in this high-risk population.

Contexte: Les personnes atteintes d'insuffisance rénale présentent un risque élevé d'hémorragie. Des outils permettant de déceler les personnes les plus exposées au risque pourrait aider à mettre en œuvre des stratégies d'atténuation. Objectifs: Nous avons mis au point et validé une équation prédictive (BLEED-HD) afin d'identifier les patients sous hémodialyse d'entretien qui présentent un risque élevé d'hémorragie. Type d'étude: Étude de cohorte prospective internationale (développement); étude de cohorte rétrospective (validation). Cadre: Développement: dans 15 pays (étude DOPPS phases 2 à 6 entre 2002 et 2018); validation: en Ontario (Canada). Sujets: Développement: 53 147 patients; validation: 19 318 patients. Mesures: Hospitalisation pour un événement hémorragique. Méthodologie: Modèles à risques proportionnels de Cox. Résultats: Dans la cohorte DOPPS (âge moyen: 63,7 ans; 39,7 % de femmes), 2 773 patients avaient subi un événement hémorragique (5,2 %; taux d'événements: 32 pour 1 000 années-personnes) avec un suivi médian de 1,6 an (ÉIQ: 0,9 à 2,1). BLEED-HD prend six variables en compte: âge, sexe, pays d'origine, saignement gastro-intestinal antérieur, présence d'une valve cardiaque prothétique et utilisation d'un antagoniste de la vitamine K. La probabilité observée de saignements dans les 3 ans par déciles de risque allait de 2,2 à 10,8 %. La discrimination du modèle variait de faible à modérée (statistique c: 0,65) avec un excellent étalonnage (plage de score de Brier: 0,036-0,095). La discrimination et l'étalonnage de se sont avérés semblables lors de la validation externe auprès de 19 318 patients de l'Ontario (Canada). Par rapport aux scores d'hémorragie existants, l'équation BLEED-HD a démontré une meilleure discrimination et un meilleur étalonnage (statistique c: HEMORRHAGE 0,59; HAS-BLED 0,59 et ATRIA 0,57; différence dans les c-stat, indices NRI et IDI toutes valeurs de p < 0,0001). Limites: L'information sur l'anticoagulant utilisé dans la procédure de dialyse n'était pas disponible; la cohorte de validation était beaucoup plus âgée que la cohorte de développement. Conclusion: Pour les patients sous hémodialyse d'entretien, BLEED-HD est une équation simple de calcul du risque qui peut être plus facilement applicable que les outils existants pour prédire le risque d'hémorragie dans cette population à haut risque.

Invasive pulmonary aspergillosis in the intensive care unit: current challenges and best practices.

The prevalence of invasive pulmonary aspergillosis (IPA) is growing in critically ill patients in the intensive care unit (ICU). It is increasingly recognized in immunocompetent hosts and immunocompromised ones. IPA frequently complicates both severe influenza and severe coronavirus disease 2019 (COVID-19) infection. It continues to represent both a diagnostic and therapeutic challenge and can be associated with significant morbidity and mortality. In this narrative review, we describe the epidemiology, risk factors and disease manifestations of IPA. We discuss the latest evidence and current published guidelines for the diagnosis and management of IPA in the context of the critically ill within the ICU. Finally, we review influenza-associated pulmonary aspergillosis (IAPA), COVID-19-associated pulmonary aspergillosis (CAPA) as well as ongoing and future areas of research.

Admission Rates, Time Trends, Risk Factors, and Outcomes of Ischemic and Hemorrhagic Stroke From German Nationwide Data.

BACKGROUND AND OBJECTIVES: In the last decade, there have been major improvements in the control of risk factors, acute stroke therapies and rehabilitation following the availability of high-quality evidence and guidelines on best practices in the acute phase. In this changing landscape, we aimed to investigate the stroke admission rates, time-trends, risk factors, and outcomes during the period of 2014-2019 using German nationwide data. METHODS: We obtained data of all acute stroke hospitalizations by the Federal Statistical Office. All hospitalized cases of adults (age ≥ 18 years) with acute stroke from the years 2014-2019 were analyzed regarding time trends, risk factors, treatments, morbidity and in-hospital mortality according to stroke subtype (all-cause/ischaemic/haemorrhagic). RESULTS: Between 2014 and 2019, overall stroke hospitalizations in adults (median age = 76 years, [IQR: 65-83 years]) initially increased from 306,425 in 2014 to peak at 318,849 in 2017 before falling to again to 312,692 in 2019, whereas percentage stroke hospitalizations that resulted in death remained stable during this period at 8.5% in 2014 and 8.6% in 2019. In a multivariate model of 1,882,930 cases, the strongest predictors of in-hospital stroke mortality were haemorrhagic subtype (Adjusted OR [aOR] = 3.06, 95% CI 3.02-3.10; p<0.001), cancer (aOR = 2.11, 2.06-2.16; p<0.001), congestive heart failure (aOR = 1.70, 1.67-1.73; p<0.001), and lower extremity arterial disease (aOR =1.76, 1.67-1.84; p<0.001). DISCUSSION: Despite recent advances in acute stroke care over the last decade, the percentage of stroke hospitalizations resulting in death remained unchanged. Further research is needed to determine how best to optimize stroke care pathways for multimorbid patients.

Disentangling the Relationship Between Chronic Kidney Disease and Cognitive Disorders.

Chronic kidney disease (CKD) is a rapidly rising global health burden that affects nearly 40% of older adults. Epidemiologic data suggest that individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing cognitive disorders and dementia, and thus represent a vulnerable population. It is currently unknown to what extent this risk may be attributable to a clustering of traditional risk factors such as hypertension and diabetes mellitus leading to a high prevalence of both symptomatic and subclinical ischaemic cerebrovascular lesions, or whether other potential mechanisms, including direct neuronal injury by uraemic toxins or dialysis-specific factors could also be involved. These knowledge gaps may lead to suboptimal prevention and treatment strategies being implemented in this group. In this review, we explore the mechanisms of susceptibility and risk in the relationship between CKD and cognitive disorders.

Associations of Chronic Kidney Disease With Dementia Before and After TIA and Stroke: Population-Based Cohort Study.

BACKGROUND AND OBJECTIVES: Individuals with chronic kidney disease (CKD) appear to be at increased risk of cognitive impairment, with both vascular and neurodegenerative mechanisms postulated. To explore the vascular hypothesis, we studied the association between CKD and dementia before and after TIA and stroke. METHODS: In a prospective, population-based cohort study of TIA and stroke (Oxford Vascular Study; 2002-2012), pre-event and new postevent dementia were ascertained through direct patient assessment and follow-up for 5 years, supplemented by review of hospital/primary care records. Associations between pre-event dementia and CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) were examined using logistic regression and between postevent dementia and CKD using Cox and competing risk regression models, adjusted for age, sex, education, stroke severity, prior stroke, white matter disease, diabetes mellitus, and dysphasia. RESULTS: Among 2,305 patients with TIA/stroke (median [interquartile range] age, 77 [67-84] years, 1,133 [49%] male, 688 [30%] TIA), 1,174 (50.9%) had CKD. CKD was associated with both pre-event (odds ratio [OR] 2.04 [95% confidence interval (CI) 1.52-2.72]; p < 0.001) and postevent dementia (hazard ratio [HR] 2.01 [95% CI 1.65-2.44]; p < 0.001), but these associations attenuated after adjustment for covariates (OR 0.92 [0.65-1.31]; p = 0.65 and HR 1.09 [0.85-1.39]; p = 0.50). The results were similar when a competing risk model was used (subdistribution HR [SHR] 1.74 [1.43-2.12]; p < 0.001, attenuating to 1.01 [0.78-1.33]; p = 0.92 with adjustment). CKD was more strongly associated with late (>1 year) postevent dementia (SHR 2.32 [1.70-3.17]; p < 0.001), particularly after TIA and minor stroke (SHR 3.08 [2.05-4.64]; p < 0.001), but not significantly so after adjustment (SHR 1.53 [0.90-2.60]; p = 0.12). DISCUSSION: In patients with TIA and stroke, CKD was not independently associated with either pre- or postevent dementia, suggesting that renal-specific mechanisms are unlikely to play an important role in aetiology.

Stroke and Chronic Kidney Disease.

Chronic kidney disease (CKD) is strongly associated with the full spectrum of cerebrovascular disease including ischaemic and haemorrhagic stroke, small vessel disease, and vascular cognitive impairment. Shared conventional vascular risk factors such as age, hypertension, and diabetes mellitus may account for many of these associations, but novel renal-specific risk factors such as uraemia-related coagulopathy or endothelial dysfunction have also been proposed. In this chapter, we will explore the impact of CKD on stroke risk, mechanisms, and outcomes. We will also outline potential challenges and inequities in stroke care delivery and research for these patients along with some strategies to help improve stroke prevention and management for this high-risk group.

Chronic Kidney Disease and Cerebrovascular Disease: Consensus and Guidance From a KDIGO Controversies Conference.

The global health burden of chronic kidney disease is rapidly rising, and chronic kidney disease is an important risk factor for cerebrovascular disease. Proposed underlying mechanisms for this relationship include shared traditional risk factors such as hypertension and diabetes, uremia-related nontraditional risk factors, such as oxidative stress and abnormal calcium-phosphorus metabolism, and dialysis-specific factors such as cerebral hypoperfusion and changes in cardiac structure. Chronic kidney disease frequently complicates routine stroke risk prediction, diagnosis, management, and prevention. It is also associated with worse stroke severity, outcomes and a high burden of silent cerebrovascular disease, and vascular cognitive impairment. Here, we present a summary of the epidemiology, pathophysiology, diagnosis, and treatment of cerebrovascular disease in chronic kidney disease from the Kidney Disease: Improving Global Outcomes Controversies Conference on central and peripheral arterial disease with a focus on knowledge gaps, areas of controversy, and priorities for research.

Central and peripheral arterial diseases in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Chronic kidney disease (CKD) affects about 10% of all populations worldwide, with about 2 million people requiring dialysis. Although patients with CKD are at high risk of cardiovascular disease and events, they are often underrepresented or excluded in clinical trials, leading to important knowledge gaps about how to treat these patients. KDIGO (Kidney Disease: Improving Global Outcomes) convened the fourth clinical Controversies Conference on the heart, kidney and vasculature in Dublin, Ireland, in February 2020, entitled Central and Peripheral Arterial Diseases in Chronic Kidney Disease. A global panel of multidisciplinary experts from the fields of nephrology, cardiology, neurology, surgery, radiology, vascular biology, epidemiology, and health economics attended. The objective was to identify key issues related to the optimal detection, management, and treatment of cerebrovascular diseases, central aortic disease, renovascular disease, and peripheral artery disease in the setting of CKD. This report outlines the common pathophysiology of these vascular processes in the setting of CKD, describes best practices for their diagnosis and management, summarizes areas of uncertainty, addresses ongoing controversial issues, and proposes a research agenda to address key gaps in knowledge that, when addressed, could improve patient care and outcomes.

International Society of Nephrology Global Kidney Health Atlas: structures, organization, and services for the management of kidney failure in Western Europe.

Populations in the high-income countries of Western Europe are aging due to increased life expectancy. As the prevalence of diabetes and obesity has increased, so has the burden of kidney failure. To determine the global capacity for kidney replacement therapy and conservative kidney management, the International Society of Nephrology conducted multinational, cross-sectional surveys and published the findings in the International Society of Nephrology Global Kidney Health Atlas. In the second iteration of the International Society of Nephrology Global Kidney Health Atlas, we aimed to describe the availability, accessibility, quality, and affordability of kidney failure care in Western Europe. Among the 29 countries in Western Europe, 21 (72.4%) responded, representing 99% of the region's population. The burden of kidney failure prevalence varied widely, ranging from 760 per million population (pmp) in Iceland to 1612 pmp in Portugal. Coverage of kidney replacement therapy from public funding was nearly universal, with the exceptions of Germany and Liechtenstein where part of the costs was covered by mandatory insurance. Fourteen (67%) of 21 countries charged no fees at the point of care delivery, but in 5 countries (24%), patients do pay some out-of-pocket costs. Long-term dialysis services (both hemodialysis and peritoneal dialysis) were available in all countries in the region, and kidney transplantation services were available in 19 (90%) countries. The incidence of kidney transplantation varied widely between countries from 12 pmp in Luxembourg to 70.45 pmp in Spain. Conservative kidney care was available in 18 (90%) of 21 countries. The median number of nephrologists was 22.9 pmp (range: 9.47-55.75 pmp). These data highlight the uniform capacity of Western Europe to provide kidney failure care, but also the scope for improvement in disease prevention and management, as exemplified by the variability in disease burden and transplantation rates.

Associations of blood biomarkers with glomerular filtration rate in patients with TIA and stroke: population-based study.

BACKGROUND AND PURPOSE: Non-traditional risk factors such as chronic inflammation, oxidative stress and thrombogenic factors are believed to contribute to the excess stroke risk in chronic kidney disease (CKD) by triggering vascular injury and endothelial dysfunction. We aimed to determine how well a panel of biomarkers representative of these factors would correlate with estimated glomerular filtration rate (eGFR) in patients with recent transient ischaemic attack (TIA) or stroke. We also investigated whether eGFR would confound previously reported associations between biomarkers and mortality. METHODS: We studied a panel of 16 blood biomarkers related to inflammation, thrombosis, atherogenesis and cardiac or neuronal cell damage in TIA or ischaemic stroke in a population-based study (Oxford Vascular Study). Biomarker levels were log-transformed and correlated with eGFR, adjusted for age. Cox proportional hazard models were used for survival analysis. RESULTS: Among 1297 patients with TIA or stroke, 52.7% (n=684) of patients had CKD (eGFR <60 mL/min/1.73 m2). There was a moderate correlation between log-eGFR and the log-transformed soluble tumour necrosis factor receptor-1 (R2=0.21), attenuating with adjustment for age (R2=0.12). There were moderate-to-strong correlations with markers of cardiac injury, N-terminal pro-brain natriuretic peptide and heart-type fatty acid binding protein (hFABP, R2=0.14 and 0.34, respectively). The strongest correlation after adjustment for age was between hFABP and eGFR (R2=0.20). Adjusting for eGFR did not impact any biomarker associations with mortality. CONCLUSIONS: Correlations between biomarkers related to inflammation and thrombosis with renal dysfunction in the setting of cerebrovascular events were generally modest after adjustment for age, suggesting that putative risk factors such as chronic inflammation or coagulopathy are unlikely to be important stroke mechanisms in patients with CKD.

Impact of multimorbidity on risk and outcome of stroke: Lessons from chronic kidney disease.

With both an aging population and greater post-stroke survival, multimorbidity is a growing healthcare challenge, affecting over 40% of stroke patients, and rising rapidly and predictably with increasing age. Commonly defined as the co-occurrence of two or more chronic conditions, multimorbidity burden is a strong adverse prognostic factor, associated with greater short- and long-term stroke mortality, worse rehabilitation outcomes, and reduced use of secondary prevention. Chronic kidney disease can be considered as the archetypal comorbidity, being age-dependent and also affecting about 40% of stroke patients. Chronic kidney disease and stroke share very similar traditional cardiovascular risk factor profiles such as hypertension and diabetes, though novel chronic kidney disease-specific risk factors such as inflammation and oxidative stress have also been proposed. Using chronic kidney disease as an exemplar condition, we explore the mechanisms of risk in multimorbidity, implications for management, impact on stroke severity, and downstream consequences such as post-stroke cognitive impairment and dementia.

Etiological Subtypes of Transient Ischemic Attack and Ischemic Stroke in Chronic Kidney Disease: Population-Based Study.

BACKGROUND AND PURPOSE: Chronic kidney disease (CKD) is strongly associated with stroke risk, but the mechanisms underlying this association are unclear and might be informed by subtype-specific analyses. However, few studies have reported stroke subtypes in CKD according to established classification systems, such as the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria. We, therefore, aimed to determine which transient ischemic attack and ischemic stroke subtypes using the TOAST classification occur most frequently in patients with CKD. METHODS: In a population-based study of all transient ischemic attack and stroke (OXVASC [Oxford Vascular Study]; 2002-2017), all ischemic events were classified by TOAST subtypes (cardioembolism, large artery disease, small vessel disease, undetermined, multiple, other etiology, or incompletely investigated). Logistic regression was used to determine the relationship between CKD (defined as an estimated glomerular filtration rate <60 mL/min per 1.73 m2) and transient ischemic attack/stroke subtypes adjusted for age, sex, and hypertension and then stratified by age and estimated glomerular filtration rate category. RESULTS: Among 3178 patients with transient ischemic attack (n=1167), ischemic stroke (n=1802), and intracerebral hemorrhage (n=209), 1267 (40%) had CKD. Although there was a greater prevalence of cardioembolic events (31.8% versus 21.2%; P<0.001) in patients with CKD, this association was lost after adjustment for age, sex, and hypertension (adjusted odds ratio=1.20 [95% CI, 0.99-1.45]; P=0.07). Similarly, although patients with CKD had a lower prevalence of small vessel disease (8.8% versus 13.6%; P<0.001), undetermined (26.1% versus 39.4%; P<0.001), and other etiology (1.0% versus 3.6%; P<0.001) subtypes, these associations were also lost after adjustment (adjusted odds ratio=0.86 [0.65-1.13]; P=0.27 and 0.73 [0.36-1.43]; P=0.37 for small vessel disease and other defined etiology, respectively) for all but undetermined (adjusted odds ratio=0.81 [0.67-0.98]; P=0.03). CONCLUSIONS: There were no independent positive associations between CKD and specific TOAST subtypes, which suggest that renal-specific risk factors are unlikely to play an important role in the etiology of particular subtypes. Future studies of stroke and CKD should report subtype-specific analyses to gain further insights into potential mechanisms.

Proteinuria as an independent predictor of stroke: Systematic review and meta-analysis.

BACKGROUND: Proteinuria has emerged as an important vascular risk factor for adverse cardiovascular events including stroke. Hypertension has been proposed as the principal confounder of this relationship but its role has not been systematically examined. AIM: We aimed to determine if proteinuria remains an independent predictor of stroke after more complete adjustment for blood pressure. SUMMARY OF REVIEW: We performed a systematic review, searching MEDLINE and EMBASE (to February 2018) for cohort studies or randomized controlled trials that reported stroke incidence in adults according to baseline proteinuria ± glomerular filtration rate. Study and participant characteristics and relative risks were extracted. Estimates were combined using a random effects model. Heterogeneity was assessed by χ 2 statistics and I2, and by subgroup strata and meta-regression, with a particular focus on the impact of more complete adjustment for blood pressure on the association. The quality of cohort studies and post hoc analyses was assessed using the Newcastle-Ottawa Scale. We identified 38 studies comprising 1,735,390 participants with 26,405 stroke events. Overall, the presence of any level of proteinuria was associated with greater stroke risk (18 studies; pooled crude relative risk 2.00, 95%CI 1.63-2.46; p < 0.001) even after adjustment for established cardiovascular risk factors (33 studies; pooled adjusted relative risk 1.72, 1.51-1.95; p < 0.001), albeit with considerable heterogeneity between studies (p < 0.001; I2 = 77.3%). Moreover, the association did not substantially attenuate with more thorough adjustment for hypertension: single baseline blood pressure measure (10 studies; pooled adjusted relative risk = 1.92, 1.39-2.66; p < 0.001); history or treated hypertension (four studies; pooled adjusted relative risk = 1.76, 1.13-2.75, p = 0.013); multiple blood pressure measurements over months to years (four studies; relative risk = 1.68, 1.33-2.14; p < 0.001). CONCLUSIONS: Even after extensive adjustment for hypertension, proteinuria is strongly and independently associated with incident stroke risk, possibly indicating a shared renal and cerebral susceptibility to vascular injury that is not fully explained by traditional vascular risk factors.