Serological and cellular inflammatory signatures in end-stage kidney disease and latent tuberculosis.

OBJECTIVES: Tuberculosis comorbidity with chronic diseases including diabetes, HIV and chronic kidney disease is of rising concern. In particular, latent tuberculosis infection (LTBI) comorbidity with end-stage kidney disease (ESKD) is associated with up to 52.5-fold increased risk of TB reactivation to active tuberculosis infection (ATBI). The immunological mechanisms driving this significant rise in TB reactivation are poorly understood. To contribute to this understanding, we performed a comprehensive assessment of soluble and cellular immune features amongst a unique cohort of patients comorbid with ESKD and LTBI. METHODS: We assessed the plasma and cellular immune profiles from patients with and without ESKD and/or LTBI (N = 40). We characterised antibody glycosylation, serum complement and cytokine levels. We also assessed classical and non-classical monocytes and T cells with flow cytometry. Using a systems-based approach, we identified key immunological features that discriminate between the different disease states. RESULTS: Individuals with ESKD exhibited a highly inflammatory plasma profile and an activated cellular state compared with those without ESKD, including higher levels of inflammatory antibody Fc glycosylation structures and activated CX3CR1+ monocytes that correlate with increased inflammatory plasma cytokines. Similar elevated inflammatory signatures were also observed in ESKD+/LTBI+ compared with ESKD-/LTBI+, suggesting that ESKD induces an overwhelming inflammatory immune state. In contrast, no significant inflammatory differences were observed when comparing LTBI+ and LTBI- individuals. CONCLUSION: Our study highlights the highly inflammatory state induced by ESKD. We hypothesise that this inflammatory state could contribute to the increased risk of TB reactivation in ESKD patients.

Toluene Toxicity: A Case Report of Transdermal Exposure Causing Hypokalemic Paralysis.

RATIONALE: Hypokalemia is a common finding. Typically asymptomatic presentations of neuromuscular weakness emerge at levels below 2.5 mmol/L. Causes include gastrointestinal losses, renal losses, or intracellular shift, with gastrointestinal losses and diuretics accounting for the majority. Although the cause is often apparent on clinical assessment, a systematic approach incorporating urine biochemistry can aid in narrowing the differential in obscure cases. PRESENTATION: We describe a case of a previously healthy 27-year-old man who presented with acute ascending paralysis, with an associated severe hypokalemia and metabolic acidosis. There were no apparent causes on clinical assessment. DIAGNOSIS: Based on analysis of urine biochemistry, we concluded that a pathologic kaluresis was present, and given his acidemia and transient pathology, we diagnosed the patient with hypokalemic paralysis secondary to toluene toxicity. INTERVENTIONS: We provided supportive care and electrolyte repletion for our patient; no specific therapies for toluene were required. Our patient was counseled regarding appropriate protective measures when handling toluene. OUTCOMES: Complete neurologic recovery and biochemical normalization occurred within 48 hours of presentation with supportive care. He continued to use proper precautions when handling toluene, and experienced no symptom relapse, or further abnormalities on both blood and urine chemistry. LESSONS LEARNED: Using this case, we review an algorithmic approach incorporating urine biochemistries to aid in the workup of hypokalemia. We review toluene as a toxicologic entity and highlight its role as a cause of hypokalemia.

JUSTIFICATION: L'hypokaliémie est fréquente et généralement asymptomatique. Les symptômes de faiblesse neuromusculaire se manifestent à des concentrations inférieures à 2,5 mmol/L. Les pertes de potassium au niveau gastro-intestinal ou rénal et les déplacements intracellulaires sont parmi les causes; les pertes gastro-intestinales et les diurétiques constituant les principales causes. Bien que l'étiologie soit souvent apparente à l'évaluation clinique, une approche systématique intégrant la biochimie de l'urine pourrait aider à réduire le diagnostic différentiel dans les cas plus incertains. PRÉSENTATION DU CAS: Nous discutons du cas d'un homme de 27 ans précédemment en bonne santé qui présentait une paralysie ascendante aigüe associée à une grave hypokaliémie et à une acidose métabolique. Aucune étiologie n'était apparente lors de l'évaluation clinique. DIAGNOSTIC: L'analyse biochimique de l'urine a permis de confirmer la présence d'une kaliurèse pathologique et, compte tenu de l'acidémie et de la pathologie transitoire, de diagnostiquer une paralysie hypokaliémique consécutive à une intoxication au toluène. INTERVENTIONS: Le patient a reçu le traitement médical et la supplémentation en électrolytes appropriés. Aucun traitement spécifique pour le toluène n'était nécessaire. Le patient a été informé des mesures de protection adéquates à prendre pour la manipulation du toluène. RÉSULTATS: Une récupération neurologique complète et une normalisation biochimique ont été constatées dans les 48 heures suivant le début du traitement. Le patient a pris les mesures de protection appropriées lors de la manipulation du toluène et n'a éprouvé aucun symptôme de rechute ou anomalie biochimique du sang ou de l'urine depuis. ENSEIGNEMENTS TIRÉS: Avec ce cas, nous avons analysé une approche algorithmique intégrant la biochimie urinaire pour faciliter le diagnostic de l'hypokaliémie. Nous avons également examiné le toluène en tant qu'agent toxique et souligné son rôle comme étiologie de l'hypokaliémie.

Mucosal-Associated Invariant T Cells Are Depleted and Exhibit Altered Chemokine Receptor Expression and Elevated Granulocyte Macrophage-Colony Stimulating Factor Production During End-Stage Renal Disease.

Background: End-stage renal disease (ESRD) is associated with an increased susceptibility to infectious diseases, including infection with Mycobacterium tuberculosis (Mtb). Mucosal-associated invariant T (MAIT) cells recognize vitamin B metabolites produced by many bacterial species, including Mtb, and may play an important role in providing protective immunity against tuberculosis infection in the lung. To date, little is known about MAIT cell frequency, phenotype, or function in ESRD patients. Methods: MAIT cells, identified by surface marker expression or MR1 tetramer binding, were characterized in 20 ESRD and 20 healthy control participants by multicolor flow cytometry. Ex vivo MAIT cell phenotype and cytokine production following PMA/ionomycin, IL-12/IL-18, or Escherichia coli stimulation were determined. Monocyte phenotype and plasma C-reactive protein/inflammatory cytokine levels were quantified by flow cytometry, ELISA, and multiplex bead array. Results: Peripheral blood MAIT cells were significantly depleted among ESRD patients compared to controls by both phenotypic and tetramer analysis and exhibited a loss of CXCR3 expression coupled to increased expression of CCR6 and CXCR6. ESRD was also associated with a shift in MAIT PMA-induced cytokine production away from IFNγ production and toward granulocyte macrophage-colony stimulating factor (GM-CSF) secretion, and a loss of E. coli-stimulated tumor necrosis factor α expression. Loss of IFNγ expression was associated with a combination of age, alterations in Tbet and Eomes expression, and inflammatory plasma cytokine levels. Conclusion: The loss of peripheral blood MAIT cells and associated shifts in tissue homing receptor expression and GM-CSF production may contribute to an immune environment that is permissive to bacterial replication, particularly in the lungs.

Risk-Based Triage for Nephrology Referrals Using the Kidney Failure Risk Equation.

BACKGROUND: In some jurisdictions, routine reporting of the estimated glomerular filtration rate (eGFR) has led to an increase in nephrology referrals and wait times. OBJECTIVE: We describe the use of the Kidney Failure Risk Equation (KFRE) as part of a triage process for new nephrology referrals for patients with chronic kidney disease stages 3 to 5 in a Canadian province. DESIGN: A quasi-experimental study design was used. SETTING: This study took place in Manitoba, Canada. MEASUREMENTS: Demographics, laboratory values, referral numbers, and wait times were compared between periods. METHODS: In 2012, we adopted a risk-based cutoff of 3% over 5 years using the KFRE as a threshold for triage of new referrals. Referrals who did not meet other prespecified criteria (such as pregnancy, suspected glomerulonephritis, etc) and had a kidney failure risk of <3% over 5 years were returned to primary care with recommendations based on diabetes and hypertension guidelines. The average wait time and number of consults seen between the pretriage (January 1, 2011, to December 31, 2011) and posttriage period (January 1, 2013, to December 31, 2013) were compared using a general linear model. RESULTS: In the pretriage period, the median number of referrals was 68/month (range: 44-76); this increased to 94/month (range: 61-147) in the posttriage period. In the posttriage period, 35% of referrals were booked as urgent, 31% as nonurgent, and 34% of referrals were not booked. The median wait times improved from 230 days (range: 126-355) in the pretriage period to 58 days (range: 48-69) in the posttriage period. LIMITATIONS: We do not have long-term follow-up on patients triaged as low risk. Our study may not be applicable to nephrology teams operating under capacity without wait lists. We did not collect detailed information on all referrals in the pretriage period, so any differences in our pretriage and posttriage patient groups may be unaccounted for. CONCLUSIONS: Our risk-based triage scheme is an effective health policy tool that led to improved wait times and access to care for patients at highest risk of progression to kidney failure.

CONTEXTE: Dans certaines régions administratives, la déclaration systématique des valeurs de débit de filtration glomérulaire estimé (DFGe) a conduit à une augmentation des recommandations de patients pour un suivi en néphrologie et, par conséquent, du temps d'attente pour obtenir une consultation. OBJECTIF DE L'ÉTUDE: Dans cette étude, nous décrivons l'utilisation de l'équation de risque pour l'insuffisance rénale terminale (KFRE) dans le cadre du processus de triage des nouvelles recommandations pour un suivi en néphrologie de patients atteints d'insuffisance rénale chronique de stade 3 à stade 5 dans une province canadienne. TYPE D'ÉTUDE: On a utilisé un modèle quasi expérimental pour cette étude. CADRE DE L'ÉTUDE: Cette étude a eu lieu dans la province du Manitoba au Canada. MESURES: Nous avons comparé les données démographiques et les valeurs de laboratoire des patients, de même que le nombre de nouvelles recommandations de patients en néphrologie et le temps d'attente pour obtenir une consultation entre les périodes choisies. MÉTHODOLOGIE: En 2012, à l'aide de la KFRE, nous avons établi un risque de défaillance rénale de 3 % sur 5 ans comme valeur seuil pour le triage des nouvelles recommandations de patients pour un suivi en néphrologie. Les patients redirigés qui ne respectaient pas les autres critères de triage spécifiés au préalable, notamment la grossesse ou une glomérulonéphrite soupçonnée, de même que ceux qui présentaient un risque de défaillance rénale inférieur à 3 % sur 5 ans ont été retournés vers les soins primaires avec une recommandation fondée sur les directives du diabète et de l'hypertension. Le délai d'attente moyen et le nombre de consultations observés entre la période prétriage (du 1er janvier 2011 au 31 décembre 2011) et la période suivant le triage (du 1er janvier 2013 au 31 décembre 2013) ont été comparés à l'aide d'un modèle linéaire général. RÉSULTATS: Au cours de la période de prétriage, le nombre médian de recommandations en néphrologie a été de 68 par mois (intervalle : 44 à 76 par mois). Ce nombre est passé à 94 par mois (intervalle : 61 à 147 par mois) dans la période suivant le triage. Au cours de cette période, 35 % des recommandations étaient identifiées comme étant urgentes, 31 % comme étant non urgents et 34 % ne portaient aucune mention. Le temps d'attente médian s'est amélioré, passant de 230 jours (intervalle : 126 à 355 jours) en période de prétriage à 58 jours (intervalle : 48 à 69 jours) dans la période post-triage. LIMITES DE L'ÉTUDE: Nous n'avons aucun suivi à long terme pour les patients classés à faible risque de défaillance rénale sur 5 ans. De plus, il est possible que notre étude ne puisse s'appliquer aux équipes de néphrologues qui opèrent en dessous de leur capacité et donc, sans liste d'attente. Enfin, nous ne pouvons tenir compte des différences susceptibles d'être observées entre les groupes de patients vus en prétriage et en post-triage puisque nous n'avons pas recueilli de renseignements détaillés sur tous les patients recommandés. CONCLUSIONS: Notre système de triage axé sur les risques de défaillance rénale sur 5 ans est un outil efficace d'élaboration de politiques en santé. Ce système conduit à l'amélioration du temps d'attente et à un accès plus facile aux soins pour les patients à haut risque de voir leur état progresser vers l'insuffisance rénale.

γδ T-cell function is inhibited in end-stage renal disease and impacted by latent tuberculosis infection.

Patients with end-stage renal disease (ESRD) are at elevated risk of acquiring infectious diseases, including tuberculosis (TB). Inflammation and uremia negatively impact immune function in this population, but specific pathways involved in TB immunity have not been identified. Although γδ T cells are known to contribute to protection from TB, their phenotype and function in patients with ESRD is relatively unknown. To determine this we recruited 20 patients with and 20 without ESRD (controls), with or without latent TB infection to assess γδ T cell frequency, surface phenotype, and cytokine production by flow cytometry in response to stimulation. γδ T cells derived from patients with ESRD exhibited significantly lower expression of CCR5, CXCR3, and CD26 compared to controls. Furthermore, patients with ESRD, particularly the group with latent TB infection, exhibited poor IFNγ, TNFα, and GMCSF responses to stimulation with either phosphoantigen HMB-PP, IL-12/IL-18, E. coli, or phorbol myristate acetate and ionomycin. Similar dysfunctional responses were observed in patients with active TB. Surprisingly, neither the γδ phenotype nor its function was associated with plasma markers of inflammation or microbial translocation. Thus, there is significant perturbation of the γδ T-cell population in patients with ESRD, particularly in those with latent TB infection.

The Safety and Efficacy of Mineralocorticoid Receptor Antagonists in Patients Who Require Dialysis: A Systematic Review and Meta-analysis.

BACKGROUND: Patients who require dialysis are at high risk for cardiovascular mortality, which may be improved by mineralocorticoid receptor antagonists (MRAs). STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials. SETTING & POPULATION: Adults undergoing long-term hemodialysis or peritoneal dialysis with or without heart failure. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials evaluating an MRA in dialysis and reported at least one outcome of interest. INTERVENTION: Spironolactone (8 trials) or eplerenone (1 trial) compared to placebo (7 trials) or standard of care (2 trials). OUTCOMES: Cardiovascular and all-cause mortality, hyperkalemia, serum potassium level, hypotension, change in blood pressure, and gynecomastia. RESULTS: We identified 9 trials including 829 patients. The overall quality of evidence was low due to methodologic limitations in most of the included trials. The relative risk (RR) for cardiovascular mortality was 0.34 (95% CI, 0.15-0.75) for MRA-treated compared with control patients. The RR for all-cause mortality was 0.40 (95% CI, 0.23-0.69). The RR for hyperkalemia for MRA treatment was 3.05 (95% CI, 1.21-7.70). Sensitivity analyses demonstrated wide variability in RRs for cardiovascular mortality, all-cause mortality, and hyperkalemia, suggesting further uncertainty in the confidence of the primary results. LIMITATIONS: Trial quality and size insufficient to robustly and precisely identify a treatment effect. CONCLUSIONS: Given the uncertainty of both the benefits and harms of MRAs in dialysis, large high-quality trials are required.

Maintenance of Mycobacterium tuberculosis-specific T cell responses in End Stage Renal Disease (ESRD) and implications for diagnostic efficacy.

End-stage renal disease (ESRD) patients exhibit elevated risk of tuberculosis (TB) reactivation, but current diagnostics, including the interferon gamma release assay (IGRA), exhibit poor sensitivity in ESRD. We tested 80 ESRD patients and found an 18.75% prevalence of IGRA positivity. A subset of patients was assessed for Mtb-specific expression of 44 cytokines/chemokines, and CD4+ T cell phenotype and function. Similar to non-ESRD IGRA+ individuals, Mtb-specific IFNγ, IL-1RA, IP-10, MCP-3 and IL-2 responses were identified in the ESRD IGRA+ group. 27% of the ESRD IGRA- group exhibited MCP-3 or IL-2 Mtb-specific responses, which may identify cases of latent TB infection in ESRD. Stimulation of PBMC with PPD demonstrated similar CD4+ T cell production of IFNγ, TNFα and GM-CSF by ESRD patients. The reported low sensitivity of the IGRA in ESRD cohorts is therefore unlikely to be due to poor T cell cytokine secretion, and may instead reflect defects in antigen presentation.

The Safety of Eplerenone in Hemodialysis Patients: A Noninferiority Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Mineralocorticoid receptor antagonism reduces morbidity and mortality in patients with heart failure, but the safety of these drugs in patients receiving dialysis is unclear. This study evaluated whether hyperkalemia and/or hypotension limited the use of eplerenone, a selective mineralocorticoid receptor antagonist, in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a randomized controlled trial of prevalent patients receiving hemodialysis at five Canadian centers. Participants were randomly allocated to 13 weeks of eplerenone titrated to 50 mg daily (n=77) or a matching placebo (n=77). The primary outcome was permanent discontinuation of the drug because of hyperkalemia or hypotension. Secondary outcomes included hyperkalemia, hypotension, and cardiovascular events. RESULTS: Seventy-five eplerenone-treated patients and 71 placebo-treated patients were included in the per protocol population. The primary outcome occurred in three patients (4.0%) in the eplerenone group and two (2.8%) in the placebo group, for an absolute risk difference of 1.2 percentage points (95% confidence interval, -4.7 to 7.1 percentage points). Eplerenone was interpreted as noninferior to placebo with respect to the primary outcome (i.e., a discontinuation rate for these reasons >10% was excluded). In the eplerenone group, nine patients (11.7%) developed hyperkalemia (potassium level >6.5 mEq/L), compared with two patients (2.6%) in the placebo group (relative risk, 4.5; 95% confidence interval, 1.0 to 20.2). There was no significant effect on predialysis or postdialysis BP. CONCLUSION: Eplerenone increased the risk of hyperkalemia but did not result in an excess need to permanently discontinue the drug. Further trials are required to determine whether mineralocorticoid receptor antagonism improves cardiovascular outcomes in patients receiving long-term dialysis.

Effect of time on dialysis and renal transplantation on endothelial function: a longitudinal analysis.

BACKGROUND: Soluble vascular cell adhesion molecule-1 (sVCAM-1) is a marker of endothelial injury and a potent predictor of cardiovascular mortality in patients with kidney failure on dialysis. The longitudinal effects of dialysis on endothelial dysfunction and in particular the effects of renal transplantation on markers of endothelial function including sVCAM-1 have not been well characterized. METHODS: We used the Transplant Manitoba registry and biobank to assemble a retrospective cohort of all patients receiving a first kidney transplant between January 1, 2000, and December 31, 2005 (n=186). One hundred seventy-four patients had at least two serum samples pretransplant and at least two samples posttransplant. In total, 1,004 serial samples (median 5/patient) were analyzed. Factors associated with sVCAM-1 were examined using mixed linear models. RESULTS: The sVCAM-1 levels increased progressively on dialysis (0.15 [0.10 to 0.20] ng/mL/day; P<0.0001), fell significantly within 1 month after transplantation (-625 ng/mL/day; P<0.0001) and continued to fall thereafter (-0.23 [-0.34 to -0.12] ng/mL/day). Smoking and heart failure were associated with higher sVCAM-1 levels, whereas transplantation was associated with lower sVCAM-1 levels. The relationship between sVCAM-1 and transplantation was not changed by multivariate adjustment. CONCLUSION: Endothelial injury worsens over time on dialysis but improves significantly after renal transplantation.

Underutilization of peritoneal dialysis: the role of the nephrologist's referral pattern.

BACKGROUND: The incidence of end-stage renal disease is increasing, placing a tremendous burden on health care resources. Peritoneal dialysis (PD) is cheaper than hemodialysis and has many potential advantages and few contraindications as an initial modality selection. This study examined differences in patient PD attempt rates between nephrologists using technique survival and mortality as outcomes. METHODS: We performed a retrospective review of the Manitoba Renal Program databases from January 2004 to January 2010. Analysis of 630 patients who commenced dialysis and had demographic data available was performed. A genetic matching algorithm was used to balance potential differences between patient characteristics. Each nephrologist was then compared against their peers to calculate a PD attempt rate. The highest attempt rate group was compared with the lowest. RESULTS: When comparing PD attempt rates between groups, all the results were significant. PD technique survival at >90 days showed no significant differences (P = 0.42). Patient mortality at >90 days was also not significant when comparing groups (P = 0.14). CONCLUSIONS: Our data suggest that when comparing the low- with high-attempt groups, the factors limiting PD utilization do not include on-site availability of PD, case mix, funding, patient location or reimbursement. Aggressive approaches of starting more patients on PD did not lead to lower technique survival or higher mortality rates. If the PD attempt rate was maximized, a significant amount of money and resources could be saved or directed toward helping a larger population without significant harm to patients.

Serum creatinine measurement immediately after cardiac surgery and prediction of acute kidney injury.

BACKGROUND: After heart surgery, acute kidney injury (AKI) confers substantial long-term risk of death and chronic kidney disease. We hypothesized that small changes in serum creatinine (SCr) levels measured within a few hours of exit from the operating room could help discriminate those at low versus high risk of AKI. STUDY DESIGN: Prospective cohort of 350 elective cardiac surgery patients (valve or coronary artery bypass grafting) recruited in Winnipeg, Canada. Baseline SCr level was obtained at the preoperative visit 2 weeks before surgery. The postoperative SCr level was drawn within 6 hours of completion of surgery and then daily while the patient was in the hospital. PREDICTOR: Immediate (ie, <6 hours) postoperative SCr level change (ΔSCr), categorized as within 10% (reference), decrease >10%, or increase >10% relative to baseline. OUTCOME: AKI, defined according to the new KDIGO (Kidney Disease: Improving Global Outcomes) consensus definition as an increase in SCr level >0.3 mg/dL within 48 hours or >1.5 times baseline within 1 week. MEASUREMENTS: We compared the C statistic of logistic models with and without inclusion of immediate postoperative ΔSCr. RESULTS: After surgery, 176 patients (52%) experienced a decrease >10% in SCr level, 26 (7.4%) experienced an increase >10%, and 143 had ΔSCr within ±10% of baseline. During hospitalization, 53 (14%) developed AKI. Bypass pump time, baseline estimated glomerular filtration rate, and European System for Cardiac Operative Risk Evaluation (euroSCORE) were associated with AKI in a parsimonious base logistic model. Added to the base model, immediate postoperative ΔSCr was associated strongly with subsequent AKI and significantly improved model discrimination over the base model (C statistic, 0.78 [95% CI, 0.71-0.85] vs 0.69 [95% CI, 0.62-0.77]; P < 0.001). A ≥10% SCr level decrease predicted significantly lower AKI risk (OR, 0.37; 95% CI, 0.18-0.76), whereas a ≥10% SCr level increase predicted significantly higher (OR, 6.38; 95% CI, 2.37-17.2) AKI risk compared with the reference category. LIMITATIONS: We used a surrogate marker of AKI. External validation of our results is warranted. CONCLUSION: In elective cardiac surgery patients, measurement of immediate postoperative ΔSCr improves prediction of AKI.

The role of functional status in discharge to assisted care facilities and in-hospital death among dialysis patients.

BACKGROUND: Functional status is an important component in the assessment of hospitalized patients. We set out to determine the scope, severity, and prognostic significance of impaired functional status in acutely hospitalized dialysis patients. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 1,286 hospitalized dialysis patients admitted and discharged from 1 of 11 area hospitals in Manitoba, Canada, from September 2003 to September 2010 with an activity of daily living (ADL) assessment within 24 hours of admission. PREDICTOR: The 12-point ADL score assesses 6 domains (bathing, toileting, dressing, incontinence, feeding, and transferring) and scores them as independent or supervision only (score, 0), partial assistance (1), and full assistance (2). Thus, higher score indicates worse functional status. Parametric and nonparametric tests were used as appropriate to determine differences in baseline characteristics. OUTCOMES: Multivariable logistic regression and Cox proportional hazards assessed the association between functional status, in-hospital death, and discharge to an assisted care facility. RESULTS: During the study period, 250 (19.4%) and 72 (5.6%) patients experienced the outcomes of in-hospital death or discharge to an assisted care facility. Abnormalities in functional status were present in >70% of the cohort. ADL score within 24 hours of admission combined with age differentiated risks of death and discharge to an assisted care facility home, ranging from 4.8%-46.6% and 0.6%-17.8%, respectively. After adjustment, ORs of death and discharge to an assisted care facility were 1.16 (95% CI, 1.11-1.22; P < 0.001; C statistic = 0.79) and 1.25 (95% CI, 1.14-1.36; P < 0.001; C statistic = 0.91) per 1-point increase in ADL score, respectively. Findings were consistent after accounting for the competing outcomes of in-hospital death or discharge to an assisted care facility versus discharge to home. LIMITATIONS: A 1-time measurement of ADLs could not differentiate temporary from long-term deterioration in functional status. CONCLUSIONS: Impaired functional status is common at the time of admission in the dialysis population. A single ADL score measurement at admission combined with age is highly predictive of poor outcomes in the hospitalized dialysis population.

Long-term outcomes of end-stage renal disease patients admitted to the ICU.

BACKGROUND: End-stage renal disease (ESRD) patients admitted to the intensive care unit (ICU) have poor survival and high rates of readmission; however, little evidence exists on long-term outcomes. We set out to investigate the long-term (6 and 12 months) survival of ESRD patients admitted to the ICU and whether differential survival could be explained by dialysis modality and vascular access. METHODS: We compared the admission characteristics, outcomes and readmission rates of 619 ESRD [95 peritoneal dialysis (PD), 334 hemodialysis with a catheter (HD CVC), 190 hemodialysis with an AV fistula (HD AVF)] patients admitted to 11 ICU's in Winnipeg, Manitoba, Canada. Parametric and nonparametric tests were used as appropriate to determine differences in baseline characteristics. Multivariable Cox and logistic regression was used to assess outcomes between the groups. RESULTS: The 6- and 12-month crude survival was 62 and 52%, respectively. In a univariate model, modality and vascular access were associated with an increased hazard ratio (HR) of death [PD HR 1.60 95% confidence interval (CI) 1.20-2.13, HD CVC HR 1.55 95% CI 1.25-1.93] compared to patients on HD with an AVF. In three different multivariate adjusted models, this association persisted with HRs for death of 1.63-1.75 for PD and 1.50-1.58 for HD CVC. CONCLUSIONS: Overall long-term survival of ESRD patients after admission to the ICU is poor. Being on PD or being dialyzed with a catheter was independently associated with an increased mortality.

End-stage renal disease status and critical illness in the elderly.

BACKGROUND AND OBJECTIVES: Elderly patients (> 65 years old) are a rapidly growing demographic in the ESRD and intensive care unit (ICU) populations, yet the effect of ESRD status on critical illness in elderly patients remains unknown. Reliable estimates of prognosis would help to inform care and management of this frail and vulnerable population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The effect of ESRD status on survival and readmission rates was examined in a retrospective cohort of 14,650 elderly patients (>65 years old) admitted to 11 ICUs in Winnipeg, Manitoba, Canada between 2000 and 2006. Logistic regression models were used to adjust odds of mortality and readmission to ICU for baseline case mix and illness severity. RESULTS: Elderly ESRD patients had twofold higher crude in-hospital mortality (22% versus 13%, P < 0.0001) and readmission rate (6.4 versus 2.7%, P = 0.001). After adjustment for illness severity alone or illness severity and case mix, the odds ratio for mortality decreased to 0.85 (95% CI: 0.57 to 1.25) and 0.82 (95% CI: 0.55 to 1.23), respectively. In contrast, ESRD status remained significantly associated with readmission to ICU after adjustment for other risk factors (OR 2.06 [95% CI: 1.32, 3.22]). CONCLUSIONS: Illness severity on admission, rather than ESRD status per se, appears to be the main driver of in-hospital mortality in elderly patients. However, ESRD status is an independent risk factor for early and late readmission, suggesting that this population might benefit from alternative strategies for ICU discharge.

Cardiovascular disease in end-stage renal disease: the challenge of assessing and managing cardiac disease in dialysis patients.

Cardiovascular disease (CVD) is the leading cause of mortality in end-stage renal disease (ESRD), approximating a 10- to 20-fold higher risk of death in dialysis patients than in the general population. Despite this, dialysis patients often undergo fewer investigations, receive less invasive procedures, and are prescribed fewer medications compared with age-matched non-ESRD patients. A lack of randomized control trials for evidence-based treatment strategies in this population may explain some of these discrepancies, but there is concern that an attitude of "therapeutic nihilism" may be impacting on the medical care of these patients. In this review, we will explore CVD in the ESRD population. Specifically, we will try to address the following issues in patients with ESRD: (1) mechanisms of CVD, (2) cardiac evaluation and the role of coronary revascularization with percutaneous or coronary artery bypass procedures, and (3) cardiac pharmacotherapy use.

Acute kidney injury in critically ill patients infected with 2009 pandemic influenza A(H1N1): report from a Canadian Province.

BACKGROUND: 2009 pandemic influenza A(H1N1) has led to a global increase in severe respiratory illness. Little is known about kidney outcomes and dialytic requirements in critically ill patients infected with pandemic H1N1. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 50 patients with pandemic H1N1 admitted to any of 7 intensive care units in Manitoba, Canada, were prospectively followed. OUTCOME & MEASUREMENTS: Outcomes were kidney injury and kidney failure defined using RIFLE (risk, injury, failure, loss, end-stage disease) criteria or need for dialysis therapy. RESULTS: The pandemic H1N1 group was composed of 50 critically ill patients with pandemic H1N1 with severe respiratory syndrome (47 confirmed cases, 3 probable). Kidney injury, kidney failure, and need for dialysis occurred in 66.7%, 66%, and 11% of patients, respectively. Mortality was 16%. Kidney failure was associated with increased death (OR, 11.29; 95% CI, 1.29-98.9), whereas the need for dialysis was associated with an increase in length of stay (RR, 2.38; 95% CI, 2.13-25.75). LIMITATIONS: Small population studied from single Canadian province; thus, limited generalizability. CONCLUSIONS: In critically ill patients with pandemic H1N1, kidney injury, kidney failure, and the need for dialysis are common and associated with an increase in mortality and length of intensive care unit stay.

The intersection of risk and benefit: is warfarin anticoagulation suitable for atrial fibrillation in patients on hemodialysis?

The risks and benefits of anticoagulation for stroke prevention with atrial fibrillation is clearly delineated in the general population. Little evidence exists for patients with end-stage renal disease (ESRD) about whether the extrapolation of these guidelines is appropriate. In patients with ESRD who are undergoing hemodialysis, the rates for both stroke and bleeding are 3 to 10 times higher than that for the general population. Furthermore, the proportion of hemorrhagic to ischemic strokes has increased, making the decision of whether to initiate anticoagulation problematic. In this commentary, we discuss the existing literature for stroke in atrial fibrillation, stroke type, risk reduction with anticoagulation, and bleeding risks in the hemodialysis population. We comment on validated risk stratification models of stroke prevention and bleeding and their applicability to patients undergoing hemodialysis. Finally, we recommend treatment strategies that are based on the existing state of knowledge.

Outcomes of chronic dialysis patients admitted to the intensive care unit.

Admission rates and outcomes of patients who have ESRD and are admitted to an intensive care unit (ICU) are not well defined. We conducted a historical cohort study using a prospective regional ICU database that captured all 11 adult ICUs in Winnipeg, Canada. Between 2000 and 2006, there were 34,965 total admissions to the ICU, 1173 (3.4%) of which were patients with ESRD. The main admission diagnoses among patients with ESRD were cardiac disease (31%), sepsis (15%), and arrest (10%). Compared with other patients in the ICU, those with ESRD were significantly younger but had more diabetes, peripheral arterial disease, and higher APACHE II (Acute Physiology and Chronic Health Evaluation II) scores; mean length of stay in the ICU was similar, however, between these two groups. Restricting the analysis to first admissions to the ICU, unadjusted in-hospital mortality was higher for patients with ESRD (16 versus 11%; P < 0.0001), but this difference did not persist after adjustment for baseline illness severity. In conclusion, although ESRD associates with increased mortality among patients who are admitted to the ICU, this effect is mostly a result of comorbidity.

Thrice weekly warfarin administration in haemodialysis patients.

BACKGROUND: Medication adherence in haemodialysis patients is often challenging due to a high pill burden, complex and dynamic medication regimens and limited patient self-interest in care. The purpose of this study was to investigate the time within target INR and safety profile of thrice weekly warfarin administration in haemodialysis patients with a clinical indication for anticoagulation and documented nonadherence to medications. METHODS: Thirty-seven patients from two haemodialysis units in Winnipeg, Manitoba, Canada, were recruited, and 17 patients were treated with thrice weekly warfarin and compared to 20 patients treated with daily warfarin therapy. The patients were followed for 1 year with weekly international normalized ratio (INR), dosage and adverse events recorded. The primary outcome was percentage of time with INR in target and sub (<1.5)- and supra (>4)-therapeutic INR. Adverse events were recorded in the two groups. RESULTS: The thrice weekly group had a higher burden of comorbidity (Charlson comorbidity index of 6.35 +/- 1.77 versus 4.55 +/- 1.64, P = 0.003) compared to the daily dosage group. In the thrice weekly dosage group, time within target INR was higher (56.9 versus 49.3%, P = 0.008), and time with supra-therapeutic INR > 4 lower (2.7 versus 4.3%, P = 0.03). Total bleeding events (7 versus 6) and major bleeding events (3 versus 2 events) were similar between the two groups. CONCLUSION: In this pilot study, thrice weekly warfarin appears to be a safe and feasible dosing strategy in a select patient population. A randomized controlled trial of thrice weekly warfarin is warranted.