Martina Reslerova

Guidelines for the management of chronic kidney disease

New guidelines for the management of chronic kidney disease have been developed by the Canadian Society of Nephrology (Appendix 1 contains the full-text guidelines; available at [www.cmaj.ca/cgi/content/full/179/11/1154/DC1][1]). These guidelines describe key aspects of the management of chronic

Mass spectrometry-based proteomic analysis of urine in acute kidney injury following cardiopulmonary bypass: a nested case-control study.

BACKGROUND The early evolution of acute kidney injury (AKI) in humans is difficult to study noninvasively. We hypothesized that urine proteomics could provide insight into the early pathophysiology of human AKI. STUDY DESIGN A prospective nested case-control study (n = 250) compared serial urinary proteomes of 22 patients with AKI and 22 patients without AKI before, during, and after cardiopulmonary bypass surgery. OUTCOMES AKI was defined as a greater than 50% increase in serum creatinine level, and non-AKI, as less than 10% increase from baseline. MEASUREMENTS Serum creatinine, urine protein-creatinine ratio, neutrophil gelatinase-associated lipocalin (NGAL), alpha1-microglobulin, interferon-inducible protein-10 (IP-10), monokine induced by interferon gamma (Mig), interferon-inducible T cell alpha chemoatractant (I-TAC), interleukin 6 (IL-6), IL-1beta, and IL-10. Urine protein profiling by means of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). RESULTS SELDI-TOF-MS showed intraoperative tubular stress in both groups on arrival to the intensive care unit, evidenced by beta2-microglobulinuria. Non-AKI proteomes returned toward baseline postoperatively. In contrast, AKI proteomes showed a second phase of tubular injury/stress with the reappearance of beta2-microglobulin and multiple unidentified peaks (3 to 5 and 6 to 8 kDa) and the appearance of established tubular injury markers: urinary protein, alpha1-microglobulin, and NGAL. Furthermore, 2 novel peaks (2.43 and 2.78 kDa) were found to be dominant in postoperative non-AKI urine samples. The 2.78-kDa protein was identified as the active 25-amino acid form of hepcidin (hepcidin-25), a key regulator of iron homeostasis. Finally, an inflammatory component of reperfusion injury was evaluated by means of enzyme-linked immunosorbent assay analysis of candidate chemokines (IP-10, I-TAC, and Mig) and cytokines (IL-6, IL-1beta, and IL-10). Of these, IP-10 was upregulated in patients with versus without AKI postoperatively. LIMITATIONS This is an observational study. SELDI-TOF-MS is a semiquantitative technique. CONCLUSIONS Evaluation of human AKI revealed early intraoperative tubular stress in all patients. A second phase of injury observed in patients with AKI may involve IP-10 recruitment of inflammatory cells. The enhancement of hepcidin-25 in patients without AKI may suggest a novel role for iron sequestration in modulating AKI.

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.

Urinary Hepcidin-25 and Risk of Acute Kidney Injury Following Cardiopulmonary Bypass

BACKGROUND AND OBJECTIVES Acute kidney injury (AKI) complicating cardiopulmonary bypass (CPB) results in increased morbidity and mortality. Urinary hepcidin-25 has been shown to be elevated in patients who do not develop AKI after CPB using semiquantitative mass spectrometry (SELDI TOF-MS). The goals of this study were to quantitatively validate these findings with ELISA and evaluate the diagnostic performance of hepcidin-25 for AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A nested, case-control analysis of urinary hepcidin-25 in AKI (n = 22) and non-AKI (n = 22) patients was conducted to validate the SELDI TOF-MS data at the following times: preoperatively; the start of CPB; 1 hour on CPB; on arrival to the intensive care unit; and postoperative days (POD) 1 and 3 to 5. The diagnostic performance of hepcidin-25 was then evaluated in the entire prospective observational cohort (n = 338) at POD 1. AKI was defined as Cr >50% from baseline, within 72 hours postoperatively. RESULTS Urinary hepcidin-25/Cr ratio was significantly elevated in all patients at POD 1 compared with baseline (P < 0.0005) and was also significantly elevated in non-AKI versus AKI patients at POD 1 (P < 0.0005). Increased log(10) hepcidin-25/Cr ratio was strongly associated with avoidance of AKI on univariate analysis. On multivariate analysis, the log(10) hepcidin-25/Cr ratio (P < 0.0001) was associated with avoidance of AKI with an area under the curve of 0.80, sensitivity 0.68, specificity 0.68, and negative predictive value 0.96. CONCLUSIONS Elevated urinary hepcidin-25 on POD 1 is a strong predictor of avoidance of AKI beyond postoperative day 1.

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.

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 ICUs 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.

Adverse outcomes among Aboriginal patients receiving peritoneal dialysis

Background: The Aboriginal population in Canada experiences high rates of end-stage renal disease and need for dialytic therapies. Our objective was to examine rates of mortality, technique failure and peritonitis among adult aboriginal patients receiving peritoneal dialysis in the province of Manitoba. We also aimed to explore whether differences in these rates may be accounted for by location of residence (i.e., urban versus rural). Methods: We included all adult patients residing in the province of Manitoba who received peritoneal dialysis during the period from 1997–2007 (n = 727). We extracted data from a local administrative database and from the Canadian Organ Replacement Registry and the Peritonitis Organism Exit-sites/Tunnel infections (POET) database. We used Cox and logistic regression models to determine the relationship between outcomes and Aboriginal ethnicity. We performed Kaplan–Meier analyses to examine the relationship between outcomes and urban (i.e., 50 km or less from the primary dialysis centre in Winnipeg) versus rural (i.e., more than 50 km from the centre) residency among patients who were aboriginal. Results: One hundred sixty-one Aboriginal and 566 non-Aboriginal patients were included in the analyses. Adjusted hazard ratios for mortality (HR 1.476, CI 1.073–2.030) and adjusted time to peritonitis (HR 1.785, CI 1.352–2.357) were significantly higher among Aboriginal patients than among non-Aboriginal patients. We found no significant differences in mortality, technique failure or peritonitis between urban- or rural-residing Aboriginal patients. Interpretation: Compared with non-Aboriginal patients receiving peritoneal dialysis, Aboriginal patients receiving peritoneal dialysis had higher mortality and faster time to peritonitis independent of comorbidities and demographic characteristics. This effect was not influenced by place of residence, whether rural or urban.

Early reversible acute kidney injury is associated with improved survival in septic shock

INTRODUCTION The fact that acute kidney injury (AKI) is associated with worse clinical outcomes forms the basis of most AKI prognostic scoring systems. However, early reversibility of renal dysfunction in acute illness is not considered in such systems. We sought to determine whether early (≤24 hours after shock documentation) reversibility of AKI was independently associated with in-hospital mortality in septic shock. METHODS Patient information was derived from an international database of septic shock cases from 28 different institutions in Canada, the United States and Saudi Arabia. Data from a final cohort of 5443 patients admitted with septic shock between Jan 1996 and Dec 2009 was analyzed. The following 4 definitions were used in regards to AKI status: (1) reversible AKI = AKI of any RIFLE severity prevalent at shock diagnosis or incident at 6 hours post-diagnosis that reverses by 24 hours, (2) persistent AKI = AKI prevalent at shock diagnosis and persisting during the entire 24 hours post-shock diagnosis, (3) new AKI = AKI incident between 6 and 24 hours post-shock diagnosis, and (4) improved AKI = AKI prevalent at shock diagnosis or incident at 6 hours post followed by improvement of AKI severity across at least one RIFLE category over the first 24 hours. Cox proportional hazards were used to determine the association between AKI status and in-hospital mortality. RESULTS During the first 24 hours, reversible AKI occurred in 13.0%, persistent AKI in 54.9%, new AKI in 11.7%, and no AKI in 22.4%. In adjusted analyses, reversible AKI was associated with improved survival (HR, 0.64; 95% CI, 0.53-0.77) compared to no AKI (referent), persistent AKI (HR, 0.99; 95% CI, 0.88-1.11), and new AKI (HR, 1.41; 95% CI, 1.22-1.62). Improved AKI occurred in 19.1% with improvement across any RIFLE category associated with a significant decrease in mortality (HR, 0.53; 95% CI, 0.45-0.63). More rapid antimicrobial administration, lower Acute Physiology and Chronic Health Evaluation II score, lower age, and a smaller number of failed organs (excluding renal) on the day of shock as well as community-acquired infection were independently associated with reversible AKI. CONCLUSION In septic shock, reversible AKI within the first 24 hours of admission confers a survival benefit compared to no, new, or persistent AKI. Prognostic AKI classification schemes should consider integration of early AKI reversibility into the scoring system.

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.

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.