Christian G. Rabbat

Meta-Analysis: Peritoneal Membrane Transport, Mortality, and Technique Failure in Peritoneal Dialysis

Peritoneal membrane solute transport in peritoneal dialysis (PD) patients is assessed by the peritoneal equilibration test, which measures the ratio of creatinine in the dialysate to plasma after a standardized 4-h dwell (D/Pc). Patients then are classified as high, high-average, low-average, or low transporters on the basis of this result. A meta-analysis of observational studies was carried out to characterize the relationship between D/Pc and mortality and technique failure in patients who are on PD. Citations were identified in Medline by using a combination of Medical Subject Heading search terms and key words related to PD, peritoneal membrane permeability/transport, and mortality and technique failure. The table of contents of relevant journals and bibliographies of relevant citations were reviewed in duplicate. Twenty studies that met study criteria were identified. Nineteen studies were pooled to generate a summary mortality relative risk of 1.15 for every 0.1 increase in the D/Pc (95% confidence interval 1.07 to 1.23; P < 001). This result equated to an increased mortality risk of 21.9, 45.7, and 77.3% in low-average, high-average, and high transporters, respectively, as compared with patients with low transport status. Meta-regression analysis showed that the proportion of patients who were on continuous cycler PD within a study was inversely proportional to the mortality risk (P = 0.05). The pooled summary relative risk for death-censored technique failure was 1.18 (95% confidence interval 0.96 to 1.46; P = 0.12) for every 0.1 increase in the D/Pc. This meta-analysis demonstrates that a higher peritoneal membrane solute transport rate is associated with a higher mortality risk and a trend to higher technique failure.

Prognostic Value of Myocardial Perfusion Studies in Patients with End-Stage Renal Disease Assessed for Kidney or Kidney-Pancreas Transplantation: A Meta-Analysis

The prognostic utility of myocardial perfusion studies (MPS) such as thallium scintigraphy and dobutamine stress echocardiography (DSE) for stratifying cardiac risk among candidates for kidney or kidney-pancreas transplantation is uncertain. This study is a meta-analysis to determine the prognostic significance of MPS results on future myocardial infarction (MI) and cardiac death (CD) in patients with end-stage renal disease (ESRD) assessed for kidney or kidney-pancreas transplantation. MEDLINE was searched using combinations of MeSH headings and text words for transplantation, coronary artery disease, prognosis, end-stage renal disease, and noninvasive cardiac testing (nuclear scintigraphy and DSE) for primary studies. Studies were included if they reported MPS results and cardiac events in patients assessed for kidney or kidney-pancreas transplantation. Methodologic study quality and outcome data were independently abstracted in duplicate by two researchers. The relative risks (RR) of MI and CD were calculated using a random effects model. Twelve articles met all inclusion criteria; 12 studies reported CD, and 9 reported MI. In eight studies, thallium scintigraphy was used (four with pharmacologic stress, four with exercise stress), whereas four used DSE. When compared with negative tests, positive tests had a significantly increased RR of MI (2.73 [95% CI, 1.25 to 5.97]; P = 0.01) and CD (2.92 [95% CI, 1.66 to 5.12]; P < 0.001). Subgroup analyses of studies of diabetic patients indicated that positive tests were associated with a RR of CD 3.95 (95% CI, 1.48 to 10.5; P = 0.006) and a RR of MI 2.68 (95% CI, 0.95 to 7.57; P = 0.06) when compared with negative tests. In studies evaluating mixed populations of diabetic and nondiabetic patients, positive tests were associated with a RR of CD 2.52 (95% CI, 1.25 to 5.08; P = 0.01) and with a RR of MI 2.79 (95% CI, 0.85 to 9.21; P = 0.09) when compared with a negative test. The presence of reversible defects was associated with an increased risk of MI in diabetic patients and of CD in both subgroups; fixed defects were associated with an increased risk of CD but not MI. It is concluded that positive MPS are useful in identifying patients with significantly increased risk of future MI and CD in both diabetic and nondiabetic ESRD patients.

Prophylaxis Against Deep Vein Thrombosis in Critically Ill Patients With Severe Renal Insufficiency With the Low-Molecular-Weight Heparin Dalteparin An Assessment of Safety and Pharmacodynamics: The DIRECT Study

BACKGROUND Use of low-molecular-weight heparins is avoided in patients with renal insufficiency because of concerns about an excessive anticoagulant effect and increased bleeding risk. To challenge this premise, we evaluated if deep vein thrombosis (DVT) prophylaxis with dalteparin sodium confers an excessive anticoagulant effect in critically ill patients with severe renal insufficiency. METHODS We conducted a multicenter, single-arm clinical trial of DVT prophylaxis with dalteparin sodium, 5000 IU once daily in critically ill patients with a creatinine clearance lower than 30 mL/min (to convert to milliliters per second, multiply by 0.0167). Bioaccumulation was defined by a trough anti-Xa level higher than 0.40 IU/mL, measured twice weekly. The pharmacodynamic properties of dalteparin were assessed by serial anti-Xa levels measured on days 3, 10, and 17. RESULTS We enrolled 156 patients with a mean (SD) creatinine clearance of 18.9 (6.5) mL/min; 18 were excluded because they died or were discharged before testing (n = 3) or had prevalent DVT (n = 15). Of 138 patients included, the median (interquartile range [IQR]) duration of dalteparin exposure was 7 (4-12) days. In 120 patients who had at least 1 trough anti-Xa level (427 total measurements), no patient had bioaccumulation (0%; 95% confidence interval [CI]: 0%-3.0%); the median (IQR) trough anti-Xa level was undetectable (<0.10 IU/mL [<0.10 to <0.10 IU/mL]). Based on serial measurements, peak anti-Xa levels were 0.29 to 0.34 IU/mL and trough levels were lower than 0.06 IU/mL. Deep vein thrombosis occurred in 7 of 138 patients (5.1%; 95% CI, 2.5%-10.1%); major bleeding occurred in 10 patients (7.2%; 95% CI, 4.0%-12.8%), all with trough anti-Xa levels of 0.18 IU/mL or lower. CONCLUSION In critically ill patients with severe renal insufficiency, DVT prophylaxis with dalteparin sodium, 5000 IU once daily, is not associated with an excessive anticoagulant effect due to drug bioaccumulation and is unlikely to contribute to bleeding. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00138099.

Venous thromboembolism and bleeding in critically ill patients with severe renal insufficiency receiving dalteparin thromboprophylaxis: prevalence, incidence and risk factors

BackgroundCritically ill patients with renal insufficiency are predisposed to both deep vein thrombosis (DVT) and bleeding. The objective of the present study was to evaluate the prevalence, incidence and predictors of DVT and the incidence of bleeding in intensive care unit (ICU) patients with estimated creatinine clearance <30 ml/min.MethodsIn a multicenter, open-label, prospective cohort study of critically ill patients with severe acute or chronic renal insufficiency or dialysis receiving subcutaneous dalteparin 5,000 IU once daily, we estimated the prevalence of proximal DVT by screening compression venous ultrasound of the lower limbs within 48 hours of ICU admission. DVT incidence was assessed on twice-weekly ultrasound testing. We estimated the incidence of major and minor bleeding by daily clinical assessments. We used Cox proportional hazards regression to identify independent predictors of both DVT and major bleeding.ResultsOf 156 patients with a mean (standard deviation) creatinine clearance of 18.9 (6.5) ml/min, 18 had DVT or pulmonary embolism within 48 hours of ICU admission, died or were discharged before ultrasound testing – leaving 138 evaluable patients who received at least one dose of dalteparin. The median duration of dalteparin administration was 7 days (interquartile range, 4 to 12 days). DVT developed in seven patients (5.1%; 95% confidence interval, 2.5 to 10.1). The only independent risk factor for DVT was an elevated baseline Acute Physiology and Chronic Health Evaluation II score (hazard ratio for 10-point increase, 2.25; 95% confidence interval, 1.03 to 4.91). Major bleeding developed in 10 patients (7.2%; 95% confidence interval, 4.0 to 12.8), all with trough anti-activated factor X levels ≤ 0.18 IU/ml. Independent risk factors for major bleeding were aspirin use (hazard ratio, 6.30; 95% confidence interval, 1.35 to 29.4) and a high International Normalized Ratio (hazard ratio for 0.5-unit increase, 1.68; 95% confidence interval, 1.07 to 2.66).ConclusionIn ICU patients with renal insufficiency, the incidence of DVT and major bleeding are considerable but appear related to patient comorbidities rather than to an inadequate or excessive anticoagulant from thromboprophylaxis with dalteparin.Clinical Trial RegistrationNumber NCT00138099.

Neither baseline tests of molecular hypercoagulability nor D-dimer levels predict deep venous thrombosis in critically ill medical-surgical patients

ObjectivePredicting patients who are harboring asymptomatic deep venous thrombosis (DVT), or who are at particular risk of developing DVT, is a desirable clinical goal since prevention or early treatment of DVT might reduce the risk of fatal pulmonary embolism. Thus validation of simple laboratory tests that reliably predict venous thromboembolism (VTE) would be clinically very important. Tests that might be useful for these applications include markers of hypercoagulability (predicting patients at risk of DVT) and D-dimer (predicting which patients may have acute DVT).MethodsIn a prospective cohort study we measured a panel of hypercoagulability markers at the time of ICU admission, and six commercial D-dimer assays were performed serially during the ICU stay in medical-surgical ICU patients who were screened for DVT with biweekly lower limb compression ultrasonography. Ultrasonography was also performed at the time of any clinically suspected DVT events. We matched cases with DVT with controls without DVT for length of stay in the ICU to generate receiver operating characteristics (ROC) curves.ResultsOne hundred ninety-seven patients were enrolled. Blood was collected on a total of 763 occasions (median number of occasions per patient: 3, range 1–21). None of the assays predicted DVT, as indicated by the areas under the ROC curves, that did not differ significantly from 50%.ConclusionIn critically ill patients, neither tests of hypercoagulability nor D-dimer levels predict patients at risk of DVT and thus they should not be used to guide diagnostic testing for DVT.

The Clinical Utility of Doppler Ultrasound Prior to Arteriovenous Fistula Creation

Arteriovenous fistula (AVF) is the preferred access for long‐term hemodialysis, with superior long‐term patency rates; however, early failure rates are significant. Recent evidence has brought into question the preferred site of AVF creation in many patient groups. A preoperative test that could reliably predict the outcome of a proposed AVF would be of great benefit. Doppler ultrasound has been the most extensively studied and widely used test to guide access creation. Accurate and validated measurements of internal vessel diameter, both arterial and venous, and blood flow in the upper extremity are obtainable by Doppler ultrasound. Studies evaluating the utility of Doppler ultrasound prior to AVF creation suggest that vessel size and blood flow are predictive of AVF outcome. An AVF created using a cephalic vein and/or radial artery smaller than 1.5–2.0 mm is likely to fail; such preoperative data may indicate that an upper arm AVF should be the primary access attempted. Further prospective studies are needed to evaluate the utility of Doppler ultrasound.

Protocolized Anemia Management with Erythropoietin in Hemodialysis Patients: A Randomized Controlled Trial

Treatment of the anemia of chronic renal failure with exogenous recombinant human erythropoietin (rHuEpo) is well established. The objective of this randomized clinical trial was to evaluate an anemia management team protocol in hemodialysis patients, using subcutaneous rHuEpo and intravenous iron. A total of 215 patients were randomized to either usual care or the protocol. The primary outcome was the proportion of patient hemoglobin (Hgb) values between 11.0 and 12.5 g/dl over the final 8 wk. The study was halted after 240 d because of an institutional change to intravenous rHuEpo. The proportion of Hgb values in the target range increased from 47.4% to 62.8% overall (P = 0.001); there was no difference between treatment groups. The proportion of baseline Hgb values between 11.0 and 12.5 g/dl increased from 44.6% in patients who had enrolled within the first 3 mo of study inception to 75.0% in those who started later (P = 0.017), suggesting a Hawthorne effect. A nonsignificant decrease in rHuEpo dose was observed in the protocol group; subgroup analysis in patients who were enrolled for at least 5 mo demonstrated a reduction in the rHuEpo dose of 2788 units/wk in the protocol group (P < 0.05), independent of intravenous iron dose. Multivariate analysis demonstrated that a higher transferrin saturation and albumin and protocol group assignment were associated with a lower final rHuEpo dose. This study demonstrated that a protocolized approach to anemia management in hemodialysis patients results in comparable Hgb levels and may reduce rHuEpo requirements, independent of iron use.

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.

Impact of haemoglobin and erythropoietin dose changes on mortality: a secondary analysis of results from a randomized anaemia management trial

BACKGROUND Anaemia is a common complication of chronic kidney disease. A number of studies have identified an adverse association between haemoglobin (Hgb) variability and mortality. To date, no study has evaluated the impact of Hgb variability on mortality in the setting of a uniform Hgb target and erythropoiesis-stimulating agents (ESA) dosing strategy. METHODS One hundred and fifty-four haemodialysis (HD) patients from a previous randomized anaemia management study were followed up for up to 6 years. The impact of Hgb variability and ESA dosing parameters on subsequent mortality risk were evaluated. RESULTS More rapid rises in Hgb (Hgb deflect(pos)) and ESA dose increases were independently associated with mortality in multivariate analysis, whereas more rapid Hgb declines (Hgb deflect(neg)) and ESA dose decreases were not. Each gram per litre per week increase in Hgb deflect(pos) was associated with an adjusted hazard ratio (HR) of 1.23 (1.03-1.48), while for every 1000-unit increase in ESA dose, the adjusted HR was 1.12 (1.01-1.24). Factors associated with positive Hgb deflections included frequency and magnitude of ESA dose changes, baseline Hgb, patient weight and presence of an HD catheter. CONCLUSIONS Rapid Hgb rises and greater average Eprex dose increases were independently associated with a higher mortality risk in HD patients after adjustment for baseline Hgb and Eprex dose. A randomized controlled trial evaluating different ESA dosing strategies in response to individual patient ESA responsiveness is needed.

Adjudication of bleeding outcomes in an international thromboprophylaxis trial in critical illness

INTRODUCTION Measuring bleeding in critical care trials is challenging. We determined the reliability of adjudicated bleeding assessments in a large thromboprophylaxis trial in the intensive care unit (ICU). MATERIALS AND METHODS PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT) was an international randomized controlled trial that compared dalteparin to unfractionated heparin for the prevention of deep vein thrombosis in the ICU. Daily bleeding data were collected prospectively using a validated tool. Bleeds were adjudicated in duplicate by 2 of 4 members comprising a central adjudication committee. Bleeds were stratified by severity and study drug, then randomly assigned to adjudicator pairs. Adjudicators were blinded to treatment allocation, study centre and peer-assessments. We calculated agreement on bleeding severity and examined the effect of adjudication on overall trial results. RESULTS In PROTECT, 491 patients had bleeding events including 208 with major bleeding and 283 with minor bleeding only. Of 491 patients, 446 were adjudicated in duplicate: 182 with major, 250 with minor and 14 with no bleeding. After adjudication, 52 of 244 bleeds were downgraded to minor; whereas only 15 of 244 were upgraded to major. Overall agreement among adjudicators was excellent (crude agreement=86.3%; kappa=0.76). Hazard ratios for major or any bleeding with dalteparin or unfractionated heparin were similar when analyzed using non-adjudicated events. CONCLUSIONS Major bleeds were sometimes over-called by research coordinators in a large ICU thromboprohylaxis trial. Adjudicator agreement was excellent. Central adjudication allowed reliable bleeding assessment and enhanced the rigor and validity of this major safety outcome.