Leveraging pragmatic clinical trial design to advance phosphate management in end-stage renal disease.

PURPOSE OF REVIEW: Phosphate lowering toward the normal range is advocated and widely practiced in patients with end-stage renal disease receiving dialysis. This approach is guided by basic science data and large observational studies that have demonstrated a consistent association between hyperphosphatemia and adverse events, including cardiovascular morbidity and all-cause mortality. There has never been a clinical trial to assess the efficacy of phosphate lowering in maintenance dialysis recipients. RECENT FINDINGS: Despite several trials comparing the effect of different phosphate-binding agents on biochemical targets, no trial has evaluated whether targeting normophosphatemia using phosphate binders mediates better patient outcomes. Recent work has highlighted the feasibility of conducting a randomized trial comparing two strategies for phosphate control. We believe that this research question is optimally suited to a pragmatic trial design. SUMMARY: There is a pressing need for a well-designed randomized controlled trial to evaluate whether intensive phosphate lowering confers improved cardiovascular outcomes in patients receiving maintenance dialysis. We propose a broad framework for such a trial using the principles of pragmatic trial design. The ultimate objective of such a trial will be to provide patients and clinicians with reliable and broadly applicable information on whether reducing serum phosphate toward the normal range improves patient-important outcomes.

Plasmapheresis for the treatment of kidney diseases.

The purpose of this review is to examine the evidence supporting the application of plasma exchange in renal disease. Our review focuses on the following 6 most common renal indications for plasma exchange based on 2014 registry data from the Canadian Apheresis Group: (i) thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome; (ii) renal transplantation, (iii) anti-neutrophil cytoplasm antibodies-associated vasculitis, (iv) cryoglobulinemia, (v) focal segmental glomerulosclerosis, and (vi) Goodpasture syndrome. The rarity of these diseases and their rapid, often fatal course mean that randomized controlled studies of plasma exchange are rarely conducted. Although evidence from an adequately powered randomized controlled trial supports the use of plasma exchange to treat thrombotic thrombocytopenic purpura, the use of plasma exchange to treat other renal diseases is only supported by observational and mechanistic studies. Larger well-designed trials are needed to clarify the potential role of plasma exchange in renal disease. Growing international collaboration will improve the quality of future studies in this area.

Timing the initiation of renal replacement therapy for acute kidney injury in Canadian intensive care units: a multicentre observational study.

PURPOSE: The optimal timing for starting renal replacement therapy (RRT) in patients with acute kidney injury (AKI) is unknown. Defining current practice is necessary to design interventional trials. We describe the current Canadian practice regarding the timing of RRT initiation for AKI. METHODS: An observational study of patients undergoing RRT for AKI was undertaken at 11 intensive care units (ICUs) across Canada. Data were captured on demographics, clinical and laboratory findings, indications for RRT, and timing of RRT initiation. RESULTS: Among 119 consecutive patients, the most common ICU admission diagnosis was sepsis/septic shock, occurring in 54%. At the time of RRT initiation, the median and interquartile range (IQR) serum creatinine level was 322 (221-432) µmol·L(-1). The mean (SD) values for other parameters were as follows: Sequential Organ Failure Assessment (SOFA) score 13.4 (4.1), pH 7.25 (0.15), potassium 4.6 (1.0) mmol·L(-1). Also, 64% fulfilled the serum creatinine-based criterion for Acute Kidney Injury Network (AKIN) stage 3. Severity of illness, measured using Acute Physiology and Chronic Health Evaluation (APACHE II) and SOFA scores, did not correlate with AKI severity as defined by the serum creatinine-based AKIN criteria. Median (IQR) time from hospital and ICU admission to the start of RRT was 2.0 (1.0-7.0) days and 1.0 (0-2.0) day, respectively. CONCLUSION: Patients admitted to an ICU who were started on RRT generally had advanced AKI, high-grade illness severity, and multiorgan dysfunction. Also, they were started on RRT shortly after hospital presentation. We describe the current state of practice in Canada regarding the initiation of RRT for AKI in critically ill patients, which can inform the designs of future interventional trials.

Predicting Myocardial Injury and Other Cardiac Complications After Elective Noncardiac Surgery with the Revised Cardiac Risk Index: The VISION Study.

BACKGROUND: The Revised Cardiac Risk Index (RCRI) is widely used to estimate risk of cardiac complications after noncardiac surgery; its estimates do not capture myocardial injury after noncardiac surgery (MINS). We evaluated the incidence of cardiac complications including MINS across RCRI risk classes and the RCRI's ability to discriminate, before surgery, between patients who will experience these complications and those who will not. METHODS: This was a secondary analysis of a prospective cohort study of 35,815 patients ≥ 45 years old who had elective inpatient noncardiac surgery from 2007 to 2013 at 28 centres in 14 countries. The primary outcome was a composite of MINS, myocardial infarction, nonfatal cardiac arrest, or cardiac death within 30 days after surgery. The secondary outcome was this composite without MINS. RESULTS: The primary outcome occurred in 4725 patients (13.2%); its incidences across RCRI classes I (no risk factors), II (1 risk factor), III (2 risk factors), and IV (≥ 3 risk factors) were, respectively, 8.2%, 15.4%, 26.6%, and 40.2% (C-statistic for discrimination 0.65 [95% confidence interval 0.62-0.68]). The secondary outcome occurred in 1174 patients (3.3%) with incidences of 1.6%, 4.0%, 7.9%, and 12.9%, respectively (C-statistic 0.69 [0.65-0.72]). Thirty-five percent of primary outcome events and 26.9% of secondary outcome events occurred in patients with no RCRI risk factors. CONCLUSION: The RCRI alone is not sufficient to guide postoperative cardiac monitoring because 1 in 12 patients ≥ 45 years of age without any RCRI risk factors have a cardiac complication after major noncardiac surgery, and most of them would be missed without systematic troponin testing.

Kidney disease after preeclampsia: a systematic review and meta-analysis.

BACKGROUND: Preeclampsia (the development of proteinuria and hypertension after 20 weeks of gestation) is common; however, there is uncertainty about the natural history of subsequent kidney disease. Our objective is to undertake a systematic review and meta-analysis to determine whether women with a history of preeclampsia are at increased risk of subsequent kidney disease. STUDY DESIGN: Systematic review and meta-analyses of observational studies. SETTING & POPULATION: Studies examining kidney outcomes in women with a history of preeclampsia compared with women with unaffected pregnancies. SELECTION CRITERIA: From MEDLINE and EMBASE searches, we included case-control and cohort studies of kidney outcomes at least 6 weeks postpartum in women with and without a history of preeclampsia. 2 independent reviewers determined study eligibility, extracted data, and assessed quality. STUDY FACTOR: Preeclampsia. OUTCOMES: Microalbuminuria, proteinuria, serum creatinine level, and estimated glomerular filtration rate. RESULTS: 7 cohort studies were included, involving 273 patients with preeclampsia and 333 patients with uncomplicated pregnancies. At a weighted mean of 7.1 years postpartum, 31% of women with a history of preeclampsia had microalbuminuria compared with 7% of women with uncomplicated pregnancies, a 4-fold increased risk, whereas women with severe preeclampsia had an 8-fold increase. Serum creatinine level and estimated glomerular filtration rate were not significantly different at follow-up in women with and without preeclampsia, making it unlikely that they would have been different at baseline. LIMITATIONS: Limitations of this systematic review include potential confounders that were not explored in most or any of the original studies, the small size of many studies, and possible publication bias (lack of negative studies). CONCLUSION: Women with a history of preeclampsia have an increased risk of microalbuminuria with a prevalence similar to the published prevalence in patients with type 1 diabetes mellitus. Further research is needed to determine whether the increased risk of microalbuminuria persists after adjustment for a thorough set of confounding factors in larger populations and the mechanisms underlying this association.

Nocturnal hemodialysis does not improve overall measures of quality of life compared to conventional hemodialysis.

We conducted a randomized controlled trial to compare the quality of life of 52 patients undergoing nocturnal hemodialysis and conventional hemodialysis. Quality of life was measured using a number of established methods including the Kidney Disease Quality of Life Short Form and the preference-based Euroqol EQ-5D questionnaire (whose scores varied from 0 to 1). The primary outcome was a change in the Euroqol EQ-5D index scores between baseline and 6 months. We performed additional analyses comparing change in quality of life from pre-randomization (when patients were unaware of treatment allocation) to 6 months. Other analyses considered the impact of nocturnal hemodialysis on four pre-selected Kidney Disease Quality of Life Short Form domains, and the longer term impact of nocturnal hemodialysis on quality of life. Compared with conventional hemodialysis, nocturnal hemodialysis increased Euroqol-EQ-5D index scores by 0.05, which was not significantly different from baseline. When six-month values were compared with pre-randomization values rather than baseline values, the between group difference was larger (0.12) though it was still not statistically significant (P=.06). Nocturnal hemodialysis was associated with clinically and statistically significant improvements in selected kidney-specific quality of life domains (P=.01 for effects of kidney disease; P=.02 for burden of kidney disease). Our primary quality of life analysis did not demonstrate a statistically significant change between nocturnal hemodialysis and conventional hemodialysis, though statistically significant and clinically important changes in some secondary kidney-disease- specific measures were observed.

Low-molecular-weight heparin venous thromboprophylaxis in critically ill patients with renal dysfunction: A subgroup analysis of the PROTECT trial.

INTRODUCTION: There is concern about excessive bleeding when low-molecular-weight heparins (LMWHs) are used for venous thromboembolism (VTE) prophylaxis in renal dysfunction. Our objective was to evaluate whether LMWH VTE prophylaxis was safe and effective in critically ill patients with renal dysfunction by conducting a subgroup analysis of PROTECT, a randomized blinded trial. METHODS: We studied intensive care unit (ICU) patients with pre-ICU dialysis-dependent end-stage renal disease (ESRD; pre-specified subgroup; n = 118), or severe renal dysfunction at ICU admission (defined as ESRD or non-dialysis dependent with creatinine clearance [CrCl] <30 ml/min; post hoc subgroup; n = 590). We compared dalteparin, 5000 IU daily, with unfractionated heparin (UFH), 5000 IU twice daily, and considered outcomes of proximal leg deep vein thrombosis (DVT); pulmonary embolism (PE); any VTE; and major bleeding. Adjusted hazard ratios [HR] were calculated using Cox regression. RESULTS: In patients with ESRD, there was no significant difference in DVT (8.3% vs. 5.2%, p = 0.76), any VTE (10.0% vs. 6.9%; p = 0.39) or major bleeding (5.0% vs. 8.6%; p = 0.32) between UFH and dalteparin. In patients with severe renal dysfunction, there was no significant difference in any VTE (10.0% vs. 6.4%; p = 0.07) or major bleeding (8.9% vs. 11.0%; p = 0.66) but an increase in DVT with dalteparin (7.6% vs. 3.7%; p = 0.04). Interaction p-values for comparisons of HRs (ESRD versus not) were non-significant. CONCLUSIONS: In critically ill patients with ESRD, or severe renal dysfunction, there was no significant difference in any VTE or major bleeding between UFH and dalteparin. Patients with severe renal dysfunction who received dalteparin had more proximal DVTs than those on UFH; this finding did not hold in patients with ESRD alone.

Clinical factors associated with initiation of renal replacement therapy in critically ill patients with acute kidney injury-a prospective multicenter observational study.

PURPOSE: Our objective was to describe the current practice for initiation of RRT in this population. There is uncertainty regarding the optimal time to initiate renal replacement therapy (RRT) in critically ill patients with acute kidney injury (AKI). METHODS: Prospective study of patients receiving RRT in 6 intensive care units (ICUs) at 3 hospitals from July 2007 to August 2008. We characterized factors associated with start of RRT and evaluated their relationship with mortality. RESULTS: We included 234 patients. RRT was initiated 1 day (0-4) after ICU admission (median [interquartile range]). Median creatinine was 331 µmol/L (225-446 µmol/L), urea 22.9 mmol/L (13.9-32.9 mmol/L), and RIFLE-Failure in 76.9%. Of traditional indications, Pao(2)/Fio(2) < 200 (54.5%) and oliguria (32.9%) were most common. ICU and hospital mortality were 45.3% and 51.9%, respectively. In adjusted analysis, mortality at RRT initiation was associated with creatinine <332 µmol/L (odds ratio [OR] 2.8; 95% confidence interval [CI] 1.5-5.4), change in urea from admission >8.9 mmol/L (OR 1.8; 95% CI, 1.0-3.4), urine output <82 mL/24 hours (OR 3.0; 95% CI, 1.4-6.5), fluid balance >3.0 L/24 hours (OR 2.3; 95% CI, 1.2-4.5), percentage of fluid overload >5% (OR 2.3; 95% CI, 1.2-4.7), 3 or more failing organs (OR 4.5; 95% CI, 1.2-4.2), Sequential Organ Failure Assessment score >14 (OR 2.3; 95% CI, 1.3-4.3), and start 4 days or more after admission (OR 4.3; 95% CI, 1.9-9.5). Mortality was higher as factors accumulated. CONCLUSION: In ICU patients requiring RRT, there was marked variation in factors that influence start of RRT. RRT initiation with fewer clinical triggers was associated with lower mortality. Timing of RRT may modify survival but requires appraisal in a randomized trial.