Accurate and reliable assessment of kidney quality before transplantation is needed to predict recipient outcomes and to optimize management and allocation of the allograft. The aim of this study was to systematically review the published literature on biomarkers in two mediums (the perfusate from deceased-donor kidneys receiving machine perfusion and deceased-donor urine) that were evaluated for their possible association with outcomes after kidney transplantation.
We searched the Ovid Medline and Scopus databases using broad keywords related to deceased-donor biomarkers in kidney transplantation (limited to humans and the English language). Studies were included if they involved deceased-donor kidneys, measured perfusate or urine biomarkers and studied a possible relationship between biomarker concentrations and kidney allograft outcomes. Each included article was assessed for methodological quality.
Of 1430 abstracts screened, 29 studies met the inclusion criteria. Of these, 23 were studies of perfusate (16 biomarkers examined) and 6 were studies of urine (18 biomarkers examined). Only 3 studies (two perfusate) met the criteria of ‘good’ quality and only 12 were published since 2000. Perfusate lactate dehydrogenase, glutathione-S-transferase (GST) and aspartate transaminase were all found to be significantly associated with delayed graft function in a majority of their respective studies (6/9, 4/6 and 2/2 studies, respectively). Urine neutrophil gelatinase-associated lipocalin, GST, Trolox-equivalent antioxidant capacity and kidney injury molecule-1 were found to be significantly associated with allograft outcomes in single studies that examined diverse end points.
Higher quality studies are needed to investigate modern kidney injury biomarkers, to validate novel biomarkers in larger donor populations and to determine the incremental predictive value of biomarkers over traditional clinical variables.
biomarkers; deceased donors; delayed graft function; kidney transplantation
Acute kidney injury (AKI) after cardiac surgery confers a significant increased risk of mortality. Several risk models have been developed to predict postoperative kidney failure after cardiac surgery. The objective of this systematic review is to evaluate the available risk models for AKI after cardiac surgery.
Literature searches were performed in the Web of Science/Knowledge, Scopus, and MEDLINE databases for articles reporting the primary development of a risk model and articles reporting validation of existing risk models for AKI after cardiac surgery. Data on model variables, internal and/or external validation, measures of discrimination, and measures of calibration were extracted.
Seven articles with a primary development of a prediction score for AKI after cardiac surgery and 8 articles with external validation of established models were included in the systematic review. The models for AKI requiring dialysis are the most robust and externally validated. Among the prediction rules for AKI requiring dialysis after cardiac surgery, the Cleveland Clinic model has been the most widely tested thus far and has shown high discrimination in most of the tested populations. A validated score to predict non-dialysis requiring AKI is lacking.
Further studies are required to develop risk models to predict milder, non-dialysis requiring AKI after cardiac surgery. Standardizing risk factor and AKI definitions will facilitate both the development and validation of risk models predicting AKI.
Statistics; risk analysis/modeling; kidney Ischemia/reperfusion injury; cardiac surgery; CABG
Acute kidney injury may increase the risk for chronic kidney disease and end-stage renal disease. In an attempt to summarize the literature and provide more compelling evidence, we conducted a systematic review comparing the risk of CKD, ESRD and death in patients with and without AKI. From electronic databases, web search engines, and bibliographies, 13 cohort studies were selected, evaluating long-term renal outcomes and non-renal outcomes in patients with AKI. The pooled incidence of CKD and ESRD were 25.8/100 person-years and 8.6 per 100 person-years, respectively. Patients with AKI had higher risks of developing CKD (pooled adjusted hazard ratio 8.8, 95% CI 3.1-25.5), ESRD (pooled adjusted HR 3.1, 95% CI 1.9-5.0) and mortality (pooled adjusted HR 2.0, 95% CI 1.3-3.1) than patients without AKI. The relationship between AKI and CKD or ESRD was graded depending on the severity of AKI and the effect size was dampened by decreased baseline glomerular filtration rate. Data were limited, but AKI was also independently associated with the risk for cardiovascular disease and congestive heart failure, but not with hospitalization for stroke or all-cause hospitalizations. Meta-regression did not identify any study level factors that were associated with the risk for CKD or ESRD. Our review identifies AKI as an independent risk factor for CKD, ESRD, and death and other important non-renal outcomes.
Acute kidney injury (AKI) duration following cardiac surgery is associated with poor survival in a dose-dependent manner. However, it is not known what peri-operative risk factors contribute to prolonged AKI and delayed recovery. We sought to identify peri-operative risk factors that predict duration of AKI, a complication that effects short and long term survival.
We studied 4,987 consecutive cardiac surgery patients from 2002 through 2007. AKI was defined as a ≥0.3 (mg/dL) or ≥50% increase in SCr from baseline. Duration of AKI was defined by the number of days AKI was present. Step-wise multivariable negative binomial regression analysis was conducted using peri-operative risk factors for AKI duration. C-index was estimated by Kendall’s tau.
AKI developed in 39% of patients with a median duration of AKI at 3 days and ranged from 1 to 108 days. Patients without AKI had duration of zero days. Independent predictors of AKI duration included baseline patient and disease characteristics, operative and post-operative factors. Prediction for mean duration of AKI was developed using coefficients from the regression model and externally validated the model on 1,219 cardiac surgery patients in a separate cardiac surgery cohort (TRIBE-AKI). The C-index was 0.65 (p<0.001) for the derivation cohort and 0.62 (p<0.001) for the validation cohort.
We identified and externally validated peri-operative predictors of AKI duration. These risk-factors will be useful to evaluate a patient’s risk for the tempo of recovery from AKI after cardiac surgery and subsequent short and long term survival. The level of awareness created by working with these risk factors have implications regarding positive changes in processes of care that have the potential to decrease the incidence and mitigate AKI.
acute kidney injury; cardiac surgery; risk model; risk prediction; Statistics; risk analysis/modeling; Surgery; complications; Kidney; CABG; Heart Valve surgery
To perform a systematic review of randomized controlled trials to determine whether prevention or slowing of progression of chronic kidney disease would translate into improved mortality, and if so, the attributable risk due to CKD itself on mortality.
CKD is associated with increased mortality. This association is largely based on evidence from the observational studies and evidence from randomized controlled trials is lacking.
We searched Ovid, Medline and Embase for RCTs in which an intervention was given to prevent or slow the progression of CKD and mortality was reported as primary, secondary or adverse outcomes were eligible and selected. For the first phase, pooled relative risks for renal endpoints were assessed. For the second phase, we assessed the effect on mortality in trials of interventions that definitively reduced CKD endpoints.
Among 52 studies selected in first phase, only renin-angiotensin-aldosterone-system blockade vs. placebo (n = 18 trials, 32,557 participants) met the efficacy criteria for further analysis in the second phase by reducing renal endpoints 15 to 27% compared to placebo. There was no difference in all-cause mortality (RR 0.99, 95% CI 0.92 to 1.08) or CV death (RR 0.97, 95% CI 0.78 to 1.21) between the treatment and control groups in these trials. There was sufficient statistical power to detect a 9% relative risk reduction in all-cause mortality and a 14% relative risk reduction in cardiovascular mortality.
Firm evidence is lacking that prevention of CKD translates into reductions in mortality. Larger trials with longer follow-up time are needed to determine the benefit of CKD prevention on survival.
Approximately 15% of HIV-infected individuals have comorbid diabetes. Studies suggest that HIV and diabetes have an additive effect on chronic kidney (CKD) progression; however, this observation may be confounded by differences in traditional CKD risk factors.
We studied a national cohort of HIV-infected and matched HIV-uninfected individuals who received care through the Veterans Healthcare Administration. Subjects were divided into four groups based on baseline HIV and diabetes status, and the rate of progression to an estimated glomerular filtration rate (eGFR) < 45ml/min/1.73m2 was compared using Cox-proportional hazards modeling to adjust for CKD risk factors.
31,072 veterans with baseline eGFR ≥ 45ml/min/1.73m2 (10,626 with HIV only, 5,088 with diabetes only, and 1,796 with both) were followed for a median of 5 years. Mean baseline eGFR was 94ml/min/1.73m2, and 7% progressed to an eGFR < 45ml/min/1.73m2. Compared to those without HIV or diabetes, the relative rate of progression was increased in individuals with diabetes only [adjusted hazard ratio (HR) 2.48; 95% confidence interval (CI) 2.19–2.80], HIV only [HR 2.80, 95% CI 2.50–3.15], and both HIV and diabetes [HR 4.47, 95% CI 3.87–5.17].
Compared to patients with only HIV or diabetes, patients with both diagnoses are at significantly increased risk of progressive CKD even after adjusting for traditional CKD risk factors. Future studies should evaluate the relative contribution of complex comorbidities and accompanying polypharmacy to the risk of CKD in HIV-infected individuals, and prospectively investigate the use of cART, glycemic control, and adjunctive therapy to delay CKD progression.
non-AIDS complications; HIV; chronic kidney disease; diabetes; risk factors
Aggressive glycemic control has been hypothesized to prevent renal disease in type 2 diabetics. A systematic review was conducted to summarize the benefits of intensive versus conventional glucose control on kidney-related outcomes for adults with type 2 diabetes.
Three databases were systematically searched (January 1950 to December 2010) with no language restrictions to identify randomized trials that compared surrogate renal endpoints (micro and macroalbuminuria) and clinical renal endpoints (doubling of serum creatinine, End Stage Renal Disease [ESRD] and death from renal disease) in patients with type 2 diabetes receiving intensive glucose control versus receiving conventional glucose control.
Seven trials involving 28,065 adults who were followed-up for 2 to 15 years. Compared with conventional control, intensive glucose control reduced the risk for microalbuminuria (risk ratio [RR], 0.86 [95% CI, 0.76 to 0.96]) and macroalbuminuria (RR 0.74 [95% CI, 0.65–0.85]), but not doubling of serum creatinine (RR 1.06 [95% CI, 0.92 to 1.22]), ESRD (RR 0.69 [95% CI, 0.46–1.05]), or death from renal disease (RR 0.99 [95% CI 0.55–1.79]). Meta-regression revealed that larger differences in HbA1C between intensive and conventional therapy at the study level were associated with greater benefit for both micro- and macroalbuminuria. The pooled cumulative incidence of doubling of creatinine, ESRD, and death from renal disease was low (< 4%, <1.5%, and <0.5%, respectively) compared with the surrogate renal endpoints of micro- (23%) and macroalbuminuria (5%).
Intensive glucose control reduces the risk for microalbuminuria and macroalbuminuria but evidence is lacking that intensive glycemic control reduces the risk for significant clinical renal outcomes such as doubling of creatinine, ESRD or death from renal disease during the years of follow-up of the trials.
Proteinuria; creatinine; chronic kidney disease; end-stage renal disease; prognosis
Chronic kidney disease (CKD) is associated with worse outcomes among patients with acute coronary syndrome (ACS). Less is known about the impact of CKD on longitudinal outcomes among clopidogrel treated patients following ACS.
Using a retrospective cohort design, we identified patients hospitalized with ACS between 10/1/2005 and 1/10/10 at Department of Veterans Affairs (VA) facilities and who were discharged on clopidogrel. Using outpatient serum creatinine values, estimated glomerular filtration rate [eGFR (1.73 ml/min/m2)] was calculated using the CKD-EPI equation. The association between eGFR and mortality, hospitalization for acute myocardial infarction (AMI), and major bleeding were examined using Cox proportional hazards models.
Among 7413 patients hospitalized with ACS and discharged taking clopidogrel, 34.5% had eGFR 30–60 and 11.6% had eGFR < 30. During 1-year follow-up after hospital discharge, 10% of the cohort died, 18% were hospitalized for AMI, and 4% had a major bleeding event. Compared to those with eGFR > =60, individuals with eGFR 30–60 (HR 1.45; 95% CI: 1.18-1.76) and < 30 (HR 2.48; 95% CI: 1.97-3.13) had a significantly higher risk of death. A progressive increased risk of AMI hospitalization was associated with declining eGFR: HR 1.20; 95% CI: 1.04-1.37 for eGFR 30–60 and HR 1.47; 95% CI: 1.22-1.78 for eGFR < 30. eGFR < 30 was independently associated with over a 2-fold increased risk in major bleeding (HR 2.09; 95% CI: 1.40-3.12) compared with eGFR > = 60.
Lower levels of kidney function were associated with higher rates of death, AMI hospitalization, and major bleeding among patients taking clopidogrel after hospitalization for ACS.
Kidney disease; Myocardial infarction; Hospitalization; Bleeding
Acute kidney injury (AKI) following cardiac surgery is associated with poor outcomes and is difficult to predict. We conducted a prospective study to evaluate whether pre-operative brain natriuretic peptide (BNP) levels predict postoperative AKI among patients undergoing cardiac surgery.
Methods and Results
The TRIBE-AKI Consortium enrolled 1,139 adults undergoing cardiac surgery at six hospitals from 2007–2009, who were selected for high AKI risk. Pre-operative BNP was categorized into quintiles. AKI was common using Acute Kidney Injury Network definitions; at least mild AKI was a ≥0.3mg/dL or 50% rise in creatinine, n=407 (36%), and severe AKI was either a doubling of creatinine or the requirement of acute renal replacement therapy, n=58 (5.1%). In analyses adjusted for pre-operative characteristics, pre-operative BNP was a strong and independent predictor of mild and severe AKI. Compared with the lowest BNP quintile the highest quintile had significantly higher risk of at least mild AKI (risk ratio [RR] 1.87; 1.40–2.49) and severe AKI (RR 3.17; 1.06–9.48). After adjustment for clinical predictors, addition of BNP improved the area under the curve to predict at least mild AKI (0.67 to 0.69, p=0.02) and severe AKI (0.73 to 0.75, p=0.11). Compared with clinical parameters alone, BNP modestly improved risk prediction of AKI cases into lower and higher risk (continuous net reclassification index at least mild AKI 0.183; 0.061, 0.314; severe AKI 0.231; 0.067, 0.506).
Pre-operative BNP level is associated with post-operative AKI in high-risk patients undergoing cardiac surgery. If confirmed in other types of patients and surgeries, pre-operative BNP may be a valuable component of future efforts to improve pre-operative risk stratification and discrimination among surgical candidates.
brain natriuretic peptide; cardiac surgery; acute renal failure; creatinine
Advances in hematopoietic cell transplantation (HCT) have broadened its indications for use and resulted in more long-term HCT survivors. Some survivors develop chronic kidney disease (CKD), however, the incidence and risk factors are unclear. We performed a systematic review of studies identified from databases (MEDLINE, EMBASE, Science Citation Index), conference abstracts, and reference lists from selected manuscripts. From 927 manuscripts, 28 patient cohorts were identified in which 9,317 adults and children underwent HCT and 7,317 (79%) survived to at least 100 days, permitting inclusion of 5,337 (73% of survivors) in quantitative analyses. Although definitions and measurements varied widely, approximately 16.6% of HCT patients developed CKD and estimated glomerular filtration rate (eGFR in ml/min/1.73m2) decreased by 24.5 after 24 months. This decrease was greater amongst patients undergoing allogeneic HCT (ΔeGFR = −40.0 versus −18.6 for autologous transplants). Several commonly reported risk factors for CKD were investigated, including acute renal failure, total body irradiation, graft versus host disease, and long-term cyclosporine use. In conclusion, CKD following HCT is likely to be common, however, prospective studies with uniform definitions of CKD and risk factors are needed to confirm these findings and better define the underlying mechanisms to promote therapies that prevent this complication.
chronic kidney disease (CKD); hematopoietic stem cell transplantation; bone marrow transplantation; renal failure; meta-analysis; systematic review; risk factor; complications
Progressive disruption of renal tubular integrity in the setting of increased cellular proliferation and apoptosis is a feature of ADPKD. Here we evaluated the effect of these processes on the expression of NGAL and IL-18, markers of tubular injury, in rodent models and in the cyst fluid and urine of patients with ADPKD. Two mouse models where Pkd2 was inactivated which resulted in early or adult onset cysts, were used to evaluate NGAL levels. Further, the Han:SPRD rat model of polycystic disease was used to study IL-18 levels. In four annual serial urine samples from 107 patients with ADPKD in the Consortium for Radiologic Imaging for the Study of Polycystic Kidney Disease (CRISP) study, NGAL and IL-18 excretion rates were determined in conjunction with measures of total kidney volume and estimated GFR (eGFR) by the MDRD equation. Kidneys from affected mice and rats showed prominent expression of NGAL and IL-18/IL-18R, respectively, in epithelial cells lining kidney cysts. In human ADPKD cyst fluid, both NGAL and IL-18 were elevated. In CRISP patients, the mean percentage increase in total kidney volume was 5.4 /year and the mean decline in eGFR 2.4 mL/min/year. The trend of increased mean urine NGAL and IL-18 over three years was statistically significant; however, there was no association of tertiles of IL-18 or quartiles of NGAL and the change in total kidney volume or eGFR over this period. Thus, urinary NGAL and IL-18 excretion are mildly and stably elevated in ADPKD, but do not correlate with changes in total kidney volume or kidney function. This may be due, in part, to the lack of communication between individual cysts and the urinary collecting system in this disorder.
surrogate; NGAL; IL-18; biomarker
Acute kidney injury (AKI) following cardiac surgery is associated with poor outcomes, but is challenging to predict from information available prior to surgery.
Prospective cohort study
Setting & Participants
The TRIBE-AKI Consortium enrolled 1,147 adults undergoing cardiac surgery at six hospitals from 2007–2009; participants were selected for high AKI risk.
Pre-surgical cystatin C, creatinine, and creatinine-based estimated glomerular filtration rate (eGFR) were categorized into quintiles and grouped as ‘Best’ (quintiles 1–2), ‘Intermediate’ (quintiles 3–4), and ‘Worst’ (quintile 5) kidney function.
The primary outcome was AKI Network (Acute Kidney Injury Network) Stage 1 or higher; ≥0.3mg/dL or 50% rise in creatinine.
Analyses were adjusted for characteristics used clinically for pre-surgical risk stratification.
The average age and kidney function were: 71±10 years (mean ± standard deviation), serum creatinine 1.1±0.3 mg/dL, eGFR-Cr, 74±9 mL/min/1.73m2, and cystatin C, 0.9 ±0.3 mg/L. A total of 407 (36%) participants developed AKI during hospitalization. Adjusted odds ratios for intermediate and worst kidney function by cystatin C were 1.9 (95% CI, 1.4–2.7) and 4.8 (95% CI, 2.9–7.7) compared with 1.2 (95% CI, 0.9–1.7) and 1.8 (95% CI, 1.2–2.6) for creatinine and 1.0 (95% CI, 0.7–1.4) and 1.7 (95% CI, 1.1–2.3) for eGFR-Cr categories, respectively. After adjustment for clinical predictors, the C statistic to predict AKI was 0.70 without kidney markers, 0.69 with creatinine, and 0.72 with cystatin C. Cystatin C also substantially improved AKI risk classification compared to creatinine, based on a net reclassification index of 0.21 (p<0.001).
The ability of these kidney biomarkers to predict risk for dialysis-requiring AKI or death could not be reliably assessed in our study due to a small number of patients with either outcome.
Pre-surgical cystatin C is better than creatinine or creatinine-based eGFR at forecasting the risk of AKI after cardiac surgery.
acute renal failure; creatinine; prognosis
Acute kidney injury is a serious complication of elective major surgery. Acute dialysis is used to support life in the most severe cases. We examined whether rates and outcomes of acute dialysis after elective major surgery have changed over time.
We used data from Ontario’s universal health care databases to study all consecutive patients who had elective major surgery at 118 hospitals between 1995 and 2009. Our primary outcomes were acute dialysis within 14 days of surgery, death within 90 days of surgery and chronic dialysis for patients who did not recover kidney function.
A total of 552 672 patients underwent elective major surgery during the study period, 2231 of whom received acute dialysis. The incidence of acute dialysis increased steadily from 0.2% in 1995 (95% confidence interval [CI] 0.15–0.2) to 0.6% in 2009 (95% CI 0.6–0.7). This increase was primarily in cardiac and vascular surgeries. Among patients who received acute dialysis, 937 died within 90 days of surgery (42.0%, 95% CI 40.0–44.1), with no change in 90-day survival over time. Among the 1294 patients who received acute dialysis and survived beyond 90 days, 352 required chronic dialysis (27.2%, 95% CI 24.8–29.7), with no change over time.
The use of acute dialysis after cardiac and vascular surgery has increased substantially since 1995. Studies focusing on interventions to better prevent and treat perioperative acute kidney injury are needed.
To determine the incidence, severity and risk-factors of AKI in children undergoing cardiac surgery for congenital heart defects.
Prospective observational multicenter cohort study
Three pediatric intensive care units at academic centers.
311 children between the ages of 1 month and 18 years undergoing pediatric cardiac surgery.
Measurements and Main Results
AKI was defined as a ≥ 50% increase in serum creatinine from the pre-operative value. Secondary outcomes were length of mechanical ventilation, length of ICU and hospital stays, acute dialysis, and in-hospital mortality. The cohort had an average age of 3.8 years with 45% females and was mostly white (82%). One third had prior cardiothoracic surgery, 91% of the surgeries were elective, and almost all patients required cardiopulmonary bypass (CPB). AKI occurred in 42% (130 patients) within 3 days after surgery. Children ≥ 2 years old and less than 13 years old had 72% lower likelihood of AKI (adjusted OR: 0.28, 95% CI: 0.16, 0.48), and patients 13 years and older had 70% lower likelihood of AKI (adjusted OR: 0.30, 95% CI: 0.10, 0.88) compared to patients less than 2 years old. Longer CPB time was linearly and independently associated with AKI. Development of AKI was independently associated with prolonged ventilation and with increased length of hospital stay.
AKI is common after pediatric cardiac surgery and is associated with prolonged mechanical ventilation and increased hospital stay. CPB time and age were independently associated with AKI risk. CPB time may be a marker for case complexity.
Renal Insufficiency, Acute; Heart Defects, Congenital; Cardiac Surgical Procedures; Intensive Care Units, Pediatric; Cardiopulmonary Bypass; Risk Factors
Clinical methods to predict allograft function soon after kidney transplantation are ineffective.
We analyzed urine cystatin C (CyC) in a prospective multicenter observational cohort study of deceased-donor kidney transplants to determine its peritransplant excretion pattern, utility for predicting delayed graft function (DGF) and association with 3-month graft function. Serial urine samples were collected for 2 days following transplant and analyzed blindly for CyC. We defined DGF as any hemodialysis in the first week after transplant, slow graft function (SGF) as a serum creatinine reduction <70% by the first week and immediate graft function (IGF) as a reduction ≥70%.
Of 91 recipients, 33 had DGF, 34 had SGF and 24 had IGF. Urine CyC/urine creatinine was highest in DGF for all time-points. The area under the curve (95% CI) for predicting DGF at 6 h was 0.69 (0.57–0.81) for urine CyC, 0.74 (0.62–0.86) for urine CyC/urine creatinine and 0.60 (0.45–0.75) for percent change in urine CyC. On the first postoperative day, urine CyC/urine creatinine and percent change in urine CyC were associated with 3-month graft function.
Urine CyC on the day after transplant differs between degrees of perioperative graft function and modestly corresponds with 3-month function.
Transplantation; Biomarkers; Ischemia/reperfusion; Outcomes
Recipients of hematopoietic cell transplantation may be at risk for developing acute kidney injury and this risk may increase in patients who undergo transplantation for severe systemic sclerosis due to underlying scleroderma renal disease. Acute kidney injury after transplantation can increase transplant related mortality. To better define these risks, we analyzed 91 patients with systemic sclerosis who were enrolled in three clinical trials in the United States of autologous or allogeneic hematopoietic cell transplantation. Eleven (12%) of the 91 scleroderma patients in these studies (8 autologous, 1 allogeneic, 1 pre-transplant, 1 given intravenous cyclophosphamide on transplant trial) experienced acute kidney injury of whom eight required dialysis and/or total plasma exchange. Acute kidney injury in the 9 transplant recipients developed a median of 35 (range, 0–90) days after transplantation. Ten of 11 patients with acute kidney injury received angiotensin converting enzyme-inhibitors (ACE-I) treatment. The etiology of acute kidney injury was attributed to scleroderma renal crisis in 6 patients (including two with normotensive renal crisis), acute kidney injury of uncertain etiology in 2 patients and acute kidney injury superimposed on scleroderma kidney disease in 3 patients. Eight of the 11 patients died: causes of death included progression of SSc (1), multiorgan failure (1), gastrointestinal and pulmonary bleeding (1), pericardial tamponade and pulmonary complications (1), diffuse alveolar hemorrhage (1), pulmonary embolism (1), graft-versus-host disease (1) and malignancy (1). Limiting nephrotoxins, cautious use of corticosteroids, renal shielding during total body irradiation, strict control of blood pressure and aggressive use of ACE-I may be of importance in preventing renal complications after hematopoietic cell transplantation for systemic sclerosis.
Acute kidney injury; systemic sclerosis; scleroderma; hematopoietic cell transplant
To examine the utility of using proteinuria in pre-operative risk stratification for acute kidney injury (AKI). AKI is a common and important complication for patients undergoing cardiac surgery. Proteinuria, which reflects structural damage to the glomeruli or renal tubules, may aid the prediction of AKI.
The ratio of urine albumin to creatinine (UACR) and dipstick proteinuria concentration were prospectively measured in 1159 patients undergoing cardiac surgery. The cohort was organized into four clinical risk categories based on the pre-operative UACR: UACR ≤ 10 mg/g (≤ 1.1 mg/mmol), 11–29 mg/g (1.2–3.3 mg/mmol), 30–299 mg/g (3.4–33.8 mg/mmol), and ≥ 300 mg/g (≥ 33.9 mg/mmol). The primary outcome was post-operative AKI, defined by the AKIN stage I criterion (serum creatinine rise by ≥50% or ≥ 0.3 mg/dL (26.5 μmol/L)).
An increase in the incidence of AKI was noted across the UACR categories. Adding UACR to the clinical model to predict AKI improved the AUC from 0.64 to 0.67 (p < 0.001) and the continuous net reclassification improvement (NRI) was 30% (p < 0.001). UACR was also independently associated with risk of in-hospital dialysis, and ICU and hospital length of stay. Surgery status and pre-operative GFR were effect modifiers; the association was stronger amongst those undergoing elective surgery and those with eGFR ≥ 45 mL/min per 1.73 m2.
Pre-operative proteinuria provides graded stratification risk for AKI and is an independent predictor of other outcomes in patients undergoing cardiac surgery.
CORONARY is a large international randomised controlled trial comparing coronary artery bypass graft (CABG) surgery done with and without a bypass pump. Compared with on-pump, off-pump surgery may prevent acute kidney injury (AKI) in the short term and may better preserve kidney function 1 year following surgery. Secondary analyses may also clarify whether effects are similar in patients with and without pre-operative chronic kidney disease and whether AKI avoidance mediates preserved 1-year kidney function.
Methods and analysis
With respect to the study schedule, the last of 4752 patients from 79 sites in 19 countries were randomised in November 2011 to cardiac surgery performed with an on-pump or off-pump procedure. The authors will use regression models to compare the groups in the outcome of peri-operative AKI (per cent change in serum creatinine, ≥50% increase in serum creatinine) and 1-year kidney function (per cent change in estimated glomerular filtration rate (eGFR), ≥20% eGFR loss 1 year after surgery). The authors will use interaction terms in regression models to determine if there is a differential impact of the intervention in those with and without pre-existing chronic kidney disease. The authors will use regression-based tests to determine the proportion of the total effect of surgery type (off-pump vs on-pump CABG) on 1-year eGFR that is mediated by peri-operative AKI.
Ethics and dissemination
In the year 2009, the authors were competitively awarded a grant from the Canadian Institutes of Health Research to answer these kidney questions in CORONARY. Ethics approval was obtained for additional renal data collection in centres that agreed to study participation (>90% of participating centres). This collection began for patients enrolled after 1 January 2010. Remaining 1-year renal outcome data will be collected throughout 2012. Results will be reported in 2013.
Clinical trial registration number
CORONARY is a large international randomised controlled trial comparing coronary artery bypass graft (CABG) surgery done with and without a bypass pump.
Compared with on-pump, off-pump surgery may prevent AKI in the short term and may better preserve kidney function 1 year after surgery.
Secondary analyses may also clarify whether effects are similar in patients with and without pre-operative chronic kidney disease and whether AKI avoidance mediates preserved 1-year kidney function.
Presented is this pre-specified CORONARY kidney substudy analytic protocol.
Data collection and analysis will be completed in 2013.
Understanding the degree to which avoiding AKI preserves longer term kidney function has broader implications for the acceptability of side effects and costs of interventions which prevent AKI.
Strengths and limitations of this study
This will be largest AKI prevention trial conducted to date.
It will be one of the first trials to consider the impact of a peri-operative intervention on longer term kidney function.
International recruitment across 19 countries will provide generalisable estimates of the treatment effect.
Numerous biomedical software applications access databases maintained by the US National Center for Biotechnology Information (NCBI). To ease software automation, NCBI provides a powerful but complex Web-service-based programming interface, eUtils. This paper describes a toolset that simplifies eUtils use through a graphical front-end that can be used by non-programmers to construct data-extraction pipelines. The front-end relies on a code library that provides high-level wrappers around eUtils functions, and which is distributed as open-source, allowing customization and enhancement by individuals with programming skills.
We initially created an application that queried eUtils to retrieve nephrology-specific biomedical literature citations for a user-definable set of genes. We later augmented the application code to create a general-purpose library that accesses eUtils capability as individual functions that could be combined into user-defined pipelines.
The toolset’s use is illustrated with an application that serves as a front-end to the library and can be used by non-programmers to construct user-defined pipelines. The operation of the library is illustrated for the literature-surveillance application, which serves as a case-study. An overview of the library is also provided.
The library simplifies use of the eUtils service by operating at a higher level, and also transparently addresses robustness issues that would need to be individually implemented otherwise, such as error recovery and prevention of overloading of the eUtils service.
Entrez Programming Utilities; Proteomics Analysis; Pubmed filters
In this multicenter, prospective study of 288 children (half under 2 years of age) undergoing cardiac surgery, we evaluated whether the measurement of pre- and postoperative serum cystatin C (CysC) improves the prediction of acute kidney injury (AKI) over that obtained by serum creatinine (SCr). Higher preoperative SCr-based estimated glomerular filtration rates predicted higher risk of the postoperative primary outcomes of stage 1 and 2 AKI (adjusted odds ratios (ORs) 1.5 and 1.9, respectively). Preoperative CysC was not associated with AKI. The highest quintile of postoperative (within 6 h) CysC predicted stage 1 and 2 AKI (adjusted ORs of 6 and 17.2, respectively). The highest tertile of percent change in CysC independently predicted AKI, whereas the highest tertile of SCr predicted stage 1 but not stage 2 AKI. Postoperative CysC levels independently predicted longer duration of ventilation and intensive care unit length of stay, whereas the postoperative SCr change only predicted longer intensive care unit stay. Thus, postoperative serum CysC is useful to risk-stratify patients for AKI treatment trials. More research, however, is needed to understand the relation between preoperative renal function and the risk of AKI.
acute renal failure; cardiovascular; creatinine; epidemiology and outcomes; renal function
It is crucial to carefully screen donors and essential to resist compromises. If this is respected the survival, the co-morbidity, ESRD or even acute renal failure, as shown by Lam et al. in the current issue of this journal, appear to be similar to those in the general population.
Reduced kidney function confers a higher risk of acute kidney injury at the time of an inciting event, such as sepsis. Whether the same is true in those with reduced renal mass from living kidney donation is unknown.
We conducted a population-based matched cohort study of all living kidney donors in the province of Ontario, Canada who underwent donor nephrectomy from 1992 to 2009. We manually reviewed the medical records of these living kidney donors and linked this information to provincial health care databases. Non-donors were selected from the healthiest segment of the general population.
There were 2027 donors and 20 270 matched non-donors. The median age was 43 years (interquartile range 34–50) and individuals were followed for a median of 6.6 years (maximum 17.7 years). The primary outcome was acute dialysis during any hospital stay. Reasons for hospitalization included infectious diseases, cardiovascular diseases and hematological malignancies. Only one donor received acute dialysis in follow-up (6.5 events per 100 000 person-years), a rate which was statistically no different than 14 non-donors (9.4 events per 100 000 person-years).
These results are reassuring for the practice of living kidney donation. Longer follow-up of this and other donor cohorts will provide more precise estimates about this risk.
acute kidney injury; administrative health database; dialysis; living kidney donors
Serum creatinine is a delayed marker of acute kidney injury (AKI). Our purpose was to discover and validate novel early urinary biomarkers of AKI after cardiac surgery.
Diagnostic test study.
Setting & Participants
Children undergoing cardiopulmonary bypass surgery. The test set included 15 subjects with AKI and 15 matched controls (median age 1.5 years) among 45 subjects without AKI. The validation set included 365 children (median age 1.9 years).
Biomarkers identified by proteomic profiling: α1-microglobulin, α1-acid glycoprotein, and albumin.
AKI, defined as a 50% or greater increase in serum creatinine from baseline within three days of surgery.
Proteomic profiling by SELDI-TOF MS revealed three protein peaks that consistently appeared within 2 hours in children who developed AKI after cardiopulmonary bypass surgery. The proteins were identified as α1-microglobulin, α1-acid glycoprotein, and albumin. Using clinical assays, the results were confirmed in a test set and validated in an independent prospective cohort. In the validation set, 135 (37%) developed AKI, in whom there was a progressive increase in urinary biomarker concentrations with severity of AKI. The area under the curve (AUC) for urinary α1-microglobulin, α1-acid glycoprotein, and albumin at 6 hours after cardiac surgery were 0.84 (CI 0.79–0.89), 0.87 (CI 0.83–0.91), and 0.76 (CI 0.71–0.81) respectively. Subjects with increasing quartiles of biomarkers demonstrated increasing length of hospital stay and duration of AKI (P<0.001).
Single center study of children with normal kidney function at recruitment. The SELDI-TOF MS technique has limited sensitivity for the detection of proteins above the 20 kDa range.
Urinary α1-microglobulin, α1-acid glycoprotein, and albumin represent early, accurate, inexpensive and widely available biomarkers of AKI after cardiac surgery. They also offer prognostic information on duration of AKI and length of hospitalization after cardiac surgery.
Large multi-center clinical studies often involve the collection and analysis of biological samples. It is necessary to ensure timely, complete and accurate recording of analytical results and associated phenotypic and clinical information. The TRIBE-AKI Consortium http://www.yale.edu/tribeaki supports a network of multiple related studies and sample biorepository, thus allowing researchers to take advantage of a larger specimen collection than they might have at an individual institution.
We describe a biospecimen data management system (BDMS) that supports TRIBE-AKI and is intended for multi-center collaborative clinical studies that involve shipment of biospecimens between sites. This system works in conjunction with a clinical research information system (CRIS) that stores the clinical data associated with the biospecimens, along with other patient-related parameters. Inter-operation between the two systems is mediated by an interactively invoked suite of Web Services, as well as by batch code. We discuss various challenges involved in integration.
Our experience indicates that an approach that emphasizes inter-operability is reasonably optimal in allowing each system to be utilized for the tasks for which it is best suited.
Biospecimen data management; clinical research information systems; multi-center clinical studies; biorepositories
Acute kidney injury (AKI) is common in patients undergoing cardiac surgery and is associated with a high rate of death, long-term sequelae and healthcare costs. We conducted a systematic review of randomized controlled trials for strategies to prevent or treat AKI in cardiac surgery.
We screened Medline, Scopus, Cochrane Renal Library, and Google Scholar for randomized controlled trails in cardiac surgery for prevention or treatment of AKI in adults.
We identified 70 studies that contained a total of 5,554 participants published until November 2008. Most studies were small in sample size, were single-center, focused on preventive strategies, and displayed wide variation in AKI definitions. Only 26% were assessed to be of high quality according to the Jadad criteria. The types of strategies with possible protective efficacy were dopaminergic agents, vasodilators, anti-inflammatory agents, and pump/perfusion strategies. When analyzed separately, dopamine and N-acetylcysteine did not reduce the risk for AKI.
This summary of all the literature on prevention and treatment strategies for AKI in cardiac surgery highlights the need for better information. The results advocate large, good-quality, multicenter studies to determine whether promising interventions reliably reduce rates of acute renal replacement therapy and mortality in the cardiac surgery setting.
Acute kidney injury, prevention; Cardiac surgery; Healthcare costs
Acute kidney injury (AKI) is primarily defined and staged according to the magnitude of rise in serum creatinine. We sought to determine if another dimension of AKI, duration, adds additional prognostic information above magnitude alone. We prospectively studied 35,302 diabetic patients from 123 Veterans Affairs Medical Centers undergoing their first non-cardiac surgery between 2000 and 2004. The main outcome was long-term mortality in those that survived the index hospitalization. The exposure, AKI, was stratified by magnitude according to the AKI Network (AKIN) stages (stages 1, 2 and 3), and by duration (short [≤2 days], medium [3-6 days], long [≥ 7 days]). Overall, 17.8% of the patients experienced at least stage 1 AKI or greater after surgery. Both the magnitude and duration of AKI were associated with long-term survival in a dose-dependent manner (p < 0.001 for both). Within each AKIN stage, longer duration of AKI was associated with a graded higher rate of mortality (p < 0.001 for each stratum). However, within each of the categories of AKI duration, the AKIN stage was not associated was mortality. When considered separately in multivariate analyses, both a higher AKIN stage and duration were independently associated with increased risk of long-term mortality. In conclusion, duration of AKI adds additional information to predict long-term mortality in patients with AKI.