Anitha Vijayan

Intensity of renal support in critically ill patients with acute kidney injury.

BACKGROUND The optimal intensity of renal-replacement therapy in critically ill patients with acute kidney injury is controversial. METHODS We randomly assigned critically ill patients with acute kidney injury and failure of at least one nonrenal organ or sepsis to receive intensive or less intensive renal-replacement therapy. The primary end point was death from any cause by day 60. In both study groups, hemodynamically stable patients underwent intermittent hemodialysis, and hemodynamically unstable patients underwent continuous venovenous hemodiafiltration or sustained low-efficiency dialysis. Patients receiving the intensive treatment strategy underwent intermittent hemodialysis and sustained low-efficiency dialysis six times per week and continuous venovenous hemodiafiltration at 35 ml per kilogram of body weight per hour; for patients receiving the less-intensive treatment strategy, the corresponding treatments were provided thrice weekly and at 20 ml per kilogram per hour. RESULTS Baseline characteristics of the 1124 patients in the two groups were similar. The rate of death from any cause by day 60 was 53.6% with intensive therapy and 51.5% with less-intensive therapy (odds ratio, 1.09; 95% confidence interval, 0.86 to 1.40; P=0.47). There was no significant difference between the two groups in the duration of renal-replacement therapy or the rate of recovery of kidney function or nonrenal organ failure. Hypotension during intermittent dialysis occurred in more patients randomly assigned to receive intensive therapy, although the frequency of hemodialysis sessions complicated by hypotension was similar in the two groups. CONCLUSIONS Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour. (ClinicalTrials.gov number, NCT00076219.)

Urinary Biomarkers and Renal Recovery in Critically Ill Patients with Renal Support

BACKGROUND AND OBJECTIVES Despite significant advances in the epidemiology of acute kidney injury (AKI), prognostication remains a major clinical challenge. Unfortunately, no reliable method to predict renal recovery exists. The discovery of biomarkers to aid in clinical risk prediction for recovery after AKI would represent a significant advance over current practice. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted the Biological Markers of Recovery for the Kidney study as an ancillary to the Acute Renal Failure Trial Network study. Urine samples were collected on days 1, 7, and 14 from 76 patients who developed AKI and received renal replacement therapy (RRT) in the intensive care unit. We explored whether levels of urinary neutrophil gelatinase-associated lipocalin (uNGAL), urinary hepatocyte growth factor (uHGF), urinary cystatin C (uCystatin C), IL-18, neutrophil gelatinase-associated lipocalin/matrix metalloproteinase-9, and urine creatinine could predict subsequent renal recovery. RESULTS We defined renal recovery as alive and free of dialysis at 60 days from the start of RRT. Patients who recovered had higher uCystatin C on day 1 (7.27 versus 6.60 ng/mg·creatinine) and lower uHGF on days 7 and 14 (2.97 versus 3.48 ng/mg·creatinine; 2.24 versus 3.40 ng/mg·creatinine). For predicting recovery, decreasing uNGAL and uHGF in the first 14 days was associated with greater odds of renal recovery. The most predictive model combined relative changes in biomarkers with clinical variables and resulted in an area under the receiver-operator characteristic curve of 0.94. CONCLUSIONS We showed that a panel of urine biomarkers can augment clinical risk prediction for recovery after AKI.

Altruistic living donors: evaluation for nondirected kidney or liver donation.

A program was established within our regional procurement organization to permit evaluation of altruistic living donors (LD) interested in nondirected kidney or liver segment donation prior to transplant center referral.

Insulin-like growth factor I improves renal function in patients with end-stage chronic renal failure.

There is no pharmacological treatment to increase the glomerular filtration rate in end-stage renal disease (ESRD). The administration of 100 μg/kg of insulin-like growth factor (IGF) I twice a day to patients with ESRD increases inulin clearance. However, its effect is short-lived and IGF-I has major side effects when given this way. To assess whether the use of a lower intermittent dose of IGF-I would effect sustained improved function with tolerable side effects we performed 1) a prospective open-labeled 24-day trial in which we enrolled five patients and 2) a 31-day randomized, double-blinded, placebo-controlled trial in which we enrolled 10 patients. Patients with ESRD [creatinine clearance of <15 ml ⋅ min-1 ⋅ (1.73 m2)-1] and scheduled to initiate renal replacement therapy received subcutaneous IGF-I, 50 μg ⋅ kg-1 ⋅ day-1, or vehicle. Treatment with IGF I resulted in significantly increased glomerular filtration rates (inulin clearances) during the 3rd and 4th wk of therapy in both prospective and double-blinded studies. Vehicle had no effect. No patient required discontinuation of drug secondary to side effects. We conclude that IGF-I effects sustained improvement of renal function (clearances comparable to those generally achieved by dialysis) in patients with ESRD and is well tolerated.There is no pharmacological treatment to increase the glomerular filtration rate in end-stage renal disease (ESRD). The administration of 100 microgram/kg of insulin-like growth factor (IGF) I twice a day to patients with ESRD increases inulin clearance. However, its effect is short-lived and IGF-I has major side effects when given this way. To assess whether the use of a lower intermittent dose of IGF-I would effect sustained improved function with tolerable side effects we performed 1) a prospective open-labeled 24-day trial in which we enrolled five patients and 2) a 31-day randomized, double-blinded, placebo-controlled trial in which we enrolled 10 patients. Patients with ESRD [creatinine clearance of <15 ml. min-1. (1.73 m2)-1] and scheduled to initiate renal replacement therapy received subcutaneous IGF-I, 50 microgram. kg-1. day-1, or vehicle. Treatment with IGF I resulted in significantly increased glomerular filtration rates (inulin clearances) during the 3rd and 4th wk of therapy in both prospective and double-blinded studies. Vehicle had no effect. No patient required discontinuation of drug secondary to side effects. We conclude that IGF-I effects sustained improvement of renal function (clearances comparable to those generally achieved by dialysis) in patients with ESRD and is well tolerated.

Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy

BACKGROUND Survivors of critical illness complicated by acute kidney injury requiring renal replacement therapy (RRT) are at an increased risk of dialysis dependence and death but the mechanisms are unknown. METHODS In a multicenter, prospective, cohort study of 817 critically ill patients receiving RRT, we examined association between Day 1 plasma inflammatory [interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-18; macrophage migration inhibitory factor (MIF) and tumor necrosis factor]; apoptosis [tumor necrosis factor receptor (TNFR)-I and TNFR-II and death receptor (DR)-5]; and growth factor (granulocyte macrophage colony stimulating factor) biomarkers and renal recovery and mortality at Day 60. Renal recovery was defined as alive and RRT independent. RESULTS Of 817 participants, 36.5% were RRT independent and 50.8% died. After adjusting for differences in demographics, comorbid conditions; premorbid creatinine; nephrotoxins; sepsis; oliguria; mechanical ventilation; RRT dosing; and severity of illness, increased concentrations of plasma IL-8 and IL-18 and TNFR-I were independently associated with slower renal recovery [adjusted hazard ratio (AHR) range for all markers, 0.70-0.87]. Higher concentrations of IL-6, IL-8, IL-10 and IL-18; MIF; TNFR-I and DR-5 were associated with mortality (AHR range, 1.16-1.47). In an analysis of multiple markers simultaneously, increased IL-8 [AHR, 0.80, 95% confidence interval (95% CI) 0.70-0.91, P < 0.001] and TNFR-I (AHR, 0.63, 95% CI 0.50-0.79, P < 0.001) were associated with slower recovery, and increased IL-8 (AHR, 1.26, 95% CI 1.14-1.39, P < 0.001); MIF (AHR, 1.18, 95% CI 1.08-1.28, P < 0.001) and TNFR-I (AHR, 1.26, 95% CI 1.02-1.56, P < 0.03) were associated with mortality. CONCLUSIONS Elevated plasma concentrations of inflammatory and apoptosis biomarkers are associated with RRT dependence and death. Our data suggest that future interventions should investigate broad-spectrum immune-modulation to improve outcomes.

Proximal tubule haptoglobin gene activation is an integral component of the acute kidney injury “stress response”

Haptoglobin (Hp) synthesis occurs almost exclusively in liver, and it is rapidly upregulated in response to stress. Because many of the pathways that initiate hepatic Hp synthesis are also operative during acute kidney injury (AKI), we tested whether AKI activates the renal cortical Hp gene. CD-1 mice were subjected to six diverse AKI models: ischemia-reperfusion, glycerol injection, cisplatin nephrotoxicity, myoglobinuria, endotoxemia, and bilateral ureteral obstruction. Renal cortical Hp gene induction was determined either 4-72 h or 1-3 wk later by measuring Hp mRNA and protein levels. Relative renal vs. hepatic Hp gene induction during endotoxemia was also assessed. Each form of AKI induced striking and sustained Hp mRNA increases, leading to ∼10- to 100-fold renal Hp protein elevations (ELISA; Western blot). Immunohistochemistry, and isolated proximal tubule assessments, indicated that the proximal tubule was the dominant (if not only) site of the renal Hp increases. Corresponding urinary and plasma Hp elevations were surrogate markers of this response. Endotoxemia evoked 25-fold greater Hp mRNA increases in kidney vs. liver, indicating marked renal Hp gene reactivity. Clinical relevance of these findings was suggested by observations that urine samples from 16 patients with established AKI had statistically higher (∼12×) urinary Hp levels than urine samples from either normal subjects or from 15 patients with chronic kidney disease. These AKI-associated urinary Hp increases mirrored those seen for urinary neutrophil gelatinase-associated lipoprotein, a well accepted AKI biomarker gene. In summary, these studies provide the first evidence that AKI evokes rapid, marked, and sustained induction of the proximal tubule Hp gene. Hps known antioxidant, as well as its protean pro- and anti-inflammatory, actions imply potentially diverse effects on the evolution of acute tubular injury.

Dosing of Renal Replacement Therapy in Acute Kidney Injury

The impact of the intensity of renal replacement therapy on outcomes in patients with acute kidney injury has been studied intensively during the past decade. In this review, we consider the concept of dose of renal replacement therapy in acute kidney injury and summarize the recent clinical trials addressing this topic. Although several single-center trials suggest that more intensive therapy is associated with improved outcomes, 2 large multicenter randomized trials do not find a benefit with higher doses of therapy. Based on these studies, we provide recommendations for the delivered intensity of renal replacement therapy in acute kidney injury.

Vascular access for continuous renal replacement therapy.

A working vascular access is essential for performing continuous renal replacement therapy (CRRT) efficiently and without interruption. Dual‐lumen temporary hemodialysis catheters are the catheters of choice, although tunneled catheters can also be utilized if therapy is expected to be prolonged. Hemodialysis catheters have to be inserted under ultrasound guidance by trained personnel, using aseptic conditions. The right internal jugular vein is the preferred site. Catheter malfunction and catheter‐related infections can be reduced by adhering to preventive guidelines such as ultrasound guidance for placement, strict hand hygiene, gauze dressings, and sterile techniques during catheter handling. Antibiotic or antiseptic‐coated catheters and lock solutions may be beneficial in certain patients, but these are not widely used due to the concern for resistant organisms and allergic reactions.

The Impact of Tax Policies on Living Organ Donations in the United States

In an effort to increase living organ donation, fifteen states passed tax deductions and one a tax credit to help defray potential medical, lodging and wage loss costs between 2004 and 2008. To assess the impact of these policies on living donation rates, we used a differences‐in‐differences strategy that compares the pre‐ and postlegislation change in living donations in states that passed legislation against the same change in those states that did not. We found no statistically significant effect of these tax policies on donation rates. Furthermore, we found no evidence of any lagged effects, differential impacts by gender, race or donor relationship, or impacts on deceased donation. Possible hypotheses to explain our findings are: the cash value of the tax deduction may be too low to defray costs faced by donors, lack of public awareness about the existence of these policies, and that states that were proactive enough to pass tax policy laws may have already depleted donor pools with previous interventions.

Biomarker Enhanced Risk Prediction for Adverse Outcomes in Critically Ill Patients Receiving RRT

BACKGROUND AND OBJECTIVES Higher plasma concentrations of inflammatory and apoptosis markers in critically ill patients receiving RRT are associated with RRT dependence and death. This study objective was to examine whether plasma inflammatory (IL-6, -8, -10, and -18; macrophage migration inhibitory factor) and apoptosis (death receptor-5, tumor necrosis factor receptor I and II) biomarkers augment risk prediction of renal recovery and mortality compared with clinical models. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Biologic Markers of Recovery for the Kidney study (n=817) was a prospective, nested, observational cohort study conducted as an ancillary to the Veterans Affairs/National Institutes of Health Acute renal failure Trial Network study, a randomized trial of intensive versus less intensive RRT in critically ill patients with AKI conducted between November 2003 and July 2007 at 27 Veterans Affairs- and university-affiliated centers. Primary outcomes of interest were renal recovery and mortality at day 60. RESULTS A parsimonious clinical model consisting of only four variables (age, mean arterial pressure, mechanical ventilation, and bilirubin) predicted renal recovery (area under the receiver-operating characteristic curve [AUROC], 0.73; 95% confidence interval [95% CI], 0.68 to 0.78) and mortality (AUROC, 0.74; 95% CI, 0.69 to 0.78). By contrast, individual biomarkers were only modestly predictive of renal recovery (AUROC range, 0.55-0.63) and mortality (AUROC range, 0.54-0.68). Adding plasma IL-8 to a parsimonious model augmented prediction of recovery (AUROC, 0.76; 95% CI, 0.71 to 0.81; P=0.04) and mortality (AUROC, 0.78; 95% CI, 0.73 to 0.82; P<0.01) compared with the clinical model alone. CONCLUSIONS This study suggests that a simple four-variable clinical model with plasma IL-8 had predictive value for renal recovery and mortality. These findings require external validation but could easily be used by clinicians.