Raghavan Murugan

Acute kidney injury: what’s the prognosis?

Acute kidney injury (AKI) is common (especially during critical illness), increasing in incidence, and is associated with considerable morbidity and mortality. The Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE) classification currently provides a standardized estimate of incidence and outcomes from AKI. Despite advances in the understanding of the pathogenesis of human AKI, our ability to assess kidney function is limited and functional impairment poorly correlates with structural injury to the kidneys. Emerging novel biomarkers are, however, likely to further enhance risk stratification, facilitate early diagnosis, enable early enrollment in therapeutic trials, and assess prognosis. Sepsis remains the leading cause of AKI among the critically ill and over the past few years insights into the pathogenesis of AKI in sepsis are beginning to shift attention from renal blood flow to inflammation-mediated organ injury. Emerging evidence suggests that survivors of AKI incur long-term risks for developing chronic kidney disease and end-stage renal disease compared with those without AKI. Despite decades of research, no specific therapy for AKI other than supportive care currently exists and further work is required to better understand the pathogenesis of AKI during critical illness and to develop novel treatments.

Acute kidney injury in non-severe pneumonia is associated with an increased immune response and lower survival

While sepsis is a leading cause of acute kidney injury in critically ill patients, the relationship between immune response and acute kidney injury in less severely ill patients with infection is not known. Here we studied the epidemiology, 1-year mortality, and immune response associated with acute kidney injury in 1836 hospitalized patients with community-acquired severe and non-severe pneumonia. Acute kidney injury developed in 631 patients of whom 329 had severe and 302 had non-severe sepsis. Depending on the subgroup classification, 16-25% of the patients with non-severe pneumonia also developed acute kidney injury. In general, patients with acute kidney injury were older, had more comorbidity, and had higher biomarker concentrations (interleukin-6, tumor necrosis factor, D-dimer) even among patients without severe sepsis. The risk of death associated with acute kidney injury varied when assessed by Grays survival model and after adjusting for differences in age, gender, ethnicity, and comorbidity. This risk was significantly higher immediately after hospitalization but gradually fell over time in the overall cohort and in those with non-severe pneumonia. A significantly higher risk of death (hazard ratio 1.29) was also present in those never admitted to an intensive care unit. Hence acute kidney injury is common even among patients with non-severe pneumonia and is associated with higher immune response and an increased risk of death.

Classifying AKI by Urine Output versus Serum Creatinine Level

Severity of AKI is determined by the magnitude of increase in serum creatinine level or decrease in urine output. However, patients manifesting both oliguria and azotemia and those in which these impairments are persistent are more likely to have worse disease. Thus, we investigated the relationship of AKI severity and duration across creatinine and urine output domains with the risk for RRT and likelihood of renal recovery and survival using a large, academic medical center database of critically ill patients. We analyzed electronic records from 32,045 patients treated between 2000 and 2008, of which 23,866 (74.5%) developed AKI. We classified patients by levels of serum creatinine and/or urine output according to Kidney Disease Improving Global Outcomes staging criteria for AKI. In-hospital mortality and RRT rates increased from 4.3% and 0%, respectively, for no AKI to 51.1% and 55.3%, respectively, when serum creatinine level and urine output both indicated stage 3 AKI. Both short- and long-term outcomes were worse when patients had any stage of AKI defined by both criteria. Duration of AKI was also a significant predictor of long-term outcomes irrespective of severity. We conclude that short- and long-term risk of death or RRT is greatest when patients meet both the serum creatinine level and urine output criteria for AKI and when these abnormalities persist.

Pathophysiology of Acute Kidney Injury: A New Perspective

Acute kidney injury (AKI) in critically ill patients is a devastating illness associated with prolonged hospital stay and high mortality. Limited progress has been made in the field of AKI, and its treatment using renal replacement therapy, at best, only provides partial renal support. Ischemia-reperfusion rodent AKI models do not resemble human renal injury and the absence of renal biopsy data limits our understanding of the pathophysiology of human AKI. However, laboratory and clinical evidence suggests that the inflammatory milieu leads to dysfunction of renal cells and this may be the key factor leading to AKI. Cells in injured tissues release immunological danger signals or danger-associated molecular pattern molecules which communicate with remote organs including the kidney, where they activate dendritic cells and T cells and thus initiate inflammation. Once the initial insult has passed, tubular epithelial cells undergo dedifferentiation, reacquire progenitorial ability to proliferate, migrate, and redifferentiate into mature intrinsic cells. Dissonance of mediator secretion and cell responses may lead to persistent injury and de novo chronic kidney disease. A number of soluble mediators including transforming growth factor-beta (TGF-beta) initiate a variety of pathophysiological processes at the beginning of kidney injury. TGF-beta also plays a fundamental role in cell proliferation and interstitial fibrosis in later phases. The renin-angiotensin-aldosterone system, especially angiotensin II, contributes to kidney injury through the angiotensin II type 1 receptor, TGF-beta receptor Smad and epidermal growth factor receptor by affecting general angiostasis and vascular remodeling, indirectly modulating inflammation and cell reactions. We review the pathophysiology of AKI in light of new information regarding renal injury and repair.

Plasma neutrophil gelatinase-associated lipocalin predicts recovery from acute kidney injury following community-acquired pneumonia

Although plasma neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker for early detection of acute kidney injury, its ability to predict recovery is unknown. Using RIFLE criteria to define kidney injury, we tested whether higher plasma NGAL concentrations on the first day of RIFLE-F would predict failure to recover in a post hoc analysis of a multicenter, prospective, cohort study of patients with community-acquired pneumonia. Recovery was defined as alive and not requiring renal replacement therapy during hospitalization or having a persistent RIFLE-F classification at hospital discharge. Median plasma NGAL concentrations were significantly lower among the 93 of 181 patients who recovered. Plasma NGAL alone predicted failure to recover with an area under the receiver operating characteristic curve of 0.74. A clinical model using age, serum creatinine, pneumonia severity, and nonrenal organ failure predicted failure to recover with area under the curve of 0.78. Combining this clinical model with plasma NGAL concentrations did not improve prediction. The reclassification of risk of renal recovery, however, significantly improved by 17% when plasma NGAL was combined with the clinical model. Thus, in this cohort of patients with pneumonia-induced severe acute kidney injury, plasma NGAL appears to be a useful biomarker for predicting renal recovery.

Blood Purification and Mortality in Sepsis: A Meta-analysis of Randomized Trials

Objectives:Although blood purification improves outcomes in animal studies of sepsis, results of clinical trials have been mixed. We conducted a systematic review and meta-analysis of randomized trials to determine the association between various blood purification techniques and all-cause mortality in humans with sepsis. Data Sources:We searched for relevant studies in MEDLINE, EMBASE, and the Cochrane Library database from January 1966 to May 2012. Study Selection:Inclusion required a diagnosis of sepsis and comparison of blood purification techniques including hemofiltration, hemoperfusion, plasma exchange, or hemodialysis with no blood purification (control group). Data Extraction:Two authors independently selected studies and extracted data. Summary statistics, risk ratios, and CIs were calculated using random-effects modeling. Study quality was assessed using Jadad score, and publication bias was assessed using funnel plots and Egger’s statistic. Data Synthesis:Overall, blood purification decreased mortality compared with no blood purification (35.7% vs 50.1%; risk ratio, 0.69 [95% CI, 0.56–0.84]; p < 0.001; 16 trials, n = 827). However, these results were driven mainly by hemoperfusion (risk ratio, 0.63 [95% CI, 0.50–0.80]; p < 0.001; 10 trials, n = 557) and plasma exchange (risk ratio, 0.63 [95% CI, 0.42–0.96]; p = 0.03; two trials, n = 128). Pooling of all trials of blood purification for treatment of sepsis was no longer associated with lower mortality (risk ratio, 0.89 [95% CI, 0.71–1.13]; p = 0.36; eight trials, n = 457) after excluding trials using polymyxin B hemoperfusion. Conclusions:Blood purification techniques including hemoperfusion, plasma exchange, and hemofiltration with hemoperfusion were associated with lower mortality in patients with sepsis. These results were mainly influenced by studies using polymyxin B hemoperfusion from Japan.

Increased plasma interleukin-6 in donors is associated with lower recipient hospital-free survival after cadaveric organ transplantation

Objectives:Brain death induces a massive inflammatory response. However, the influence of this inflammatory response on organ procurement, transplantation, and recipient outcome is unknown. We describe the inflammatory response characteristics in brain-dead organ donors and examine associations with organ transplantation and recipient survival. We test the hypothesis that increased inflammatory response is associated with fewer organs transplanted and decreased recipient survival. Design:Prospective, observational, cohort study. Setting:Two large intensive care units of tertiary care university hospitals in the United States. Patients:We recruited 30 consecutive brain-dead organ donors and 78 recipients between April 11, 2004, and November 23, 2004; recipients were followed through May 2005. Following declaration of brain death, we collected data on donor demographics, mechanism of brain death, number of organs procured and transplanted, and recipient characteristics. Plasma cytokines (tumor necrosis factor, interleukin-6, interleukin-10) were measured in donors at baseline following study enrollment, every hour for the first 4 hrs, and immediately before organ procurement for transplantation. Interventions:None. Measurements and Main Results:We examined the relationships among clinical characteristics, demographics, and cytokine response in donors and their influence on organ procurement and transplantation using multivariable regression and recipient’s 6-month hospital-free survival using a Cox proportional hazards regression. One hundred-eighteen organs were procured from 30 donors, and 91 (77%) were transplanted (mean of three organs transplanted per donor). All cytokines were increased following brain death. Older age in donors was significantly associated with lower number of organs transplanted (p < .001). Higher plasma interleukin-6 concentrations in donors before organ procurement was significantly associated with lower 6-month hospital-free survival in recipients (hazard ratio 1.77; 95% confidence interval, 1.17–2.69, p < .007). Conclusions:Among brain-dead organ donors, older age donors contribute fewer organs for transplantation, and increased donor interleukin-6 level before organ procurement is associated with lower recipient six-month hospital-free survival.

Angiotensin II for the Treatment of Vasodilatory Shock

Background Vasodilatory shock that does not respond to high‐dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. Methods We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 μg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. Results A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (‐1.75 vs. ‐1.28, P=0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P=0.12). Conclusions Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS‐3 ClinicalTrials.gov number, NCT02338843.)

Intensivist-Led Management of Brain-Dead Donors Is Associated with an Increase in Organ Recovery for Transplantation

The disparity between the number of patients in need of organ transplantation and the number of available organs is steadily rising. We hypothesized that intensivist‐led management of brain dead donors would increase the number of organs recovered for transplantation. We retrospectively analyzed data from all consented adult brain dead patients in the year before (n = 35) and after (n = 43) implementation of an intensivist‐led donor management program. Donor characteristics before and after implementation were similar. After implementation of the organ donor support team, the overall number of organs recovered for transplantation increased significantly (66 out of 210 potentially available organs vs. 113 out of 258 potentially available organs, p = 0.008). This was largely due to an increase in the number of lungs (8 out of 70 potentially available lungs vs. 21 out of 86 potentially available lungs; p = 0.039) and kidneys (31 out of 70 potentially available kidneys vs. 52 out of 86 potentially available kidneys; p = 0.044) recovered for transplantation. The number of hearts and livers recovered for transplantation did not change significantly. Institution of an intensivist‐led organ donor support team may be a new and viable strategy to increase the number of organs available for transplantations.

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.