Emil P. Paganini

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.)

A Clinical Score to Predict Acute Renal Failure after Cardiac Surgery

The risk of mortality associated with acute renal failure (ARF) after open-heart surgery continues to be distressingly high. Accurate prediction of ARF provides an opportunity to develop strategies for early diagnosis and treatment. The aim of this study was to develop a clinical score to predict postoperative ARF by incorporating the effect of all of its major risk factors. A total of 33,217 patients underwent open-heart surgery at the Cleveland Clinic Foundation (1993 to 2002). The primary outcome was ARF that required dialysis. The scoring model was developed in a randomly selected test set (n = 15,838) and was validated on the remaining patients. Its predictive accuracy was compared by area under the receiver operating characteristic curve. The score ranges between 0 and 17 points. The ARF frequency at each score level in the validation set fell within the 95% confidence intervals (CI) of the corresponding frequency in the test set. Four risk categories of increasing severity (scores 0 to 2, 3 to 5, 6 to 8, and 9 to 13) were formed arbitrarily. The frequency of ARF across these categories in the test set ranged between 0.5 and 22.1%. The score was also valid in predicting ARF across all risk categories. The area under the receiver operating characteristic curve for the score in the test set was 0.81 (95% CI 0.78 to 0.83) and was similar to that in the validation set (0.82; 95% CI 0.80 to 0.85; P = 0.39). In conclusion, a score is valid and accurate in predicting ARF after open-heart surgery; along with increasing its clinical utility, the score can help in planning future clinical trials of ARF.

Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury

Fluid accumulation is associated with adverse outcomes in critically ill patients. Here, we sought to determine if fluid accumulation is associated with mortality and non-recovery of kidney function in critically ill adults with acute kidney injury. Fluid overload was defined as more than a 10% increase in body weight relative to baseline, measured in 618 patients enrolled in a prospective multicenter observational study. Patients with fluid overload experienced significantly higher mortality within 60 days of enrollment. Among dialyzed patients, survivors had significantly lower fluid accumulation when dialysis was initiated compared to non-survivors after adjustments for dialysis modality and severity score. The adjusted odds ratio for death associated with fluid overload at dialysis initiation was 2.07. In non-dialyzed patients, survivors had significantly less fluid accumulation at the peak of their serum creatinine. Fluid overload at the time of diagnosis of acute kidney injury was not associated with recovery of kidney function. However, patients with fluid overload when their serum creatinine reached its peak were significantly less likely to recover kidney function. Our study shows that in patients with acute kidney injury, fluid overload was independently associated with mortality. Whether the fluid overload was the result of a more severe renal failure or it contributed to its cause will require clinical trials in which the role of fluid administration to such patients is directly tested.

Timing of Initiation of Dialysis in Critically Ill Patients with Acute Kidney Injury

Among critically ill patients, acute kidney injury (AKI) is a relatively common complication that is associated with an increased risk for death and other complications. To date, no treatment has been developed to prevent or attenuate established AKI. Dialysis often is required, but the optimal timing of initiation of dialysis is unknown. Data from the Program to Improve Care in Acute Renal Disease (PICARD), a multicenter observational study of AKI, were analyzed. Among 243 patients who did not have chronic kidney disease and who required dialysis for severe AKI, we examined the risk for death within 60 d from the diagnosis of AKI by the blood urea nitrogen (BUN) concentration at the start of dialysis (BUN < or = 76 mg/dl in the low degree of azotemia group [n = 122] versus BUN > 76 mg/dl in the high degree of azotemia group [n = 121]). Standard Kaplan-Meier product limit estimates, proportional hazards (Cox) regression methods, and a propensity score approach were used to account for selection effects. Crude survival rates were slightly lower for patients who started dialysis at higher BUN concentrations, despite a lesser burden of organ system failure. Adjusted for age, hepatic failure, sepsis, thrombocytopenia, and serum creatinine and stratified by site and initial dialysis modality, the relative risk for death that was associated with initiation of dialysis at a higher BUN was 1.85 (95% confidence interval 1.16 to 2.96). Further adjustment for the propensity score did not materially alter the association (relative risk 1.97; 95% confidence interval 1.21 to 3.20). Among critically ill patients with AKI, initiation of dialysis at higher BUN concentrations was associated with an increased risk for death. Although the results could reflect residual confounding by severity of illness, they provide a rationale for prospective testing of alternative dialysis initiation strategies in critically ill patients with severe AKI.

Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function?

OBJECTIVES This study sought to determine whether changes in intra-abdominal pressure (IAP) with aggressive diuretic or vasodilator therapy are associated with improvement in renal function in acute decompensated heart failure (ADHF). BACKGROUND Elevated IAP (>or=8 mm Hg) is associated with intra-abdominal organ dysfunction. There is potential for ascites and visceral edema causing elevated IAP in patients with ADHF. METHODS Forty consecutive patients admitted to a specialized heart failure intensive care unit for management of ADHF with intensive medical therapy were studied. The IAP was measured using a simple transvesical technique at time of admission and before removal of the pulmonary artery catheter. RESULTS In our study cohort (mean age 59 +/- 13 years, mean left ventricular ejection fraction 19 +/- 9%, baseline serum creatinine 2.0 +/- 0.9 mg/dl), the mean baseline IAP was 8 +/- 4 mm Hg, with 24 (60%) patients having elevated IAP. Elevated IAP was associated with worse renal function (p = 0.009). Intensive medical therapy resulted in improvement in both hemodynamic measurements and IAP. A strong correlation (r = 0.77, p < 0.001) was observed between reduction in IAP and improved renal function in patients with baseline elevated IAP. However, changes in IAP or renal function did not correlate with changes in any hemodynamic variable. CONCLUSIONS Elevated IAP is prevalent in patients with ADHF and is associated with impaired renal function. In the setting of intensive medical therapy for ADHF, changes in IAP were better correlated with changes in renal function than any hemodynamic variable.

Fluid accumulation, recognition and staging of acute kidney injury in critically-ill patients

IntroductionSerum creatinine concentration (sCr) is the marker used for diagnosing and staging acute kidney injury (AKI) in the RIFLE and AKIN classification systems, but is influenced by several factors including its volume of distribution. We evaluated the effect of fluid accumulation on sCr to estimate severity of AKI.MethodsIn 253 patients recruited from a prospective observational study of critically-ill patients with AKI, we calculated cumulative fluid balance and computed a fluid-adjusted sCr concentration reflecting the effect of volume of distribution during the development phase of AKI. The time to reach a relative 50% increase from the reference sCr using the crude and adjusted sCr was compared. We defined late recognition to estimate severity of AKI when this time interval to reach 50% relative increase between the crude and adjusted sCr exceeded 24 hours.ResultsThe median cumulative fluid balance increased from 2.7 liters on day 2 to 6.5 liters on day 7. The difference between adjusted and crude sCr was significantly higher at each time point and progressively increased from a median difference of 0.09 mg/dL to 0.65 mg/dL after six days. Sixty-four (25%) patients met criteria for a late recognition to estimate severity progression of AKI. This group of patients had a lower urine output and a higher daily and cumulative fluid balance during the development phase of AKI. They were more likely to need dialysis but showed no difference in mortality compared to patients who did not meet the criteria for late recognition of severity progression.ConclusionsIn critically-ill patients, the dilution of sCr by fluid accumulation may lead to underestimation of the severity of AKI and increases the time required to identify a 50% relative increase in sCr. A simple formula to correct sCr for fluid balance can improve staging of AKI and provide a better parameter for earlier recognition of severity progression.

Establishing a dialysis therapy/patient outcome link in intensive care unit acute dialysis for patients with acute renal failure

Abstract The aim of this study was to describe a relationship between intensive care unit (ICU) patient acuity, delivered dialysis dosing, and patient mortality from newly acquired acute renal failure (ARF) requiring dialytic support. A prospectively collected ICU ARF registry formed the basis for data comparison. All data was verified. Eight hundred forty-four ICU patients were identified who met biochemical or clinical criteria of ARF and required first-time dialytic support. An acute dialysis scoring system was established using 23 independent variables identified with univariant analysis, and reduced to eight variables with multiple regression analysis in 512 patients. These eight variables were assigned a weighted score derived from their odds ratio, and the scoring system was than validated prospectively to either registry data not involved in the generation of the system (n = 148), or double-blinded score assignment at time of first dialysis (n = 130). Several established scoring systems were also appliedto the database for external comparison. Dialysis dosing was analyzed using either direct dialysate quantification or blood side urea kinetics once appropriate formulae were identified from paired blood/dialysate results. Using our database and four published ARF acuity/predictive models (Lohr, Cioffi, Bullock, Acute Physiology and Chronic Health Evaluation [APACHEii]), outcome predictions were grossly inaccurate. Application of the Cleveland Clinic Foundation (CCF) ARF acuity score showed highly predictable outcomes when compared using the Lemeshow, Hosmer goodness-of-fit statistics, and highly reproducible results in both the prospective database and double-blinded prospective clinical trials. When comparing dialytic support techniques received (intermittent dialysis v continuous therapies), the CCF scoring system remained highly predictive of mortality. When one compares dose of delivered dialysis to patients with ARF in the ICU setting, there seems to be no effect on outcome at the two ends of the scoring system. Those with very low ( 15) CCF scores had survivals of 78% and 0%, respectively, regardless of the dose of dialysis. Patients with intermediate scores seemed to be the most effected by dialysis dose delivery, with higher delivery (>58% urea reduction ratio for intermittent hemodialysis; UREA ) for continuous renal replacement therapy [CRRT]) associated with a significant reduction in mortality when compared with the same CCF scoring quartile with low-dialysis dose delivery. While underlying patient comorbidity has a significant effect on survival in ARF, the dose of delivered dialysis also seems to play a major role in patients with moderated levels of severity. Methods that allow a higher delivered dialysis dose to this group of patients will be rewarded with improved patient outcome.

Efficacy and Safety of Renal Tubule Cell Therapy for Acute Renal Failure

The mortality rate for patients with acute renal failure (ARF) remains unacceptably high. Although dialysis removes waste products and corrects fluid imbalance, it does not perform the absorptive, metabolic, endocrine, and immunologic functions of normal renal tubule cells. The renal tubule assist device (RAD) is composed of a conventional hemofilter lined by monolayers of renal cells. For testing whether short-term (up to 72 h) treatment with the RAD would improve survival in patients with ARF compared with conventional continuous renal replacement therapy (CRRT), a Phase II, multicenter, randomized, controlled, open-label trial involving 58 patients who had ARF and required CRRT was performed. Forty patients received continuous venovenous hemofiltration + RAD, and 18 received CRRT alone. The primary efficacy end point was all-cause mortality at 28 d; additional end points included all-cause mortality at 90 and 180 d, time to recovery of renal function, time to intensive care unit and hospital discharge, and safety. At day 28, the mortality rate was 33% in the RAD group and 61% in the CRRT group. Kaplan-Meier analysis revealed that survival through day 180 was significantly improved in the RAD group, and Cox proportional hazards models suggested that the risk for death was approximately 50% of that observed in the CRRT-alone group. RAD therapy was also associated with more rapid recovery of kidney function, was well tolerated, and had the expected adverse event profile for critically ill patients with ARF.

ARF after open-heart surgery: Influence of gender and race.

BACKGROUND Both acute renal failure (ARF) and female sex are strongly associated with mortality after open-heart surgery. This study analyzes the effect of sex and race on the incidence of ARF after open-heart surgery and its influence on mortality. METHODS A total of 24,660 patients underwent open-heart surgery at the Cleveland Clinic Foundation (Cleveland, OH) from 1993 to 2000. The primary outcome was ARF defined as ARF requiring dialysis, 50% or greater decline in glomerular filtration rate (GFR) not requiring dialysis, or 50% or greater decline in GFR relative to baseline or requirement of dialysis. The secondary outcome was all-cause hospital mortality. RESULTS The overall frequency of ARF requiring dialysis after open-heart surgery was 1.82%. The frequency was greater in women (2.36%) than men (1.60%; P < 0.0001) and blacks (2.94%) than nonblacks (1.70%; P < 0.0001) by univariate analysis. By multivariate analysis, risk for ARF requiring dialysis in women was 1.61 (confidence interval [CI], 1.27 to 2.05; P < 0.0001), but race was not a risk factor. The overall postoperative mortality rate was 2.2%, and for patients with ARF requiring dialysis, it was 61.2% (women, 68.6% versus men, 56.5%; P = 0.01) with an odds ratio of 49.29, whereas in patients with ARF not requiring dialysis, it was 14.1% (women, 13.3% versus men 14.6%; P = 0.63) with an odds ratio of 7.18. CONCLUSION Female sex is an independent risk factor for developing ARF after open-heart surgery. The influence of race on risk for ARF is less clear. Regardless of its definition, ARF is strikingly associated with a high risk for mortality.

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.