Efficacy and Safety of Renal Tubule Cell Therapy for Acute Renal Failure
James Tumlin*,
Ravinder Wali,
Winfred Williams,
Patrick Murray,
Ashita J. Tolwani||,
Anna K. Vinnikova¶,
Harold M. Szerlip**,
Jiuming Ye,
Emil P. Paganini,
Lance Dworkin,
Kevin W. Finkel||||,
Michael A. Kraus¶¶ and
H. David Humes***
* Southeast Renal Associates/Presbyterian Hospital, Charlotte, North Carolina; Department of Medicine, University of Maryland, Baltimore, Maryland; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, University of Chicago, Chicago, Illinois; || Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; ¶ Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia; ** Department of Medicine, Medical College of Georgia, Augusta, Georgia; Western New England Renal and Transplant Associates, Springfield, Massachusetts; Department of Nephrology and Hypertension, Cleveland Clinic Foundation, Cleveland, Ohio; Rhode Island Hospital, Providence, Rhode Island; |||| Department of Internal Medicine, University of Texas, Houston, Texas; ¶¶ Department of Medicine, Indiana University, Indianapolis, Indiana; and *** Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
Correspondence: Dr. H. David Humes, Division of Nephrology, Department of Internal Medicine, 4520 MSRB I, SPC 5651, 1150 W. Medical Center Drive, Ann Arbor, MI 48109. Phone: 734-647-8018; Fax: 734-763-4851; E-mail: dhumes{at}med.umich.edu
Received for publication August 14, 2007.
Accepted for publication December 12, 2007.
The mortality rate for patients with acute renal failure (ARF)remains unacceptably high. Although dialysis removes waste productsand corrects fluid imbalance, it does not perform the absorptive,metabolic, endocrine, and immunologic functions of normal renaltubule cells. The renal tubule assist device (RAD) is composedof a conventional hemofilter lined by monolayers of renal cells.For testing whether short-term (up to 72 h) treatment with theRAD would improve survival in patients with ARF compared withconventional continuous renal replacement therapy (CRRT), aPhase II, multicenter, randomized, controlled, open-label trialinvolving 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 endpoint was all-cause mortality at 28 d; additional end pointsincluded all-cause mortality at 90 and 180 d, time to recoveryof renal function, time to intensive care unit and hospitaldischarge, and safety. At day 28, the mortality rate was 33%in the RAD group and 61% in the CRRT group. Kaplan-Meier analysisrevealed that survival through day 180 was significantly improvedin the RAD group, and Cox proportional hazards models suggestedthat the risk for death was approximately 50% of that observedin the CRRT-alone group. RAD therapy was also associated withmore rapid recovery of kidney function, was well tolerated,and had the expected adverse event profile for critically illpatients with ARF.
Acute renal failure (ARF) arising from acute kidney injury (AKI)and acute tubular necrosis (ATN) secondary to nephrotoxic and/orischemic renal tubule cell injury commonly results in a cascadeof events culminating in multiorgan failure and death. Mortalityrates from AKI requiring renal replacement therapy range from50 to 70%.1,2 This high mortality rate has persisted over thepast several decades despite greater understanding of the pathophysiologyof the disorder and improvements in hemodialysis and hemofiltrationtherapy.
The pathophysiology of this disease is initiated with injuryto the cellular elements of the kidney, predominantly the proximaltubule cells, leading to tubule cell necrosis and apoptosisand extensive microvascular abnormalities.3 This process evolvesinto intratubular obstruction, backleak of glomerular filtrate,and diminished peritubular capillary blood flow. When severeenough, renal failure evolves with diminished solute and waterexcretion and total organ failure. Current renal replacementtherapies substitute for this small solute and volume clearancefunction of the kidney but do not replace the lost reclamation,metabolic, and endocrine functions of this solid organ. Thesesynthetic functions reside in the cellular elements of the kidney.Furthermore, renal tubule cells may play an important immunoregulatoryrole in stressful clinical conditions. Accordingly, the additionof renal tubule cell therapy to continuous hemofiltration techniquesmay add more complete short-term renal replacement to allowthe natural regenerative recovery of the damaged kidney to normalfunction and improve the multiorgan dysfunction resulting inpoor outcomes in patients with AKI.4
An extracorporeal device has been fabricated with a standardhemofiltration cartridge containing approximately 0.5 to 1.0x 108 nonautologous human renal tubule cells grown along theinner surface of the hollow fibers of the device.5,6 The nonbiodegradabilityand pore size of the hollow fibers allow the synthetic membranesto act as both a scaffold and an immunoprotective barrier forthe cells. Preclinical studies of this renal tubule cell assistdevice (RAD) to provide renal cell therapy have demonstratedthat these cells retain transport, metabolic, and endocrinologicactivities.5 When the RAD is incorporated in series with a separatehemofiltration cartridge in an extracorporeal perfusion circuit,the two cartridge system replaces filtration, transport, metabolic,and endocrine functions in acutely uremic animals7 and amelioratesmultiorgan dysfunction in Gram-negative septic shock in large-animalmodels.8,9 In an open-label Phase I/II human clinical trialat two clinical sites, the addition of human renal tubule celltherapy to continuous venovenous hemofiltration (CVVH) in 10severely ill intensive care unit (ICU) patients with AKI andmultiorgan failure demonstrated that the RAD was safely administeredfor up to 24 h. Importantly, acute physiologic improvementsin several organ systems were temporally related to RAD andimproved 30-d survival compared with predicted mortality fromICU scoring systems in these patients.10 We therefore evaluatedwhether addition of the RAD would reduce all-cause mortalityat 28 d and later time points in ICU patients who had AKI andrequired continuous renal replacement therapy (CRRT) and whetherthe RAD has an acceptable safety profile during a treatmentperiod up to 72 h.
Patient Disposition, Demographics, and Baseline Assessments
Fifty-eight patients were randomly assigned to the study, 40to receive the RAD and 18 to receive CRRT alone. One patientwho was randomly assigned to the RAD group died after randomizationbut before the addition of the RAD to the CVVH circuit. A totalof 25 of the 58 patients completed the study as planned, 31patients died before day 180, and two patients withdrew prematurelyfrom the study (one patient in each treatment group). A higherproportion of patients in the RAD group completed the study(21 [53%] of 40) compared with patients who received CRRT alone(four [22%] of 18).
As detailed in Table 1, with the exception of a trend towarda greater proportion of black patients in the RAD group, baselinedemographics and clinical characteristics were similar. Themajority of patients in both treatment groups were male (73and 72% in the RAD and CRRT-alone groups, respectively). Meanage was 61 yr in the RAD group and 64 yr in the CRRT-alone group.The majority of patients in both treatment groups were white(58 and 89% in the RAD and CRRT-alone groups, respectively);the RAD group was composed of 38% black patients compared with11% in the CRRT-alone group (P = 0.071). Mean sepsis-relatedorgan failure assessment (SOFA) score at screening was 12.4in the RAD group and 11.5 in the CRRT-alone group (range 5 to19). Mean SOFA renal organ dysfunction subscores were 2.9 and2.7 in the RAD and CRRT groups, respectively. Acute physiologyand chronic health evaluation II (APACHE II)scores11 were slightlyhigher in the CRRT-alone group. Key clinical laboratory valueswere also similar between the two groups, including blood counts,electrolytes, blood urea nitrogen, creatinine, and albumin (datanot shown). The acuity of illness upon study entry of the patientsenrolled in the RAD and CRRT-alone groups is detailed in Table 2.By most parameters, the RAD group had a higher degree of diseaseseverity and multiorgan failure than the CRRT-alone group (butno significant differences).
Table 2. Disease severity upon study entry (screening)a
RAD Integrity and Performance
Median time to initiation of RAD therapy was 21.2 h (time ofrandomization to inclusion of the RAD in the CVVH circuit) witha range of 15.4 to 37.4 h. Median time on RAD therapy was 35.9h with a range of 1.8 to 72.1 h. Malfunction of the RAD cartridge(leakage) was reported in only 1 (2.5%) of the 40 patients.None of the RAD cartridges was reported to have excessive cellrelease, membrane leakage, or clinically significant hemolysis.
Ten patients were treated for the full 72 h. Seven patientswere discontinued before 72 h because of clinical improvement(21 to 68 h), whereas four patients were discontinued early(5 to 34 h) because of worsening clinical conditions. Two patientswho were randomly assigned to RAD were not treated because ofdeath before RAD integration into the blood circuit and incorrectinsertion of the RAD into the circuit, respectively. Two patientshad treatment terminated early because of vascular access problems(44 and 53 h). One RAD was disconnected prematurely becauseof leakage at one of the tubing connectors (57 h). The remaining14 patients were terminated early in the treatment regimen becauseof clotting (3 to 57 h). In the majority of cases, clottingthat resulted in early termination was due to initiation ofclot within the hemofiltration cartridge with extension intothe pre-RAD bloodline.
Efficacy
A summary of all-cause mortality at days 28, 90, and 180 isdisplayed in Table 3. By day 28, 33 of the 58 patients werealive, 24 patients had died, and one (RAD group) had withdrawnconsent. In the RAD group, 13 (33%) of the 39 patients had diedby day 28 compared with 11 (61%) of the 18 patients in the CRRT-alonegroup (P = 0.082). The absolute reduction in mortality observedin the RAD group was sustained at days 90 and 180. As determinedby Kaplan-Meier methods, survival through 180 d was significantlyimproved in the RAD group as compared with the CRRT-alone group(P = 0.034; Figure 1). The hazard ratio (HR) for death in theRAD group compared with the CRRT-alone group adjusted for diseasecause was 0.481 (95% confidence interval [CI] 0.23 to 0.99),indicating that the relative risk for death in the RAD groupwas approximately 50% of that observed in the CRRT-alone group.
Figure 1. Kaplan-Meier estimates of survival between patients in the RAD and conventional CRRT groups.
Renal Recovery
By day 28, 21 (53%) of the 40 patients in the RAD group hadrecovered renal function, 10 (25%) had died before recovery,eight (20%) remained on renal support, and one (3%) had withdrawnconsent. In the CRRT-alone group, a lower proportion of patientshad recovered renal function (five [28%] of 18) by day 28, ahigher proportion had died before recovery (nine [50%] of 18),and a similar proportion remained on renal support (four [22%]of 18) compared with the RAD group. The Kaplan-Meier plot oftime to renal recovery in the two groups is displayed in Figure 2.At day 180, only one (3%) patient in the RAD group and one (6%)patient in the CRRT-alone group were still on long-term dialysis.
Figure 2. Kaplan-Meier estimates of time to renal recovery in the RAD and CRRT-alone groups.
Patient Subgroup Analysis
Subgroup analyses, including severity of illness (SOFA and APACHEscores), number of organ failures (Table 4), and presence ofsepsis at study entry were evaluated. Consistently higher survivalrates at 28 d were observed in the RAD group compared with theCRRT-alone group, regardless of the number of organ failures.Of note, patients with five or more organ failures had a 60%mortality rate in the RAD group compared with a 100% rate inthe CRRT-alone group. The incidence of sepsis in the two groupswas high, at 73 and 67% in RAD and CRRT-alone groups, respectively.RAD therapy decreased the mortality rate in patients with sepsisfrom 67% in the CRRT-alone group to 34%. In this regard, theRAD was associated with a reduction in the risk for death comparedwith CRRT alone when analyzed by age, race, and baseline SOFAor APACHE II score (Table 5). Cox proportional hazards modelswere fit separately for patients with high and low values ofthe baseline illness severity scores APACHE II and SOFA. Thesemodels were unadjusted. For APACHE II 26 (n = 34), an HR ofRAD to CVVH alone of 0.47 (95% CI 0.20 to 1.10; P = 0.08) wasseen versus 0.58 (95% CI 0.14 to 2.33; P = 0.44) for APACHEII <26 (n = 24). Similarly, for SOFA 12 (n = 35), an HR of0.39 (95% CI 0.16 to 0.90; P = 0.03) was observed versus 0.45(95% CI 0.11 to 1.80; P = 0.26) in the SOFA <12 group (n= 23). Thus, it seems that treatment effects may be more pronouncedwith greater illness severity at baseline, although given thesmall sample sizes, the CI are overlapping.
Table 5. Cox HR: Risk for death by day 180 by patient subgroup (intention-to-treat population)
Safety Table 6 summarizes all severe adverse events (SAE) reportedin two or more patients in either treatment group. SAE werereported in 68% of patients (27 of 40) receiving the RAD andin 89% of patients (16 of 18) receiving CRRT alone. The reportedSAE were typical of a seriously ill patient population in theICU with ARF and receiving dialysis therapy. Only two of theSAE (hypoglycemia in one patient in the RAD group and supraventriculartachycardia in one patient in the CRRT-alone group) were consideredto be treatment related by the investigator.
In this randomized, multicenter trial, the addition of renaltubule cell therapy to CVVH treatment trended to reduce all-causemortality at 28 d in ICU patients with AKI. This primary endpoint of 28-d mortality, however, did not reach statisticalsignificance (P = 0.08). The cumulative survival benefit wasobserved over the 180 d of follow-up as a secondary end point,with a 50% reduction in mortality risk that was statisticallysignificant (P = 0.038). This treatment effect was observeddespite a heterogeneous spectrum of patients. A consistent survivalbenefit with cell therapy was observed in various subgroup analyses,including age, race, baseline disease severity (SOFA and APACHEII), number of organ failures, and the presence of sepsis. Ahigher percentage of patients from the RAD group demonstratedrenal recovery at 28 d compared with the CRRT control group.Thus, the primary effect of RAD therapy was to improve overallpatient survival and earlier renal recovery, which was associatedwith long-term survival benefit. Of note, a recent epidemiologicstudy has reported a lower in-hospital mortality rate in blackpatients with ARF and AKI than in white patients.12 The RADgroup had a higher number of black patients compared with theconventional CRRT group. This difference may have had an influencein the results.
The most common cause of early RAD treatment termination wasclotting of the hemofilter cartridge with extension into thepre-RAD bloodlines and into the RAD cartridge itself. The RADalso demonstrated integrity, with minor cell loss and functionalityin critically ill patients for up to 72 h of therapy.
Treatment with the RAD was well tolerated, and the adverse eventprofile was consistent with that expected for a seriously illpopulation with AKI. The most common clinically meaningful adverseevents observed during RAD treatment were hypotension, thrombocytopenia,and hypoglycemia. Hypotension most frequently occurred duringthe first few minutes of RAD treatment and was generally responsiveto standard therapy. The development of thrombocytopenia inpatients exposed to an extracorporeal circuit and heparin therapyis not uncommon, and, although a relationship to RAD treatmentcannot be excluded at this time, no significant clinical sequelaerelated to thrombocytopenia have been reported. Hypoglycemiahas been observed after insertion of the RAD into the extracorporealcircuit, which was attributed to nonspecific adsorption of insulinto the cartridge membrane from the culture medium, which wasthen released when the RAD was perfused.10 This issue has beenaddressed by instituting a flushing procedure before shipment,as well as instituting guidelines in the protocol for supplementalintravenous glucose administration and careful glucose monitoringduring the initial 24 h of RAD therapy.
The degree of impact of this therapeutic approach in this studyis compelling. The mortality rate of these patients has consistentlybeen in the range of 50 to 70% during the past four decadesdespite improvements in ICU care and advances in synthetic materialsand extracorporeal circuits.1,2 Hemodialysis and hemofiltrationinterventions have made an impact on preventing death from hyperkalemia,acidemia, uremia, and volume overload, but these patients continueto progress into a vicious spiral of events, including systemicinflammatory response syndrome, sepsis, cardiovascular collapse,ischemic damage to solid organs, and multiorgan failure anddeath.13,14 Dialysis dosage has not been consistently shownto have an impact on the mortality outcome of these types ofpatients. In fact, a lower small solute clearance would be expectedfrom use of the RAD, which re-processes effluent already clearedby CVVH and returns half of this volume to the circulation (Figure 3).No differences in serum blood urea nitrogen or creatinine valueswere observed during the first 3 d after randomization (datanot shown). The mechanism by which renal tubule cell therapyreverses this spiraling cascade of clinical events is unknown,although it is most likely multifactorial. The critical natureof renal tubule cells in the development of AKI is clearly recognized.Although the pathologic findings in this disorder are patchynecrosis and apoptosis of proximal renal epithelial cells, theoverall ability of renal epithelium during this disorder topromote paracrine and endocrine effects to alter immunologicand distant organ performance is limited not only because ofcell injury but also because of severe microvascular damageand reductions in tubular blood flow.3
Figure 3. Schematic of the extracorporeal perfusion circuit for renal cell therapy. Flow rates approximate those used clinically. The hemofilter perfusion PUMP system used the BBraun's (Bethlehem, PA) Diapact System; the RAD perfusion system used an Alaris (San Diego, CA) intravenous pump for the pre-RAD ultrafiltrate line and a Minntech (Minneapolis, MN) blood pump for the post-RAD blood line. Qb, blood flow; Qf, rate of fluid filtration.
Evaluation of a potential mechanism of action of renal tubulecell therapy has been directed toward an immunoregulatory roleof tubule cells in stressful clinical conditions. Preclinical8,9and initial clinical data10,15–17 have demonstrated analteration of this form of cell therapy on the systemic inflammatorycascade, which is activated by AKI. Further evaluation in ongoingclinical studies of the RAD will further test this possibilitybecause of the small number of patients in this study, especiallyin the control group. Of importance, a subsequent 53-patientPhase IIb bridging study was initiated to evaluate a commercialscale-up manufacturing process, use of citrate as a regionalanticoagulation process, and incorporating a blinded sham non–cell-containingcartridge into the study design. This follow-up clinical studywas discontinued after an interim analysis projected that completingthe study would not meet its efficacy goal. Preliminary analysisof the clinical data suggested that the multiple changes incorporatedinto this more recent Phase IIb clinical study influenced thenegative results. At least two changes are being further evaluatedand followed up with additional preclinical studies. As thesedata develop to a conclusion, we plan to publish the resultsof these further analyses.
Despite the critical nature and life-threatening illnesses ofthe patients enrolled in this clinical study, the addition ofrenal tubule cell therapy to CVVH resulted in a substantiveclinical impact on survival compared with a conventional CRRTgroup. RAD treatment for up to 72 h promoted a statisticallysignificant survival advantage over 180 d of follow-up in ICUpatients with AKI and demonstrated an acceptable safety profile.Ultimately, a pivotal Phase III randomized, multicenter trialis required to evaluate further this new therapeutic approachfor this disorder with an unacceptably high mortality rate.
Patients
From March 2004 through December 2005, this prospective, randomized,controlled, open-label, clinical trial was conducted at 12 medicalcenters in the United States. The study was carried out undera corporate-sponsored (RenaMed Biologics, Inc., Lincoln, RI)Investigational New Drug application in accordance with theDeclaration of Helsinki and good clinical practice. The institutionalreview board at each medical center approved the protocol, alongwith the Cleveland Clinic institutional review board as a coordinatingreview group. Written informed consent was obtained from allparticipants or their authorized representatives. A centralizedtelephone randomization system was established with 24-h availability.
Enrollment Criteria
Adult male and female (nonpregnant) patients who were aged 18to 80 yr and required CRRT for the treatment of ARF secondaryto ATN in an ICU setting were enrolled in the study. ATN wasdefined as acute renal failure occurring in a setting of acuteischemic or nephrotoxic injury and oliguria (<20 ml/h) for>24 h or an increase in serum creatinine concentration 2mg/dl (1.5 mg/dl in women) during a period of 4 d. Patientswere required to have received CRRT for a minimum of 4 h butnot longer than 48 h before randomization. Eligible patientswere also required to have at least one nonrenal organ failure(modified SOFA score 2) or presence of sepsis as defined byBone et al.18,19 Exclusion criteria were irreversible braindamage, presence of organ transplant, preexisting chronic renalinsufficiency (baseline serum creatinine 3.0 mg/dl for men or2.5 mg/dl for women), chronic immunosuppression, Xigris therapyat time of randomization, nonpregnancy status, and do-not-resuscitatestatus. Before randomization, each patient was reviewed by theRenaMed Biologics, Inc., Medical Monitor to confirm study eligibility.
Treatment Assignment
Patients were randomly assigned (2:1) to receive CVVH plus RADor CRRT consisting of CVVH, continuous venovenous hemodialysis,or continuous venovenous hemodiafiltration (control). Patientswere categorized at randomization into one of five classificationson the basis of the likely cause of AKI: (1) postvascular surgery,(2) postcardiac surgery, (3) chronic liver disease, (4) infectionor trauma, or (5) other. Randomization was accomplished froma central source and was stratified by ATN classification andby site so that treatment balance was maintained within strataand within site, using an institution-balancing algorithm.20Because the number of patients per site and per stratum wassmall, true randomization concealment may not have been achievedand needs to be considered as a limitation in this trial. ConventionalCRRT in the control group was determined by the clinical teamaccording to patient need and conventional CRRT protocols usedat each specific clinical site.
All hemofilters contained noncellulose biocompatible membranes.A new hemofilter was placed into the circuit at the time ofrandomization and replaced with a new cartridge according toinstitutional policy. For patients who were randomly assignedto control therapy (CVVH, continuous venovenous hemodialysis,or continuous venovenous hemodiafiltration), the effluent ratewas 2 L/h (i.e., replacement fluid plus dialysate). The CVVH+ RAD group received hemofiltration at a rate 2 L/h with a pre-RADultrafiltrate (UF) flow rate of 900 ± 50 ml/h and a post-RADUF rate of 50 ± 5% of the pre-RAD UF rate. The recommendedCRRT blood flow rate for both treatment groups was 200 ml/min.The extracorporeal circuit for CVVH + RAD is schematized inFigure 3. Because of the time required to prepare and ship theRAD to a clinical site from the manufacturing and storage site(Walkersville, MD, or Lincoln, RI), there was an inherent delaybetween randomization and initiation of RAD therapy (8 to 28h). The manufacture and storage of RAD have been detailed inprevious publications.10 Only one RAD was used for each patient.Reasons for early termination from RAD treatment were documented.Supportive care required for the treatment of these criticallyill patients (e.g., antibiotics, fluid balance, vasopressors,ventilatory support) was provided according to institutionalpolicy and recommendations of the treating physician(s).
Patient Evaluation
The primary objective of this study was to evaluate the impactof the RAD on all-cause mortality at day 28. Additional efficacyend points included 90- and 180-d all-cause mortality, recoveryof renal function (time on dialysis), time to ICU discharge,and time to hospital discharge.
Safety assessments included monitoring for adverse events, vitalsigns, and laboratory evaluations. In addition, RAD integrityand cell loss were assessed. An independent data monitoringcommittee, composed of three clinicians and a statistician,conducted unblinded safety and effectiveness assessments atperiodic intervals during the course of the trial.
Statistical Analyses
The primary efficacy end point was all-cause mortality 28 dafter randomization (intent-to-treat population). Statisticaldifferences between the two groups were evaluated at 28, 90,and 180 d after randomization with the exact Pearson 2 test.Kaplan-Meier methods were also used to assess differences insurvival between groups. The log-rank test statistic was computedto assess the overall differences through 180 d. Cox proportionalhazards models were used to identify risk factors. HR and corresponding95% CI were computed. The Cox model provided estimate of riskcompared with control for each Kaplan-Meier (180-d survival,time to renal recovery) as well as by patient subgroup: Agegreater or less than 65 yr, race, and SOFA and APACHE II scoresat study entry during screening period. Also, the variablesincluded in the Cox model were age, race, baseline APACHE IIscore, and baseline SOFA score.
Enrollment of at least 90 patients with 60 randomly assignedto CVVH + RAD and 30 assigned to conventional CRRT treatmentwas initially planned. This Phase II "screening" trial was basedon a three-category decision guideline: Whether the estimatedimprovement in 28-d survival for the RAD + CVVH arm versus theCRRT-alone arm was <10%, between 10 and 23.3%, or >23.3%.A 10 to 23.3% effect would suggest P < 0.2 and would be reasonto go forward with additional confirmatory trials. Because ofslow patient enrollment and the corporate need to assess theprogram, an interim analysis was conducted after 58 patientshad been enrolled (40 patients assigned to CVVH + RAD and 18patients to CRRT alone). Enrollment was suspended pending reviewof the results from the interim analysis by the independentdata monitoring committee. After the interim analysis, a corporatedecision was made to discontinue enrollment in this study andproceed to the design of a confirmatory Phase II study.
H.D.H. is a shareholder of Nephrion (formerly RenaMed Biologics,Inc.), a biotechnology spinout company of the University ofMichigan.
Acknowledgments
Abstracts regarding the results of this study were previouslypublished (J Am Soc Nephrol 16: 46A, 2005 and J Am Soc Nephrol17: 49A, 2006).
We are grateful for the contributions of staff of RenaMed Biologics,Inc., in particular Bradley Maroni, MD, Michael F. DeBruin,MD, Karen M. Brennan, BSN, MBA, and J. Ricardo Da Silva, RN,BSN.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
See related editorial, "Toward the Promise of Renal ReplacementTherapy," on pages 839–840.
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Top
Abstract
Introduction
26 (n = 34), an HR of RAD to CVVH alone of 0.47 (95% CI 0.20 to 1.10; P = 0.08) was seen versus 0.58 (95% CI 0.14 to 2.33; P = 0.44) for APACHE II <26 (n = 24). Similarly, for SOFA 
4 d. Patients were required to have received CRRT for a minimum of 4 h but not longer than 48 h before randomization. Eligible patients were also required to have at least one nonrenal organ failure (modified SOFA score 
2 test. Kaplan-Meier methods were also used to assess differences in survival between groups. The log-rank test statistic was computed to assess the overall differences through 180 d. Cox proportional hazards models were used to identify risk factors. HR and corresponding 95% CI were computed. The Cox model provided estimate of risk compared with control for each Kaplan-Meier (180-d survival, time to renal recovery) as well as by patient subgroup: Age greater or less than 65 yr, race, and SOFA and APACHE II scores at study entry during screening period. Also, the variables included in the Cox model were age, race, baseline APACHE II score, and baseline SOFA score. 
