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Up Front MattersBrief Reviews
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Bridging Translation by Improving Preclinical Study Design in AKI

Mark de Caestecker, Ben D. Humphreys, Kathleen D. Liu, William H. Fissell, Jorge Cerda, Thomas D. Nolin, David Askenazi, Girish Mour, Frank E. Harrell, Nick Pullen, Mark D. Okusa and Sarah Faubel
JASN December 2015, 26 (12) 2905-2916; DOI: https://doi.org/10.1681/ASN.2015070832
Mark de Caestecker
*Division of Nephology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee;
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Ben D. Humphreys
†Division of Renal Diseases, Washington University School of Medicine, St. Louis, Missouri;
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Kathleen D. Liu
‡Division of Nephrology, Department of Medicine, University of California, San Francisco, California;
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William H. Fissell
*Division of Nephology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee;
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Jorge Cerda
§Division of Nephrology and Hypertension, Albany Medical College, Albany, New York;
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Thomas D. Nolin
‖Renal-Electrolyte Division, Department of Medicine and Center for Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
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David Askenazi
¶Department of Pediatrics, Division of Nephrology, University of Alabama, Birmingham, Alabama;
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Girish Mour
‖Renal-Electrolyte Division, Department of Medicine and Center for Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
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Frank E. Harrell Jr.
**Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee;
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Nick Pullen
††Pfizer Global Research and Development, Inflammation & Immunology Research Unit, Cambridge, Massachusetts;
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Mark D. Okusa
‡Division of Nephrology, Department of Medicine, University of California, San Francisco, California;
‡Division of Nephrology, Department of Medicine, University of California, San Francisco, California;
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Sarah Faubel
§§Renal Division, University of Colorado Denver and Denver Veterans Affairs Medical Center, Aurora, Colorado
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Abstract

Despite extensive research, no therapeutic interventions have been shown to prevent AKI, accelerate recovery of AKI, or reduce progression of AKI to CKD in patients. This failure in translation has led investigators to speculate that the animal models being used do not predict therapeutic responses in humans. Although this issue continues to be debated, an important concern that has not been addressed is whether improvements in preclinical study design can be identified that might also increase the likelihood of translating basic AKI research into clinical practice using the current models. In this review, we have taken an evidence-based approach to identify common weaknesses in study design and reporting in preclinical AKI research that may contribute to the poor translatability of the findings. We focused on use of N-acetylcysteine or sodium bicarbonate for the prevention of contrast-induced AKI and use of erythropoietin for the prevention of AKI, two therapeutic approaches that have been extensively studied in clinical trials. On the basis of our findings, we identified five areas for improvement in preclinical study design and reporting. These suggested and preliminary guidelines may help improve the quality of preclinical research for AKI drug development.

  • acute kidney injury
  • preclinical research
  • reproducibility

Severe AKI requiring dialysis affects >90,000 patients in the United States each year, and milder, nondialysis–dependent AKI affects >1.5 million per year.1–3 The underlying causes of AKI are frequently multifactorial, most commonly arising from ischemic, obstructive, toxic, and infectious insults.2 There is a bidirectional relationship between AKI and CKD. Mild AKI may lead to CKD, and there is marked increased risk of ESRD in patients with severe AKI requiring dialysis.4–10 Conversely, random sampling of a large integrated health care delivery system suggests that CKD also predisposes to AKI.11 Despite this, no therapeutic interventions have been proven to prevent AKI, improve the rate of renal recovery, or prevent postinjury CKD or ESRD after AKI.10,12 The lack of effective drug therapies is surprising, because there has been extensive basic research into the pathogenesis of AKI and preclinical testing of numerous therapies to prevent and treat AKI.

There is a number of reasons for this failure to translate from the bench to the bedside in AKI research. Failure of translation is, in part, because of problems with clinical trial design that include underpowering, late patient enrollment, and a lack of sensitive and accurate techniques to quantify the severity of injury and recovery in patients with AKI.13 However, an additional response to this lack of clinical translation is to conclude that the animal models of AKI are not predictive of therapeutic responses in patients. This has triggered a vigorous debate, and many excellent reviews on this topic have already been written.14–17 However, the question whether it is the design and execution of the AKI preclinical studies that are the root causes in the translational uncertainty has had significantly less review and debate in nephrology. The goal of this review, therefore, is to evaluate whether improvements in preclinical study design and statistical rigor can be identified that will increase the likelihood of translating basic research using the animal models that we are currently using into care of patients with AKI.

Common Concerns about Preclinical Study Design and Reporting That Affect Data Reproducibility

A key concern of the scientific community is that investigators cannot reproduce many of the published basic and preclinical research studies. It is estimated that 51%–89% of published research cannot be reproduced in other laboratories.18–22 This problem has been highlighted by a number of recent, high–profile commentaries from the pharmaceutical industry,18,19,23 funding agencies, including the National Institutes of Health,24,25 scientific journals,26,27 veterinarians,28 academics, and biostatisticians.29–36 This is of particular importance when animal models are used to advance the development of clinical therapeutics. Not only does this level of uncertainty potentially waste millions of funding dollars,37 but there are also genuine ethical concerns regarding the clinical evaluation of agents with supporting rationale that is solely on the basis of experimental evidence derived from studies in animal models. Problems with data reproducibility can arise at any of the different stages of scientific discovery ranging from exploratory, hypothesis–generating experiments to validation studies designed to evaluate therapeutic interventions. Systematic reviews have identified recurring methodologic weaknesses in preclinical studies.18,19,23,24,34,35 Vulnerabilities include errors in statistical design (inadequate power, ad hoc, interim, and retrospective end point analysis), lack of randomization and blinding, and incomplete methods reporting. In addition, lack of transparency in data reporting allows investigators to selectively report positive results without including information about experiments that fail to support the desired effect. This contrasts with the stringent requirements for study design, data collection, and reporting required for clinical trials. There has also been interest in promoting the analysis of continuous rather than dichotomous measures in clinical trials and preclinical research.38 In AKI, power analysis would be on the basis of the anticipated changes in actual creatinine values rather than setting an artificial dichotomy for what is deemed to be a clinically important effect (such as a 50% reduction in eGFR). This would increase the statistical power of a study without requiring larger numbers. These concerns are, in part, being addressed by scientific journals, many of which allow additional space to report complete methodology.26–28 Other key concerns include persistent bias in the publication of positive data and the lack of suitable forums for publication of intrinsically well conducted studies with outcomes that did not support the key hypothesis under evaluation (i.e., negative studies). Research that is selectively reported or cannot be reproduced ultimately hinders long–term therapeutic developments by increasing costs and causing delays when attempts are made to replicate preclinical studies. A recent analysis performed on the basis of a conservative estimate that 50% of scientific research is not reproducible, concluded that as much as $28 billion each year are spent in the United States on basic and preclinical research that is not reproducible.37 Despite these important concerns, potential limitations in the design and reporting of preclinical studies of AKI have received scant attention from the nephrology community.

To address concerns about preclinical study design and reporting in AKI, we have evaluated the quality of a selection of preclinical studies that have been used to support clinical trials in AKI, focusing specifically on issues related to data reproducibility and scientific and statistical rigor. For this, we have focused on two AKI–specific therapeutic approaches that have been extensively studied in clinical trials: (1) use of N-acetylcysteine (NAC) or sodium bicarbonate (NaHCO3) for the prevention of contrast-induced AKI (CI-AKI) and (2) use of erythropoietin (EPO) for the prevention of AKI. We chose these as examples of situations in which a lack of preclinical research may account for failures to translate into the clinical arena (NAC and NaHCO3 in CI-AKI) or a large number of preclinical studies have been performed, but many of them are poorly designed and of uncertain significance (EPO in AKI). On the basis of our findings, we have identified a number of areas for improvement in preclinical study design and reporting. These preliminary guidelines will help improve the quality of preclinical research for AKI drug development.

Therapeutic Intervention Studies in CI-AKI

A large number of therapeutic intervention studies has been performed to prevent the development of AKI in patients exposed to intravascular radiocontrast agents, often in the context of percutaneous cardiac interventions.39 To date, however, no intervention, other than preprocedure volume expansion, has been conclusively shown to reduce the incidence and severity or improve outcome in CI-AKI.40 In a recent meta-analysis, 11,071 study participants in 55 randomized controlled trials (RCTs) using NAC or NaHCO3 were included for analysis for the prevention of CI-AKI; 23 studies involving 2980 participants reported positive results, whereas 32 studies involving 8091 participants reported negative results. With a single exception (the Acetylcysteine for Contrast-Induced Nephropathy Trial, which failed to show therapeutic benefit of NAC for the prevention of coronary and peripheral vascular angiography–induced AKI41), these studies were small, with 500 study participants or less. In addition, all of these studies evaluated early changes in kidney function as primary end points and did not track long–term patient outcomes (such as death, dialysis, or long-term CKD). Because of the equivocal nature of these studies, a large, definitive study of 8680 participants is now being conducted to evaluate the efficacy of NAC and/or NaHCO3 for prevention of CI-AKI (the Prevention of Serious Adverse Events following Angiography [PRESERVE] Trial).40 Irrespective of the outcome of the PRESERVE Trial, the performance of these 55 clinical trials represents a significant investment of time and resources by clinical investigators, study sponsors, and study participants but has not yielded a definitive answer. To determine whether this could be attributed to the quality of preclinical research, we evaluated preclinical research that was used to support the use of NaHCO3 and NAC as therapeutic interventions for CI-AKI.

The scientific justification for clinical trials of NaHCO3 to prevent CI-AKI was on the basis of the observation that there was increased toxicity of contrast agents in cultured cells exposed to acidic environments and the idea that alkalinizing the urine might reduce free radical production by injured tubular epithelial cells.42 The first clinical study reporting a positive effect of NaHCO3 for the prevention of CI-AKI was published in 2004.43 In this study, 1 of 60 patients receiving NaHCO3 developed AKI, whereas 8 of 59 patients receiving normal saline developed AKI (P=0.02). Unfortunately, it has been persuasively argued that too few patients were enrolled to reliably exclude the possibility of a false-positive result.40 Notably, at the time that this clinical study was published, there were no preclinical animal studies supporting the use of NaHCO3 for the prevention of CI-AKI. Two studies had been reported in rats undergoing ischemia-reperfusion–induced AKI (IR-AKI), one of which showed beneficial short–term effects on serum creatinine,44 whereas the other showed no effect on GFR after injury.45 Since then, a number of studies have failed to show beneficial effects of NaHCO3 in rodent models of CI-AKI.46,47 Only one preclinical study has reported beneficial effects of NaHCO3 in CI-AKI.48 This study was performed in rats that had been water deprived and treated with a loop diuretic before treatment with the contrast agent. In addition, this study did not include a normal saline control to correct the effects of volume expansion resulting from the intravenous (iv) NaHCO3 infusion.48 Thus, despite the large number of clinical trials examining the use of NaHCO3 in patients with CI-AKI, there are negligible preclinical data to support the use of NaHCO3 as a therapeutic intervention in CI-AKI, and published supporting data used a model of CI-AKI that does not reflect clinical practice. If there had been clear published data showing that NaHCO3 did not improve the incidence or severity of AKI in clinically relevant preclinical models of CI-AKI at the time that these clinical trials were being performed, many of these early, underpowered clinical studies might have been avoided.

Like NaHCO3, there were few preclinical data supporting the use of NAC for the prevention of CI-AKI at the time of the first clinical study. NAC is an antioxidant that may improve renal function in AKI by inhibiting the generation of reactive oxygen species (ROS), thus limiting cell injury and inflammation. Widespread interest in the use and study of NAC for the prevention of CI-AKI began after the publication of a prospective RCT of 83 patients in 2000.49 In this study, 600 mg oral NAC was administered twice a day on the day of and day after contrast administration; one patient in the NAC-treated group developed CI-AKI, whereas nine in the placebo group developed CI-AKI. The rationale for the use of NAC was on the basis of animal evidence that ROS plays a role in toxicity (e.g., gentamicin and myoglobin)50 and CI-AKI.50–52 Evidence for the role of ROS in CI-AKI included animal data that ROS were increased in the kidney after iv contrast administration53 and that free radical scavengers, such as superoxide dismutase or catalase, improved renal function in CI-AKI.51,52 Remarkably, no study of NAC had been performed in an animal model of CI-AKI before 2000; iv NAC had been studied in IR-AKI, and improvement in GFR but not tubular necrosis occurred within 24 hours.54,55 Thus, although preclinical data supported the hypothesis that ROS may contribute to kidney injury in CI-AKI, preclinical studies supporting the use of NAC for the prevention of CI-AKI were inadequate. Particularly notable is that preclinical studies examined iv NAC just before kidney injury, whereas human trials examined oral NAC. Missing were key studies testing the half-life, dose-response, and duration of antioxidant effects of oral NAC in the kidney during injury.

Therapeutic Intervention Studies with EPO in AKI

Unlike studies on NaHCO3 and NAC for CI-AKI, a large number of preclinical studies supports the use of EPO to prevent AKI. The rationale supporting the use of EPO as a preventive treatment for AKI is that EPO has been shown to reduce cell death, reduce renal inflammation, and increase cellular repair after AKI.56 We identified 36 preclinical studies published over the last 20 years that evaluated the use of EPO in AKI (Table 1). The majority of studies used EPO as pretreatment (before the procedure used to induce AKI). In the remainder, treatment was initiated within a few hours of AKI induction; 34 of 36 studies showed protection against AKI assessed by reduced serum creatinine, reduced BUN, or increased GFR. A wide variety of animal models of AKI has been tested, including cisplatin AKI (10 studies), IR-AKI (12 studies), sepsis-associated AKI (SA-AKI; 7 studies), aortic occlusion (1 study), cardiopulmonary bypass (2 studies), perinatal asphyxia (1), iv contrast (1 study), amikacin (1 study), extreme exercise (1 study), and rhabdomyolysis (iv glycerol; 1 study). Thus, preclinical studies from numerous investigators using multiple models of AKI support the study of EPO for the prevention but not the treatment of AKI in a wide variety of clinical settings wherein patients may be at risk for AKI.

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Table 1.

Summary of preclinical EPO efficacy studies in AKI

EPO has been evaluated in nine RCTs in a variety of clinical scenarios associated with risk of AKI, including AKI associated with cardiac surgery, aortic surgery with hypothermic cardiac arrest, renal transplantation, and medical and surgical intensive care unit (Table 2). Two studies examined EPO after the inciting event causing AKI and did not show a benefit. However, seven of nine RCTs appropriately used EPO to prevent AKI, although only two of these showed a positive effect.57,58 Notably, however, the number of patients in these prevention trials was small, ranging between 39 and 100 patients. As previously discussed, prevention trials in AKI require a large number of patients to be adequately powered to detect a plausible reduction in the rate of AKI; depending on the rate of AKI and the expected benefit, >500 patients would be needed.13 Thus, clinical trial data to date are inadequate to reach conclusions regarding the potential benefit of EPO to prevent AKI. Because the clinical trial data are inconclusive, we further examined the strength of the preclinical studies to identify gaps in research that might aid in the development of future clinical trials. We specifically evaluated issues relating to preclinical study design and reporting as well as comorbidities, sex, and genetic heterogeneity in the animal models being tested.

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Table 2.

Summary of completed clinical EPO intervention studies in patients with AKI

Preclinical Study Design and Reporting

On the basis of our analysis of 36 published preclinical studies on the effects of EPO in AKI (Table 1), a number of common weaknesses was identified in study design and reporting, which is similar to those reported in the non-AKI literature.18,19,23,24,34,35

  • Only one study described prespecified end points (primary outcome measures) and used them to perform a power analysis and determine the sample size required to detect a specified effect size.59 Designing adequately powered animal studies is just as important as in clinical studies, because underpowered studies may lead to both false-negative and false-positive results. Because the number of animals needed to adequately power a study is dependent on variability in the primary outcome measures and because there may be significant inconsistency in primary outcome measures inherent to different models used in different laboratories, power needs to be determined on the basis of preliminary experience in each laboratory using each model. For example, if a mouse model of AKI was characterized by a serum creatinine increase of 1.6 mg/dl with an SD of 0.7 mg/dl, then 22 mice per group would be needed to detect a 40% reduction in serum creatinine (to 1.0 mg/dl) with an 80% power to detect a difference if one exists and a probability of detecting a difference by chance (α-error rate) of <5%. If, however, the SD for creatinine values was 0.4 mg/dl, only seven mice would be required per group to detect a 40% reduction in serum creatinine. In the EPO studies that we have reviewed, 24 of 36 studies used ≤10 animals per group, which may be too few to produce a result that is not caused by chance alone.

  • In 35 of 36 studies, there was no documentation that the investigators were fully blinded to the treatment groups over the whole course of the study (often this was only for histologic analyses).

  • Animal mortality was only reported in 4 of 36 studies,60–63 despite the fact that most of the models used (including cisplatin AKI, IR-AKI, and SA-AKI) have recognized mortality rates. These observations are likely to reflect the lack of transparency and accountability in preclinical study data reporting.

  • Only three studies reported negative outcomes.64–66 Of these, one study reported a positive outcome with another treatment being compared with EPO,65 and one study reported contrasting positive effects of EPO using a different model of AKI.64 These data likely reflect the strong and persistent publication bias for reporting only positive outcomes of studies throughout the medical literature.

  • Although a variety of doses and timing intervals for EPO treatment were included in the different studies, only one study evaluated dose-response effects of EPO on AKI.67 Importantly, only one study attempted to confirm target engagement and the mechanism of action of EPO through the β-common receptor in a preclinical SA-AKI model.68 This study showed that the β-common receptor mediates the beneficial effects of EPO in SA-AKI. Because the β-common receptor has lower affinity for EPO than the erythropoietin receptor (which mediates EPO-dependent erythropoiesis),69 one additional possibility is that the dose of EPO used in AKI may not be the same as that needed to stimulate erythropoiesis. This suggests that many of the preclinical studies, which used doses of EPO normally used to stimulate erythropoiesis, may have been using submaximal therapeutic doses.

Heterogeneity of Animals Used to Evaluate Therapeutic Responses

There are three major areas of heterogeneity in human AKI that need to be considered in animal models of AKI: multifactorial causes of AKI, which may have different pathobiologic bases; genetic and sex heterogeneity of affected patients; and common confounding comorbidities. Preclinical studies on EPO have included a diverse range of toxin, ischemic, and SA-AKI models, and although it can be argued that individual studies using single models may not be representative of specific human AKI pathophysiologies, involvement of multiple models showing similar beneficial effects provides a strong argument for potential translatability. In addition, the fact that studies were performed in not only genetically inbred mice but also, pigs, macaques, and outbred (genetically heterogeneous) rat strains (e.g., Sprague–Dawley rats) suggests that the efficacy signal for EPO use in animal models is likely to extend to human disease. However, two key confounding issues that have not been addressed in these studies may account for the current failure to translate EPO efficacy from animal models of AKI into humans: (1) modeling common clinical comorbidities (unlike clinical scenarios in which the majority of patents are elderly or have CKD and/or diabetes,1 none of the preclinical studies were performed in diabetic animals, older animals, or animals with baseline impaired kidney function) and (2) sex heterogeneity. The majority of studies were conducted in males, with 5 of 36 studies in females. Only two studies compared responses in males and females,70,71 with one of these studies showing a sex–dependent EPO response.71 Thus, the majority of preclinical AKI EPO studies do not reflect clinical comorbidities or sex-dependent variability in therapeutic responses that result from the inherent heterogeneity of most human study populations. Introduction of these variables into preclinical study design would increase variability and expense of these experiments; however, early investment of time and resources is likely to result in significant savings in the long run.

Recommendations, Implementation, and Challenges

On the basis of this review of the preclinical AKI EPO literature, we suggest five areas for improvement in study design that will increase the probability that preclinical research is translated into clinical practice.

  1. Randomization and blinding to treatment.

  2. Statistical rigor, particularly determination of sample size on the basis of defined, predetermined categorical or (better) continuous measurements of responses to therapy.

  3. Publication bias favoring the publication of positive results. This is associated with lack of data transparency and accountability in reporting published preclinical data.

  4. Lack of sex heterogeneity and lack of modeling for common clinical comorbidities. Studies performed in young, male, inbred mice are more reproducible than studies in old, mixed sex, outbred populations but do not reflect the true heterogeneity of human population pathobiology and therapeutic responses.

  5. Lack of pharmacokinetic and pharmacodynamics, studies including dose-response studies to evaluate efficacy and methods to show efficient target engagement (therefore, adequate dosing).

Although we recognize that these weaknesses in preclinical AKI research are shared with other areas of preclinical research that have already been extensively reported,18,19,23,24,34,35 there remain significant challenges to implementing change. Despite the large number of publications on deficiencies in preclinical research design in other areas of medicine, an expectation gap remains between the academic research community and pharmaceutical industry. Underlying this are fundamental differences in practices: although academic faculty are under constant pressure to publish positive findings to sustain their careers, the pharmaceutical industry faces increasing costs as new molecular entities advance along the development pipeline. Thus, there is strong financial pressure to abandon a therapy if success seems in jeopardy. The first practice pattern leads to unjustified optimism for particular therapies and may squander resources by advancing clinical trials that are ultimately destined to be negative studies. The second pattern risks prematurely abandoning therapies with genuine promise to alleviate disease. Therefore, the key to success in practice modification is the involvement of all of the stakeholders with their varied and often conflicting expectations and demands in an effort to develop guidelines that can be implemented by everyone. Participants who will benefit from the success of this effort include:

  • Academic investigators who generate preclinical data used to support clinical trials in AKI;

  • Project leaders from pharmaceutical companies who are using published and in–house preclinical AKI research to support the development of costly, sponsored clinical trials;

  • Clinical scientists and statisticians who conduct and monitor clinical trials in AKI;

  • Food and Drug Administration reviewers who evaluate investigational new drug applications on the basis of preclinical AKI research; and

  • Patients who might benefit from intervention studies.

Other interested parties, including journal editors who publish preclinical AKI research as well as the funding bodies supporting preclinical AKI research, might also be involved. We anticipate that, through these deliberations, the goals of different stakeholders will be more clearly understood and aligned to ultimately improve preclinical studies and enhance the likelihood of successful AKI clinical trials. Examples of issues that will need to be discussed and addressed include (1) mechanisms to improve communication between preclinical investigators and investigators involved in clinical AKI research, (2) the ability of published preclinical data to be reproduced by industry, (3) improvements in preclinical study design, and (4) appropriateness of the application of preclinical data to human clinical trials.

The solutions to some of these problems should be relatively straightforward. For example, there should be wide agreement that animal experiments involving a test compound should be blinded, that power calculations should be performed with predefined primary outcomes, and that all outcomes, including unanticipated experimental mortality, should be reported. However, implementation of even these relatively straightforward changes will present significant logistical and financial challenges to many laboratories, and therefore, practical challenges to implementation would need to be addressed. For example, investigators may be concerned that additional costs incurred by performing properly powered preclinical research studies may make these experiments prohibitively expensive, particularly in this era of financial constraints. However, alternative approaches for statistical analysis on the basis of the use of continuous versus dichotomous end point variables (such as creatinine) could be used to mitigate the effect of these requirements of research costs.38 Other problems will be even more difficult to address, and potential solutions will be less obvious. For example, calling for the publication of negative results is unquestionably good for the science community at large but consumes an individual scientist’s time and resources with limited academic reward. Alternative strategies for complete data reporting might be considered, such as the development of secure, web–based data portals. These could be developed as repositories for pharmaceutical industry and academic research used to support new therapeutic applications in humans. All data could be sealed until the studies are completed and/or published but would be open to the public thereafter. This could also be used to enable data monitoring and accountability and could provide a centralized and secure system to ensure new standards in research design (such as identification of prespecified end points and power analysis). It is also important to recognize that many of the solutions may be costly, a significant issue in our current era of declining federal support for biomedical research. Notwithstanding this, it is also clear that our current strategies have failed to deliver new therapies that are urgently needed.10,12 We would argue that as a significant part of this process, many of the preclinical study design and reporting methods that are currently in use are in immediate need of change.

Disclosures

M.d.C. performs consultancy work for NephroGenex (Raleigh, NC). No financial support was utilized for this report.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • See related editorial, “Models of Human AKI: Resemblance, Reproducibility, and Return on Investment,” on pages 2891–2893.

  • Copyright © 2015 by the American Society of Nephrology

References

  1. ↵
    1. Rewa O,
    2. Bagshaw SM
    : Acute kidney injury-epidemiology, outcomes and economics. Nat Rev Nephrol 10: 193–207, 2014pmid:24445744
    OpenUrlCrossRefPubMed
  2. ↵
    1. Bellomo R,
    2. Kellum JA,
    3. Ronco C
    : Acute kidney injury. Lancet 380: 756–766, 2012pmid:22617274
    OpenUrlCrossRefPubMed
  3. ↵
    1. Lameire NH,
    2. Bagga A,
    3. Cruz D,
    4. De Maeseneer J,
    5. Endre Z,
    6. Kellum JA,
    7. Liu KD,
    8. Mehta RL,
    9. Pannu N,
    10. Van Biesen W,
    11. Vanholder R
    : Acute kidney injury: An increasing global concern. Lancet 382: 170–179, 2013pmid:23727171
    OpenUrlCrossRefPubMed
  4. ↵
    1. Coca SG,
    2. Singanamala S,
    3. Parikh CR
    : Chronic kidney disease after acute kidney injury: A systematic review and meta-analysis. Kidney Int 81: 442–448, 2012pmid:22113526
    OpenUrlCrossRefPubMed
    1. Chawla LS,
    2. Kimmel PL
    : Acute kidney injury and chronic kidney disease: An integrated clinical syndrome. Kidney Int 82: 516–524, 2012pmid:22673882
    OpenUrlCrossRefPubMed
    1. Wald R,
    2. Quinn RR,
    3. Adhikari NK,
    4. Burns KE,
    5. Friedrich JO,
    6. Garg AX,
    7. Harel Z,
    8. Hladunewich MA,
    9. Luo J,
    10. Mamdani M,
    11. Perl J,
    12. Ray JG,
    13. University of Toronto Acute Kidney Injury Research Group
    : Risk of chronic dialysis and death following acute kidney injury. Am J Med 125: 585–593, 2012pmid:22516564
    OpenUrlCrossRefPubMed
    1. Bucaloiu ID,
    2. Kirchner HL,
    3. Norfolk ER,
    4. Hartle JE 2nd,
    5. Perkins RM
    : Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury. Kidney Int 81: 477–485, 2012pmid:22157656
    OpenUrlCrossRefPubMed
    1. Wu VC,
    2. Huang TM,
    3. Lai CF,
    4. Shiao CC,
    5. Lin YF,
    6. Chu TS,
    7. Wu PC,
    8. Chao CT,
    9. Wang JY,
    10. Kao TW,
    11. Young GH,
    12. Tsai PR,
    13. Tsai HB,
    14. Wang CL,
    15. Wu MS,
    16. Chiang WC,
    17. Tsai IJ,
    18. Hu FC,
    19. Lin SL,
    20. Chen YM,
    21. Tsai TJ,
    22. Ko WJ,
    23. Wu KD
    : Acute-on-chronic kidney injury at hospital discharge is associated with long-term dialysis and mortality. Kidney Int 80: 1222–1230, 2011pmid:21832983
    OpenUrlCrossRefPubMed
    1. Chawla LS,
    2. Amdur RL,
    3. Amodeo S,
    4. Kimmel PL,
    5. Palant CE
    : The severity of acute kidney injury predicts progression to chronic kidney disease. Kidney Int 79: 1361–1369, 2011pmid:21430640
    OpenUrlCrossRefPubMed
  5. ↵
    1. Cerda J,
    2. Liu KD,
    3. Cruz DN,
    4. Jaber BL,
    5. Koyner JL,
    6. Heung M,
    7. Okusa MD,
    8. Faubel S,
    9. AKI Advisory Group of the American Society of Nephrology
    : Promoting kidney function recovery in patients with AKI requiring RRT. Clin J Am Soc Nephrol 10: 1859–1857, 2015
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Hsu CY,
    2. Ordoñez JD,
    3. Chertow GM,
    4. Fan D,
    5. McCulloch CE,
    6. Go AS
    : The risk of acute renal failure in patients with chronic kidney disease. Kidney Int 74: 101–107, 2008pmid:18385668
    OpenUrlCrossRefPubMed
  7. ↵
    1. Molitoris BA,
    2. Okusa MD,
    3. Palevsky PM,
    4. Kimmel PL,
    5. Star RA
    : Designing clinical trials in acute kidney injury. Clin J Am Soc Nephrol 7: 842–843, 2012pmid:22442185
    OpenUrlFREE Full Text
  8. ↵
    1. Palevsky PM,
    2. Molitoris BA,
    3. Okusa MD,
    4. Levin A,
    5. Waikar SS,
    6. Wald R,
    7. Chertow GM,
    8. Murray PT,
    9. Parikh CR,
    10. Shaw AD,
    11. Go AS,
    12. Faubel SG,
    13. Kellum JA,
    14. Chinchilli VM,
    15. Liu KD,
    16. Cheung AK,
    17. Weisbord SD,
    18. Chawla LS,
    19. Kaufman JS,
    20. Devarajan P,
    21. Toto RM,
    22. Hsu CY,
    23. Greene T,
    24. Mehta RL,
    25. Stokes JB,
    26. Thompson AM,
    27. Thompson BT,
    28. Westenfelder CS,
    29. Tumlin JA,
    30. Warnock DG,
    31. Shah SV,
    32. Xie Y,
    33. Duggan EG,
    34. Kimmel PL,
    35. Star RA
    : Design of clinical trials in acute kidney injury: Report from an NIDDK workshop on trial methodology. Clin J Am Soc Nephrol 7: 844–850, 2012pmid:22442182
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Sanz AB,
    2. Sanchez-Niño MD,
    3. Martín-Cleary C,
    4. Ortiz A,
    5. Ramos AM
    : Progress in the development of animal models of acute kidney injury and its impact on drug discovery. Expert Opin Drug Discov 8: 879–895, 2013pmid:23627598
    OpenUrlCrossRefPubMed
    1. Heyman SN,
    2. Rosen S,
    3. Rosenberger C
    : Animal models of renal dysfunction: Acute kidney injury. Expert Opin Drug Discov 4: 629–641, 2009pmid:23489156
    OpenUrlCrossRefPubMed
    1. Doi K,
    2. Leelahavanichkul A,
    3. Yuen PS,
    4. Star RA
    : Animal models of sepsis and sepsis-induced kidney injury. J Clin Invest 119: 2868–2878, 2009pmid:19805915
    OpenUrlCrossRefPubMed
  10. ↵
    1. Ortiz A,
    2. Sanchez-Niño MD,
    3. Izquierdo MC,
    4. Martin-Cleary C,
    5. Garcia-Bermejo L,
    6. Moreno JA,
    7. Ruiz-Ortega M,
    8. Draibe J,
    9. Cruzado JM,
    10. Garcia-Gonzalez MA,
    11. Lopez-Novoa JM,
    12. Soler MJ,
    13. Sanz AB,
    14. Red de Investigacion Renal (REDINREN) and Consorcio Madrileño para investigación del fracaso renal agudo (CIFRA)
    : Translational value of animal models of kidney failure. Eur J Pharmacol 759: 205–220, 2015pmid:25814248
    OpenUrlCrossRefPubMed
  11. ↵
    1. Begley CG,
    2. Ellis LM
    : Drug development: Raise standards for preclinical cancer research. Nature 483: 531–533, 2012pmid:22460880
    OpenUrlCrossRefPubMed
  12. ↵
    1. Prinz F,
    2. Schlange T,
    3. Asadullah K
    : Believe it or not: How much can we rely on published data on potential drug targets? Nat Rev Drug Discov 10: 712, 2011pmid:21892149
    OpenUrlCrossRefPubMed
    1. Hartshorne JK,
    2. Schachner A
    : Tracking replicability as a method of post-publication open evaluation. Front Comput Neurosci 6: 8, 2012pmid:22403538
    OpenUrlCrossRefPubMed
    1. Vasilevsky NA,
    2. Brush MH,
    3. Paddock H,
    4. Ponting L,
    5. Tripathy SJ,
    6. Larocca GM,
    7. Haendel MA
    : On the reproducibility of science: Unique identification of research resources in the biomedical literature. PeerJ 1: e148, 2013pmid:24032093
    OpenUrlCrossRefPubMed
  13. ↵
    1. Glasziou P,
    2. Meats E,
    3. Heneghan C,
    4. Shepperd S
    : What is missing from descriptions of treatment in trials and reviews? BMJ 336: 1472–1474, 2008pmid:18583680
    OpenUrlFREE Full Text
  14. ↵
    1. Pullen N,
    2. Birch CL,
    3. Douglas GJ,
    4. Hussain Q,
    5. Pruimboom-Brees I,
    6. Walley RJ
    : The translational challenge in the development of new and effective therapies for endometriosis: A review of confidence from published preclinical efficacy studies. Hum Reprod Update 17: 791–802, 2011pmid:21733981
    OpenUrlCrossRefPubMed
  15. ↵
    1. Landis SC,
    2. Amara SG,
    3. Asadullah K,
    4. Austin CP,
    5. Blumenstein R,
    6. Bradley EW,
    7. Crystal RG,
    8. Darnell RB,
    9. Ferrante RJ,
    10. Fillit H,
    11. Finkelstein R,
    12. Fisher M,
    13. Gendelman HE,
    14. Golub RM,
    15. Goudreau JL,
    16. Gross RA,
    17. Gubitz AK,
    18. Hesterlee SE,
    19. Howells DW,
    20. Huguenard J,
    21. Kelner K,
    22. Koroshetz W,
    23. Krainc D,
    24. Lazic SE,
    25. Levine MS,
    26. Macleod MR,
    27. McCall JM,
    28. Moxley RT 3rd,
    29. Narasimhan K,
    30. Noble LJ,
    31. Perrin S,
    32. Porter JD,
    33. Steward O,
    34. Unger E,
    35. Utz U,
    36. Silberberg SD
    : A call for transparent reporting to optimize the predictive value of preclinical research. Nature 490: 187–191, 2012pmid:23060188
    OpenUrlCrossRefPubMed
  16. ↵
    1. Collins FS,
    2. Tabak LA
    : Policy: NIH plans to enhance reproducibility. Nature 505: 612–613, 2014pmid:24482835
    OpenUrlCrossRefPubMed
  17. ↵
    1. McNutt M
    : Journals unite for reproducibility. Science 346: 679, 2014pmid:25383411
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Anonymous
    : Journals unite for reproducibility. Nature 515: 7, 2014pmid:25373636
    OpenUrlCrossRefPubMed
  19. ↵
    1. Kilkenny C,
    2. Browne WJ,
    3. Cuthill IC,
    4. Emerson M,
    5. Altman DG
    : Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. PLoS Biol 8: e1000412, 2010pmid:20613859
    OpenUrlCrossRefPubMed
  20. ↵
    1. Manolagas SC,
    2. Kronenberg HM
    : Reproducibility of results in preclinical studies: A perspective from the bone field. J Bone Miner Res 29: 2131–2140, 2014
    OpenUrlCrossRefPubMed
    1. Macleod MR,
    2. Fisher M,
    3. O’Collins V,
    4. Sena ES,
    5. Dirnagl U,
    6. Bath PM,
    7. Buchan A,
    8. van der Worp HB,
    9. Traystman R,
    10. Minematsu K,
    11. Donnan GA,
    12. Howells DW
    : Good laboratory practice: Preventing introduction of bias at the bench. Stroke 40: e50–e52, 2009pmid:18703798
    OpenUrlAbstract/FREE Full Text
    1. Mobley A,
    2. Linder SK,
    3. Braeuer R,
    4. Ellis LM,
    5. Zwelling L
    : A survey on data reproducibility in cancer research provides insights into our limited ability to translate findings from the laboratory to the clinic. PLoS One 8: e63221, 2013pmid:23691000
    OpenUrlCrossRefPubMed
    1. Hackam DG,
    2. Redelmeier DA
    : Translation of research evidence from animals to humans. JAMA 296: 1731–1732, 2006pmid:17032985
    OpenUrlCrossRefPubMed
    1. Ioannidis JP
    : Extrapolating from animals to humans. Sci Transl Med 4: 151ps15, 2012pmid:22972841
    OpenUrlFREE Full Text
  21. ↵
    1. Hess KR
    : Statistical design considerations in animal studies published recently in cancer research. Cancer Res 71: 625, 2011pmid:21239476
    OpenUrlFREE Full Text
  22. ↵
    1. Ritskes-Hoitinga M,
    2. Leenaars M,
    3. Avey M,
    4. Rovers M,
    5. Scholten R
    : Systematic reviews of preclinical animal studies can make significant contributions to health care and more transparent translational medicine. Cochrane Database Syst Rev 3: ED000078, 2014pmid:24719910
    OpenUrlCrossRefPubMed
  23. ↵
    1. Perrin S
    : Preclinical research: Make mouse studies work. Nature 507: 423–425, 2014pmid:24678540
    OpenUrlCrossRefPubMed
  24. ↵
    1. Freedman LP,
    2. Cockburn IM,
    3. Simcoe TS
    : The economics of reproducibility in preclinical research. PLoS Biol 13: e1002165, 2015pmid:26057340
    OpenUrlCrossRefPubMed
  25. ↵
    1. Fedorov V,
    2. Mannino F,
    3. Zhang R
    : Consequences of dichotomization. Pharm Stat 8: 50–61, 2009pmid:18389492
    OpenUrlCrossRefPubMed
  26. ↵
    1. Aurelio A,
    2. Durante A
    : Contrast-induced nephropathy in percutaneous coronary interventions: Pathogenesis, risk factors, outcome, prevention and treatment. Cardiology 128: 62–72, 2014pmid:24557146
    OpenUrlCrossRefPubMed
  27. ↵
    1. Weisbord SD,
    2. Gallagher M,
    3. Kaufman J,
    4. Cass A,
    5. Parikh CR,
    6. Chertow GM,
    7. Shunk KA,
    8. McCullough PA,
    9. Fine MJ,
    10. Mor MK,
    11. Lew RA,
    12. Huang GD,
    13. Conner TA,
    14. Brophy MT,
    15. Lee J,
    16. Soliva S,
    17. Palevsky PM
    : Prevention of contrast-induced AKI: A review of published trials and the design of the prevention of serious adverse events following angiography (PRESERVE) trial. Clin J Am Soc Nephrol 8: 1618–1631, 2013pmid:23660180
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. ACT Investigators
    : Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: Main results from the randomized Acetylcysteine for Contrast-induced nephropathy Trial (ACT). Circulation 124: 1250–1259, 2011pmid:21859972
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Burgess WP,
    2. Walker PJ
    : Mechanisms of contrast-induced nephropathy reduction for saline (NaCl) and sodium bicarbonate (NaHCO3). BioMed Res Int 2014: 510385, 2014pmid:24826379
    OpenUrlPubMed
  30. ↵
    1. Merten GJ,
    2. Burgess WP,
    3. Gray LV,
    4. Holleman JH,
    5. Roush TS,
    6. Kowalchuk GJ,
    7. Bersin RM,
    8. Van Moore A,
    9. Simonton CA 3rd,
    10. Rittase RA,
    11. Norton HJ,
    12. Kennedy TP
    : Prevention of contrast-induced nephropathy with sodium bicarbonate: A randomized controlled trial. JAMA 291: 2328–2334, 2004pmid:15150204
    OpenUrlCrossRefPubMed
  31. ↵
    1. Atkins JL
    : Effect of sodium bicarbonate preloading on ischemic renal failure. Nephron 44: 70–74, 1986pmid:3018600
    OpenUrlCrossRefPubMed
  32. ↵
    1. Sporer H,
    2. Lang F,
    3. Oberleithner H,
    4. Greger R,
    5. Deetjen P
    : Inefficacy of bicarbonate infusions on the course of postischaemic acute renal failure in the rat. Eur J Clin Invest 11: 311–315, 1981pmid:6795048
    OpenUrlCrossRefPubMed
  33. ↵
    1. Ladwig M,
    2. Flemming B,
    3. Seeliger E,
    4. Sargsyan L,
    5. Persson PB
    : Renal effects of bicarbonate versus saline infusion for iso- and lowosmolar contrast media in rats. Invest Radiol 46: 672–677, 2011pmid:21623210
    OpenUrlPubMed
  34. ↵
    1. Efrati S,
    2. Berman S,
    3. Ilgiyeav I,
    4. Siman-Tov Y,
    5. Averbukh Z,
    6. Weissgarten J
    : Differential effects of N-acetylcysteine, theophylline or bicarbonate on contrast-induced rat renal vasoconstriction. Am J Nephrol 29: 181–191, 2009pmid:18781062
    OpenUrlCrossRefPubMed
  35. ↵
    1. Barlak A,
    2. Akar H,
    3. Yenicerioglu Y,
    4. Yenisey C,
    5. Meteoğlu I,
    6. Yilmaz O
    : Effect of sodium bicarbonate in an experimental model of radiocontrast nephropathy. Ren Fail 32: 992–999, 2010pmid:20722568
    OpenUrlCrossRefPubMed
  36. ↵
    1. Tepel M,
    2. van der Giet M,
    3. Schwarzfeld C,
    4. Laufer U,
    5. Liermann D,
    6. Zidek W
    : Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 343: 180–184, 2000pmid:10900277
    OpenUrlCrossRefPubMed
  37. ↵
    1. Baliga R,
    2. Ueda N,
    3. Walker PD,
    4. Shah SV
    : Oxidant mechanisms in toxic acute renal failure. Am J Kidney Dis 29: 465–477, 1997pmid:9041227
    OpenUrlCrossRefPubMed
  38. ↵
    1. Yoshioka T,
    2. Fogo A,
    3. Beckman JK
    : Reduced activity of antioxidant enzymes underlies contrast media-induced renal injury in volume depletion. Kidney Int 41: 1008–1015, 1992pmid:1513081
    OpenUrlCrossRefPubMed
  39. ↵
    1. Bakris GL,
    2. Lass N,
    3. Gaber AO,
    4. Jones JD,
    5. Burnett JC Jr.
    : Radiocontrast medium-induced declines in renal function: A role for oxygen free radicals. Am J Physiol 258: F115–F120, 1990pmid:2301588
    OpenUrlPubMed
  40. ↵
    1. Parvez Z,
    2. Rahman MA,
    3. Moncada R
    : Contrast media-induced lipid peroxidation in the rat kidney. Invest Radiol 24: 697–702, 1989pmid:2807823
    OpenUrlCrossRefPubMed
  41. ↵
    1. Salom MG,
    2. Ramírez P,
    3. Carbonell LF,
    4. López Conesa E,
    5. Cartagena J,
    6. Quesada T,
    7. Parrilla P,
    8. Fenoy FJ
    : Protective effect of N-acetyl-L-cysteine on the renal failure induced by inferior vena cava occlusion. Transplantation 65: 1315–1321, 1998pmid:9625012
    OpenUrlCrossRefPubMed
  42. ↵
    1. DiMari J,
    2. Megyesi J,
    3. Udvarhelyi N,
    4. Price P,
    5. Davis R,
    6. Safirstein R
    : N-acetyl cysteine ameliorates ischemic renal failure. Am J Physiol 272: F292–F298, 1997pmid:9087670
    OpenUrlPubMed
  43. ↵
    1. Bartnicki P,
    2. Kowalczyk M,
    3. Rysz J
    : The influence of the pleiotropic action of erythropoietin and its derivatives on nephroprotection. Med Sci Monit 19: 599–605, 2013pmid:23872600
    OpenUrlCrossRefPubMed
  44. ↵
    1. Tasanarong A,
    2. Duangchana S,
    3. Sumransurp S,
    4. Homvises B,
    5. Satdhabudha O
    : Prophylaxis with erythropoietin versus placebo reduces acute kidney injury and neutrophil gelatinase-associated lipocalin in patients undergoing cardiac surgery: A randomized, double-blind controlled trial. BMC Nephrol 14: 136, 2013pmid:23829828
    OpenUrlCrossRefPubMed
  45. ↵
    1. Song YR,
    2. Lee T,
    3. You SJ,
    4. Chin HJ,
    5. Chae DW,
    6. Lim C,
    7. Park KH,
    8. Han S,
    9. Kim JH,
    10. Na KY
    : Prevention of acute kidney injury by erythropoietin in patients undergoing coronary artery bypass grafting: A pilot study. Am J Nephrol 30: 253–260, 2009pmid:19494484
    OpenUrlCrossRefPubMed
  46. ↵
    1. Sølling C,
    2. Christensen AT,
    3. Krag S,
    4. Frøkiaer J,
    5. Wogensen L,
    6. Krog J,
    7. Tønnesen EK
    : Erythropoietin administration is associated with short-term improvement in glomerular filtration rate after ischemia-reperfusion injury. Acta Anaesthesiol Scand 55: 185–195, 2011pmid:21226860
    OpenUrlCrossRefPubMed
  47. ↵
    1. Souza AC,
    2. Volpini RA,
    3. Shimizu MH,
    4. Sanches TR,
    5. Camara NO,
    6. Semedo P,
    7. Rodrigues CE,
    8. Seguro AC,
    9. Andrade L
    : Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-κB and upregulating endothelial nitric oxide synthase. Am J Physiol Renal Physiol 302: F1045–F1054, 2012pmid:22237800
    OpenUrlCrossRefPubMed
    1. Ishii Y,
    2. Sawada T,
    3. Murakami T,
    4. Sakuraoka Y,
    5. Shiraki T,
    6. Shimizu A,
    7. Kubota K,
    8. Fuchinoue S,
    9. Teraoka S
    : Renoprotective effect of erythropoietin against ischaemia-reperfusion injury in a non-human primate model. Nephrol Dial Transplant 26: 1157–1162, 2011pmid:20935018
    OpenUrlCrossRefPubMed
    1. Spandou E,
    2. Tsouchnikas I,
    3. Karkavelas G,
    4. Dounousi E,
    5. Simeonidou C,
    6. Guiba-Tziampiri O,
    7. Tsakiris D
    : Erythropoietin attenuates renal injury in experimental acute renal failure ischaemic/reperfusion model. Nephrol Dial Transplant 21: 330–336, 2006pmid:16221709
    OpenUrlCrossRefPubMed
  48. ↵
    1. Mohamed HE,
    2. El-Swefy SE,
    3. Mohamed RH,
    4. Ghanim AM
    : Effect of erythropoietin therapy on the progression of cisplatin induced renal injury in rats. Exp Toxicol Pathol 65: 197–203, 2013
    OpenUrlCrossRefPubMed
  49. ↵
    1. Abdelrahman M,
    2. Sharples EJ,
    3. McDonald MC,
    4. Collin M,
    5. Patel NS,
    6. Yaqoob MM,
    7. Thiemermann C
    : Erythropoietin attenuates the tissue injury associated with hemorrhagic shock and myocardial ischemia. Shock 22: 63–69, 2004pmid:15201704
    OpenUrlCrossRefPubMed
  50. ↵
    1. Wang Z,
    2. Schley G,
    3. Türkoglu G,
    4. Burzlaff N,
    5. Amann KU,
    6. Willam C,
    7. Eckardt KU,
    8. Bernhardt WM
    : The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment. Nephrol Dial Transplant 27: 929–936, 2012pmid:21742784
    OpenUrlCrossRefPubMed
  51. ↵
    1. Matějková Š,
    2. Scheuerle A,
    3. Wagner F,
    4. McCook O,
    5. Matallo J,
    6. Gröger M,
    7. Seifritz A,
    8. Stahl B,
    9. Vcelar B,
    10. Calzia E,
    11. Georgieff M,
    12. Möller P,
    13. Schelzig H,
    14. Radermacher P,
    15. Simon F
    : Carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine kidney ischemia/reperfusion injury. Intensive Care Med 39: 497–510, 2013pmid:23291730
    OpenUrlCrossRefPubMed
  52. ↵
    1. Liu X,
    2. Zhang T,
    3. Xia W,
    4. Wang Y,
    5. Ma K
    : Recombinant human erythropoietin pretreatment alleviates renal glomerular injury induced by cardiopulmonary bypass by reducing transient receptor potential channel 6-nuclear factor of activated T-cells pathway activation. J Thorac Cardiovasc Surg 146: 681–687, 2013pmid:23535151
    OpenUrlCrossRefPubMed
  53. ↵
    1. Coldewey SM,
    2. Khan AI,
    3. Kapoor A,
    4. Collino M,
    5. Rogazzo M,
    6. Brines M,
    7. Cerami A,
    8. Hall P,
    9. Sheaff M,
    10. Kieswich JE,
    11. Yaqoob MM,
    12. Patel NS,
    13. Thiemermann C
    : Erythropoietin attenuates acute kidney dysfunction in murine experimental sepsis by activation of the β-common receptor. Kidney Int 84: 482–490, 2013pmid:23594675
    OpenUrlCrossRefPubMed
  54. ↵
    1. Brines M,
    2. Grasso G,
    3. Fiordaliso F,
    4. Sfacteria A,
    5. Ghezzi P,
    6. Fratelli M,
    7. Latini R,
    8. Xie QW,
    9. Smart J,
    10. Su-Rick CJ,
    11. Pobre E,
    12. Diaz D,
    13. Gomez D,
    14. Hand C,
    15. Coleman T,
    16. Cerami A
    : Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A 101: 14907–14912, 2004pmid:15456912
    OpenUrlAbstract/FREE Full Text
  55. ↵
    1. Stojanović V,
    2. Vučković N,
    3. Spasojević S,
    4. Barišić N,
    5. Doronjski A,
    6. Zikić D
    : The influence of EPO and hypothermia on the kidneys of rats after perinatal asphyxia. Pediatr Nephrol 27: 139–144, 2012pmid:21720803
    OpenUrlCrossRefPubMed
  56. ↵
    1. Eshraghi-Jazi F,
    2. Nematbakhsh M,
    3. Pezeshki Z,
    4. Nasri H,
    5. Talebi A,
    6. Safari T,
    7. Mansouri A,
    8. Mazaheri S,
    9. Ashrafi F
    : Sex differences in protective effect of recombinant human erythropoietin against cisplatin-induced nephrotoxicity in rats. Iran J Kidney Dis 7: 383–389, 2013pmid:24072151
    OpenUrlPubMed
    1. Vaziri ND,
    2. Zhou XJ,
    3. Liao SY
    : Erythropoietin enhances recovery from cisplatin-induced acute renal failure. Am J Physiol 266[3 Pt 2]: F360–F366, 1994pmid:24072151
    OpenUrlPubMed
    1. Bagnis C,
    2. Beaufils H,
    3. Jacquiaud C,
    4. Adabra Y,
    5. Jouanneau C,
    6. Le Nahour G,
    7. Jaudon MC,
    8. Bourbouze R,
    9. Jacobs C,
    10. Deray G
    : Erythropoietin enhances recovery after cisplatin-induced acute renal failure in the rat. Nephrol Dial Transplant 16: 932–938, 2001pmid:24072151
    OpenUrlCrossRefPubMed
    1. Salahudeen AK,
    2. Haider N,
    3. Jenkins J,
    4. Joshi M,
    5. Patel H,
    6. Huang H,
    7. Yang M,
    8. Zhe H
    : Antiapoptotic properties of erythropoiesis-stimulating proteins in models of cisplatin-induced acute kidney injury. Am J Physiol Renal Physiol 294: F1354–F1365, 2008pmid:24072151
    OpenUrlCrossRefPubMed
    1. Bi B,
    2. Guo J,
    3. Marlier A,
    4. Lin SR,
    5. Cantley LG
    : Erythropoietin expands a stromal cell population that can mediate renoprotection. Am J Physiol Renal Physiol 295: F1017–F1022, 2008pmid:24072151
    OpenUrlCrossRefPubMed
    1. Lee DW,
    2. Kwak IS,
    3. Lee SB,
    4. Song SH,
    5. Seong EY,
    6. Yang BY,
    7. Lee MY,
    8. Sol MY
    : Post-treatment effects of erythropoietin and nordihydroguaiaretic acid on recovery from cisplatin-induced acute renal failure in the rat. J Korean Med Sci 24(Suppl): S170–S175, 2009
    OpenUrlCrossRefPubMed
    1. Choi DE,
    2. Jeong JY,
    3. Lim BJ,
    4. Lee KW,
    5. Shin YT,
    6. Na KR
    : Pretreatment with darbepoetin attenuates renal injury in a rat model of cisplatin-induced nephrotoxicity. Korean J Intern Med 24(3): 238–246, 2009
    OpenUrlCrossRefPubMed
    1. Rjiba-Touati K,
    2. Boussema IA,
    3. Belarbia A,
    4. Achour A,
    5. Bacha H
    : Protective effect of recombinant human erythropoietin against cisplatin-induced oxidative stress and nephrotoxicity in rat kidney. Int J Toxicol 30(5): 510–517, 2011
    OpenUrlCrossRefPubMed
  57. Kong D, Zhuo L, Gao C, Shi S, Wang N, Huang Z, Li W, Hao L: Erythropoietin protects against cisplatin-induced nephrotoxicity by attenuating endoplasmic reticulum stress-induced apoptosis. J Nephrol 26: 219–227, 2013pmid:24072151
    OpenUrlCrossRefPubMed
  58. Yang CW, Li C, Jung JY, Shin SJ, Choi BS, Lim SW, Sun BK, Kim YS, Kim J, Chang YS, Bang BK: Preconditioning with erythropoietin protects against subsequent ischemia-reperfusion injury in rat kidney. FASEB J 17: 1754–1755, 2003pmid:24072151
    OpenUrlCrossRefPubMed
  59. Sharples EJ, Patel N, Brown P, Stewart K, Mota-Philipe H, Sheaff M, Kieswich J, Allen D, Harwood S, Raftery M, Thiemermann C, Yaqoob MM: Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. J Am Soc Nephrol 15: 2115–2124, 2004pmid:24072151
    OpenUrlAbstract/FREE Full Text
    1. Johnson DW,
    2. Pat B,
    3. Vesey DA,
    4. Guan Z,
    5. Endre Z,
    6. Gobe GC
    : Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure. Kidney Int 69(10): 1806–1813, 2006
    OpenUrlCrossRefPubMed
    1. Esposito C,
    2. Pertile E,
    3. Grosjean F,
    4. Castoldi F,
    5. Diliberto R,
    6. Serpieri N,
    7. Arra M,
    8. Villa L,
    9. Mangione F,
    10. Esposito V,
    11. Migotto C,
    12. Valentino R
    , Dal Canton A: The improvement of ischemia/reperfusion injury by erythropoetin is not mediated through bone marrow cell recruitment in rats. Transplant Proc 41(4): 1113–1115, 2009
    OpenUrlCrossRefPubMed
  60. Moeini M, Nematbakhsh M, Fazilati M, Talebi A, Pilehvarian AA, Azarkish F, Eshraghi-Jazi F, Pezeshki Z: Protective role of recombinant human erythropoietin in kidney and lung injury following renal bilateral ischemia-reperfusion in rat model. Int J Prev Med 4: 648–655, 2013pmid:24072151
    OpenUrlPubMed
  61. Gobe GC, Bennett NC, West M, Colditz P, Brown L, Vesey DA, Johnson DW: Increased progression to kidney fibrosis after erythropoietin is used as a treatment for acute kidney injury. Am J Physiol Renal Physiol 306: F681–F692, 2014pmid:24072151
    OpenUrlCrossRefPubMed
  62. Gardner DS, Welham SJ, Dunford LJ, McCulloch TA, Hodi Z, Sleeman P, O'Sullivan S, Devonald MA: Remote conditioning or erythropoietin before surgery primes kidneys to clear ischemia-reperfusion-damaged cells: A renoprotective mechanism? Am J Physiol Renal Physiol 306: F873–F884, 2014pmid:24072151
    OpenUrlCrossRefPubMed
  63. Shen S, Jin Y, Li W, Liu X, Zhang T, Xia W, Wang Y, Ma K: Recombinant human erythropoietin pretreatment attenuates acute renal tubular injury against ischemia-reperfusion by restoring transient receptor potential channel-6 expression and function in collecting ducts. Crit Care Med 42: e663–e672, 2014pmid:24072151
    OpenUrlCrossRefPubMed
    1. Sølling C,
    2. Christensen AT,
    3. Krag S,
    4. Frøkiaer J,
    5. Wogensen L,
    6. Krog J,
    7. Tønnesen EK
    : Erythropoietin administration is associated with short-term improvement in glomerular filtration rate after ischemia-reperfusion injury. Acta Anaesthesiol Scand 55(2): 185–195, 2011
    OpenUrlCrossRefPubMed
    1. Matějková Š,
    2. Scheuerle A,
    3. Wagner F,
    4. McCook O,
    5. Matallo J,
    6. Gröger M,
    7. Seifritz A,
    8. Stahl B,
    9. Vcelar B,
    10. Calzia E,
    11. Georgieff M,
    12. Möller P,
    13. Schelzig H,
    14. Radermacher P,
    15. Simon F
    : Carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine kidney ischemia/reperfusion injury. Intensive Care Med 39(3): 497–510, 2013
    OpenUrlCrossRefPubMed
  64. Wang G, Huang H, Wu H, Wu C, Xu Y, Wang L, Liu X, Wang C, Shen Y, Li D, Jing H: Erythropoietin attenuates cardiopulmonary bypass-induced renal inflammatory injury by inhibiting nuclear factor-κB p65 expression. Eur J Pharmacol 689: 154–159, 2012pmid:24072151
    OpenUrlCrossRefPubMed
  65. Stojanović V, Vučković N, Spasojević S, Barišić N, Doronjski A, Zikić D: The influence of EPO and hypothermia on the kidneys of rats after perinatal asphyxia. Pediatr Nephrol 27: 139–144, 2012pmid:24072151
    OpenUrlCrossRefPubMed
    1. Goldfarb M,
    2. Rosenberger C,
    3. Ahuva S,
    4. Rosen S,
    5. Heyman SN
    : A role for erythropoietin in the attenuation of radiocontrast-induced acute renal failure in rats. Ren Fail 28(4): 345–350, 2006
    OpenUrlCrossRefPubMed
  66. Mitra A, Bansal S, Wang W, Falk S, Zolty E, Schrier RW: Erythropoietin ameliorates renal dysfunction during endotoxaemia. Nephrol Dial Transplant 22: 2349–2353, 2007pmid:24072151
    OpenUrlCrossRefPubMed
  67. Eren Z, Coban J, Ekinci ID, Kaspar C, Kantarci G: Evaluation of the effects of a high dose of erythropoietin-beta on early endotoxemia using a rat model. Adv Clin Exp Med 21: 321–329, 2012pmid:24072151
    OpenUrlPubMed
    1. Coldewey SM1,
    2. Khan AI,
    3. Kapoor A,
    4. Collino M,
    5. Rogazzo M,
    6. Brines M,
    7. Cerami A,
    8. Hall P,
    9. Sheaff M,
    10. Kieswich JE,
    11. Yaqoob MM,
    12. Patel NS,
    13. Thiemermann C
    : Erythropoietin attenuates acute kidney dysfunction in murine experimental sepsis by activation of the β-common receptor. Kidney Int 84(3): 482–490, 2013
    OpenUrlCrossRefPubMed
  68. Stoyanoff TR, Todaro JS, Aguirre MV, Zimmermann MC, Brandan NC: Amelioration of lipopolysaccharide-induced acute kidney injury by erythropoietin: involvement of mitochondria-regulated apoptosis. Toxicology 318: 13–21, 2014pmid:24072151
    OpenUrlCrossRefPubMed
  69. Kaynar K, Aliyazioglu R, Ersoz S, Ulusoy S, Al S, Ozkan G, Cansiz M: Role of erythropoietin in prevention of amikacin-induced nephropathy. J Nephrol 25: 744–749, 2012pmid:24072151
    OpenUrlCrossRefPubMed
  70. Lin X, Qu S, Hu M, Jiang C: Protective effect of erythropoietin on renal injury induced by acute exhaustive exercise in the rat. Int J Sports Med 31: 847–853, 2010pmid:24072151
    OpenUrlCrossRefPubMed
  71. Yang FL, Subeq YM, Chiu YH, Lee RP, Lee CJ, Hsu BG: Recombinant human erythropoietin reduces rhabdomyolysis-induced acute renal failure in rats. Injury 43: 367–373, 2012pmid:24072151
    OpenUrlCrossRefPubMed
  72. Dardashti A, Ederoth P, Algotsson L, Brondén B, Grins E, Larsson M, Nozohoor S, Zinko G, Bjursten H: Erythropoietin and protection of renal function in cardiac surgery (the EPRICS Trial). Anesthesiology 121: 582–590, 2014pmid:24072151
    OpenUrlCrossRefPubMed
  73. Kim JH, Shim JK, Song JW, Song Y, Kim HB, Kwak YL: Effect of erythropoietin on the incidence of acute kidney injury following complex valvular heart surgery: a double blind, randomized clinical trial of efficacy and safety. Crit Care 17: R254, 2013pmid:24072151
    OpenUrlCrossRefPubMed
    1. Tasanarong A,
    2. Duangchana S,
    3. Sumransurp S,
    4. Homvises B,
    5. Satdhabudha O
    : Prophylaxis with erythropoietin versus placebo reduces acute kidney injury and neutrophil gelatinase-associated lipocalin in patients undergoing cardiac surgery: a randomized, double-blind controlled trial. BMC Nephrol 14: 136, 2013
    OpenUrlCrossRefPubMed
  74. de Seigneux S, Ponte B, Weiss L, Pugin J, Romand JA, Martin PY, Saudan P: Epoetin administrated after cardiac surgery: effects on renal function and inflammation in a randomized controlled study. BMC Nephrol 13: 132, 2012pmid:24072151
    OpenUrlCrossRefPubMed
    1. Endre ZH1,
    2. Walker RJ,
    3. Pickering JW,
    4. Shaw GM,
    5. Frampton CM,
    6. Henderson SJ,
    7. Hutchison R,
    8. Mehrtens JE,
    9. Robinson JM,
    10. Schollum JB,
    11. Westhuyzen J,
    12. Celi LA,
    13. McGinley RJ,
    14. Campbell IJ,
    15. George PM
    : Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial). Kidney Int 77(11): 1020–1030, 2010
    OpenUrlCrossRefPubMed
    1. Oh SW,
    2. Chin HJ,
    3. Chae DW,
    4. Na KY
    : Erythropoietin improves long-term outcomes in patients with acute kidney injury after coronary artery bypass grafting. J Korean Med Sci 27(5):506–511, 2012
    OpenUrlCrossRefPubMed
  75. Sureshkumar KK, Hussain SM, Ko TY, Thai NL, Marcus RJ: Effect of high-dose erythropoietin on graft function after kidney transplantation: A randomized, double-blind clinical trial. Clin J Am Soc Nephrol 7: 1498–1506, 2012pmid:24072151
    OpenUrlAbstract/FREE Full Text
  76. Coupes B, de Freitas DG, Roberts SA, Read I, Riad H, Brenchley PE, Picton ML: rhErythropoietin-b as a tissue protective agent in kidney transplantation: A pilot randomized controlled trial. BMC Res Notes 8: 21, 2015pmid:24072151
    OpenUrlCrossRefPubMed
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Journal of the American Society of Nephrology: 26 (12)
Journal of the American Society of Nephrology
Vol. 26, Issue 12
December 2015
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Bridging Translation by Improving Preclinical Study Design in AKI
Mark de Caestecker, Ben D. Humphreys, Kathleen D. Liu, William H. Fissell, Jorge Cerda, Thomas D. Nolin, David Askenazi, Girish Mour, Frank E. Harrell, Nick Pullen, Mark D. Okusa, Sarah Faubel
JASN Dec 2015, 26 (12) 2905-2916; DOI: 10.1681/ASN.2015070832

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Bridging Translation by Improving Preclinical Study Design in AKI
Mark de Caestecker, Ben D. Humphreys, Kathleen D. Liu, William H. Fissell, Jorge Cerda, Thomas D. Nolin, David Askenazi, Girish Mour, Frank E. Harrell, Nick Pullen, Mark D. Okusa, Sarah Faubel
JASN Dec 2015, 26 (12) 2905-2916; DOI: 10.1681/ASN.2015070832
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  • Article
    • Abstract
    • Common Concerns about Preclinical Study Design and Reporting That Affect Data Reproducibility
    • Therapeutic Intervention Studies in CI-AKI
    • Therapeutic Intervention Studies with EPO in AKI
    • Recommendations, Implementation, and Challenges
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