Table 1.

Challenges and recommendations relating to AKI drug development research identified by breakout groups

Breakout GroupChallengesRecommendationsOther Considerations
Delayed Transplant Graft Function groupTiming of therapeutic intervention (before organ procurement, during storage, during transplantation or postoperatively). Potential ethical issues regarding donor informed consent, including challenges with blinding and randomization.Develop therapeutic interventions to use in the operating room to decrease dialysis after transplantationa; include standardized immunosuppressive regimen. Timing of intervention should account for regional differences in practice patterns.Research is needed to enhance understanding of the biologic pathways involved in transplantation:
End point for phase 2 trials is evidence of delayed graft function, defined by UNOS as dialysis within 7 d of transplantation.Refine definition to include a shorter time (<7 d) to require dialysis or a change in kidney function.• Episodes of warm and cold ischemia
Fidelity of delayed graft function animal models to the human condition.Develop small and large animal models of transplantation that include immune responses and comorbidities reflecting the transplant patient population.• Prolonged ischemia
Human transplant AKI is poorly understood.Develop a central repository of biologic samples. Use existing biorepositories to support these efforts (1214).• Reperfusion injury
• Autologous versus allogeneic transplantation
• Orthotopic versus heterotopic placement
• Transplantation in patients with comorbidities
Bioinformatic approaches may help identify extreme clinical or mechanistic phenotypes that could enable sufficiently powered trials with fewer participants.
Primary Prevention groupInterventions that have succeeded in animal models have shown mixed results in clinical trials (9).Identify priority populations; design prevention studiesa:Research evaluating molecular targets in animal models should include well designed, blinded, and appropriately powered dose-response studies that pay close attention to strain background, diet, and other relevant variables (4,9).
• Prevention of cisplatin nephrotoxicity in elderly patients with head, neck, or lung cancer
• Prevention of AKI after PCI
Animal models reflecting priority populations are needed.Develop and refine animal models of chronic, repeated cisplatin administration with comorbidities and/or in older animals (28), building from successful models with cancer (20,21).
Develop and refine animal models for contrast nephropathy; build on existing models involving volume depletion or radiocontrast dye use. Include patient comorbidities and drugs consistent with polypharmacy in older patients.
Pathogenesis of human AKI in prevention settings is poorly understood.Define a molecular signature for AKI in priority populations (AKI related to PCI); profile tissue, blood, and urine. Correlate tissue parameters with urinary and blood markers.
Secondary Prevention groupThere are multiple clinical settings of AKI for secondary prevention studies (e.g., vascular surgery, nephrotoxicity, rhabdomyolysis, postcardiac surgery, sepsis).Define and enrich patient population for phase 2 proof-of-concept studies to decrease costs and facilitate enrollment. Define AKI endophenotypes on the basis of clinical features (e.g., differing baseline kidney function, hemodynamic factors, associated organ dysfunction), comorbidities (e.g., CKD, age, diabetes), genetics (e.g., APOL1 variants), biomarker expression, and population-specific factors. Focus on endophenotypes specific to postcardiac surgeryb and sepsis associated AKIc.
Timing of therapeutic intervention is critical.Develop a point-of-care device to measure real-time change in GFR.Serum creatinine concentration is an imperfect clinical trials tool and a relatively poor measure of GFR (25).
Animal models do not faithfully reflect human AKI.Refine the kidney ischemia–reperfusion injury model to incorporate key components of the cardiac bypass procedure, such as mechanical ventilation or cardiopulmonary arrest (26), as well as patient comorbidities. Use large animals (pigs, sheep), which may offer a more comprehensive range of physiologic readouts (e.g., urine output, BP, GFR, urine electrolytes, albuminuria), and models of comorbid disease (e.g., pneumonia in rabbits/dogs) in AKI research. Credential AKI animal models against patient endophenotypes. Evaluate targets and pathways in animal models and patients; develop assays to measure target engagement.Strengths of animal models:
• Defined the effects of ischemia and toxins on the various kidney cell types
• Led to definition of basic cellular principles of AKI (e.g., cell hierarchies, changes in cell differentiation, phases of injury and repair), which appear to reflect human AKI
• Allow evaluation and testing of molecular targets to determine their contribution to cell function during AKI
• Allow interactions between various cell types to be explored to establish hypotheses to build potential therapeutic approaches
Complex AKI animal models will increase cost and potentially decrease “throughput” of studies.
Hasten Recovery groupAssessing kidney recovery and reserve.Develop and use methods to understand and assess kidney recovery and kidney function reserve.Kidney biopsies may allow clinicians to determine if or when patients achieve full kidney recovery.
Carry out phase 2 proof-of-concept studies in the context of kidney recovery and patient recoverya:
• Patients with relatively normal baseline kidney function who experience AKI and recover by improving kidney function (e.g., patients with sepsis in the absence of known baseline CKD)
• Patients with AKI superimposed on CKD
Develop and refine animal models.Ischemic and septic animal models should include comorbidities and should be standardized across sites to enable data comparison. Develop hypotensive animal models and animal models of “stuttering” disease.
Metrics for kidney recovery should include kidney function, histology, and biomarkers of injury and fibrosis.
  • UNOS, United Network for Organ Sharing; PCI, percutaneous coronary intervention.

  • a See Table 2.

  • b Population-specific factors could include differences in the surgical procedure (e.g., coronary artery bypass grafting versus valvular surgery, on-pump versus off-pump, presurgical versus intraoperative contrast administration, role and type of anesthesia).

  • c Population-specific factors could include sepsis etiology (i.e., infection site, organism, endotoxin levels).