Background: Acute renal failure (ARF) in intensive care unit patients continues to have mortality rates exceeding 70%, despite hemodialysis or continuous renal replacement therapy (CRRT). The delivery of cellular metabolic function to CRRT may provide more complete renal replacement therapy, thereby changing the natural history of this disease process. An FDA-approved Phase I/II clinical trial on 10 patients has been completed, and demonstrated that this experimental treatment can be delivered safely for up to 24 hours.
Methods: The bioartificial kidney is a synthetic hemofilter connected in series with a bioreactor cartridge containing approximately 10(9) human proximal tubule cells, as a renal tubule assist device (RAD), within an extracorporeal perfusion circuit utilizing standard hemofiltration pump systems. All 10 patients had ARF and multiorgan failure (MOF), with predicted hospital mortality rates averaging above 85%.
Results: Data indicate that the RAD maintains viability, durability, and functionality in this ex vivo clinical setting. The device also demonstrated differentiated metabolic and endocrinologic activity, with glutathione degradation and endocrinologic conversion of 25-OH-D(3) to 1,25-(OH)(2)-D(3). All but one treated patient with more than a 3-day follow-up in the intensive care unit showed improvement as assessed by acute physiologic scores 1 to 7 days following therapy. Six of the 10 treated patients survived past 30 days. One patient expired within 12 hours after RAD treatment due to his family's request to withdraw ventilatory life support. Three other patients died due to complications from acute or chronic comorbidities unrelated to ARF or RAD therapy. Plasma cytokine levels suggest that RAD therapy produced dynamic and individualized responses in patients. For the subset of patients who had excessive proinflammatory levels, RAD treatment resulted in significant declines in granulocyte colony stimulating factor (G-CSF), interleukin (IL)-6, IL-10, and IL-6/IL-10 ratios.
Conclusion: The addition of human renal tubule cell therapy to CRRT has been accomplished and demonstrates metabolic activity with systemic effects in patients with ARF and MOF. These initial clinical results are encouraging, so that a randomized, controlled Phase II clinical trial is underway to further assess the clinical safety and efficacy of this new therapeutic approach.