Acute renal failure and chronic renal disease (CRD) are distinctly different disease processes. The current therapy for both disorders is suboptimal. ARF arises from toxic or ischemic (usually simultaneous) tubule damage from antibiotics, chemo-therapeutic agents, or shock during infectious or major operative procedures. The development of ARF in a hospitalized patient results in a 5 to 8 fold higher risk of death (Chertow et al. (1998), AM. J. MED. 104:343-348; Bates et al. (2001), CLIN. INFECT. DIS. 32:686-693; Humes (1995), KIDNEY INT. 48:S26-S32) with overall mortality rates exceeding 50%. However, if the patient survives the episode of ARF, the regenerative repair processes within the kidney can result in a return of kidney function in 90 to 95% of patients with this acute disorder. Sepsis and cardiorenal syndrome are also acute renal diseases and lead to multiorgan dysfunction.
Sepsis frequently leads to ATN, ARF and MOF with approximately 700,000 cases per year in the United States. The most serious forms of sepsis result in severe sepsis (250,000 annual cases in the U.S.) or septic shock (85,000 annual cases in the U.S.) with mortality rates of greater than 30 and 50 percent, respectively (Schrier et al. (2004), N. ENGL. J. MED. 351(2):159-169).
CRS is defined as a clinical disorder in patients with concomitant cardiac congestive heart failure (CHF) and renal dysfunction in which the therapy to relieve the congestive symptoms of heart failure, usually with diuretics, results and is limited by further declines in renal function. Currently, five million people in the U.S. have cardiac failure, with 350,000 of them having CRS (Shlipak et al. (2004), CIRCULATION 110(12):1514-1517). Declining renal function in patients with CHF is the most predictive variable for survival rates, not cardiac function (Gottlieb et al. (2002), J. CARD. FAIL. 8(3):136-141; Fonarow et al. (2005), JAMA 293(5):572-580), thus highly suggestive of a nephrogenic etiology of this syndrome. Current therapies for acute decompensation of heart failure with renal insufficiency are ineffective. In fact, diuretic resistance in CRS results in an increased use of inotropic agents with higher risk of cardiac arrhythmias and ischemia.
Unlike ARF, CRD is an irreversible process of progressive kidney damage commonly from diabetes and hypertension which leads to end-stage renal disease. Patients with ESRD on dialysis continue to have major medical, social and economic problems and a life expectancy of only 4-5 years (Iglehart (1993), N. ENGL. J. MED. 328:366-371; Excerpts from United States Renal Data System: Annual Data Report (1998), AM. J. KIDNEY DIS. 32:S69-S80; Xue et al. (2001), J. AM. SOC. NEPHROL. 12:2753-8; Cukor et al. (2007), J. AM. SOC. NEPHROL. 18:3042-3055). While the standard for kidney replacement therapy for ESRD remains organ transplant, with less than 10,000 kidney transplants completed each year and the current number of patients awaiting transplantation approaching 60,000 (Collins et al. (2005), AM. J. KIDNEY DIS. 45(1 Suppl 1):A5-7), the need far exceeds availability. For all disease processes, available renal replacement therapies consisting of hemofiltration, hemodialysis or chronic ambulatory peritoneal dialysis are non-physiologic and fail to address the homeostatic, regulatory, metabolic, and endocrine functions of the kidney. Patients with ESRD are at high risk for cardiovascular and infectious diseases despite conventional renal replacement therapy. A recent clinical trial failed to show survival benefit from increased doses of dialysis above the current standard of care (Iglehart (1993), N. ENGL. J. MED. 328:366-371), suggesting that there are important metabolic derangements not adequately treated with conventional dialytic treatment. Survival of renal transplant recipients far exceeds that of age-, sex-, and risk-matched controls awaiting transplant, indicating that there is some metabolic function provided by the kidney beyond filtration. Candidate biological markers that are known to be dysregulated in ESRD, correlated with poor outcome and linked to known mechanisms of disease, are markers of inflammation and oxidative stress. ESRD currently effects over 430,000 U.S. patients and has an annual cost of more than 25 billion dollars, and patient numbers are expected to increase to 2.24 million by 2030 (Collins et al. (2005), AM. J. KIDNEY DIS. 45(1 Suppl 1):A5-7). Thus, the development of renal epithelial cell (REC) therapy to replace these functions of the kidney promises to add significant value to the current suboptimal treatments of renal failure.