acute kidney injury

Acute kidney injury impairs kidney function and, when severe, can result in kidney failure and death. Although acute kidney injury commonly occurs after kidney transplantation and cardiac surgery, no effective therapies currently exist. 1

ACUTE KIDNEY INJURY AFTER KIDNEY TRANSPLANTATION
(DELAYED GRAFT FUNCTION)

Delayed graft function is a severe form of acute kidney injury resulting from ischemia-reperfusion injury following kidney transplantation. It is distinct from transplant rejection and is most commonly seen in recipients of deceased-donor kidneys. In delayed graft function, the kidney fails to adequately filter the blood and patients require dialysis within the first week after transplantation. 2 Dialysis is expensive and associated with risks, including infection.3 Dialysis does not treat acute kidney injury, but instead is renal replacement therapy for impaired kidneys. Patients with delayed graft function are more likely to experience transplant failure and have higher mortality rate. 4, 5, 6 Delayed graft function is expensive to the system. Increased hospitalization, re-admissions, and other care amounts to an increase in costs of approximately $20,000 per patient for the transplant center. Dialysis, for which Medicare spending per ESRD patient per year was approximately $90,000 in 2017, is also a contributing factor to the economic burden of DGF.

CARDIAC SURGERY-ASSOCIATED
ACUTE KIDNEY INJURY (CSA-AKI)

Acute kidney injury associated with cardiac surgery is another form of acute organ injury. During cardiac surgery, cardiopulmonary bypass (the use of a heart-lung machine) is often employed to support the patient’s heart and lung function. CSA-AKI is caused by many factors, including shear stress during cardiopulmonary bypass and injuries from nephrotoxic drugs and contrast agents. In addition, an important driver of CSA-AKI is ischemia-reperfusion injury, which is similar to the injury seen in DGF.

CSA-AKI is a frequent complication of cardiac surgery, with approximately 145,000 cases per year in the United States, or nearly one-third of the approximately 470,000 coronary bypass and valve replacement surgeries performed annually in the United States. 5,8,9

THE SCIENCE BEHIND

ANG-3777

ANG-3777 is a small molecule designed to mimic the biological activity of HGF, thereby activating the c-Met cascade of pathways involved in tissue repair and organ recovery. ANG-3777 has demonstrated several similarities to HGF, including c-Met dependence and selective c-Met receptor activation, without acting on other growth factor receptors. In addition, it has a substantially longer half-life than HGF.*

*ANG-3777 is currently being studied in clinical trials to determine if it is safe and effective. It is not approved by any regulatory authority.

THE ROLE OF THE HEPATOCYTE GROWTH FACTOR/C-MET PATHWAY IN ACUTE ORGAN INJURY

Decades of research have led to a deep understanding of the hepatocyte growth factor (HGF)/c-MET pathway and the role it plays in the repair of injured organs.

When an organ is injured, the body releases HGF into the blood. HGF then travels to the site of the injury and binds to the promoter region of the c-Met receptor gene on cells in that location. HGF is the only ligand known to bind to c-Met and cause its activation. The binding of HGF to c-Met triggers a series of downstream proteins responsible for preventing apoptosis (cell death), stimulating cell proliferation, promoting angiogenesis (formation of new blood vessels), improving cellular motility, and remodeling the extracellular matrix, all in order to restore normal structure and function to the injured organ.

In the illustrative diagram to the left, some of the essential proteins in transducing and amplifying the c-Met signal are shown, along with a representative set of actions that these proteins are responsible for inducing. For instance, the adaptor proteins Grb2, SHC, and Gab1, among others, are responsible for recruiting downstream signaling proteins including the following (and some of their respective actions):  Ras-Raf-MEK-ERK/MAPK: increase in mRNA translation, promote angiogenesis, stimulate cell proliferation, prevent apoptosis and promote tubulogenesis (restoring normal tissue architecture);  PI3K: increase cell motility, promote tubulogenesis, prevent apoptosis and induce cellular differentiation;  AKT/mTOR: prevent apoptosis, increase metabolism, increase cell motility, promote angiogenesis and transcription regulation;  Stat-3: stimulate cell proliferation, prevent apoptosis and induce cellular differentiation; and  FAK: alter cellular adhesion, increase cell motility and promote angiogenesis.

HGF/c-Met also downregulates the pro-fibrotic cytokine, TGF- (transforming growth factor beta) to prevent the organ from entering the progressive cycle of fibrosis (growth inhibition, extracellular matrix deposition and cell death). These interactions are influenced by the cellular environment in which these pathways are activated. For example, in the setting of ischemia-reperfusion injury, c-Met is upregulated and HGF/c-Met signaling is amplified, thereby initiating the cascade of organ repair.

As shown in the following figure, HGF is released into circulation and reaches peak concentration levels approximately two hours after acute organ injury (the solid blue line). However, the c-Met receptor is synthesized more slowly (dashed orange line) and peaks approximately 24 hours following the injury, resulting in insufficient levels of HGF available relative to the peak expression levels of c-Met on the cell surface. 10

Our founder and current Executive Chairman and Chief Scientific Officer, Itzhak Goldberg, M.D., has made seminal contributions to the understanding of HGF and fibrotic pathways.

REFERENCES

  1. Bellomo R, et al. “Acute kidney injury.” The Lancet (2012); 380: 756-766.
  2. Perico N, et al. “Delayed graft function in kidney transplantation.” The Lancet (2004); 364:1814-1827.
  3. Centers for Disease Control and Prevention. “Dialysis Safety.” October 2017.
  4. Shoskes D, et al. “Delayed Graft Function in Renal Transplantation: Etiology,cManagmeent and Long-term Significance.” The Journal of Urology (1996); 155: 1831-1840.
  5. Brown, et al., “Duration of acute kidney injury impacts long-term survival after cardiac surgery. The Annals of thoracic surgery. (2010); 90(4).
  6. Schnuellee, P et al., “Comparison of early renal function parameters for the prediction of 5-year graft survival after kidney transplantation.” Nephrology Dialysis Transplantation (2006); 22: 235–245.
  7. Mannon, RB “Delayed Graft Function: The AKI of Kidney Transplantation.” Nephron (2018); 140 (2): 94-98.
  8. Benjamin et al. “Forecasting the future of cardiovascular disease in the United States; a policy statement from the American Heart Association.” Circulation. (2018);137:e67–e492.
  9. O’Neal JB, et al., “Acute kidney injury following cardiac surgery; current understanding and future directions.” Critical Care (2016); 20:187.
  10. Liu Y, et al. Up-regulation of hepatocyte growth receptor: an amplification and targeting mechanism for hepatocyte growth factor action in acute renal failure.” Kidney International (1999); 55: 442–453.