An unresolved medical problem: acute kidney injury
Acute kidney Injury (AKI) is a syndrome that results in a sudden decrease in kidney function and currently is one of the most serious and common health problems in the world associated with severe morbidity and mortality as well as the development of chronic kidney disease (CKD).
Every year, it affects around 13.3 million people, causing 1,7 million deaths. It therefore represents a true epidemic in today's nephrology where 1 in 5 adults and 1 in 3 children worldwide experience AKI during a hospital episode of care with a mortality rate of 50-80%.
Although toxic drug-induced AKI has increased exponentially with an overall mortality of 40.7% (due to more aggressive diagnostic and therapeutic techniques; polymedication and the progressive ageing of the population), 45-70% of all AKIs are associated with sepsis, with mortality as high as 90%.
Sepsis affects nearly 30 million people a year, 9 million of whom eventually die, with one sepsis death occurring every 3.5 seconds. The occurrence of AKI in sepsis is an independent risk factor associated with increased mortality, and it is associated with a poor prognosis in the context of multi-organ dysfunction syndrome.
Early treatment of AKI is one of the best maneuvers to limit damage, but unfortunately, there is still no approved drug therapy for this indication.
Cilastatin, a new therapeutic alternative for acute renal injury
Cilastatin is a specific competitive blocker of renal dehydropeptidase I (DHP-I) enzyme which is located on brush-border cholesterol rafts of renal tubular cells.
Cilastatin has been extensively used in combination with the antibiotic imipenem (Primaxin®, Tienam®) since 1985. Therefore, the efficacy and safety of this combination product in humans is well known ever since and still is being used in the clinical setting.
Our preclinical in vitro and in vivo studies have demonstrated that cilastatin protects the kidney against tubular cell injury and acute kidney injury (AKI) caused by nephrotoxic drugs such as cisplatin, cyclosporine and gentamicin, and other non-toxic conditions such as sepsis.
The binding of cilastatin to DHP-I produces an interruption of cholesterol raft internalization and a reduction in membrane turnover, with two main effects:
1 ) Decreased nephrotoxic compounds uptake.
2 ) Reduction or cancellation of signaling pathway by death receptors.
Specifically, cilastatin prevents internalization, trimerization and signaling through the Fas/Fas ligand complex.
The result is the prevention of programmed cell death and the subsequent damage expansion phase by inhibiting oxidative and inflammatory amplifying cascade of cell damage.