Mesenchymal Stem Cells In Cisplatin-Induced Acute Renal Failure In Patients With Solid Organ Cancers

Since its introduction into clinical trials, cisplatin (cis-diammine-dichloro-platinum) has had a major impact in cancer medicine, changing the course of therapeutic management of several tumors, such as those of ovary, testes, and the head and neck. Unfortunately, in addition to causing bone marrow suppression, ototoxicity, and anaphylaxis, dose-dependent and cumulative nephrotoxicity is the major toxicity of this compound, sometimes requiring a reduction in dose or discontinuation of treatment. Approximately 25-35% of patients develop evidence of nephrotoxicity following an initial dose (50-100 mg/m2) of cisplatin, due to its preferential accumulation within the proximal tubular cells in the outer medulla of the kidney. Tubular cell events activated by cisplatin toxicity translate into the fact that cisplatin predictably lowers glomerular filtration rate (GFR) in a clear dose-dependent manner even after a single drug exposure. Early proteinuria is mild, as it is glycosuria. Overall these findings indicate that there is a pressing need for way to protect the kidney while administering effective chemotherapeutic agents such as cisplatin.

Present strategies for the treatment of acute renal failure have focused on targeting individual mechanisms thought to contribute to ischemic or toxic insults to the kidney.An alternative possibility is to adopt a novel strategy that would allow regeneration of the injured renal tissue. Renal recovery following acute tubular injury, like that induced by cisplatin treatment, is often a slow process requiring many days to weeks to occur. Attempts to accelerate recovery have focused on the administration of growth factors, hepatocyte growth factor, or insulin-like growth factor-1. While growth factor therapy has been successful in experimental models, no beneficial effects have been observed in limited clinical trials. The ability of extrarenal cells to participate in the regenerative response following post-transplant acute renal failure may hold true for acute renal failure that develops in native kidneys after cisplatin therapy. The rationale for this approach rests on the recent demonstration in mice and in athymic nude rats that stem cells from bone marrow can be used to grow new muscle or blood vessels in heart tissue that has been damaged after myocardial infarction. Similarly, consistent evidence of the beneficial effect of bone-marrow derived cell therapy has been recently reported in humans with ischemic heart disease. This approach has been also successfully extended to repair ischemically and cisplatin injured renal tubules in mice. The observation raises the possibility that adult-derived bone marrow cells could be administered to enhance the recovery from renal injury. Although no human data so far are available, we expect that ex-vivo expanded donor bone-marrow derived mesenchymal stromal cells (MSC) infusion would allow to accelerate tubular regeneration and thus renal function recovery in patients with cisplatin-induced acute renal failure, a disease that, like ischemically-induced acute renal injury, so far has no cure.

Up to now there is no clinical study of repair tissue injury in patients with acute renal failure due to ischemic or toxic insults. Nevertheless, there are clinical data on the effectiveness of MSC infusion in other diseases/conditions like as inborn errors of metabolism,osteogenesis imperfecta,allogeneic HSC transplantation, treatment of acute GVHD, acute myocardial infarction.

The aim of this pilot, explorative, study is to test the feasibility and safety of systemic infusion of donor ex-vivo expanded MSC to repair the kidney and improve function in patients with solid organ cancers who develop acute renal failure after chemotherapy with cisplatin.