Ex-Vivo Expanded Mesenchymal Stem Cells To Repair The Kidney And Improve Function 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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Serum creatinine concentration.
To evaluate the rate of renal function loss up to 15 days post-cisplatin infusion.
15 days post-cisplatin infusion
Giuseppe Remuzzi, MD
Department of Immunology and Clinical Transplantation/Mario Negri Institute for Pharmacological Research and Ospedali Riuniti of Bergamo
Italy: Ministry of Health