Various Cancer Types, Drugs May Cause Thrombotic Microangiopathy, Impact Kidney Health

In an interview with Pharmacy Times, professor of medicine Nelson Leung, MD, consultant of both the Division of Nephrology and Hypertension as well as the Division of Hematology, Department of Internal Medicine, notes the importance of understanding and managing kidney diseases associated with hematologic malignancies and drug therapies. Leung also highlights advancements in treatment and potential research directions. He will be presenting at the panel “Thrombotic Microangiopathy: Drugs and Cancer” during ASN Kidney Week in Philadelphia, Pennsylvania (November 2, 2023, to November 5, 2023).

Pharmacy Times: What drugs and cancer types are known to cause thrombotic microangiopathy (TMA), and how do they manifest in terms of kidney health?

Nelson Leung: That's a great question. There are actually a number of different cancer types that can cause TMA; however, the most common ones are the mucin-producing cancers, such as those from the GI tract or breast cancer. In terms of drugs, a number of different drugs have been associated with TMA. The most common cancer drug is gemcitabine. Now, unfortunately, gemcitabine is used in a number of different cancer types, so you'll see that it's actually very common because of that.

Another class of drugs that is commonly associated with TMA is the vascular endothelial growth factor (VEGF) inhibitors and the multiple tyrosine kinase inhibitors. These have a direct mechanism of causing kidney injury and TMA through disruption of VEGF.

Another class of drugs that is now commonly seen causing TMA is the proteasome inhibitors used to treat multiple myeloma, and particularly of the 3 proteasome inhibitors—ixazomib, bortezomib, and carfilzomib—carfilzomib seems to be the 1 that is causing most of the TMAs. And then finally, there are miscellaneous drugs, such as interferon and ticlopidine, that can also cause drug-induced TMA.

Pharmacy Times: Leukemias and lymphomas are mentioned as causes for various kidney lesions. Can you provide examples of renal complications that can arise from these hematologic malignancies, and how these kidney-related issues may present in patients?

Leung: Kidney involvement is actually not uncommon in patients with leukemia and lymphomas. Typically, in leukemias, the complication is through direct infiltration of the leukemia into the kidneys. In lymphoma, the causes of kidney injury [are] more complex. Certainly, direct infiltration is also seen, but unlike leukemias, lymphomas can produce monoclonal proteins that can injure the kidney, either through deposition—like in monoclonal gammopathy of renal significance—or the monoclonal proteins can activate complement-causing TMA. So, a number of different mechanisms can occur, resulting in acute kidney injury (AKI) and these patients and these patients typically present with progressive AKI. It can be subtle at first, but certainly, some of these patients can develop quite AKI resulting from the TMA or the leukemic and lymphoma infiltration.

Pharmacy Times: What potential advancements or research directions do you foresee in this setting, particularly in understanding and managing kidney diseases associated with hematologic malignancies and drug therapies? How can these developments further improve patient outcomes and care?

Leung: Yeah, there's been tremendous advances in the treatment of lymphomas as well as multiple myeloma. Aside from the newer drugs, now there's immunotherapy with chimeric antigen receptor T-cell therapy, as well as bispecifics. Both of these therapies tremendously increased the hematologic response in these patients and…since the kidney function recovery is dependent on the hematologic response, we should seek greater renal response with the newer therapies.

I think that in addition to the advancement in the hematology world, there are also development in the glomerular disease world that we can take advantage of. Those are things like complement inhibitors that might help decrease the kidney injury from monoclonal immunoglobulin-induced complement activation, and other renal protective drugs such as SGLT2 inhibitors should be explored in some of these diseases as well.