In an interview with Pharmacy Timesprofessor of medicine Nelson Lung, MD, consultant to both the Division of Nephrology and Hypertension and the Division of Hematology, Department of Internal Medicine, notes the importance of understanding and managing kidney disease associated with hematologic malignancies and drug therapies. Leung also highlights treatment advances and potential research directions. He will present on the panel “Thrombotic Microangiopathy: Drugs and Cancer” during ASN Kidney Week in Philadelphia, PA (November 2, 2023 to November 5, 2023).
Pharmacy Times: What drugs and cancers 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 types of cancer that can cause TMA; however, the most common are mucin-producing cancers, such as those of the gastrointestinal tract or breast cancer. In terms of medications, a number of different medications have been associated with TMA. The most common cancer drug is gemcitabine. Now, unfortunately, gemcitabine is used in a number of different cancers, so you’ll see that it’s actually very common because of that.
Another class of drugs commonly associated with TMA are vascular endothelial growth factor (VEGF) inhibitors and multiple tyrosine kinase inhibitors. They have a direct mechanism for causing kidney damage and TMA by disrupting VEGF.
Another class of drugs now commonly seen to cause TMA is the proteasome inhibitors used to treat multiple myeloma, and in particular of the 3 proteasome inhibitors – ixazomib, bortezomib and carfilzomib – carfilzomib appears to be the first to cause most of the TMA. Finally, there are various drugs, such as interferon and ticlopidine, that can also cause drug-induced TMA.
Pharmacy Times: Leukemias and lymphomas are mentioned as causes of various kidney lesions. Can you provide examples of renal complications that can arise from these hematologic malignancies and how these kidney-related problems can manifest in patients?
Leung: Kidney involvement is actually not uncommon in patients with leukemia and lymphomas. Usually, in leukemias, the complication is through direct infiltration of the leukemia into the kidneys. In lymphoma, the causes of kidney damage [are] more complicated. Of course, direct infiltration also occurs, but unlike leukemias, lymphomas can produce monoclonal proteins that can damage the kidney, either by deposition—as in monoclonal gammopathy with renal significance—or monoclonal proteins can activate complement-inducing TMA . So, a number of different mechanisms can occur leading to acute kidney injury (AKI) and these patients, and these patients usually have progressive AKI. It may be subtle at first, but certainly some of these patients can develop quite a lot of AKI as a result of TMA or leukemic and lymphoma infiltration.
Pharmacy Times: What potential advances or research directions do you foresee in this setting, particularly in the understanding and management of kidney disease associated with hematologic malignancies and drug therapies? How can these developments further improve patient outcomes and care?
Leung: Yes, there have been tremendous advances in the treatment of lymphomas as well as multiple myeloma. In addition to newer drugs, there is now chimeric antigen receptor T-cell immunotherapy as well as bispecific. Both therapies greatly increased the hematologic response in these patients, and … because recovery of renal function is dependent on the hematologic response, we should look for a greater renal response with the newer therapies.
I think that in addition to the advances in the world of hematology, there are developments in the world of glomerular diseases that we can benefit from. These are things like complement inhibitors, which can help reduce kidney damage from monoclonal immunoglobulin-induced complement activation, and other kidney-protective drugs, like SGLT2 inhibitors, should also be investigated in some of these diseases.