Chimeric antigen receptor T-cell (CAR-T) therapy is a type of treatment in which a patient’s T cells are changed in the laboratory so they will attack cancer cells. T cells are first taken from a patient’s blood. The gene for a special receptor that binds to a certain protein pertaining to the tumor on the patient’s cancer cells is then added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR-T cells are grown in the laboratory and given to the patient via infusion. Currently, the FDA-approved CAR-T therapy products are used only for patients with adult B-cell non-Hodgkin’s lymphoma or childhood acute lymphoblastic leukemia who have already been through two unsuccessful standard treatments. However, clinical trials are starting to evaluate CAR-T therapy as a first-line or second-line of treatment for adult lymphoma, childhood acute lymphoblastic leukemia, and even multiple myeloma. 

CAR-T therapy and its complications. CAR-T therapy involves separating out a patient’s T cells using apheresis and then genetically engineering the cells to produce receptors on their surfaces, called CARs. CARs are fusion proteins of an antigen-recognition domain from a monoclonal antibody and 1 or more T-cell receptors. They allow T cells to recognize and attach to specific proteins, namely tumor antigens. T cells are expanded into hundreds of millions of cells and then infused back into the patient, selectively destroying chemotherapy-resistant cancer cells. Patients receiving CAR-T are at risk for developing cytokine release syndrome, an inflammatory response that occurs secondary to cytokine release by infused CAR-T cells. Cytokine release syndrome is characterized by fevers, hypotension, tachycardia, elevated inflammatory marker levels, and end-organ damage, including acute kidney injury and neurotoxicity. Figure 1 from Gupta et al, AJKD. Image © 2019 Dr Xavier Vela Parada, and appears courtesy of the copyright holder.

The most common side effect of CAR-T therapy is called cytokine release syndrome. It’s also known as a “cytokine storm.” About 70-90% of patients experience it, but it’s very short-term and only lasts about five to seven days. Most patients describe it as having a severe case of the flu, with high fever, fatigue, and body aches. It usually starts around the second or third day after the infusion. In all published trials of CD-19–directed CAR-T cells, cytokine release syndrome was observed in >40% of the patients, regardless of the disease studied or the construct of the CAR-T cells. Diagnostic criteria for cytokine release syndrome include fevers for at least 3 consecutive days; C-reactive protein ≥20 mg/dl; at least one clinical sign of toxicity, such as hypotension requiring pressor support; hypoxia (oxygen saturation <90%); and neurologic changes. Cytokine release syndrome can manifest in specific organ systems, including the kidneys.

In a recent study published in AJKD, Gupta et al discuss a single center experience of kidney toxicities associated with CAR-T therapy in treatment of diffuse large B-cell lymphoma. Among 78 patients receiving CAR-T therapy, cytokine release syndrome occurred in 85%, of whom 62% were treated with tocilizumab. Acute kidney injury (AKI) occurred in 15 patients (19%): 8 had decreased kidney perfusion, 6 developed acute tubular necrosis (ATN), and 1 patient had urinary obstruction related to disease progression. Those with acute tubular necrosis and obstruction had the longest lengths of stay and highest 60-day mortality. 6 patients had stage 3 AKI and 3 of these required renal replacement therapy.

Why does AKI occur? In this study, of the 15 patients with AKI, 8 had pre-renal azotemia, and 6 had presumed ATN, and one had urinary obstruction. As stated above, the ATN patients had the highest mortality. The release of high concentrations of cytokines can lead to vasodilation, decreased cardiac output, and intravascular volume depletion due to increased vascular permeability and third spacing of fluids, causing reduced perfusion to the kidneys and AKI. The rise in serum creatinine is noted at approximately 7–10 days post-infusion. Pre-renal AKI and/or acute tubular injury may develop in this setting depending on the severity of hypotension and its duration. Other presumed mechanisms mentioned in the literature for CAR-T therapy-induced AKI have been tumor lysis syndrome, cytokine release syndrome–related cardiomyopathy leading to acute cardio renal syndrome type 1, acute interstitial nephritis, and acute compartment syndrome induced rhabdomyolysis.

Cytokine storm-related toxicities can be treated with anti-cytokine therapy such as anti-IL-6 agent tocilizumab. It can quickly reverse the cytokine storm in most patients. Methylprednisolone 1–2 mg/kg intravenous every 12 hours can be tried in cytokine release syndrome that is refractory to tocilizumab. Pretreatment with chemotherapy to reduce tumor burden and steroids is also considered to be important in the prevention of cytokine release syndrome. Most centers are using anti-IL-6 agents to prevent cytokine storm-related toxicities and the hope is that the incidence of AKI will eventually be lower than reported here.

Additionally, in the initial trials of using CAR-T cells for ALL, several electrolyte disorders were reported. The most common was hypokalemia (47%), followed by hypophosphatemia (37%), and finally hyponatremia (5%). In this study by Gupta et al, electrolyte abnormalities were also common. Hypophosphatemia, hypokalemia, and hyponatremia occurred in 75%, 56%, and 51% of patients, respectively. It is unclear if this is related to CAR-T therapy directly or a result of cytokine release syndrome and the exact mechanisms of these electrolyte disorders remains unclear.

From this single-center study, a big takeaway should be that AKI requiring RRT in the setting of this treatment carries an extremely poor prognosis.  As demand for CAR-T increases for other cancers, nephrologists will be seeing much more AKI and electrolyte abnormalities related to this unique treatment.

– Prepared by Kenar Jhaveri, AJKDBlog Contributor. Follow him @kdjhaveri.

To view Gupta et al (subscription required), please visit AJKD.org.

Title: Acute Kidney Injury and Electrolyte Abnormalities After Chimeric Antigen Receptor T-Cell (CAR-T) Therapy for Diffuse Large B-Cell Lymphoma
Authors: S.Gupta, H. Seethapathy, .A. Strohbehn, M.J. Frigault, E.K. O’Donnell, C.A. Jacobson, S.S. Motwani, S.M. Parikh, G.C. Curhan, K.L. Reynolds, D.E. Leaf, and M.E. Sise
DOI: 10.1053/j.ajkd.2019.10.011