As of 24 July 2022, 224 reports involving CAR-T cells in VigiBase® were gathered in the SMQ “acute renal failure” (Fig. 1), accounting for 3.3% of the 6832 reports involving CAR-T cells. After exclusion of reports mentioning CRS, 70 cases of ARF (2.2%) were collected among the remaining 3149 reports involving CAR-T cells. Most patients were male (137, 61.2%), with a median age of 60 years (IQR 27–70, min–max 4–76). The USA issued most reports (177, 79.0%), followed by France (14, 6.3%) and Germany (12, 5.4%). Among healthcare professionals, physicians were the most frequent reporters (114, 50.9%) followed by pharmacists and others (85, 37.9%). The three most reported CAR-T cells were tisa-cel (108 reports, 48.2%, including 36 pediatric reports), axi-cel (82, 36.6%), and brexu-cel (17, 7.6%). The characteristics of the respective reports are compared in Table 1. We found respectively nine (4.0%) and eight (3.6%) reports with ide-cel and liso-cel, while no report was associated with cilta-cel.

Reports of acute renal failure involving CAR-T cells. Upper horizontal axis: absolute number of reports. Lower horizontal axis: information component with its 95% confidence interval

The median time to onset was 7 days (IQR 3–18, min–max 2–526 days). The most frequently co-reported MedDRA terms (Table 2) were cytokine release syndrome (154, 68.8%), pyrexia (85, 37.9%), neurotoxicity (72, 32.1%), hypotension (69, 30.8%), and hypoxia (46, 20.5%). Hemophagocytic lymphohistiocytosis was mentioned in 19 (8.5%) reports, and tumor lysis syndrome in 11 (4.9%) reports. Two reports (0.9%) mentioned an effect belonging to the proteinuria SMQ, both involving tisa-cel. Suspect co-reported active ingredients reported in more than five cases included only three drugs: cyclophosphamide (22, 9.8%), fludarabine (21, 9.4%), and tocilizumab (14, 6.3%). After exclusion of reports with CRS, the active ingredients reported in more than five reports were cyclophosphamide and fludarabine, each in nine (12.9%) reports. All reports were deemed serious, including 121 deaths (54.0%) and 64 life-threatening reactions (28.6%). Among surviving patients, 59 recovered or were recovering (57.3%) and 20 did not recover (19.4%). The outcome was unavailable in 24 reports (Fig. 2). Among reports without CRS, displaying an available outcome and involving surviving patients, 14 patients recovered from ARF (66.7%).

Outcome of acute renal failure reports

Disproportionality analyses are displayed in Fig. 1. The positive control, cisplatine, yielded a statistically significant IC of 1.9 (95% CI 1.85–1.93), whereas the negative control, procarbazine, showed a nonstatistically significant IC of 0.1 (95% CI −0.2 to 0.5). As a whole, CAR-T cells were significantly associated with ARF, with an IC of 1.5 (95% CI 1.3–1.7). Specifically, acute renal failure was disproportionately reported with ide-cel (IC 1.9, 95% CI 0.8–2.7), tisa-cel (IC 1.9, 95% CI 1.6–2.1), brexu-cel (IC 1.8, 95% CI 1.0–2.4), liso-cel (IC 1.6, 95% CI 0.4–2.4), and axi-cel (IC 1.1, 95% CI 0.7–1.4). ARF was mentioned in 4.2% of the total 2570 reports with tisa-cel (3.7% of the total 1945 adult reports), whereas it was mentioned in 2.4% of the 3464 reports with axi-cel (p < 0.001).

ARF was still disproportionately reported with tisa-cel after exclusion of pediatric reports (IC 1.6, 95% CI 1.3–1.9). Besides, rituximab, cyclophosphamide, doxorubicin, and vincristine (RCHO) were significantly associated with ARF (IC 0.7, 95% CI 0.66–0.74). The comparative IC of ARF with CAR-T cells (using RCHO as the background comparator) was still statistically significant (IC 0.8, 95% CI 0.6–1.0).

After exclusion of all reports mentioning CRS, there was still a significant disproportionate reporting of ARF with CAR-T cells (IC 1.0, 95% CI 0.6–1.3). Cases of ARF co-reported with CRS were compared with cases of ARF without CRS. There was no significant difference between the ages of patients suffering from ARF with and without CRS (respectively 47.8 and 52.8, p = 0.19), nor between their fatality rates (p = 0.12). However, patients presenting with ARF without CRS were more likely to be men (75.8% versus 58.4% of patients with CRS, p < 0.05). The comparison between ARF reports mentioning or not CRS is detailed in Table 3.

As of 24 July 2022, 125 reports involving CAR-T cells mentioned at least one of the queried hydroelectrolytic disorders. Most patients were male (72, 63.2%), with a median age of 59 years (IQR 18–68, min–max 4–79). Most cases were reported in the USA (106, 84.8%), specifically by physicians or other health professionals (118, 94.4%). Tisa-cell (63 reports, 50.4%), and axi-cel (50, 40.0%) were the most frequently reported CAR-T cells. No report involved cilta-cel.

The median time to onset was 7 days (IQR 3–16, min–max 2–21). The most frequently co-reported terms were cytokine release syndrome (88, 70.4%), pyrexia (63, 50.4%), neurotoxicity (42, 33.6%), and hypotension (41, 32.8%). Hydroelectrolytic disorders and ARF occurred concomitantly in 35 reports (Fig. 3). Suspect co-reported active ingredients reported in more than five cases included cyclophosphamide (10, 8.0%) and fludarabine (10, 8.0%). All reports were deemed serious, including 57 deaths (45.6%) and 32 life-threatening reactions (25.6%).

Overlap between reports of acute renal failure (ARF), hydroelectrolytic disorders (HED), and cytokine release syndrome (CRS). Numbers of reports are shown for each section

Details on the reported HED are available in Fig. 4. The most frequently reported HED was hyponatremia (42, 39.6%), followed by metabolic acidosis (34, 27.2%) and hypokalemia (19, 15.2%). CAR-T cells were involved in 0.4% and 0.3% of all reports of hyperphosphatemia and hypernatremia, respectively. They accounted for 0.1% of all reports of each hypophosphatemia and hypercalcemia, while they were involved in less than 0.1% of all reports of the other queried HEDs.

Reports of hydroelectrolytic disorders involving CAR-T cells, ranked by number of reports. Upper horizontal axis: absolute number of reports. Lower horizontal axis: information component with its 95% confidence interval

Significantly disproportionate reporting was found for hypernatremia (IC 3.1, 95% CI 2.2–3.8), hyperphosphatemia (IC 3.1, 95% CI 1.8–3.9), hypophosphatemia (IC 2.0, 95% CI 0.6–2.9), metabolic acidosis (IC 1.8, 95% CI 1.2–2.2), hyponatremia (IC 1.6, 95% CI 1.1–2.0), and hypercalcemia (IC 1.4, 95% CI 0.5–2.1). There were no reports of hypomagnesemia, nor metabolic alkalosis involving CAR-T cells. Hyperphosphatemia occurred concomitantly with CRS in all cases, and with tumor lysis syndrome in three out of seven (42.9%) cases. Otherwise, tumor lysis syndrome was mentioned in two reports of hyperkalemia, and one case of hypocalcemia.