Acute Kidney Injury and Electrolyte Abnormalities After Chimeric Antigen Receptor T-Cell (CAR-T) Therapy for Diffuse Large B-Cell Lymphoma.

RATIONALE & OBJECTIVE: Cytokine release syndrome is a well-known complication of chimeric antigen receptor T-cell (CAR-T) therapy and can lead to multiorgan dysfunction. However, the nephrotoxicity of CAR-T therapy is unknown. We aimed to characterize the occurrence, cause, and outcomes of acute kidney injury (AKI), along with the occurrence of electrolyte abnormalities, among adults with diffuse large B-cell lymphoma receiving CAR-T therapy. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: We reviewed the course of 78 adults receiving CAR-T therapy with axicabtagene ciloleucel or tisagenlecleucel at 2 major cancer centers between October 2017 and February 2019. Baseline demographics, comorbid conditions, medications, and laboratory values were obtained from electronic health records. AKI was defined using KDIGO (Kidney Disease: Improving Global Outcomes) criteria. The cause, clinical course, and outcome of AKI events and electrolyte abnormalities in the first 30 days after CAR-T infusion were characterized using data contained in electronic health records. RESULTS: Among 78 patients receiving CAR-T therapy, cytokine release syndrome occurred in 85%, of whom 62% were treated with tocilizumab. AKI occurred in 15 patients (19%): 8 had decreased kidney perfusion, 6 developed acute tubular necrosis, 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. Electrolyte abnormalities were common; hypophosphatemia, hypokalemia, and hyponatremia occurred in 75%, 56%, and 51% of patients, respectively. LIMITATIONS: Small sample size; AKI adjudicated by retrospective chart review; lack of biopsy data. CONCLUSIONS: In this case series of patients with diffuse large B-cell lymphoma receiving CAR-T therapy, AKI and electrolyte abnormalities occurred commonly in the context of cytokine release syndrome.

Increased interstitial protein because of impaired lymph drainage does not induce fibrosis and inflammation in lymphedema.

OBJECTIVE: The pathophysiology of lymphedema is incompletely understood. We asked how transcapillary fluid balance parameters and lymph flow are affected in a transgenic mouse model of primary lymphedema, which due to an inhibition of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling lacks dermal lymphatics, and whether protein accumulation in the interstitium occurring in lymphedema results in inflammation. METHODS AND RESULTS: As estimated using a new optical-imaging technique, we found that this signaling defect resulted in lymph drainage in hind limb skin of K14-VEGFR-3-Ig mice that was 34% of the corresponding value in wild-type. The interstitial fluid pressure and tissue fluid volumes were significantly increased in the areas of visible swelling only, whereas the colloid osmotic pressure in plasma, and thus the colloid osmotic pressure gradient, was reduced compared to wild-type mice. An acute volume load resulted in an exaggerated interstitial fluid pressure response in transgenic mice. There was no accumulation of collagen or lipid in skin, suggesting that chronic edema presented in the K14-VEGFR-3-Ig mouse was not sufficient to induce changes in tissue composition. Proinflammatory cytokines (interleukin-2, interleukin-6, interleukin-12) in subcutaneous interstitial fluid and macrophage infiltration in skin of the paw were lower, whereas the monocyte/macrophage cell fraction in blood and spleen was higher in transgenic compared with wild-type mice. CONCLUSIONS: Our data suggest that a high interstitial protein concentration and longstanding edema is not sufficient to induce fibrosis and inflammation characteristic for the human condition and may have implications for our understanding of the pathophysiology of this condition.

Abnormal Savda syndrome: long-term consequences of emotional and physical stress on endocrine and immune activities in an animal model.

OBJECTIVE: To investigate the relationship between emotional status, cold-dry environment and long-term immune responses to the stressors, and the potential pathological mechanisms between causative factors of abnormal Savda syndrome (ASS) and the susceptibility to disease; thus to clarify the ASS, and secondly to identify the optimal ASS animal model for further studies on traditional Uighur therapeutical formulations. METHODS: Sixty mice were randomly and equally divided into 4 groups: control and 3 stress groups. The cold-dry environment was applied by keeping the mice in a climatic chamber. The emotional stress was induced by the application of the repeated electric foot-shocks in the electric foot-shock apparatus. The mice of the combined stress group underwent the repeated electric foot-shock treatment before being housed in the climatic chamber. The experimental routine was repeated for 21 days. In order to look into endocrine and immune stress responses, ELISA was used to determine the serum levels of the hormones corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), Beta-endorphin (ß-END) and corticosterone (CORT), of the cytokines interleukin 2 (IL-2), interleukin 6 (IL-6), interferon-gamma (INF-γ) and tumor necrosis factor-alpha (TNF-α), and of the immunoglobulins immunoglobulin A (IgA), immunoglobulin M (IgM) and immunoglobulin G (IgG). Lymphocyte subsets were analyzed in duplicate in order to determine differences in the T cell ratio. RESULTS: In the cold-dry environment group, the serum levels of CRH, ACTH and CORT were significantly higher than those of the control group, whereas serum ß-END was not found significantly different. In both the repeated electric foot-shock group as well as in the combined stress group the serum levels of CRH, ACTH, ß-END and CORT were significantly higher. Compared to the control animals, the serum concentration of INF-γ was significantly lower in all three different stress groups. The serum level of IL-2 was decreased in the combined stress group whereas the serum TNF-α level was significantly higher. The serum IgG level was significantly higher in all three stress groups, whereas the IgA level was lower in both chronic electric foot-shock group and combined stress group. The IgM level was found significantly higher in the combined stress group only. The percentage of CD4(+) cells in peripheral blood was dramatically decreased in mice exposed to colddry environment, chronic electric foot-shock and combined stress, whereas the percentage of the CD8(+) subset was not significantly different. The CD4(+)/CD8(+) ratios were markedly lower in both cold-dry environment group and combined stress group. CONCLUSIONS: Combined stress can cause hyperactivity of the HPA axis, and an imbalance in the Th1/Th2 cell subset may contribute to illustrate the partial pathological mechanisms of ASS. This study identified this animal model of a combination of physical and emotional stress as an optimal model for further studies on ASS and relative therapies.

Falciparum malaria and the kidney: a model of inflammation.

Renal and renal-related disorders commonly occur in infection with Plasmodium falciparum, which can cause fluid and electrolyte disorders, glomerulonephritis, and acute renal failure (ARF). It appears that ARF and other life-threatening complications in falciparum malaria are not directly caused by the parasite itself but are the result of interaction of mechanical, immunologic, and humoral components. P. falciparum-infected erythrocytes impair microcirculation and cause hemolysis. Glycosylphosphatidylinositol moieties covalently linked to the surface antigens of falciparum malarial parasites appear to act like endotoxin. Glycosylphosphatidylinositol, via CD14, which is a receptor on monocytes, stimulates monocytes to release tumor necrosis factor, which in turn enhances synthesis of various cytokine cascades and mediators. Besides contributing to ARF, these mediators also cause changes in blood volume status. The degree of vasodilatation caused by vasodilating mediators varies with the severity of infection. Increased vascular permeability by the mediators occurs in severe infection, which results in hypovolemia and contributes to ARF. Although the cornerstone of treatment of malaria still is antimalarial drugs, several new modalities of treatment targeting toxin, signal transduction, mediators, and cytokines have great potential.

Cyclosporin immunosuppression mediated by calcium/sodium imbalance.

Cyclosporin immunosuppression is mediated by a calcium/sodium excess during G0 which inhibits further cell cycle progression. The consequences of cyclosporin on electrolyte content were measured in T-lymphocytes stimulated with concanavalin A. Cyclosporin caused an excessive accumulation of extracellular calcium for the first 4 h of lectin stimulation. The nonpermissive calcium content resulted from a reduction in the rate of calcium efflux from the cell. Because cyclosporin did not affect calcium translocation via ATPase but did permit excessive amounts of sodium to enter the resting cell we hypothesized that the calcium excess is caused by a shut-down of the Ca2+/Na+ antiport during the first hours of lectin stimulation. The subsequent normalization of calcium content is coincident with the onset of mRNA synthesis, which suggests development of compensatory mechanisms to alleviate the calcium burden. The G0 calcium excess did not affect other transductive events such as ligand recognition, phosphatidyl inositol metabolism, or adenylate cyclase activation. This study points to the causative mechanism of cyclosporin immunosuppression and emphasized the dynamic role of ions as modulators of normal cell proliferation.