Odronextamab

The kidney injury is a downstream consequence of on-target pharmacology, not direct nephrotoxicity. By synapsing T cells onto CD20+ B cells, odronextamab triggers rapid, synchronous B-cell lysis that drives two overlapping injury pathways (Joseph, Cells 2022, reviews this exact mechanism for T-cell-engaging therapies). (1) Tumor lysis syndrome: massive release of intracellular purines, phosphate, and potassium produces hyperuricemia, hyperphosphatemia, and hyperkalemia; uric acid and calcium-phosphate then precipitate as intratubular crystals, causing obstructive/inflammatory crystal nephropathy and AKI (Howard, Nat Rev Dis Primers 2024; Johnson, Am J Kidney Dis 2018). (2) Cytokine release syndrome: a surge of IL-6, IFN-gamma, TNF, and other cytokines causes fever, vasodilation, capillary leak, and hypotension that reduce renal perfusion (prerenal/hemodynamic AKI), and if sustained can progress to ischemic acute tubular necrosis; severe or septic CRS can compound this. Cytokine-mediated podocyte/tubulointerstitial injury has also been described with related CD3 engagers (Acharya, Kidney Med 2021, reports collapsing glomerulopathy and AKI during CRS with the CD19xCD3 engager blinatumomab). Electrolyte derangements — including the frequently reported hypophosphatemia, plus TLS-driven hyperphosphatemia, hyperkalemia, hyperuricemia, and secondary hypocalcemia — are part of the same on-target lysis cascade. The antibody itself is cleared by reticuloendothelial catabolism, not by the kidney.

AKI is typically part of a systemic syndrome rather than an isolated creatinine rise. With CRS the patient is febrile, tachycardic, and hypotensive (often with hypoxia), and the kidney injury appears as oliguria and a rising creatinine tracking the hemodynamic insult. With TLS the picture is a rapid rise in uric acid, phosphate, potassium, and LDH with a falling calcium, sometimes with arrhythmia, cramps/tetany, and AKI within days of an effective dose. Hypophosphatemia is a common isolated laboratory finding, and other electrolyte shifts (hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, hypomagnesemia) cluster around the lysis/CRS window. Infection/sepsis is frequent in this heavily pretreated population and can be an independent or additive driver of AKI.

Management targets the syndrome, not the antibody. For CRS-related AKI: supportive hemodynamics (IV fluids, and vasopressors if needed) with IL-6 blockade (tocilizumab) with or without corticosteroids for the CRS itself, per grade — treating the cytokine driver relieves the prerenal insult. For TLS: aggressive IV hydration, rasburicase for significant hyperuricemia (allopurinol for lower risk), management of hyperkalemia and hyperphosphatemia, and correction of calcium only if symptomatic. Provide standard supportive AKI care, avoid additional nephrotoxins, and reassess volume status frequently. Replete phosphate for symptomatic/severe hypophosphatemia and correct other electrolytes. Escalate to renal replacement therapy for refractory hyperkalemia, severe hyperphosphatemia with symptomatic hypocalcemia, volume overload, or oliguric AKI unresponsive to medical therapy. Interrupt or delay odronextamab dosing (and re-step-up) per protocol for severe CRS/TLS or significant AKI; permanent discontinuation is driven by CRS/toxicity severity rather than by an isolated renal number.Lesion-level management framework

No pharmacokinetic renal dose adjustment is defined: odronextamab is a ~150 kDa IgG4 antibody cleared by reticuloendothelial catabolism, not glomerular filtration, so creatinine clearance does not change drug exposure, and dedicated data in severe renal impairment or dialysis are limited. The clinically important dose lever is instead the cycle-1 step-up schedule (e.g., 0.7/4/20 mg), which exists to control CRS/TLS magnitude; dosing is interrupted, delayed, or re-escalated based on CRS/TLS severity and organ toxicity rather than on baseline GFR.

Not dialyzable — a full-size IgG4 monoclonal antibody vastly exceeds any dialysis-membrane cutoff and stays in the vascular/interstitial compartment, so hemodialysis does not remove the drug. This is distinct from treating its complications: renal replacement therapy is a legitimate and sometimes necessary tool for the TLS metabolites (potassium, phosphate, uric acid) and for oliguric AKI, but it clears the metabolic consequences, not the antibody.

The task is to attribute AKI to the right on-target syndrome and to exclude alternatives. TLS crystal nephropathy is favored by hyperuricemia, hyperphosphatemia, hyperkalemia, high LDH, and a falling calcium within 1-3 days of an effective dose, often with a bland urine and low fractional excretion of sodium early. CRS-related prerenal/ischemic AKI is favored by concurrent fever, hypotension, and capillary leak that respond to hemodynamic support and CRS-directed therapy (tocilizumab/steroids). Distinguish both from sepsis-associated AKI (very common in this heavily pretreated, infection-prone population), from contrast or concomitant nephrotoxin exposure, and from pre-existing CKD. Immune/cytokine-mediated glomerular or interstitial injury (as described with related CD3 engagers) is rare and would show proteinuria or an active sediment. Unlike anti-EGFR or platinum agents, this is not a primary tubular/electrolyte-channel toxin — the electrolyte chaos is a marker of tumor lysis, not of a channelopathy.