Renal Toxicity Mediated by Continuous Infusion of Recombinant lnterleukin-2

Abstract

Interleukin-2 (IL-2), a potent lymphokine with antitumoral activity, was used in continuous intravenous infusion for 5 days (18,000,000 IU/m²/day) in 9 treatment cycles in 5 patients with metastatic colorectal carcinoma. During the infusion, patients received agressive fluid replacement titrated by invasive hemodynamic monitoring, aiming at a stable central volemia. Body weight went up an average of 4.5 kg in 5 days, mean arterial blood pressure dropped slightly from day 1 to day 5 (105.4 ± 11.6 to 86.1 ± 12.5 mm Hg, p < 0.05), systemic vascular resistance decreased from 1304.7 ± 242.1 to 871.7 ± 237.2 dyn/ s/cnr5 (p < 0.05), with stable pulmonary capillary wedge pressure, cardiac output and central venous pressure. The urinary output significantly dropped from 1.9 ± 1.2 to 0.2 ± 0.1 ml/min (p < 0.05) with very significant rises in serum creatinine from 76.0 ± 28.3 to 242.2 ± 144.9 μmol/l (0.86 ± 0.32 to 2.47 ± 1.64 mg/dl) and N-acetyl-β-D-glucosaminidase urinary activity from 4.97 ± 5.0 to 23.0 ± 12.1 U/l, and significant decrement of creatinine clearance (1.86 ± 0.65 to 0.29 ± 0.27 ml/s or Ill.5 ± 38.9 to 17.1 ± 16.6 ml/min) and urinary sodium (113.8 ± 78.3 to 9.0 ± 6.7 mmol/l). Urine sediment evolved from normal at day 1 to 9.0 ± 3.7 epithelial cells/mm³ and 6.9 ± 3.6 brown casts/mm3 (p = 0.001). We concluded that cancer treatment with IL-2 in continuous infusion, even with stable hemodynamics, induces an acute renal failure in most patients treated.

Renal haemodynamics, sodium and water reabsorption during continuous intravenous infusion of recombinant interleukin-2

“…Prerenal as well as intrinsic renal lesions have been proposed [11,12,15,18,19]. The kidneys are susceptible to vascular leak [36].…”

“…A case report demonstrated a marked decrease in effective renal plasma flow and creatinine clearance [13]. Two additional studies demonstrated a decrease in creatinine clearance, urinary output and sodium clearance and an increase in urinary N-acetyl-β-D-glucosaminidase activity [18,19].…”

Renal haemodynamics, sodium and water reabsorption during continuous intravenous infusion of recombinant interleukin-2

“…Prerenal as well as intrinsic renal lesions have been proposed [11,12,15,18,19]. Prerenal as well as intrinsic renal lesions have been proposed [11,12,15,18,19].…”

“…non-steroidal antiinflammatory drugs (NSAIDs), vasopressors, volume expanders, diuretics and anti-emetics, which all may have contributed to the observed renal side-effects. Two additional studies demonstrated a decrease in creatinine clearance, urinary output and sodium clearance and an increase in urinary N-acetyl-β-D-glucosaminidase activity [18,19]. It is, however, well recognized that changes in plasma creatinine level and endogenous creatinine clearance are poor predictors of day-to-day changes in renal function [17].…”

OKT3‐induced nephrotoxicity is associated with release of group II secretory phospholipase A2

“…The nephrotoxic effect of OKT3 has been ascribed to transient intragraft T-cell activation and lympholysis, resulting in local production of cytokines that might mediate kidney damage [3.4]. However, the nephrotoxic effect of OKT3 resembles the transient acute renal failure seen in patients receiving recombinant interleukin 2 (IL-2) immunotherapy [7]. This makes it likely that circulating factors are responsible for the nephrotoxicity seen in these patient groups.…”