Preclinical Studies of a Kidney Safe Iodinated Contrast Agent

Abstract

Background and purpose: Contrast-induced acute kidney injury (CI-AKI) is a serious complication of the use of iodinated contrast agents. This problem is particularly acute in interventional neurology and interventional cardiology, probably due to the intra-arterial route of injection, high contrast volumes, and preexisting risk factors of these patients. In an attempt to develop a contrast agent that is less damaging to the kidneys, we have studied the effects of adding a small amount of the substituted cyclodextrin, sulfobutyl-ether-β-cyclodextrin (SBECD), to iohexol in rodent models of renal toxicity.

Methods: Renally compromised mice and rats were injected with iohexol and iohexol-SBECD via the tail vein. The renal pathology, creatinine clearance, and survival benefits of iohexol-SBECD were studied. The safety of direct intra-arterial injection of the iohexol-SBECD formulation was studied in a dog heart model system. Mechanism of action studies in cell culture model using a human kidney cell line was performed using flow cytometry.

Results: Nephrotoxicity was significantly reduced using iohexol-SBECD compared to iohexol alone, at mole ratios of iohexol:SBECD of 1:0.025. SBECD increased survival from 50% to 88% in a rat survival study. In the dog heart model, iohexol-SBECD was safe. Cell culture studies suggest that SBECD interferes with the early stages of contrast-induced apoptosis in a human renal cell line.

Conclusion: We have shown that the addition of a small amount of SBECD (one molecule of SBECD per 40 iohexol molecules) significantly protects rodent kidneys from CI-AKI. Further development of this new formulation of iodinated contrast is warranted.

Keywords: Contrast renal toxicity; acute kidney injury; iodinated contrast safety; kidney protection from contrast; safe contrast for interventional procedures.

Figure 1

Light microscopy of renal tissue of mouse (H&E, PAS, 200×). Iohexol‐treated kidneys indicate pathological changes in the renal cortex (A) and medulla (C) such as tubular vacuolation, tubular dilatation (big arrow), cast formation (thin arrow), loss of brush border (arrow heads), and focal edema (E). Concurrent SBECD (sulfobutyl‐ether β cyclodextrin) administration at mole ratio 1:0.025 iohexol:SBECD significantly attenuated the morphological changes in both cortex (B) and medulla (D).

Figure 2

(A) Effect of adding SBECD (sulfobutyl‐either β cyclodextrin) to iohexol on mouse outer renal cortex pathology measurements for six parameters at a mole ratio of iohexol:SBECD of 1:0.025. (B) Effect of adding SBECD to iohexol on rat outer renal cortex pathology measurements for six parameters at a mole ratio of iohexol:SBECD of 1:0.025.

Figure 3

Dose effect of SBECD (sulfobutyl‐either β cyclodextrin) addition to iohexol on mouse kidney pathology expressed as mole ratio of iohexol:SBECD. The total pathology scores were calculated by combining the six pathology parameters: tubular dilation, tubular casts, tubular vacuoles, loss of brush border, tubular degeneration, and edema.

Figure 4

Summary of rat and mouse pathology data, total pathology scores calculated by combining pathology scores for tubular dilation, tubular casts, tubular vacuoles, loss of brush border, tubular degeneration, and edema.

Figure 5

(A) Comparison of kidney protection by SBECD (sulfobutyl‐either β cyclodextrin) for iopamidol and iohexol in rats at mole ratio 1:0.025, iohexol:SBECD or iopamidol:SBECD. (B) Comparison of kidney protection by SBECD for iodixanol and iohexol in mice at mole ratio of 1:0.025, iohexol:SBECD or iodixanol:SBECD.

Figure 6

Serum creatinine levels at 24 h (mouse) or 48 h (rat) post treatment with iohexol or iohexol‐SBECD (sulfobutyl‐either β cyclodextrin) in renally compromised (RC) rodents at mole ratio 1:0.025.

Figure 7

Survival of RC rats receiving single IV 2.5 g I/kg doses of iohexol or iohexol + SBECD (sulfobutyl‐either β cyclodextrin) at mole ratio of 1:0.025 iohexol:SBECD. N = 8 in each group.

Figure 8

Annexin V, Caspase‐3/7, and SYTOX Flow Cytometry. Protective effects of SBECD (sulfobutyl‐either β cyclodextrin) against iohexol‐induced apoptosis. HK‐2 cells were exposed to treatment for 1 hour with indicated more ratio of SBECD:Iohexol. Mean percentage values were calculated by averaging the results from three independent experiments (n = 2, n = 3, and n = 3, respectively). +/‐ SEM is shown.

Figure 9

(A) Left ventricular contractility changes following bolus dosing into the left coronary artery of iohexol or iohexol:SBECD (sulfobutyl‐either β cyclodextrin) at mole ratio of 1:0.025. (B) QTcV interval changes following bolus dosing into the left coronary artery.