title: The osmolality of nonionic, iodinated contrast agents as an important factor for renal safety.
abstract: OBJECTIVE
  Nonionic iodinated contrast agents (CAs) can be divided into monomeric, low-osmolar, and dimeric, iso-osmolar classes. In clinical practice, renal tolerance of CAs is a concern, especially in patients with impaired renal function. With regard to renal safety, we wanted to evaluate the role of osmolality and viscosity in renal tolerance.
  
  
  METHODS
  We generated a formulation (iodixanol/mannitol) consisting of the dimeric iodixanol with an osmolality of the monomeric iopromide. Male Han-Wistar rats were intravenously injected with low-osmolar iopromide 300, iso-osmolar iodixanol 320, and iodixanol/mannitol. Saline and diatrizoate were used as controls. A total number of 227 rats were used in the following experiments. We compared the impact of osmolality on renal iodine retention using computed tomography 2 and 24 hours postinjection (p.i.). The animals were killed 2, 24, and 72 hours after injection, and the kidneys were excised for further investigations. Changes in renal cell proliferation were analyzed by 5-bromo-2'-deoxyuridine incorporation 48 hours p.i. as a degree of tissue regeneration after induced injury. To specify potential renal injury, we quantified the expression of acute kidney injury (AKI) markers (kidney injury marker-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL], and plasminogen activator inhibitor-1 [PAI-1]) by quantitative real-time polymerase chain reaction. Furthermore, the kidneys were analyzed histologically, including immunofluorescence analysis.
  
  
  RESULTS
  After intravenous application of the CAs into Han-Wistar rats, renal iodine concentration was increased (3-fold) for iodixanol 2 hours p.i. and iodine retention was detected to be prolonged 24 hours p.i. compared with iopromide injection (iodixanol, 520 ± 50 Hounsfield Units [HU] vs iopromide, 42 ± 5 HU). The higher iodine concentration 2 hours p.i. upon iodixanol injection was reduced almost to the level of iopromide when injecting iodixanol/mannitol (iopromide: 289 ± 68 HU vs iodixanol/mannitol: 343 ± 68 HU). In addition, iodixanol application induced increased renal cell proliferation (2.7-fold vs saline), indicating renal injury, which was significantly lower in iopromide-treated animals (1.6-fold vs saline). More detailed analysis of markers for AKI revealed that iodixanol significantly induced the expression of PAI-1 (7.7-fold at 2 hours) as well as KIM-1 (2.1-fold) and NGAL (3.2-fold) at 2 and 24 hours when compared with saline treatment. In contrast, the expression of markers for AKI was low after iopromide (1.4-fold NGAL, 1.7-fold PAI-1, KIM-1 not significant) and iodixanol/mannitol (1.6-fold NGAL, 2.6-fold PAI-1, KIM-1 not significant) injection.
  
  
  CONCLUSIONS
  The present results clearly show that prolonged iodine retention and the enhanced expression of kidney injury markers are caused mainly by the explicitly higher urine viscosity induced by iodixanol. We conclude that the osmolality of low-osmolar CAs such as iopromide induces a positive diuretic effect that is responsible for rapid iodine clearance and prevents increased expression of acute injury markers in the kidney.
authors.affiliation: MR and CT Contrast Media Research, Bayer Pharma AG, Berlin, Germany. Diana.lenhard@bayer.com
authors.forename: Diana C
authors.initials: DC
authors.lastname: Lenhard
authors.forename: Hubertus
authors.initials: H
authors.lastname: Pietsch
authors.forename: Martin A
authors.initials: MA
authors.lastname: Sieber
authors.forename: Rainer
authors.initials: R
authors.lastname: Ernst
authors.forename: Philipp
authors.initials: P
authors.lastname: Lengsfeld
authors.forename: Peter
authors.initials: P
authors.lastname: Ellinghaus
authors.forename: Gregor
authors.initials: G
authors.lastname: Jost
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced*; D000818:Animals; D015415:Biomarkers; D003287:Contrast Media / Q000009:adverse effects; D007472:Iohexol / Q000009:adverse effects / Q000031:analogs & derivatives*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008353:Mannitol; D009994:Osmolar Concentration; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D014283:Triiodobenzoic Acids / Q000009:adverse effects
chemical_list: D015415:Biomarkers; D003287:Contrast Media; D014283:Triiodobenzoic Acids; D008353:Mannitol; D007472:Iohexol; C038192:iopromide; C044834:iodixanol