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Nephrol Dial Transplant (1996) 11: Editorial Comments
Are low osmolality contrast media less neprotoxic?
G. Deray and C. Jacobs
Department of Nephrology, Hopital Pitie, Salpetriere, Paris, France
Iodinated contrast media are well recognized nephro- A major question concerning these new agents is their
toxic agents and a leading cause of hospital acquired relative nephrotoxicity compared to HOCM.
renal failure accounting for about 12% of such cases [1].
Experimental models have evaluated the effect of
HOCM and LOCM according to the various proposed
High osmolar contrast media (HOCM) versus low mechanisms of contrast nephrotoxicity which include
intrarenal vasoconstriction and direct cellular toxicity.
osmolar contrast media (LOCM)
In an in vitro model of rabbit proximal tubular cells
in suspension, LOCM caused less adverse effects on
On the basis of their chemical and pharmacologic
properties, contrast media may be distributed into two several parameters of cell viability and less cell necrosis
large groups: high- and low-osmolar agents. Low- as assessed by electron microscopy than HOCM [3].
osmolar agents may be further classified as either The same observations were then reported in cultured
rat glomerular cells, human fibroblasts [4] and renal
nonionic or ionic subgroups.
epithelial
cells in culture [5].
The iodine ratio forms the fundamental basis for
Because of precarious balance between oxygen
classifying a contrast agent molecule (i.e. the ratio of
the number of iodine atoms in the molecule to the supply and demand within the outer medulla, the
number of osmotically active particles that the molec- medullary thick ascending limb, which normally operule produces in solution). This property sets the basis ates on the verge of hypoxia, becomes a prime target
for the grouping: 1.5 ratio agents (classified as high- for ischaemic injury during renal hypoperfusion.
osmolar ionic agents) and 3.0 ratio agents (classified Radiocontrast nephropathy regularly develops in the
as low-osmolar agents). There are global differences in presence of risk factors, which are usually associated
properties between the 1.5 ratio and the 3.0 ratio with compromised medullary O2 balance. In preexgroups. In addition, within each group the two sub- isting renal failure, one of the most important of these
groups have distinguishable chemical and pharmacol- risk factors, the decrease in functioning renal mass
leads to an augmented workload per remaining
ogic properties.
Most of the currently available 1.5 ratio agents use nephron (a condition referred to as tubular hypermetadiatrizoic acid as the iodine-bearing molecule. Since bolism), intensifying mTAL hypoxia. Vascular ischthis molecule, which contains three iodine atoms, emia is thus considered a major contributor to
achieves water solubility by ionization of the carboxyl radiocontrast induced nephropathy.
group at the 1 position, it produces two osmotically
Animal experiments have shown that intravascular
active particles in solution (i.e. the molecule itself and infusion of contrast medium, in a clinically acceptable
its salifying cation). Currently, there are five different dose produces minor transient alterations in total renal
3.0 ratio molecules available, subgrouped on the basis blood flow i.e. renal vasoconstriction preceded by a
of two different strategies used to achieve their iodine short initial period of vasodilation. Renal hemodynratio. Ioxaglate is a molecule that contains six iodine amic modifications induced by HOCM and LOCM
atoms and achieves water solubility by ionization; thus, are similar in the normal kidney.
it is a 3.0 ratio ionic agent. Iohexol, iopamidol, ioversol
We have shown that the renal hemodynamic effects
and iobitridol (each of which have three iodine atoms/ of contrast media are markedly enhanced by ischemia
molecule) achieve water solubility by having nonioniz- thus explaining why under certain clinical conditions
ing but hydrophilic moieties in the 1, 3, and 5 positions; of poor renal perfusion, the administration of contrast
thus, they are 3.0 ratio nonionic agents.
agents may set a stage for the additive deleterious
effects of the potential nephrotoxic contrast medium
and hypoxia after infusion of the dye [6]. By contrast
Nephrotoxicity of low osmolar contrast media—
to
the normal kidney the magnitude and the duration
experimental studies
of the renal vasoconstriction appeared to vary directly
During the past decade low osmolar contrast media with the tonicity of the agent used in an ischemic
(LOCM) have become increasingly popular for radio- kidney, the more hypertonic the solution the greater
graphic procedures requiring intravascular contrast and the more sustained the vasoconstriction. Indeed
because they have been found to cause less discomfort in our ischemic model LOCM induced significantly
and fewer cardiovascular and anaphylactoid adverse less renal vasoconstriction than HOCM.
After a further 1 min following contrast media infueffects than high osmolar contrast media (HOCM)
[2]. However/controversy continues about the need for sion, the vasoconstriction was slightly but significantly
universal use of LOCM because of their higher cost. less pronounced with ioxaglate than with iopamidol.
931
Nephrol Dial Transplant (1996) 11: Editorial Comments
This difference may be due to the lower osmolality
(600 vs. 700 mOsm/kg) of ioxaglate.
These results were confirmed in in vitro rat models
where LOCM are clearly less nephrotoxic than HOCM
as indicated by all parameters measured [7,8].
Nephrotoxicity of low osmolar contrast media—
clinical studies
Initially many clinical studies of the nephrotoxicity of
contrast material have evaluated populations that were
too small to exclude or establish reliably a reduction
in nephrotoxicity with LOCM [9,10].
However studies of substantial numbers of patients
with pre-existing renal impairment have now been
reported and the results of some of these trials have
suggested that LOCM may be less nephrotoxic than
HOCM. Differences in nephrotoxicity between the two
contrast groups were confined to patients with preexisting renal insufficiency alone or combined with diabetes mellitus [11,12].
Those results were confirmed in a metaanalysis performed by Barret et al. [13] on 45 trials. Among 24
trials with available data, the mean change in serum
creatinine was 0.2-6.2 umol less with LOCM compared
with HOCM. Among 25 trials with available data the
pooled adds of a rise in serum creatinine level of more
than 44 umol/1 with LOCM was 0.61 times that after
HOCM.
In contrast, in patients with normal renal function,
regardless of the presence or absence of diabetes mellitus, LOCM are no less nephrotoxic compared to
HOCM. It should be outlined that in subjects without
renal insufficiency the incidence of contrast media
induced acute renal failure is very low provided risk
factors (such as dehydration) are detected and corrected.
Additional studies in high-risk patients will be
required to determine if LOCM are also associated
with a reduced incidence of severe nephrotoxicity (e.g.
that would require acute dialysis).
There have been reports on patients developing
severe renal failure after the use of LOCM [14]. A
number of underlying conditions associated with an
increased risk for the development of contrast associated nephropathy were clearly present in these patients.
We thus strongly suggest that employing a LOCM
does not suppress the need to correct carefully the risk
factors, such as dehydration, before its use.
More recently non ionic dimers which are isoosmotic with plasma have been introduced (Iotrolan
and Iodixanol). While evidence for their real advantages compared with LOCM and HOCM are lacking
they are already presented as an 'ideal physiological'
formulation. However, experimentally non ionic
dimers may alter glomerular filtration rate and renal
blood flow in a fashion at least similar to LOCM [15].
These alterations in renal haemodynamics may be due
to an increase in blood viscosity and red blood cell
aggregation. Furthermore, no randomized clinical
trials have been carried out to show a difference in the
renal tolerance between non ionic dimers and LOCM.
Conclusions and recommendations
In conclusion experimentally LOCM are clearly less
nephrotoxic than HOCM. Clinically a benefit has been
proved in patients with pre-existing renal insufficiency
alone or combined with diabetes mellitus. In contrast
in patients with normal renal function LOCM are no
less nephrotoxic compared to HOCM. The lack of
substantial benefit regarding a reduced incidence of
nephrotoxicity together with the higher cost of LOCM
should then restrict their indication to high-risk
patients. Finally, the prevention of radiocontrast
nephrotoxicity regardless of the compound used still
mainly rely on the detection and prevention of risk
factors.
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