Contrast Gilbert Georges

Deray, Bnillet,

Renal with

MD MD

Patrice

a

Bunker,

Tolerance Chronic

terms:

50.448.

Contrast

81.448

trast

media,

on,

a

media,

Coronary

50.122

a

effects,

O

I

1991;

From

quiaud, Paris,

the

accepted Corps

Departments

See

also

H#{244}pitaux

requests

(GD.,

sensitive

P.C.,

GB.,

de

by a grant Paris

and

from

in aid

from

INSERM

the (CNEP

to C. D.

1991

the

editorial

by Becker

(pp

337-338)

of contrast appears

(2).

D.B.,

(M.D.), H#{244}pital Pitie-Salpetniere. 5, 1990; revision requested August

10. Supported

des

reprint

RSNA,

of Nephrology Cardiology June

December Medical

Address ‘.

179:395-397

M.C.J.), and France. Received

cunrence nephropathy

material-related to be correlated

major renal

Hyperosmola!ity

ma! for accurate measurement of gbmerular filtration. Therefore, further work with accurate and sensitive menab function tests is needed to answer these questions. Ioxag!ate sodium meglumine (hereafter, ioxaglate) (Hexabnix; Ma!binckrodt, St Louis) is an ionic monoacid dimen that has a bow osmolality (580 mosm/kg of H2O). We have previously shown that ioxaglate is not nephrotoxic in an in vivo model of contrast material-induced nephropathy in the rat (7).

of drugs

a

The aim of the present investigation was, therefore, to investigate the renal tolerance for ioxaglate in patients with chronic renal failure and

has been cited as an important factor associated with renal failure after use of an intravascular ionic contrast agent (3,4). Therefore, new low-osmolality contrast materials were developed in an attempt to reduce renal toxicity. The results of studies in expenimental animals suggest that use of low-osmolar agents may reduce the risk of acute renal failure induced by contrast agents. These studies have shown fewer deleterious effects on systemic (5) and renal hemodynamic (3,4) variables and less direct nephrotoxic activity on renal proximal tubulam cells (6). However, clinical expenience is limited. Furthermore, in many of these studies, serum creatinine values were used to assess renal function. This approach is not opti-

50.122,

MD MD

the past 20 years, the use of intravascular contrast material has become a major cause of nephrotoxic acute renal failure (1). The ocVER

insufficiency

81.448

Radiology

a Michel Drobinski, MD a Claude Jacobs,

in Patients

with several risk factors, the one being preexisting chronic

con-

effects

loxaglate Failure’

Renal

angiography.

Kidney,

a Claude Jacquiaud, MD a Manie-Chantal Jaudon,

for

The authors sought to evaluate renal tolerance for ioxaglate sodium meglumine used as a contrast agent in patients with chronic renal failure. Eight male patients (mean age, 55 years ± 5) with chronic renal insufficiency (glomerular filtration rate < 60 mL/min) who underwent diagnostic cardiac catheterization were enrolled. Renal clearance of inulin and p-aminohippuric acid and unnary enzyme excretion were studied 1 day before and 1 day after administration of 167 mL ± 43 of ioxaglate. None of the patients expenienced any adverse reactions. All the patients had markedly depressed renal clearance values before angiography. Mean serum creatinine level, glomenular filtration rate, effective renal plasma flow, and urinary 132microglobulin excretion were unaltered by angiography. After the procedure, only one patient had an increase in serum creatinine level of more than 10% (from 115 to 159 smol/L [1.3 to 1.8 mg/dL]), with a decrease in g!omerular filtration rate from 34 to 27 mL/min. In this patient, serum creatinine level and glomerular filtration rate normalized within 72 hours. Using accurate and sensitive renal function tests, the authors have shown that ioxaglate may be used safely in patients with chronic renal failure. Index

MD MD

Cacoub,

David

a

Media

in this

issue.

C. Jacobs),

Biochemistry

83, Boulevard de 8; revision received

Fonds

d’Etudes

89 C.N.

44)

(C. l’H#{244}pital, September

et de Recherche and

AURA

(Paris).

Jac75013 10;

du

renal

MATERIALS

indexes.

AND

METHODS

Eight male patients undergoing diagnostic cardiac catheterization were enrolled in this study. Their mean age was 55 years ± 5 (range, 40-65 years). All patients had mild to severe renal insufficiency (gbomenular filtration rate [estimated with inulin clearance] < 60 mL/min). Patients with nephrotic syndrome, hepatic failure, evolving myocardial infarction, or a history of coronary angiopbasty or allergic-like reactions to contrast media were excluded. Four patients were diabetic (type II), and two had cardiac failure. Serum creatinine levels were stable for at least 2 weeks before the procedure. All patients received intravenously administered fluid (500 mL of 0.9% saline) within 24 hours before the procedure. Intravenous administration of fluid was started the evening before the procedure and was continued for 12 hours on the day of injection of contrast media. Diagnostic cardiac catheterization was performed via the femoral vein in all patients. No medication was given before or during the procedune. Left ventnicubography was performed in standard biplane or singleplane fashion. Left and right coronary angiography was performed with use of multiple views. Pigtail and coronary angiography catheters (Schneider Medintag, Zurich), each 7-F in diameter, were used for injection of the contrast agent. Indications of the need for cardiac cathetenization were cardiac failure in one patient, coronary disease in four patients, Starr-Edwards prosthetic heart valve dysfunction in one patient, aortic valve stenosis in one pa-

395

tient, and mitral valve stenosis in one patient. During the procedure, a technician or nurse recorded a detailed account of the protocol, including the volume of contrast medium used and any complications that occumred. The renal clearance studies were carried out 1 day before and 1 day aften angiography. Tests for clearance of inulin (gbomerubar filtration rate) and p-aminohippunic acid (effective renal plasma flow) were performed according to conventional methods with use of the continuous infusion technique but without cathetenization of the bladder. Clearances were determined during three periods, each 40 minutes long. In addition, a 30-mL sample of fresh urine and a venous blood sample were obtained from all patients 1 day before and 1 day after angiography to determine serum creatinine, blood urea nitrogen, uric acid, and electrolyte levels and urinary 132-microgbobulin excretion. Results were expressed as means ± standard errors. Statistical analysis was performed with use of the Number Cruncher Statistical System and paired and unpaired Student t tests. Linear regressions were obtained with use of the least squares method. Differences were considered to be significant when P values were less than .05.

RESULTS In this study, 167 mL ± 43 of ioxaglate (iodine dose, 53.4 g ± 5) was injected into each patient. None of the patients experienced any adverse meactions. Pulse rate, blood pressure, and hematologic and serum chemistry values remained stable 24 hours after the procedure (Table 1). The mean changes in serum cneatinine level, gbomerular filtration rate,

effective renal plasma nary j32-micnogbobulin

flow,

and

uri-

excretion are shown in Table 2. All the patients had markedly depressed clearance values before angiography; the range for inulin clearance was 34-60 mL/ mm, and, for p-aminohippunic acid

plasma flow averaged 258 mL/ ± 20 before and 272 mL/min ± 27 after angiography. Urinary 132-microglobulin excretion averaged 0.4 nal

mm

ng/mL ± 0.5 before 0.3 after angiography. No

patients

had

and

0.2 ng/mL

nephrotoxic

±

reac-

tions or acute oligunia that required dialysis as a result of the administration of contrast material. Only one patient had an increase in serum creatinine level of more than 10% (from 115 to 159 imol/L [1.3 to 1.8 mg/dLJ) 24 hours after the procedure, with a decrease in gbomerular filtration rate from 34 to 27 mL/min. Effective menab plasma flow remained unchanged. In this patient, serum creatmine level and glomerular filtration rate normalized within 72 hours. This patient had no other risk factors besides chronic renal failure.

DISCUSSION The true frequency of contrast media-induced acute renal failure is unknown. Recent surveys report acute renal failure in 0% to 12% of patients undergoing radiobogic procedures that require the use of intravascular contrast agents (2,8-10). This discrepancy in results is probably due mainly to differences in study design and variations in criteria for the diagnosis of acute renal failure. More recently, in a prospective, controlled study, Parfrey et a! (1 1) concluded that the risk for patients with both diabetes and preexisting renal insufficiency is about 9%. Therefore, contrast nephropathy remains a major clinical concern. loxaglate is an ionic, bow-osmobar contrast

agent

clinical

practice.

sensitive

methods

that

is widely

Using

used

accurate

to evaluate

in

and renal

function, we have shown that this contrast agent is not nephrotoxic in patients with chronic renal failure, which is the main risk factor for contrast media-induced acute renal failure (3,4). A similar result would be expected in patients with a normal gbomerular filtration rate. A major issue concerning the use of new bow-osmolar contrast agents

clearance, the range was 172-328 mL/min. Mean serum creatinine level, gbmerular filtration nate, effective renal plasma flow, and urinary 132-micnoglobulin excretion were unaltered by angiognaphy; no significant changes

is their

were

vivo model in the rat, that ioxagbate is less nephrotoxic than diatrizoate sodium megbumine (Radioselectan; Shering, France) (7). In this model,

noted

menubar mL/min ± 5 after

396

a

in the

group.

Thus,

gb-

filtration rate averaged 42 ± 4 before and 41 mL/min angiography. Effective ne-

Radiology

degree

of nephrotoxicity.

The

results of studies in experimental animals clearly suggest that use of lowosmolar contrast agents may reduce the frequency of acute renal failure induced by contrast agents (3-6). We

recently

confirmed,

in an

in

ioxagbate induced no change in serum cneatinine level and creatinine clearance in experimental animals compared with control animals. On the other hand, diatnizoate sodium meglumine induced a sharp decline in gbomerular filtration rate 24 hours after administration of contrast mediurn. Furthermore, in our model, ioxaglate induced a lesser increase in unnary N-acetyl-f3-g!ucosaminidase excretion than diatnizoate sodium meglumine, which suggests less dinect tubular toxicity. Similarly, at pathologic examination, we observed only osmotic nephrosis after use of ioxagbate, while 50% of the kidneys perfused with diatnizoate sodium meglumine showed tubular necrosis. Several studies, some of them carried out prospectively and with use of control subjects, have been undertaken to evaluate the nephnotoxicity of bow-osmolar contrast media in high-risk patients (1 1-15). These pmevious studies have not been entirely satisfactory due to the small number of patients studied, the predominant inclusion of patients at low risk, on the use of parameters-such as serum creatinine bevel-that poorly reflect May

1991

true

gbomenubar

knowledge, renal tolerance contrast in which

filtration ours

agent in accurate

function

tests

In our

renal

were

on

performed.

ioxaglate

in urinary which damage,

plasma

To our

high-risk patients and sensitive renal

patients,

no changes bin excretion, nab tubular

rate.

is the first report for a bow-osmobar

flow

induced

$2-microgbobureflects toxic or in effective

and

me-

gbomerubar

fib-

tration rate, which reflect renal hemodynamics. It has been shown that contrast material-induced renal failure usually occurs within 24 hours after exposure. Therefore, our observations suggest that ioxag!ate did not induce renal toxic reactions in our patients. The utility of serum cneatinine level as an index of gbomerular

function

stems

from

the

reduction in gbomerular poses a limitation on

cretion;

this

fact

that

filtration creatinine

impedance

any im-

to excretion,

creatinine

continues is achieved

concentration

be interpreted ubar function

take

more

24 hours

ten administration

atnice

1.

Celestin

for

unin

to occur

have

been

of patients developing failure after undergoing investigations

SH,

Med

1983; JA,

Number

3.

JT.

af-

Morris

Be-

impairment:

Martin-Pardero

Predictrenal

clinical

risk

mode!.

V, Dixon

SM,

Baker

D, et

of renal failure after major angiArch Surg 1983; 118:1417-1420.

Swartz

RD.

Parfrey

Rubin

PS,

Contrast

JE,

Leeming

BW,

following

major

1978;

Cniffiths

with

Barnett

or

BJ, et a!.

renal

diabetes

sufficiency,

failure

mellitus,

both.

Silva angiog-

65:31-37.

SM,

material-induced

patients

renal

N Eng!

in in-

J Med

1989;

KS,

et a!.

320: 143-149. 12.

Schwab

SJ,

Hlatky

A randomized ionic 13.

MA,

Pieper

controlled

and

an

ionic

agent.

N Eng!

Comes

AS,

Bunnel

trial

JF,

in

contrast

1989;

320:149-153.

Baker

JD,

Hartzman

giography: ionic contrast

of a non-

radiographic

J Med

Lois

DH,

dysfunction

14.

K.

Angiographic

um diatnizoate phy. Invest SB,

RW,

of the

hemodynamic

6.

and

Biol

LI,

JM,

in

bule

S.

McC!ade

Acute

high-risk

CT,

renal

patients

comparison media.

renal

cm-

19.

media

corn-

Nguyen of the

renal

VD,

iopamidol, AJR 1984;

Denys

after

of ionic Radiology

an-

and non1989;

BC,

ioparnidol

AH, Hamburger toxicity of contrast

iothalamate, 142:333-335.

Reddy

SP,

Uretsky

BF.

(iopamidol) contrast

the

transplant

patient

after

cardiac

moderate sufficiency.

cyclosponmne-mnduced Am J Cardiol

406. Aron NB, RI. Acute

Feinfeld DA, renal failure

ioxag!ate,

a low

Cedgar

DS,

trast

media.

Evans

JR.

1986; agents

and

ty.

Intern

Med

CP,

McCal!ister

Ann

Ilstrup

DM. after 1989;

1987;

Vliestra cardiac

13:189-193. K, Attman

2:128 Cuttle

contrast

Lynn with

insufficiency osmolar con-

SW,

osmolar

in-

radiocontrast

1989;

renal of low

Lancet Shankel

Ta!iercio

with renal 64:405-

H, Ceterud

Acute

diatriNeph-

Peters AT, associated

Dis

Her!itz

Wi-

veragent in

1989;

osmolality

J Kidney

Am

RJ,

and

rotoxicity of a nonionic sus an ionic (diatrizoate)

Cardiol

toxicity

Low

nephrotoxici107:116.

SH, RE.

1. RE.

Holmes

DR.

Nephrotoxicity

angiography.

Am

64:815-816.

and

proximal

J Pharmacol

in vitro.

agents: zoate.

media

DA,

agents,

to rabbit

18.

Br

new

ME, Robbins WC. Rena!

P0, Aure!! M. after administration

139:787-794.

radiocontrast cells

17.

Mono-

the

Cale drich

agent.

contrast

and

Comparison

diatnizoate,

A

angiography.

Cies!inski

HD.

T.

media

conventional

Humes

HW. respons-

Sherwood

agents: Messana

16.

renal angiogra13:74-80.

1974; 47:268-271. MA. Angiographic

1982;

Fischer

ma-

meglumine/sodi-

Radio! Bettmann

AJR

Malanick

contrast Am J Med

Katzberg

experimental

pared.

Am M,

study.

contrast

culation:

Alday

in canine Radio! 1978;

mer-dimer

5.

in-

study.

RE,

1W,

Russell

JB, Cohen

Hospital-acquired

es to metnizamide

4.

Wish

Gleason

comparison

reports

bow-osmoban

2

11.

DJ. acute

P. Renal failure raphy. Am J Med

74:243-248.

tu-

Exp Ther

1988; 244:1139-1144.

7.

Deray

C, Dubois

comparison

M, Baurnelou

of the and

ioxag!ate

International

Paris, July

a

10.

Roe

1983; 141:1027-1033.

a!. Risk ography.

assistance.

DA,

tenia!: a prospective 1982; 72:719-725.

the

179

thank

secretarial

a prospective

D’elia

trizoate

Volume

authors

Bushinsky

sufficiency:

mateni-

acute renal radiobogic

in which

9.

15.

Hou

of the

there

her

JJ, Hamnington

a!. Recently,

AJR

intra-

WS,

170:65-68.

should

of contrast

injected

The

C, Godfrey

In addition, an alterserum level may

than

always

Acknowledgments:

as an index of gbomeronly in a patient who is

in a steady state. ation in creatinine

was

T, Wong

angiography-induced

function

anteniabby and numerous risk factors were present, including cardiac failure and/or diabetes meblitus and inadequate hydration. These findings suggest that, with use of a bow-osmolam contrast agent, risk factors such as dehydration must still be corrected. In conclusion, we have shown that ioxagbate may be used safely in patients with chronic renal failure. However, we strongly recommend that all possible risk factors be conrected before administration of any type of contrast media. U

2.

which the daily quantity of filtered (and therefore excreted) creatinine matches the amount released in metabobism each day. Therefore, the serum

media

Cochrans ing

References

total body water in its serum concen-

tration. Accumulation til a new steady state

trast

8.

ex-

in the presence of a continued constant release of creatinine from muscle, leads to an accumulation of creat-

mine throughout and thus a rise

contrast media were used (16-19). However, it must be emphasized that in these observations of patients who had chronic renal failure, the con-

B, et a!.

nephrotoxicity in rats. Congress

A

of diaPresented of

at

Radiology,

1989.

Radiology

a

397