Ace-I and Contrast induced nehropathy

1. Please talk
slowly !!!!!
Journal Club
Ahad Lodhi
F-1 Nephrology

2. Should We Stop , Start or Continue
Angiotensin-Converting Enzyme
Inhibitors and Angiotensin Receptor
Blockers Prior to Using
Contrast Agents?

3. CIN
• Contrast-induced nephropathy (CIN) refers to
the development of acute renal impairment
following the intravascular administration of
radiocontrast in the absence of other
identifiable causes of renal failure.
• Most studies have used a 25% elevation in
serum creatinine (SCr) or an absolute increase
of 0.5 mg/dL 2 to 3 days following CM
administration

4. Does the occurrence of CIN have any
impact on
patient’s outcome?

8. Pathophysiology of CIN

9. 1. Vasoconstrictive Effects on Renal
Blood Flow

10. 2.
Regional reduction in cortical-medullary blood
flow in the kidney (inc in DM)
3.
Vasoconstrictors: Endothelin and Adenosine
• Sancak A, Derici U, Arinsoy T, Erbas D, Uenlue M, Hasanoglu E. Effects of contrast media on endothelin and nitric oxide system after computed tomography.
Gazi Med J 2002;13:81– 85.
• Klause N, Arendt T, Lins M, Gronow G. Hypoxic renal tissue damage by endothelin mediated arterial vasoconstriction during radioangiography in man. Adv Exp
Med Biol 1998;454:225–234
• Nygren A. Contrast media and regional renal blood flow: a study of theeffects of ionic and non-ionic monomeric and dimeric contrast media in the rat. Acta
Radiol Suppl 1992;378(pt 3):123–135.
• Palm F, Carlsson PO, Fasching A, Hellberg O, Nygren A, Hansell P, Liss P. Effects of the contrast medium iopromide on renal hemodynamics and oxygen tension
in the diabetic rat kidney. Adv Exp Med Biol 2003;530:653– 659

11. 4.
Impaired Nitric Oxide Production and Vasodilation
(more supression with higher osmolar agents)
5.
Reperfusion and Reactive Oxygen Species
6.
Direct Tubular Toxicity (osmotic nephrosis: intense
focal or diffuse vacuolization of the proximal
tubules or overt tubular necrosis)
• Ribeiro L, de Assuncao e Silva F, Kurihara RS, Schor N, Mieko E,vHiga S. Evaluation of the nitric oxide production in rat renal artery smooth muscle cells
culture exposed to radiocontrast agents. Kidney Int 2004;65:589 –596.
• Sandhu C, Newman DJ, Morgan R, Belli AM, Oliveira D. The role of oxygen free radicals in contrast induced nephrotoxicity. Acad Radiol 2002;9:S436 –
S437
• Moreau JF, Droz D, Noel LH, Leibowitch J, Jungers P, Michel JR. Tubular nephrotoxicity of water-soluble iodinated contrast media. Invest Radiol
1980;15:S54 –S60

12. • In Vitro Effects
– reduce the viability of cultured renal cells and
induce apoptosis
– cellular energy failure
– disturbance of calcium
– alterations in tubular cell polarity
• Hizoh I, Haller C. Radiocontrast-induced renal tubular cell apoptosis: hypertonic versus oxidative stress. Invest Radiol 2002;37:428–434
• Haller C, Hizoh I. The cytotoxicity of iodinated radiocontrast agents on renal cells in vitro. Invest Radiol 2004;39:149 –154
• Hizoh I, Strater J, Schick CS, Kubler W, Haller C. Radiocontrastinduced DNA fragmentation of renal tubular cells in vitro: role of hypertonicity. Nephrol
Dial Transplant 1998;13:911–918

13. Effects of Angiotensin

14. Renin–angiotensin–aldosterone
system
activation during administration of
Contrast?

15. • Endothelin-1, renin, and angiotensin II are some
of the potential mediators leading to intrarenal
vasoconstriction in experimental models of CIN
• A few studies on the action of angiotensin II have
been done on sodium-depleted dogs, in which
this depletion accentuates both the magnitude
and duration of the vasoconstrictive phase of the
RBF response to injection of CM, and the
blockade of the intrarenal renin–angiotensin
system (RAS) shortens the duration of this
response
• Activation of the RAS could cause
vasoconstriction of the efferent glomerular
arteriole leading to decreased flow through
peritubular capillaries and increasing hypoxia and
oxidative stress in outer medullary segments

16. Effects of Angiotensin

17. Inhibition of angiotensin II
• ACE inhibitors preferentially dilate the efferent
arteriole, therefore increase the renal medullary
plasma flow. ACE inhibitors could mitigate a
decrease in the reduction of medullary blood
flow induced by the contrast agent.
• Inhibition of angiotensin II prevents
vasoconstriction and generation of reactive
oxygenspecies and increases the synthesis and
bioactivity of nitric oxide.
Munzel T, Keaney JF Jr. Are ACE inhibitors a ‘magic bullet’ against oxidative stress? Circulation 2001;104:1571–
1574.

18. On another note
• Lee HT, Kim M, Kim J, Kim N, Emala CW TGF-beta1 release by volatile
anesthetics mediates protection against renal proximal
tubule cell necrosis. Am J Nephrol 2007;27:416–424
• J Am Soc Nephrol 1997;8:1732–1738 Junaid et.al Angiotensin II can stimulate
the formation of cytokines TGF-β1
• ACE-I can prevent formation of TGF-β1 and can cause renal
injury during contrast administration.

19. Role of angiotensin-converting
enzyme inhibitors (ACEIs)
to the occurrence of CIN and
whether they increase or decrease
the risk of CIN?

20. *Ioversol induced NRK-52E cells apoptosis in a concentration- and time-dependant
manner via an increase in oxidative stress and
subsequent to the increase in mRNA expression for bax and reduction in bcl-2
mRNA.
*Irbesartan attenuated the ioversol-induced apoptosis in
NRK-52E cells by reducing oxidative stress and reversing the enhancement of
bax mRNA and the reduction in bcl-2 mRNA

21. (J. Am. Soc. Nephrol. 1995; 6: 145 1-8)
-By measuring GFR and renal plasma flow at set intervals
following contrast administration, they demonstrated a near
immediate decline in GFR proportional to the osmolality of the
contrast media employed and showed evidence that this was
related to a renal hypo-perfusion.
-Single dose of captopril or the
calcium channel blocker nifedipine
prior to exposure to contrast media
could attenuate this decrease in GFR
and RPF by 20% in patients with CKD,

22. Indian Heart
1999;51:521–6.
• Randomized 71 diabetic patients undergoing cardiac
catheterization to captopril 25 mg tid for 3 days
starting 1 h prior to procedure vs. no ACEI therapy
• Their results showed that the captopril group had a
reduced risk of developing CIN by 79%
• They hypothesized that ACEIs have a protective effect
by opposing the arteriolar vasoconstrictive effects of
contrast media induced by the activation of the RAAS

23. • Retrospective study of over 7000 patients undergoing
percutaneous intervention
• Dangas et al. found that preprocedural ACE inhibition resulted
in a lower risk of CIN in patients with chronic kidney disease
[odds ratio (OR) 0.61, 95% confidence interval (CI) 0.44–0.86,
P=.005] but not in those with relatively normal renal function

25. So why we don’t start everyone
on ACE-I before getting contrast?

26. Can J Cardiol 2008;24(11):845-850
• Utilizing the data from the 412 patients studied in the Dialysis-
Versus-Diuresis trial
• Post-procedural hemodialysis, left ventricular ejection fraction
<35%, serum phosphate, and ACEI use were found to be
independently associated with increased incidence of CIN
• ACEI intake was associated with a sixfold increase in the
incidence of CIN post-procedure (OR 6.16, 95% CI 2.01–18.93)
• Interestingly, ARBs did not exhibit a similar effect. However, the
number of patients on ARBs was not large enough to show
statistical significance

27. Toprak O, Cirit M, Bayata S, Yesil M, Aslan SL. The effect of preprocedural
captopril on contrast-induced nephropathy in patients who underwent
coronary angiography. Anadolu Kardiyol Derg 2003;3(2):104–6
• ACEIs increased the incidence of CIN in a study performed in 2003
• 80 individuals with serum creatinine <2 mg/dl
• Captopril was administered in 48 patients. It was given at 48, 8, and 1 h prior to
procedure vs the control group who received no ACEI therapy
• 5 patients (8.3%) on the ACEI therapy vs. 1 patient (3%) in the control group
developed CIN
Cirit M, Toprak O, Yesil M, Bayata S, Postaci N, Pupim L, Esi E. Angiotensin-converting
enzyme inhibitors as a risk factor for contrast induced nephropathy.
Nephron Clin Pract 2006;104:20–7
• 230 patients with mild-moderate renal insufficiency (eGFR range of 31–88 ml/min with
a mean of 51 ml/min) and randomized them into chronic ACEI users (taking any ACEIs
for at least 2 months, n=109) and those not taking an ACEI (n=121)
• Intravenous saline, Low osmolar, nonionic contrast media was used, and diuretics and
metformin were held prior to angiography
• 17 patients in ACEI group (15.6%) and 7 patients in the control group (5.8%) developed
CIN (P=.015)

28. Should we stop ACE-I in patients
who are chronically on it, before
getting contrast media?

29. Int Urol Nephrol 2008;40:749–55
• Largest published randomized prospective trials on ACEIs and CIN.
• 283 patients on chronic ACEI therapy (>2 months) with chronic
kidney disease 3-4.
• They divided their study population into three groups: chronic ACEI
users who continued ACEI therapy through the procedure, chronic
ACEI users who discontinued ACEIs prior, and ACEI naïve patients.
• No statistically significant differences between the groups in the
incidence of CIN:
limitations of their study :
• Measurement of creatinine values 24 h post procedure

30. • No evidence to stop ACE-I/ARBs before
contrast media
• No strong evidence to start ACE-I/ARB just for
proposed protective effect.

31. Will it change your practice?

32. Does continuing ACE-I improves long
term outcomes after CIN (more
patients return to baseline gfr after
CIN)?