Journal ClubAhad Lodhi

F-1 Nephrology

Please talk slowly !!!!!

Should We Stop , Start or Continue Angiotensin-Converting Enzyme

Inhibitors and Angiotensin Receptor Blockers Prior to UsingContrast Agents?

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

Does the occurrence of CIN have any impact onpatient’s outcome?

Pathophysiology of CIN

1. Vasoconstrictive Effects on Renal Blood Flow

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

4.Impaired Nitric Oxide Production and Vasodilation (more supression with higher osmolar agents)5.Reperfusion and Reactive Oxygen Species6.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

• 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

Effects of Angiotensin

Renin–angiotensin–aldosterone systemactivation during administration of Contrast?

• 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

Effects of Angiotensin

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.

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.

Role of angiotensin-converting enzyme inhibitors (ACEIs)to the occurrence of CIN and whether they increase or

decreasethe risk of CIN?

*Ioversol induced NRK-52E cells apoptosis in a concentration- and time-dependant manner via an increase in oxidative stress andsubsequent to the increase in mRNA expression for bax and reduction in bcl-2 mRNA.

*Irbesartan attenuated the ioversol-induced apoptosis inNRK-52E cells by reducing oxidative stress and reversing the enhancement of bax mRNA and the reduction in bcl-2 mRNA

(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,

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

• 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

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

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

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)

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

media?

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

Conclusion

• No evidence to stop ACE-I/ARBs before contrast media

• No strong evidence to start ACE-I/ARB just for proposed protective effect.

Will it change your practice?

Does continuing ACE-I improves long term outcomes after CIN (more patients return to

baseline gfr after CIN)?