PCI in CKD

(percutaneous coronary intervention in chronic kidney disease)

by Vincent M. Brandenburg, MD and Jürgen Floege, MD
Department of Nephrology, University Hospital Aachen, Germany

Corresponding author:




Vincent M. Brandenburg, MD
Department of Nephrology & Clinical Immunology
University Hospital Aachen
Pauwelsstraße 30
D-52057 Aachen
Germany
Phone: 0049 - 241 - 8089532
FAX: 0049 - 241 - 8082446
Email: Vincent.Brandenburg@post.rwth-aachen.de

Case Vignette:
A 79-year old woman was referred from a primary care hospital to the cardiology department of our university hospital with the diagnosis of a non-ST segment elevation myocardial infarction (N-STEMI) five days before. She felt well and was hemodynamically stable upon arrival. The maximum creatinine kinase level was 256 U/l (normal range < 174U/L) on the day of admission in the primary care hospital. Since then she was treated with metoprolol 47.5 mg, aspirin 100 mg, clopidogrel 75 mg, ramipril 2.5 mg, and atorvastatin 40 mg each one tablet per day as well as subcutaneous enoxaparin 7000 IU bid.
Blood pressure was 138/81 mmHg and body weight was 68 kg (171 cm) upon arrival. An echocardiography examination revealed a normal systolic left ventricular function with hypokinesia at the apex of the left ventricle.
Serum creatinine levels were 1.6 mg/dL (normal range <1.1mg/dL) at the first day and 1.4 mg/dL on the day of referral to our hospital. All other laboratory parameters were in the normal range. She arrived at 04:00 pm and a coronary angiogram with percutaneous coronary intervention (PCI) was scheduled for the next day 08:00 am.
As a nephrology consultant, you are asked to give some data and recommendations concerning contrast-induced nephropathy (CIN) in this patient.

Question 1) - What is a common definition of contrast-induced nephropathy (CIN)? (chose the most appropriate answer)
>	a) Rise in serum creatinine > 1 mg/dL compared to pre-contrast levels.
>	b) Rise in serum creatinine > 0.5 mg/dL compared to pre-contrast levels.
>	c) Deterioration of glomerular filtration rate (GFR) > 25% compared to pre-contrast levels.
>	d) Need for dialysis treatment early after the administration of contrast media.
>	e) Increase of the serum creatinine concentration > 0.5 mg/dL or > 25% above baseline within 48 hrs after contrast administration (in the absence of more likely explanations).
<% if Answer1 = RightAnswer1 then Response.Write " Answer to question n. 1 is right! " else Response.Write " Answer to question n. 1 is wrong! " Response.Write " The right answer is the checked one! " end if %> The correct answer is #e: A common definition for CIN is an increase of the serum creatinine concentration > 0.5 mg/dL or > 25% above baseline within 48 hrs after contrast administration. Comment to Question 1: Most studies concerning the incidence, clinical significance, or therapeutic prevention of CIN have used an increase of the serum creatinine concentration > 0.5 mg/dL or > 25% above baseline within 48 hrs after contrast administration as endpoint (1,2). Alternatively, an increase of 0.5 mg/dl after 72 hrs has been used (3). Increase in serum creatinine or fall in GFR are the most popular end points in CIN studies. Hard endpoints (need for dialysis, demission from hospital, or mortality) have been less well investigated previously. <% newID = 2 else newID = 11 %>

Question 2) - Is the patient in the vignette at a relevant risk to develop CIN? (chose the most appropriate answer)
>	a) No
>	b) No, the risk is minimal and no further precautions need to be taken.
>	c) Yes, the risk of CIN is especially true because of here elevated baseline creatinine levels and the age of > 75 years.
>	d) Yes, the risk is extremely elevated and the administration of contrast media should be avoided.
<% if Answer2 = RightAnswer2 then Response.Write " Answer to question n. 2 is right! " else Response.Write " Answer to question n. 2 is wrong! " Response.Write " The right answer is the checked one! " end if %> The correct answer is #c: Especially here age and the impaired renal function contribute to a significant risk for CIN in this patient. Comment to Question 2: CIN is supposed to occur in previously healthy patients in less than 2% (3,4). However, this patient exhibits a higher risk for the development of CIN. Mehran et al have developed a score for CIN risk prediction. This score relies on cardiac and circulatory function, age, presence of anemia and diabetes, contrast volume as well as baseline renal function (5) (please refer to Figure 1a). According to this score, the patient has a moderate risk for CIN: 4 points for age+ 4 points for chronic renal failure+ 2 points for contrast volume = 10 points corresponding to a 14% risk for CIN (Fig. 1b). It needs to be pointed out that the presence of two concomitant risk factors at the same time may multiply the risk for CIN. Rihal et al (4) have shown that the CIN risk in coronary angiogram patients was 2% for non-diabetics with a serum creatinine < 1.1 mg/dL, 22.4% for diabetics with a serum creatinine between 2.0 to 2.9 mg/dL, and 33.9% for diabetic patients with a baseline creatinine > 3.0 mg/dL. Obviously, in this case there is no alternative to contrast media application, since a coronary angiogram is the gold standard for the diagnosis and especially intervention (percutaneous coronary intervention = PCI) in coronary artery disease. However, the patient from the vignette should be examined by an experienced cardiologist (low-volume-user) and some other precautions should be taken (see below). Figure 1a: Mehran score (5) Figure 1: The Mehran score, modified after (3). eGFR is calculated according to the modified MDRD formula; CHF denotes congestive heart failure Figure 1b: Mehran score (5) <% newID = 3 else newID = 22 %>

Question 3) - What other factors have been previously described as possible contributors to the risk of CIN?
>	a) Dehydration
>	b) Therapy with ACE-inhibitors
>	c) Diabetes mellitus
>	d) Therapy with NSAIDS
>	e) Therapy with diuretics
>	f) Female gender
>	g) Preexisting kidney disease
>	h) Volume of contrast media
>	i) Hypotension, shock
>	j) Need for vasopressor support
>	k) Older age
>	l) Intra-aortic balloon counterpulsation (IABP)
>	m) Proteinuria
>	n) Congestive heart failure
>	o) Nephrotoxic medications
>	p) Liver cirrhosis
>	q) Anemia
>	r) None of the above
>	s) All of the above
<% if Answer3 = RightAnswer3 then Response.Write " Answer to question n. 3 is right! " else Response.Write " Answer to question n. 3 is wrong! " Response.Write " The right answer is the checked one! " end if %> The correct answer is "s", ALL of the above-mentioned conditions may contribute to the development of CIN. Comment to Question 3: Previous trials concerning CIN have revealed numerous risk factors for CIN (3,6,7). A possible classification is: A) Preexisting factors negatively influencing renal perfusion / oxygen supply (e.g. low volume status, shock, hypotension, consecutive vasopressor use, sepsis, IABP, NSAIDS, ACE-I, congestive heart failure, anemia, liver cirrhosis ?) B) Preexisting renal damage (chronic kidney disease, proteinuria, arterial hypertension, older age, multiple myeloma ?) C) Additional nephrotoxin application (e.g. NSAIDS, antibiotics, diuretics ?) D) Unknown or genetic factors (female gender?) Obviously, this classification system does not allow a sharp differentiation and several of the above-mentioned factors may well be placed into another or several groups at the same time. <% newID = 4 else newID = 33 %>

After stratifying the present patient as a patient at risk for developing a CIN, the crucial question is the best way of management.

Question 4) - What are appropriate steps in the management of the patient prior to and after PCI
>	a) Give normal saline (0.9% NaCl) intravenously 80ml/h for 12 hrs before, during and 12 hrs after PCI.
>	b) Advise the cardiologist about the renal situation and advise him to avoid high-osmolality contrast agents and to use the lowest possible volume of contrast (e.g. by not performing left ventricular angiography and using echocardiography instead).
>	c) Review critically the patient chart in order to identify potentially harmful co-medications.
>	d) Obtain at least once a follow-up creatinine not less than 24 hrs or more than 72 hrs (optimal point-of-time 48 hrs).
>	e) All previous answers are true.
<% if Answer4 = RightAnswer4 then Response.Write " Answer to question n. 4 is right! " else Response.Write " Answer to question n. 4 is wrong! " Response.Write " The right answer is the checked one! " end if %> Comment to Question 4: The "Consensus Panel for CIN" (Kidney international 2006: (8)) released six recommendations concerning: "How to prevent CIN and manage risk patients: practical recommendations": -"All patients receiving contrast should be evaluated for their risk of CIN" -"All patients receiving contrast should be in optimal volume status..." -"High-risk patients should only be considered for pharmacologic prophylaxis with therapies supported by clinical evidence? (N-acetylcysteine?". -"Low osmolality contrast media should be used in all patients." -"Drugs that adversely affect renal function should be withheld prior to and immediately following contrast exposure." -"In all high-risk patients, a follow-up serum creatinine should be obtained at not less than 24 hrs or no more than 72 hrs following contrast exposure."

The patient from the vignette should receive i.v. fluid before and after contrast application. We used to give normal saline by 80 to 100 ml/h i.v. 12 hrs before and 12 hrs after PCI.
In case of an outpatient setting, an alternative to a 24hrs i.v. fluid regimen can be to advice the patient to drink 1 liter within the last ten hrs prior to contrast application and then to start high volume i.v. hydration (e.g. 300ml/h for 6 to 8 hrs) ?on call? for the intervention (9). The advise should be given to use a low-osmolality contrast agent and the lowest possible volume by omitting a left ventricular angiogram. We apply N-acetylcysteine 600 mg bid orally for 2 days (before and after) (1). Although N-acetylcysteine is not without controversy we in accordance to many others use N-acetylcysteine since the cost and risks of side-effects are low. In case of emergency angiography, the scheme of Marenzi et al (10) with a single shot NAC i.v. prior to angiography might be preventive. However, in this study high volumes of contrast media (approximately a mean of 260 ml) were used, so general recommendations cannot be made for high dose N-acetylcysteine (10).
In case of treatment with loop diuretics, if clinically possible, we stop these drugs at least for the day of the examination. We would not stop the ACE-inhibitor in the case of the vignette.

Concerning CIN, the last years have generated several publications with possibly new insights into prophylaxis and treatment.

Question 5) - Which of the following statements concerning CIN trial and interpretation are true?
>	a) Giving normal saline (0.9% NaCl) intravenously 80ml/h for 12 hrs before and 12 hrs after PCI is an efficient mode for prophylaxis.
>	b) It has clearly been shown that isoosmolar contrast agents are superior to low-osmolality contrast agents in terms of risk reduction.
>	c) Bicarbonate infusion may be superior to normal saline infusions in terms of risk reduction.
>	d) Serum creatinine measurements may be insufficient to assess all patients at risk.
>	e) The occurrence of CIN does not influence hard end-points such as in-hospital death or long-term mortality.
>	f) Answers #1, #3 and #4 are true.
<% if Answer5 = RightAnswer5 then Response.Write " Answer to question n. 5 is right! " else Response.Write " Answer to question n. 5 is wrong! " Response.Write " The right answer is the checked one! " end if %> Comment to Question 5: Answer #1 describes an appropriate approach to optimize the volume status of the patient. However, two recent studies have challenged the role of normal saline as the optimal fluid substitution (11) (12). Bicarbonate infusion has been postulated to be superior to normal saline first by Merten et al. (11). They administered a 154 mEq/L sodium bicarbonate solution: 3ml/kg for one hour prior and 1 ml/kg for 6 hours after contrast application. However, these authors used a rather short and presumably insufficient hydration regimen in the normal saline control group (720 ml of normal saline in an 80 kg patient) and they did not administer N-acetylcysteine. In contrast Briguori et al in a very recent publication (12) stratified their patients to receive either the Merten bicarbonate scheme plus N-acetylcysteine or a higher amount of normal saline (1562±585ml) plus N-acetylcysteine. All patients received NAC orally at a dose of 1200 mg twice daily on the day before and the day of administration of the contrast agent (total of 2 days). They included patients undergoing coronary angiography or peripheral procedures with relatively severely impaired renal function (mean baseline GFR was approximately 34 ml/min). The contrast agent was iodixanol (an iso-osmolar, nonionic contrast agent = Visipaque®, approximately 175±95 ml). The incidence of CIN was defined as a serum creatinine increase of 25% in 48 hrs. There was a significantly lower risk for CIN in the bicarbonate group compared to the normal saline group: 2% versus 10%. Therefore, the Merten bicarbonate scheme appears to be a superior alternative especially for the outpatient setting but also proved to be superior to a scheduled 24 hrs normal saline i.v. scheme. No serious side effects were recorded: Urine pH increased from 5.4±0.6 to 6.6±0.9; serum potassium decreased from 4.8±0.6 to 4.4±0.6 mmol/L (the latter change being similar in the normal saline group). Aspelin et al have investigated the difference between the iso-osmolar contrast iodixanol and the low-osmolality contrast iohexol (13). They found in a study with 129 patients a superior outcome for the iso-osmolar contrast agent concerning the risk for CIN. However, these results need to be confirmed before a general recommendation can be made: The group of patients with the low-osmolality iohexol contrast had more PCI (possible blood pressure drop?) and a longer history of diabetes (18 versus 12 years). It needs to be pointed out that serum creatinine may be insufficient in identifying all patients at risks. The (calculated) creatinine clearance can help to identify patients with severely reduced renal function despite serum creatinine still being within the normal range. Calculating the GFR with e.g. MDRD formula is also possible in the patient from the vignette only a couple of hours ahead from the PCI (just with "spot" blood drawing). Although definite, prospective data are still missing, it is clear that CIN is more than just a temporary change of a biomarker. CIN is associated with increased morbidity and mortality (6). However, it still needs to be elucidated, whether CIN is just a reflection for the presence of severe circulatory disturbances or whether CIN exerts an independent effect upon morbidity and mortality (CIN being a marker of versus being a mediator for reduced patient outcome).