Follow-up of patients with contrast-induced nephropathy

Transcription

1 & 2006 International Society of Nephrology Follow-up of patients with contrast-induced nephropathy R Solomon 1 and B Barrett 2 1 Fletcher Allen Health Care, University of Vermont, Burlington, Vermont, USA and 2 Memorial University of Newfoundland, Newfoundland, Canada In this chapter, we review the approach to following the patient after contrast is administered. We first discuss the clinical importance of renal injury for if there were no clinically significant consequences of this renal injury, we would have far less concern for the adequacy of follow-up. We next look at markers of renal injury and what tests are used in clinical practice to define contrast-induced nephropathy (CIN). Finally, we discuss the steps that should be taken in those who do develop CIN to limit the impact of the injury and protect them from future adverse events.. doi: /sj.ki KEYWORDS: contrast media; contrast-induced nephropathy; follow-up; outcome Correspondence: R Solomon, Fletcher Allen Health Care, University of Vermont, 2309 UHC, 1 South Prospect St., Burlington, Vermont 05401, USA. richard.solomon@vtmednet.org WHAT IS THE CLINICAL SIGNIFICANCE OF CIN? IS IT A BENIGN CONDITION OR A PROGNOSTIC RISK FACTOR FOR SUBSEQUENT MORBIDITY AND MORTALITY? The literature was reviewed to examine the prognosis and clinical course of patients having an acute decline in glomerular filtration rate (GFR) after contrast exposure. In general, the prognosis is presented relative to outcomes in people having similar interventions with contrast, but not suffering a decline in GFR. Most of the recent data is from cohorts having percutaneous coronary intervention (Table 1a). 1 8 A number of short- and long-term outcomes have been studied, including kidney function, need for dialysis, major adverse cardiovascular events, and death during the index hospitalization, as well as death rates by 1 or 5 years post-contrast. The patient profiles in the studies vary somewhat with regard to co-morbidity, level of pre-existing GFR, type and dose of contrast, and specific prophylactic measures employed against contrast-induced nephropathy (CIN). As seen in the Table 1b, dialysis for CIN was required in 0.15 to 12% of cases. It has often been claimed that CIN follows a predictable acute and reversible course. Although most cases do involve a transient and often relatively minor increase in serum creatinine, instances of permanent endstage renal disease are reported in these studies. Gruberg et al. 1 reported that almost 13% of patients dialyzed remained dialysis dependent in the long term, whereas McCullough et al. 2 reported that 50% did so in his earlier cohort. Whether patients recover to become dialysis independent may depend on the severity of the acute insult(s) as well as how close to end-stage renal disease they are at the time of exposure to contrast. Patients having coronary intervention may also be particularly likely to have multiple mechanisms of kidney injury, including hemodynamic instability and atheroembolism, which may affect the clinical course of what may be labeled as CIN. The studies analyzed in this report also consistently found an association of acute increase in serum creatinine after contrast with higher death rates both during the index hospitalization and in the longer term. The reason for this association cannot be reliably determined from these studies. One possibility is that acute renal injury initiates or aggravates pathologies (including vascular) such that later S46

2 Table 1a Studies evaluating outcomes in patients with CIN Study Design N Procedure Contrast Rihal et al. 3 Retrolective registry Bartholomew et al. 4 Retrolective registry Gruberg Cohort et al. 1 retrospective McCullough et al. 2 Dangas et al. 5 Cohort from Cohort from Marenzi, Prospective cohort Levy et al. 7 Lindsay et al. 8 Nested case control Retrospective cohort from 7586 PCI Iopamidol, avg. 290 ml Baseline kidney function SCr41.1 in 47.7% 20,479 PCI Mean CrCl 77 ml/min 439 PCI 95% Ioxaglate, mean ml 1826 and 1869 PCI Varies, 71% got all or some HOCM 7230 PCI Ioxaglate and others, avg ml 208 Post AMI PCI ml average of various types 183 case, 174 controls 58% Angiography, computed tomography, others, etc 5397 Successful PCI, no recent AMI, and no-in hospital major events All with Scr41.8 mg/dl Mean CrCl 71.6 ml/min Diabetes (%) CHF now (%) Diuretic (%) Prophylaxis 22 9 Unclear and hydrate only for undefined chronic renal failure % Saline 24 Varies and not specified % Saline if Scr41.5 mg/dl Unclear, only 5% with Scr41.5 mg/dl Median Scr 1.6 mg/dl 495% Ioxaglate Avg. 85 ml/min CrCl, all Scro2.0 mg/dl % Saline Fluid? Type and amount AMI, acute myocardial infarction; CHF, congestive heart failure; CIN, contrast-induced nephropathy;, chronic kidney disease; CrCl, creatinine clearance; HOCM, high osmolality contrast media;, not applicable; PCI, percutaneous coronary intervention; SCr, serum creatinine. death ensues even though kidney function improves. If this is true, then interventions that reduce the risk of CIN should also improve longer-term prognosis. Most trials of prophylactic measures against CIN do not address outcomes other than kidney function, and then only over a period of a few days. One exception is a randomized trial of prophylactic hemofiltration for patients with an average estimated creatinine clearance of 26 ml/min having percutaneous coronary intervention. 9 Acute increases in serum creatinine, oliguria, and need for urgent dialysis were significantly more common in the control group than among those subjected to hemofiltration, as were deaths in hospital (14 vs 2%). There was also a trend to a greater later mortality (up to 1 year) with a relative risk of 1.16 (95% confidence interval ) in the control group. However, this trial was small (N ¼ 114) and the later deaths alone were not statistically significantly reduced by the hemofiltration. A follow-up trial found increased survival with hemofiltration performed prior to contrast exposure in patients with a baseline GFR of less than 30 ml/min. 10 Alternative hypotheses include: (1) greater confounding co-morbidities and predictors of mortality and poor outcome among those who develop CIN, or (2) causes of acute renal failure other than contrast, such as atheroembolism or other acute pathologies, which may have their own long-term deleterious effects. The exact cause of the acute decline in kidney function after contrast is generally unknown and not reported. This is particularly true for the large -derived cohort studies of patients having percutaneous coronary intervention. In summary, CIN is both an adverse event that may permanently impair renal function, increase hospital length of stay, and hospital costs, as well as a predictor of future adverse cardiovascular events and mortality. Although the specific nature of the association between CIN and these adverse events remains to be elucidated, careful follow-up of patients exposed to contrast is necessary to identify those with CIN who can then be targeted for specific interventions. HOW IS CIN DEFINED? The toxic effect of contrast on the kidney occurs within a few minutes of exposure of the renal parenchyma to contrast media. GFR falls almost immediately and markers of tubular epithelia dysfunction appear in the urine within hours. 11,12 Direct measurement of GFR is not clinically practical because ideal markers of filtration such as inulin are not readily available and methodologies to measure radiolabeled markers, unlabeled inulin, or contrast media itself are not available in most institutions. Markers of tubular dysfunction in the forms of brush-border enzymes (alanine aminotransferase, aspartate aminotransferase), lyzosomal enzymes (N-acetyl-b-glucosaminidase), or increased amounts of lowmolecular weight proteins (b2-microglobulin) are very sensitive indices of tubular injury, but do not correlate with changes in GFR. Newer markers of renal injury such as KIM-1 have also not been validated as useful in identifying patients who will go on to have significant falls in GFR following exposure to contrast media. S47

3 Table 1b Outcome data in those who developed CIN Study Dialysis MACE Rihal et al % Q wave AMI RR 4.1 Bartholomew OR 15 (CI et al ) Gruberg 7.1% (N=31, with 4 et al. 1 ESRD and 3/17 dialyzed and surviving to 1 year still on dialysis) McCullough et al % (in derivation set N=14, with seven permanent); 0.2% in validation set Dangas et al % (N=38) 6.8 vs 0.9% if no ; 9.3 vs 1.1% if Marenzi et al % (N=6) Increased, but cannot combine them LOS Cost Death (early) Death (late) 22 vs 1.4% By 5 years if survived initial hospital 44.6 vs 14.5% 44 days 90 vs 20%? Timing OR 22 (CI 16 31) AMI RR vs 4.9%, RR 3.0 OR 6.56 (CI ) 3.6 vs 1.8 days if no ; 6.8 vs 2.3 days if 13 vs 8 days avg. 2.5 vs 0.1% if no ; 6.3 vs 0.8% if 31 vs 0.6%, RR Levy et al. 7 12% (N=21) Adjusted RRL 5.77 (CI ) Adjusted OR by 1 year 3.86 (CI ) By 1 year 8.0 vs 2.7% if no ; 22.6 vs 6.9% if Lindsay et al % (N=8) By 1 year 12.4 vs 3.4%, RR 3.7 Comments on quality Missing data on 2.9%; variable prophylaxis, no use GFR estimate, unclear cause acute renal failure, does not report overall MACE rates; cannot causally link the deaths to CIN per se Registry; unclear if missing data; no details on contrast or prophylaxis; post Scr very early at 8 16 h; cause acute renal failure not clear; cannot causally link deaths to CIN per se More complete assessment of late outcomes. Low power. Some adjustment for confounders. Some baseline data only given for derivation set. No data on prophylaxis. Note use of HOCM Defined as egfro60; lack data on prophylaxis details; retrospective analysis of Cause of ARF unclear; distinct population; did not report overall MACE rates Retrospective, adjusted for some confounders Note selected those more stable PCI patients; missing data at 1 year in 9% AMI, acute myocardial infarction; CI, confidence interval; CIN, contrast-induced nephropathy;, chronic kidney disease; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HOCM, high osmolality contrast media; OR, odds ratio; LOS, length of hospital stay; MACE, major adverse cardiovascular event;, not applicable; PCI, percutaneous coronary intervention; RR, relative risk; SCr, serum creatinine. A valid marker of GFR will vary inversely with changes in GFR such that a 50% fall in GFR will be reflected in a twofold increase in the marker once the steady state has been reached. Serum creatinine is the most widely available marker for GFR and changes in serum creatinine correlate with subsequent adverse events, both in the hospital and over the first year. 1 However, creatinine suffers from two significant limitations. First, creatinine is not excreted in the urine solely as a result of glomerular filtration. A significant component of renal tubular secretion occurs and the absolute amount of creatinine in urine contributed by secretion increases as glomerular filtration falls. 13 This means that changes in serum creatinine will underestimate the true fall in GFR. This is clear from the literature on changes in renal function following contrast exposure. For example, creatinine clearance (a measure of GFR) fell by more than 25% within 24 h in 14% of patients with mild renal impairment following intravenous urography, but serum creatinine rose by 25% in less than 1%. 11 Similar observations have been made by others. 14 The ability of the kidney to enhance tubular secretion is particularly evident in those with more normal levels of renal function. 13 In a careful study by Katholi et al., 15 creatinine clearance measured 48 h after contrast exposure fell in 33 of 35 patients, but serum creatinine had not changed significantly, having risen from to This discrepancy between changes in serum creatinine and GFR may explain why we find so few cases of CIN (defined by changes in serum creatinine) in patients with initially normal levels of GFR. Secondly, following an acute fall in GFR, less creatinine is excreted. The retained creatinine is distributed in total body water. Thus, the serum level can be expected to rise slowly and will continue to rise until a new steady state has occurred. Therefore, although the injury induced by contrast S48

4 impairs GFR almost immediately, it requires h for the fall in GFR to be reflected in an elevated level of serum creatinine. What about other serum markers of GFR? Another small molecule that is readily filtered but not secreted is b2- microglobulin. A rise in serum b2-microglobulin therefore reflects a loss in GFR. b2-microglobulin has been used in some studies, 12,16 but appears to offer no advantage over creatinine. Furthermore, it is not readily available in clinical practice. Cystatin C has also been used as a marker of both the chronic level of GFR and acute changes in GFR. It does not undergo tubular secretion and appears in the urine solely through filtration. Cystatin C, however, rises more quickly when GFR acutely falls, 17 and as a result more patients with CIN are captured at 24 h following contrast exposure as a result. 18 Cystatin C is also subject to less variability in production, and therefore its use as a marker of chronic renal insufficiency has been advocated. At the moment, it is not widely available in clinical laboratories. What about other markers of acute renal injury? Enzymuria has been mentioned above. It does not correlate with changes in GFR and can be observed in many patients with normal levels of renal function who have no subsequent change in GFR. For this reason, it has been considered too sensitive a marker and abandoned for predicting changes in GFR. However, there is increasing evidence that connects renal tubular injury to the generation of inflammatory cytokines that might contribute to the in-hospital adverse events discussed previously. As the association of CIN with subsequent adverse cardiovascular events has been emphasized, the role of tubular injury as reflected in enzymuria may require revisiting. Retention of contrast in the renal parenchyma noted on computed tomography scans performed h after initial contrast exposure has been reported as another marker of renal injury. 19 This radiologic observation has not been prospectively correlated with changes in GFR however. Furthermore, the scheduling issues and cost of using computed tomography for diagnosis of CIN makes this impractical as a diagnostic tool. This discussion regarding markers of acute renal injury is relevant to how we define acute renal failure in clinical practice. Regardless of etiology, acute renal failure is synonymous with an acute fall in GFR. How then do we use serum creatinine to quantitate the magnitude of the fall? Within the body of literature on CIN, both a relative change (X25 or X50% increase) or an absolute change (X0.5 or X1.0 mg/dl) in serum creatinine has been used. Using an absolute change in serum creatinine, however, means loss of different quantities of GFR depending upon the baseline level of GFR. As can be seen from Table 2a, a patient in whom the creatinine rises from 1.0 to 1.5 mg/dl losses three times as much GFR as the patient whose creatinine rises from 2.0 to 2.5 mg/dl. From a nephrocentric perspective, the patient with a rise in creatinine from 1.0 to 1.5 mg/dl has the more severe injury. A corollary of this observation is that in patients with a higher serum creatinine before contrast exposure, the likelihood of developing CIN (by a definition that uses an absolute increase in serum creatinine) will be greater because less renal function needs to be lost to reach the threshold for the definition. This is critically important when comparing studies on the incidence of CIN. It is not sufficient to look at the mean serum creatinine between different studies. It is the distribution of creatinine levels that must be similar if an absolute rise in serum creatinine will be used for the definition of CIN. To compare similar degrees of injury regardless of the baseline serum level, the relative change in serum creatinine is a preferable metric (Table 2b). With a relative change definition, all patients lose the same percentage of renal function regardless of the level of renal function at baseline. There is still a bias, however, for a smaller absolute loss of GFR to satisfy the definition of CIN when there is a lower GFR at baseline. Finally, it follows from the above discussion that in patients with milder degrees of renal insufficiency (creatinine less than 2 mg/dl), the incidence of CIN will always be less when a 0.5 mg/dl absolute increase is used as a definition compared to a 25% increase in serum creatinine. A greater loss of GFR is necessary to satisfy the definition of CIN when the absolute change in serum creatinine is used (Table 2a vs b). Which definition, absolute or relative increase in serum creatinine, reflects outcomes the best? Gruberg et al. 1 correlated outcomes following contrast exposure in patients who underwent cardiac catheterization. A worse outcome (at 1 year) was found in those patients whose creatinine increased more than 25%. The rate of adverse events increased from 18% in those with less than a 25% increase in creatinine to 37% in those with a creatinine increase of greater than 25%. These observations support the use of a relative change in creatinine as a clinically significant metric. Table 2 (a) When using an absolute increase in serum creatinine as the definition of CIN, a greater degree of injury is needed in individuals with better renal function before contrast exposure. This leads to a bias toward CIN being recognized more often in those with impaired renal function. (b) This bias is reduced but not completely eliminated when using a relative increase in serum creatinine Baseline creatinine (mg/dl) Rise of 0.5 mg/dl Change in GFR Loss of GFR (ml/min) (%) (a) (33) (25) (20) Baseline creatinine (mg/dl) Rise of 25% Change in GFR Loss of GFR (ml/min) (%) (b) (20) (20) (20) CIN, contrast-induced nephropathy; GFR, glomerular filtration rate. S49

5 SUMMARY Current clinical practice relies on the change in serum creatinine as a marker of acute changes in GFR. If one does not measure a post-contrast serum creatinine within h, patients with a clinically significant fall in GFR will obviously not be identified. The first recommendation, therefore, is to measure creatinine post-contrast exposure in all high-risk patients. A relative increase in serum creatinine will identify more individuals with a significant loss of GFR. A 25% or greater increase in serum creatinine over the baseline value within 48 h of contrast exposure identifies individuals with a worse prognosis. 1 Baseline serum creatinine is measured before volume expansion maneuvers. This avoids the frequently observed fall in serum creatinine induced by the volume expansion itself. The second recommendation, therefore, is that a X25% increase in serum creatinine should be used to identify individuals with a significant injury to the kidney (CIN) and the use of an absolute change in serum creatinine should be abandoned. Most high-risk individuals who develop CIN will have a X25% rise in serum creatinine at 24 h with only a small additional few being identified at 48 h. The third recommendation is that the post-contrast serum creatinine measurement be obtained at 24 h post-exposure in all high-risk patients (egfro60 ml/min). It is possible that the use of a marker such as cystatin C would permit identification of more patients within a 24 h period or even at an earlier period of time. Further studies regarding this and the association of changes in cystatin C with clinical outcomes are needed. FILLY, WHAT STEPS SHOULD BE TAKEN IN THOSE WHO DO DEVELOP CIN? A LIST OF RECOMMENDED STEPS FOLLOWS (OPINION) In those who develop CIN, renal function should be followed until there is a return to baseline levels. For hospitalized patients, this usually means monitoring daily serum creatinine levels. During the time that serum creatinine remains elevated, further insults to the kidney should be carefully avoided. This means withholding further contrast studies, elective surgery with general anesthesia, and nephrotoxic drugs such as nonsteriodal antiinflammatory drugs. In addition, drugs that may themselves alter GFR such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and diuretics, and drugs excreted by glomerular filtration such as metformin should also be held if possible. Finally, individuals with CIN should be considered at high risk for future cardiovascular events. As such, efforts to control glycemia, blood pressure, and dyslipidemia should be intensified. 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