Nephrotoxic Risks of Renal Angiography: Contrast MediaAssociated Nephrotoxicity and Atheroembolism—A Critical Review

Nephrotoxic Risks of Renal Angiography: Contrast MediaAssociated Nephrotoxicity and AtheroembolismA Critical Review Michael R. Rudnick, MD, Jeffrey S. Berns, MD, Raphael M. Cohen, MD, and Stanley Goldfarb, MD • Renal angiography remains the "gold standard" procedure for the detection of renal artery stenosis. However, clinicians often avoid renal angiography because of fears of contrast media-associated nephrotoxicity (CM-AN) and atheroembolism. This review focuses on these potential angiographic complications, with particular emphasis, in the case of CM-AN, on clinical features, incidence, risk factors with an emphasis on pre-existing renal insufficiency and diabetes mellitus, volume of contrast media, low osmolar versus high osmolar contrast media, and prophylaxis. For atheroembolism, areas emphasized are pathology, clinical features, precipitating features, and incidence in various settings. Although the literature contains an abundance of information about CM-AN and atheroembolism, this review identified multiple areas of uncertainty regarding features of both of these complications. For example, additional studies are needed to determine the incidence of CM-AN, both asymptomatic and clinically severe, in patients with a wide range of pre-existing renal insufficiency with and without diabetes mellitus, following low volume digital subtraction renal angiography with low osmolar contrast media. In a similar manner, studies are needed with adequate postcontrast observation periods to determine the true incidence of clinically significant atheroembolism following diagnostic renal angiography and angioplasty and techniques that may modify this complication. Until further knowledge in both of these areas is available, it is difficult to precisely determine the risks of renal angiography and/or angioplasty in the azotemic patient suspected of or having renal ischemic disease using modern radiologic techniques. © 1994 by the National Kidney Foundation, Inc. INDEX WORDS: Contrast media; acute kidney failure; cholesterol embolism.

T

HE POTENTIAL for stenosis of the renal arteries to cause renal insufficiency, socalled "renal ischemic disease," is well known. 1 The exact prevalence of renal ischemic disease has not yet been determined, but may be responsible for up to 6% to 16.5% of all end-stage renal disease cases. 2 ,3 The current uncertainties surrounding the prevalence of renal ischemic disease are due to multiple factors, but primarily to the absence of a safe, reproducible, and accurate test for diagnosing this disorder. Present noninvasive tests to detect renal artery stenosis, such as doppler duplex ultrasonography,4 magnetic resonance angiography,5 and radionuc1ide renal scans6 (especially in patients with chronic renal insufficiency [CRI]), are limited in their sensitivity and specificity and optimal results appear achievable only in selected centers. Thus, renal angiography continues to be the "gold standard" diagnostic study for the detection of renovascular disease. In the past, concerns of renal injury from contrast media-associated nephrotoxicity (CMAN) and, to a lesser extent, atheroembolism in high-risk azotemic patients have restrained enthusiasm for renal angiography in patients with clinical characteristics suggestive of renal ischemic disease. However, recent developments in radiologic techniques and contrast media formu-

lations, along with further clarification of risk factors and preventive measures, suggest that renal angiography, specifically digital angiography, in azotemic patients may be safer than traditionally believed allowing increased usage in patients suspected to have renal ischemic disease. We critically review various aspects of CM-AN and atheroembolism, with an emphasis on recent literature. CONTRAST MEDIA-ASSOCIATED NEPHROTOXICITY

Clinical Features In most patients with CM-AN, the serum creatinine usually begins to increase within the first 24 to 48 hours following contrast administration, From the Section ofNephrology and Hypertension, Graduate Hospital, and Patient Care, Education and Research, Graduate Health Systems, University of Pennsylvania School of Medicine, Philadelphia, PA. Received January 27, 1994; accepted in revised form May 24,1994. Address reprint requests to Michael R. Rudnick, MD, Section of Nephrology and Hypenension, Graduate Hospital, 703 Pepper Pavilion, 19th and Lombard Sts, Philadelphia, PA 19146. © 1994 by the National Kidney Foundation, Inc. 0272-6386/9412404-0026$3.00/0

American Journal of Kidney Diseases, Vol 24, No 4 (October), 1994: pp 713-727

713

714

CONTRAST NEPHROTOXITY AND ATHEROEMBOLISM

peaks within 3 to 5 days, then returns to baseline levels within 7 to 10 days.7-14 In patients with more severe nephrotoxicity, the serum creatinine may continue to increase for 5 to 10 days, or until such time as dialysis is required. In patients with CRI, there rarely may be persistent elevation of the serum creatinine concentration. 10,11,14-16 Except in certain high-risk patient populations, such as insulin-dependent diabetic patients with advanced CRI, the need for either temporary or permanent dialysis is rare. 1O,11,14,16-22 Mortality due to CM-AN is generally regarded as quite uncommon, but may be significant in patients with co-existent severe illnesses?3 A relatively high incidence of oliguric renal failure accompanying CM-AN was reported in older series, with oliguria often beginning within the first 12 to 24 hours. 13,15,24,25 A failure to recognize the entity of nonoliguric acute tubular necrosis 26 probably contributed to the mistaken impression of frequent oliguria in earlier studies. In more recent series, the vast majority of cases of CM-AN are nonoliguric, except in patients with advanced CRI. 12,16,27,28 The urinalysis in patients with CM-AN typically show coarse granular casts, renal tubular epithelial cells, and amorphous sediment, along with low-grade proteinuria. Urate or calcium oxalate crystals may be seen. The fractional excretion of sodium may be low « 1%), especially in oliguric patients,12 but also may be elevated. 18,29 A persistent nephrogram 24 to 48 hours following administration of contrast has been suggested to be a marker for CM-AN, although the sensitivity, specificity, and clinical utility of this finding is not clear. 30-32

Retrospective studies in patients without significant risk factors typically have reported incidences of CM-AN of less than 1%.8,9 In several recent prospective studies, the risk of CM-AN in individuals without diabetes mellitus or renal insufficiency has been reported to be between 0% and 7%,11,21,35-43 with an average incidence of 3% in the largest studies. 22,36,38,40.43 These reports encompass a wide variety of radiographic procedures and contrast agents, with no obvious differences, suggesting that neither the procedure performed nor the type of contrast media selected had any significant affect on the incidence of CM-AN in these low-risk patients. More recent studies suggest that without an appropriate control group, the observed incidence of CM-AN may be overestimated. In a controlled prospective study of renal function following contrast-enhanced computed tomography imaging, Cramer et ae 7 found a 2.1 % incidence of CM-AN in 93 patients without diabetes mellitus or CRI. This was not significantly different from the 1.3% incidence of acute renal impairment in a control group that did not receive intravenous contrast. In a similar manner, Parfrey et al,44 in a study of CM-AN, observed incidences of nephrotoxicity ranging from 1.6% to 6.7% (depending on underlying risk factors) in control patients following radiologic studies performed without contrast media. Old age has been previously suggested to be a risk factor for CMAN,8,14 possibly due to subclinical CRI or the more frequent application of intravascular contrast studies in the elderly.? However, Rich and Crecelius41 evaluated a large group of elderly patients (~70 years of age) for CM-AN following angiography and found that the incidence of CM-AN was only 1.2% in those without risk factors. Even in the presence of some risk factors, the incidence of CM-AN was still only 6.5% in the absence of diabetes mellitus and renal insufficiency, Several prospective studies have examined the effects of contrast media administration on creatinine clearance in low-risk patients. 45.47 The results of some of these studies indicate that contrast media administration may reduce glomerular filtration rate (GFR) , even in low-risk patients, but to an extent that is not reflected by significant elevations in serum creatinine from normal values. 45 ,4?

Incidence

Intravascular contrast media administration continues to be a common cause of hospital-acquired acute renal failure,33,34 although frequency data provided by these studies may be overestimated due to bias limitations inherent in retrospective analyses. The reported incidence of CMAN can vary significantly as the result of several factors, including reporting criteria, type of radiologic procedure, use of high or low osmolar contrast media and prophylactic measures, and the presence or absence of risk factors, such as azotemia, diabetes mellitus, and contrast media volume.

RUDNICK ET AL

In summary, clinically significant CM-AN (ie, necessitating extended hospital stays and/or dialysis) is rare in low-risk patients without CRI or diabetes mellitus. Should significant azotemia develop in low-risk patients, other causes of nephrotoxicity should be considered, such as that due to other nephrotoxins, intercurrent ischemia, or atheroemboli (see below).

Risk Factors Renal insufficiency. Renal insufficiency is commonly regarded as the major risk factor for CM-AN. A recent comprehensive review concluded that approximately 60% of patients with CM-AN had pre-existing CRe Numerous reports have demonstrated a significantly increased risk for CM-AN in nondiabetic patients with CRI compared with patients with normal renal function.ll.22.36,43.48 It remains uncertain, however, how much of the increased risk of CM-AN in CRI is due to the exponential relationship between serum creatinine and GFR. As a result of this relationship, there will be a greater absolute increase in the serum creatinine value in patients with pre-existing chronic renal failure compared with patients with normal renal function for any given contrast media-induced decrease in the GFR. Thus, diagnostic criteria for CM-AN are more readily met in the former compared with the latter group of patients, despite similar magnitudes of renal injury. The reported incidence of CM-AN in patients with baseline CRI varies greatly (Table 1), probably due to specific factors known to affect the incidence of CM-AN previously discussed (see above) as well as differences in the degree of baseline CRI. Several investigators have found a relationship between the severity of baseline renal insufficiency and the risk ofCM-AN. VanZee et al 14 found a 3% incidence of CM-AN in nondiabetic patients following intravenous pyelogram when the baseline serum creatinine was less than 4.5 mg/dL, but a 31 % incidence in those with a baseline serum creatinine higher than 4.5 mg/ dL. Teruel et alii found a statistically significant linear relationship between the incidence of CMAN after intravenous pyelogram and the severity of CRI. Contrast media-associated nephrotoxicity occurred in 15% of patients with normal or mildly decreased renal function (baseline creatinine <2.0 mg/dL), but in 55% of patients with

715

more advanced renal insufficiency (baseline creatinine ~2 mg/dL; mean, 4.3 :::!:: l.8 mg/dL). Barrett et ae l found a 6% incidence of CM-AN following coronary angiography or intravenous studies in nondiabetic patients with a serum creatinine between 1.4 and 2.25 mg/dL compared with a 17% incidence in nondiabetic patients with a baseline serum creatinine greater than 2.25 mg/dL. Finally, Moore et al 22 demonstrated the incidence of CM-AN to be 4.7% in patients with baseline creatinine values of 1.5 to l.9 mg/dL, 14.3% for creatinine values of 2.0 to 2.4 mg/dL, and 20% for creatinine values of 2.5 to 2.9 mg/dL. Conversely, Mason et al 45 failed to find a relationship between CM-AN and underlying CRI. Despite these observations, renal insufficiency should not be considered an absolute contraindication to intravascular radiographic contrast procedures. Current data suggest that many patients with CRI, especially if mild, can be safely studied with contrast media, and ifCM-AN should occur, the clinical consequences appear limited for most patients. 19-22,40.44 Use of noncontrast procedures (ultrasound, magnetic resonance imaging, computed tomography, etc) should, of course, be undertaken whenever possible. When necessary, however, contrast-enhanced studies can be performed in patients with CRI with attention to maintaining optimal hydration status, spacing of contrast procedures, and the use of minimum contrast volumes and low osmolar (nonionic) contrast media (LOCM) (see below). Diabetes mellitus without renal insufficiency. Diabetes mellitus is frequently cited as a risk factor for CM_AN. 708 Most, if not all, of the risk attributed in the past to diabetes mellitus, however, is probably related to underlying CRI due to diabetic nephropathy rather than to the presence of diabetes mellitus per se. 7025 Most recent studies have found an incidence of CM-AN in diabetic patients without renal insufficiency, which does not appear to be any greater than that observed in nondiabetic patients with normal kidney function.35-39.44-46 In the controlled study of Parfrey et al,44 the incidence of CM-AN was 2.4% in contrast-infused diabetic patients without renal insufficiency and 3.4% in a similar diabetic group that did not receive contrast. Lautin et al,48 however, noted CM-AN in 16% of diabetic patients without baseline renal insufficiency

716

CONTRAST NEPHROTOXITY AND ATHEROEMBOLISM

Table 1. Contrast Media-Associated Nephrotoxicity: Prospective Trials in Renal Insufficiency in Patients Without and With Diabetes Mellitus Incidence of eM-AN (nlN) (%)

Source

Procedure

Contrast

Definition of CM-AN

Shafi et al,8 Anto et al 29 Kumar et aJ35 D'Elia et al 36

IVP IVP Noncoronary angiogram Noncoronary angiogram

HOCM HOCM HOCM HOCM

Mason et al45 Moore et al38 Parfrey et al 44 Rich and Crecelius4, Lautin et al 48

Noncoronary angiogram Miscellaneous Miscellaneous Coronary angiogram Noncoronary angiogram

HOCM HOCM/LOCM HOCM/LOCM HOCM/LOCM LOCM

Rudnick et al 43

Coronary angiogram

HOCM/LOCM

Harris et al,9 Taliercio et al 20 Barrett et al 2 ,

CT scan Coronary angiogram Coronary angiogram CTscan IVP Coronary angiogram CTscan

HOCM/LOCM HOCM/LOCM HOCM/LOCM

.. 25% t S", or t C", within 5 d .,,25% t S", or t C'" within 5 d t S", .. 0.5 mgldL within 48 hr t Se, .,,0.5 mg/dL within 72 hr t So< .. 1.0 mg/dL within 72 hr t Ce, <::25% within 24 hr t Se, .. 0.5 mg/dL t Se, > 50% within 48 hr t Se, > 0.5 mg/dL within 48 hr t Se, > 0.3 mg/dL or >20% within 1 to 3 d t Se, .. 1 mgldL within 48 to 72 hr t Se, .. 25% within 48 hr t Se, > 0.5 mgldL within 1 to 5 d t Se, .. 25% within 48 hr

HOCM/LOCM

t

Moore et al22

So< > 33% and >0.4 mgldL within 48 hr

+RI/-DM

17/28 5/28 1/19 2110 1110 8/18 4194 4/101 4129 2/19

(61) (18) (5) (20) (10) (44) (4) (4) (14) (11)

+RI/+DM

11/12 3/9 0/6 5/13 3/13 2/13 4/18 3/34 5/9 4/15

(92) (33) (0) (38) (23) (15) (22) (9) (56) (27)

15/296 (5)

43/213 (20)

5n6 (7) 28/281 (10) 6/213 (3)

3/25 (12) 9/26 (35) 6/36 (17)

4/117 (3)

8/43 (19)

Abbreviations: C e," creatinine clearance; CT, computed tomography; DM, diabetes mellitus; HOCM, high osmolar contrast media; IVP, intravenous pyelogram; LOCM, low osmolar contrast media; Se" serum creatinine; RI, pre-existing renal insufficiency.

compared with 1.5% in nondiabetic patients using a very sensitive definition of CM-AN. With the application of less-sensitive definitions for CM-AN, significant differences between diabetic and nondiabetic patients with normal renal function were not found. In contrast, in several studies,21,22,28,49 multivariate logistic regression analysis demonstrated that diabetes mellitus is an independent risk factor for CM-AN, although in some this risk was limited only to insulin-dependent diabetic patients. 22 ,28.48 Thus, while most recent studies suggest that diabetic patients without renal insufficiency are not at a significantly increased risk for CM-AN, caution is probably still warranted. Whether insulin-dependent diabetic patients without renal insufficiency are at a greater risk than non-insulin-dependent diabetic patients remains to be clarified. Diabetes mellitus and renal insufficiency. Although diabetes mellitus absent of CRI probably does not increase the risk of CM-AN, diabetic patients with CRI demonstrate a significantly increased risk for this complication. It is particularly in these patients that oliguric renal failure requiring dialysis may occur following contrast media administration,'0,'4,'6,17,27 and in some of

these patients, CM-AN may not be reversible.'O.l6.'7,27 In diabetic patients with mild to moderate CRI, the risk of CM-AN has been reported to be between 9% and 40%19-21 ,36,43,44,50,51 and a 50% to 90% incidence of CM-AN has been observed in diabetic patients with more advanced CRI. 14,16-18,27 While several studies have reported the risk of eM-AN to be greater in diabetic patients with CRI than in nondiabetic patients with CRI (Table 1), in none of these studies were patients matched for the degree of CRI. Thus, the higher incidence of CM-AN in diabetic patients with CRI compared with nondiabetic patients with CRI, may in part be due to more severely impaired baseline renal insufficiency in the former group of patients. Volume of contrast media. In several large series examining CM-AN, the risk associated with volume of contrast media administered has been investigated using regression analysis. Some studies demonstrate a significant correlation between CM-AN and contrast volume,16,28,49,51,52 while in others no relationship was found. 17.21,22,36,45.53 Cigarroa et al 51 reviewed the records of 115

RUDNICK ET AL

high-risk patients (baseline serum creatmme ~ 1.8 mg/dL) undergoing cardiac angiography with high osmolar (ionic) contrast media (HOCM). Patients were divided into two groups depending on whether the total contrast volume administered was within or exceeded the limits of contrast volume predetermined by a formula designed to limit contrast volume based on body weight and magnitude of underlying CR!. In those patients in whom the total volume of contrast media exceeded the' 'formula" amount, the incidence of CM-AN was 21 % compared with an incidence of CM-AN of 2% (P < 0.001) in patients whose contrast volume was within the prescribed limit. All the patients affected with CM-AN had diabetes mellitus. Manske et al 16 evaluated 59 insulin-dependent diabetic patients undergoing pretransplant coronary angiography with LOCM. All patients had baseline creatinine clearances less than 30 mLimin. The incidence of CM-AN in patients receiving less than 30 mL of contrast media was 26% compared with 79% in patients in whom this volume of contrast was exceeded. These studies suggest that contrast media volume may be a significant risk factor, especially in diabetic, azotemic patients. Multiple myeloma. Both acute and chronic renal failure are common complications of multiple myeloma, 54-56 and mUltiple myeloma is frequently cited as a potential risk factor of CMAN.8 Intratubular precipitation of Bence-Jones protein with Tamm-Horsfall protein is likely an important factor in the development of renal failure in patients with multiple myeloma. 54.57,58 Currently used contrast media appear not to precipitate Bence-Jones protein, at least in vitro.59 Contrast media may enhance aggregation of Tamm-Horsfall protein,60 which could perhaps enhance precipitation of Bence-Jones protein, although this remains speCUlative. No prospective studies are available which suggest that patients with multiple myeloma are at greater risk for CM-AN than other patients with comparable levels of renal function. McCarthy and Becket1 recently reviewed seven retrospective studies of contrast media administration in 476 patients. While the actual incidence of CM-AN may well be underestimated in this type of analysis, the prevalence of acute renal failure in these studies was only 0.6% to 1.25%. Other investigators have also concluded that in the absence of other common

717

causes of acute renal failure in patients with multiple myeloma, such as volume depletion, hypercalcemia, sepsis, and exposure to other nephrotoxins, patients with multiple myeloma may not be at increased risk of CM_AN. 8,55,62,63 Thus, while multiple myeloma should not be considered a specific contraindication to contrast media administration, clinical prudence suggests performance of only essential contrast studies and avoidance of dehydration in these patients.

Low Osmolality Contrast Media Following their introduction in the 1980s, LOCM have become widely used because of a reduced incidence of adverse effects compared with conventional HOCM. 64 ,65 Discussions of the pharmacology of these newer contrast agents can be found elsewhere. 65.66 Experimental observations in animals 67 -78 led to speculation that these newer contrast agents would also be less clinically nephrotoxic. Specifically, experimental studies have demonstrated that LOCM, compared with HOCM, have resulted in diminished reductions in renal blood flow,67-72 albuminuria,1°,73-75 enzymuria,75,76 GFR,70,76.77 and histologic damage. 69 ,76,78 As the use of LOCM in diagnostic radiologic studies became more widespread, an increasing number of reports established that LOCM are capable of causing a wide spectrum of CM-AN, ranging from enzymuria alone to severe oliguric acute renal failure requiring acute hemodialySiS. 16,19-22,39,40,42,43,79-83 As with HOCM, pre-existing renal insufficiency alone or coupled with diabetes mellitus increases the risk of nephrotoxicity with these newer agents.20,39,43 Although LOCM are not devoid of nephrotoxicity, it remains uncertain whether the incidence of CM-AN is less with LOCM than with HOCM. In this regard, several recent prospective studies have compared the incidences of nephrotoxicity between LOCM and HOCMI9-22.40 (Table 2). In most of these studies, LOCM were not found to be less nephrotoxic than HOCM,21.22,40,44.82 and in those studies that did demonstrate less nephrotoxicity, the differences from HOCM were quantitatively small and interpreted as not clinically significant. 19,20 Although it appears that LOCM and HOCM have a similar low risk of nephrotoxicity in nonazotemic patients without or with diabetes mellitus, the small number of azotemic pa-

CONTRAST NEPHROTOXITY AND ATHEROEMBOLISM

718

Table 2. Contrast Media-Associated Nephrotoxicity: Prospective Randomized Trials of Low Osmolar Contrast Media Versus High Osmolar Contrast Media Incidence of CM-AN Based on Risk Factors (n/N) (%)

Source

LOCMI HOCM Studied

Schwab et al 40

lopamidol Diatrizoate

Harris et al 19 Taliercio et al 20

lohexol lothalamate lopamidol Diatizoate

Rudnick et al43

lohexol Diatrizoate

Barrett et al21

lohexol lopamidol lothalamate Diatrizoate lohexol Diatrizoate

Moore et al22

Incidence of CMAN (n/N) (%) Definition of CM-AN

-RI/-DM

LOCM

HOCM

LOCM

So. ",0.5 mg/dL within 48 hr t So. ",25% within 48 hr t So. >0.5 mg/dL within 1 to 5d t So. ",1.0 mg/dL within 48 to 72 hr i Scr ~25% by 48 hr

24/235 (10.2)

17/208 (8.2)

NA

1/51 (2.0) 7/147 (4.8)

715O (14) 16/142 (11.3)

19/591 (3.2)

42/592 (7.1)

5/132 (3.8)

8/117 (6.8)

t

13/479 (2.7)

13/450 (2.9)

t

So. >0.4 mg/dL and

01188 (0)

9/382t (2.4)

-RI/+DM

+RI/-DM

+RI/+DM

HOCM

LOCM

HOCM

LOCM

HOCM

LOCM

HOCM

NA

NA

NA

NN

NA'

NA"

NA"

1/35 (2.9) 31127 (2.3)

4/41 (9.8) 10/122 (8.2)

0/16 (0) 412O (20)

3/9 (33.3) 6120 (30)

6/148 (4.1)

11/148 (7.4)

12/102 (11.8)

30/111 (27)

21108 (1.9)

4/105 (3.8)

3/24 (12.5)

3/12 (25)

4/96t (4.2)

7/64t (4.2)

NA

NA

0/171 (0)

6/380t (1.6)

1/153 (0.7)

NA

1/162 (0.6)

NA

>33% within 48 hr Abbreviations: DM, diabetes mellitus; NA, not available; RI, pre-existing renal insufficiency; S'" serum creatinine. "Twenty-eight patients with RI. t Totals include 119 DM patients, of whom 43 had RI and DM.

tients evaluated in most of these studies (Table 2) limits any conclusions regarding differences in nephrotoxicity between these types of contrast agents in high-risk patients. Recently, the preliminary results of a large prospective multicentered trial evaluating the incidence of nephrotoxicity between LOCM and HOCM have been reported. 43 In this study, 1,194 patients undergoing elective coronary angiography were prospectively randomized to receive the LOCM, iohexol, or the HOCM, diatrizoate. The inclusion of 514 azotemic patients (serum creatinine ~ 1.5 mg/dL), of whom 216 also had diabetes mellitus, made this the largest trial comparing LOCM and HOCM in high-risk patients perfonned to date (Table 2). There were essentially no episodes of CM-AN in nondiabetic or diabetic patients with nonnal renal function, consistent with the results of earlier studies. However, in patients with CRI without diabetes, the incidence of CM-AN was 7% in the HOCM group and 4% in the LOCM group. In patients with both CRI and diabetes mellitus, the incidence of CM-AN was 27% in HOCM patients and 12% in those who received LOCM. The

findings of this study are supported by a recent meta-analysis, which also concluded that LOCM are associated with less nephrotoxicity than HOCM in patients with CRI. 84 The mechanism(s) for the observed diminished nephrotoxicity of LOCM in high-risk patients has yet to be elucidated. At present it remains unclear whether the protective benefit of LOCM is due to diminished osmolality, nonionicity, or specific chemical structure-toxicity relationships. Thus, at present, it cannot be stated with certainty that all LOCM are equally less nephrotoxic. In summary, in patients with nonnal renal function, regardless of the presence or absence of diabetes mellitus, the risk of CM-AN is equally low with either LOCM or HOCM. However, in patients with CRI undergoing cardiac angiography, and perhaps other radiographic procedures as well, LOCM should preferably be used because of their lower risk of CM-AN. Prophylaxis Since there is no specific treatment for CMAN once it occurs, a number of preventive measures have been recommended. 85 Hypertonic

RUDNICK ET AL

mannitol infusions have been frequently recommended, although studies specifically designed to evaluate its prophylactic role in CM-AN remain limited. In a reproducible animal model of CMAN, Vari et a1 86 were unable to demonstrate a protective role for mannitol or isotonic saline. In a frequently cited clinical study performed by Anto et al,29 37 patients with CRI (mean serum creatinine, 4.1 mg/dL) were hydrated prior to receiving contrast media for intravenous pyelogram. After contrast administration, 250 mL of 20% mannitol was given intravenously over 60 minutes followed by D5-1I2 NSS at a rate equal to hourly urinary output until the following morning. These investigators found a 22% incidence of CM-AN compared with a 70% incidence of CM-AN in a previously studied group of similar patients who received contrast media and pre-study fluids in a manner identical to that above except that they did not receive mannitol,18 leading the investigators to conclude that hypertonic mannitol conferred significant protection against CM_AN. 29 This conclusion may be questioned since the historic control group did not continue to receive intravenous fluids to match urine output following contrast media administration. The creation of a persistent sodiumdriven diuresis after contrast exposure may by itself have afforded significant protection against CM-AN. In another study of 24 patients with CRI, 100 mL of 25% mannitol or D51W alone was administered at the termination of various contrast studies in a double-blinded, prospective, randomized protocol. 87 Pre- and post-contrast peak serum creatinine values were, respectively, 2.10 mg/dL and 3.07 mg/dL in the control group and 2.37 mgldL and 2.5 mg/dL in the mannitol group (P < 0.05). Given the small changes in serum creatinine and lack of information on the proportion of patients in each group who developed CMAN, the results are not conclusive. Moreover, other studies have not clearly demonstrated a benefit of mannitol prophylaxis. 88 .89 Solomon et a1 89 prospectively randomized patients with CRI undergoing cardiac angiography to receive saline hydration alone or saline hydration with mannitol. Contrast media-associated nephrotoxicity occurred in none of 23 patients in the saline group and in three of 18 patients in the saline-mannitol group. Conversely, in a study

719

by Weisberg et al,90 patients with stable CRI undergoing cardiac angiography were randomized to receive 112 NSS or mannitol throughout cardiac catheterization. In diabetic patients, the incidence of CM-AN was 43% in the saline group and 75% in the mannitol group. In contrast, the incidence of CM-AN in nondiabetic patients was 38% in the saline group and 0% in the mannitol group. The investigators concluded that mannitol reduced the risk of CM-AN in nondiabetic patients, but increased the risk of this complication in diabetic patients. Saline infusion alone has been advocated as an effective preventive measure for CM-AN. Eisenberg et a1 91 evaluated 537 patients (27% with CRI and 33% with diabetes mellitus) undergoing a variety of angiographic procedures who received saline infusions as part of the procedure. None of the patients developed CM-AN, leading the investigators to conclude that saline infusion (in this case, approximately 800 mLlhr) is effective prevention for CM-AN, even in high-risk patients. However, the absence of a control group and the selection of extremely rigid criteria to define CM-AN weakens this conclusion. In a preliminary report, Brown et al 92 retrospectively evaluated 518 high-risk patients (serum creatinine> 1.9 mgldL) who underwent cardiac angiography. The investigators found that patients who did not develop CM-AN, compared with patients who developed this complication, more frequently were the recipients of crystallized infusions to expand the extracellular fluid compartment. Attempts at prevention of CM-AN using loopactive diuretics have yielded conflicting results. In an experimental study of CM-AN in Sabra rats, furosemide given alone prior to contrast media administration resulted in a smaller decline in GFR compared with control subjects. 93 When saline alone or saline and furosemide were administered, the decline in GFR in control rats was totally abolished. In clinical studies, Oguagha et a194 found that large doses of furosemide administered prior to contrast administration coupled with saline replacement of urinary losses in 17 patients with severe CRI reduced CM-AN to 18% compared with a 70% incidence in the "historical" control group noted above. 18 Beronaide95 reported similar results with furosemide-saline prophylaxis. However, the lack of appropriate,

720

CONTRAST NEPHROTOXITY AND ATHEROEMBOLISM

concurrent control groups and the simultaneous infusions of saline to expand extracellular fluid volume weakens any conclusions regarding a specific protective role of loop-active diuretics per se in CM-AN. In contrast, furosemide may actually increase the risk for CM-AN. In one study, CM-AN developed in seven of 20 patients who received saline and furosemide, but in none of the 23 patients who received saline alone. 89 Weinstein et al 96 found that patients with CRI undergoing angiography who received intravenous fluids and furosemide had greater increases in serum creatinine compared with a control group in which prophylaxis was left to the discretion of the treating physician, although postcontrast increases in serum creatinine were minimal in each group. Calcium channel blockers also have been reported to be beneficial in minimizing CM-AN in several randomized prospective controlled studies.97-99 In experimental studies, Deray et al 100 demonstrated that both verapamil and diltiazem, compared with controls, significantly attenuated the decrease in renal blood flow seen after administration of meglumine diatrizoate sodium in mongrel dogs. Other vasodilators also may have a protective effect against CM-AN. More recently, several reports suggest that theophylline, an antagonist of the vasoactive agent adenosine, prevented contrast media decreases in GFR in patients with and without CRI. 1OO- 103 Renal vasodilators, such as dopamine 90 and atrial natriuretic peptide,9o.l04 have been reported to minimize CM-AN. Here, too, the results are contradictory, as in one study vasodilators were of benefit in preventing CM-AN in nondiabetic patients while they tended to increase the risk in diabetic patients. 90 In summary, a number of experimental and clinical studies suggest that a variety of therapeutic interventions may be useful to prevent or ameliorate CM-AN. Unfortunately, the design of virtually all these studies is flawed in one or more respects, or the benefits demonstrated were so small to be of uncertain clinical significance, thereby preventing any definitive recommendations regarding which of these interventions would be most effective as prophylaxis against CM-AN. None of the studies clearly document a benefit of mannitol or other therapeutic interventions above and beyond the actions of saline

infusion alone as prophylaxis for CM-AN. Nonetheless, based on the currently available information, it remains reasonable for clinicians to use these prophylactic therapies, particularly in highrisk patients, until more definitive studies are available. ATHEROEMBOLISM

Atheroembolism is a known complication of angiography and is also a disorder that is a wellrecognized cause of acute renal failure. Patients with the highest likelihood of renal ischemic disease and therefore the best candidates for renal angiography (ie, those with poorly controlled hypertension or progressive renal insufficiency, middle-aged to elderly, ?usually white, heavy smoking habit, and historic and physical examination evidence of widespread atherosclerotic disease) are also those who are most susceptible to disseminated atheroembolism. L05 -117 It is therefore important to review this entity at the same time as discussing CM-AN. This syndrome of variable severity acute renal failure in the setting of protean clinical manifestations 105-119 has been attributed to occlusion of small (150 to 200 j.tm) arteries by atheroembolic material from eroded atherosclerotic plaques in diseased aortas. Birefringent, biconvex, needleshaped crystals or the biconcave clefts left behind after histologic tissue preparation are found in the lumina of terminal arterioles together with variable degrees of eosinophilic debris, multinucleated giant cells, endothelial proliferative changes, concentric fibrosis, vascular recanalization, and, rarely, frank necrotizing vasculitis. In the kidney, arcuate and interlobular arterioles are most frequently affected, leading to distal glomerular tuft ischemic retraction and basement membrane wrinkling, with wedge-shaped atrophic segments predominating on gross pathology.105.112 Clinically, predominantly lower extremity (and occasionally truncal) musculoskeletal and cutaneous manifestations are prominent "red flags" of the atheroembolic syndrome,105-121 with skin mottling ("livedo reticularis"), "blue toes," distal digital infarcts, and, occasionally, more extensive gangrene, even with intact pulses. Patients also may variably present with abdominal pain, gastrointestinal bleeding, fulminant ischemic bowel,105.112 pancreatitis, hepati-

RUDNICK ET AL

tis,105.112.116 and, less commonly, coronary ischemia or neurologic manifestations.105-107.112 Inconsistent laboratory clues106-112.122.123 include transient eosinophilia, hypocomplementemia, and elevations of sedimentation rate. The renal manifestations themselves are quite variable and unpredictable,105-116 ranging from fulminant oliguric acute renal failure to more insidious nonoliguric renal failure, with an intermittent but stepwise progression of azotemia. There is no characteristic urinalysis, but usually modest proteinuria l19 and sediments ranging from "benign" to "active," and even rare eosinophiliuria have been found. 123 New onset, worsened, or labile hypertension is felt to be a concomitant of small vessel occlusion within the kidneys.105-119.124 The renal outcome in early reports was described as quite dismal, with progression over weeks to months to end-stage renal disease and, often, patient death,105.107-125 but more recent experiences suggest less inexorable deterioration with a possibility for spontaneous recovery of renal function, even after variable periods of dialytic support. 106,107.109,IIO,I12,118,119,126-130 The multisystem findings of atheroembolism lead to a wide differential diagnosis107,112,131 and make it a great favorite for clinicopathological conferences. 130 Tissue examination of specimens, most commonly from skin, bowel, muscle, or kidney (where open-wedge biopsy has a greater chance than needle biopsy of detecting the characteristic vascular changes),105-107,112,128,129 may be particularly helpful in establishing the diagnosis of spontaneous atheroembolism,105.112,116.132 accounting for 1% to 10% of unexplained renal failure in elderly patients. 118,132,133 Atheroembolism is also present in 15% to 30% of autopsies in patients with significant atherosclerosis or abdominal aortic aneurysms. 105 .1 06,112.114.134 Antemortem diagnosis is more commonly made clinically, on the basis of renal failure and other "vasculitic" features in the arteriopathic patient profiled above. Thirty percent to 90%107.112 of reported cases occur in the setting of an inciting stimulus felt to trigger microembolic showers from a severely atherosclerotic aorta. These precipitants include traumatic manipulation of the aorta via vascular surgeryI05.107.112.114 or arteriographic procedures, including angioplastyI05-112.127.128.135-139 or denuding atherosclerotic plaques with systemic anticoagulant or thrombolytic therapy.105-112.126.128.140.141

721

In cases of angiography-associated renal failure, the distinction between atheroembolic renal damage and CM-AN can usually be made on the basis of the frequently delayed onset (days to weeks) and protracted course of the atheroembolic syndrome compared with the almost immediate onset of CM-AN following contrast infusion and its rapid resolution. When more fulminant disease does develop very rapidly after angiography, the other concomitant clinical complications referred to above usually announce the problem. The dramatically worse morbidity (both renal and patient) and mortality of disseminated atheroembolism than that of CM_AN I05 -112,125 make atheroembolism a more dreaded angiographic complication, especially since no prophylactic measures for its avoidance can be recommended and no well-documented therapeutic interventions to terminate the syndrome once triggered have been found. 105-112.135.142 However, unlike CM-AN, whose incidence can be determined by several days of observation postangiography, it remains difficult to quantify the magnitude of clinically significant angiographyassociated atheroembolism, where weeks to months of follow-up would be necessary. Autopsy data in patients dying within months of angiography likely overestimate the incidence of clinically relevant atheroemboli. Ramirez et al 136 found cholesterol emboli in 25% to 30% of autopsied patients dying within 6 months of cardiac catheterization or aortography (compared with a 4.3% incidence in disease- and age-matched controls who were not catheterized). On the other hand, cardiology and radiology observations in angiography suites likely underestimate the incidence of clinically significant atheroembolism, recognizing only the most fulminant of cases. Thus, textbooks of cardiology often ignore atheroembolism as a significant complication of catheterization,143 and three large catheterization studies from the past decade,I09.138.139 involving more than 9,000 patients, cite an incidence of less than 0.2%. In these three reports, catheterization was performed via the brachial artery (Sones technique) in only 5% of patients, none of whom developed atheroembolism. Since atheromatous plaques are most common in the abdominal aorta, less renal injury should occur with a brachial artery approach in patients with evidence of iliofemoral atherosclerosis requiring cardiac cathe-

CONTRAST NEPHROTOXITY AND ATHEROEMBOLISM

722

CHRONIC RENAL INSUFFICIENCY

DIABETES

MELLITUS

~

/

t

"

HOCM INCRI PATIENTS

ABSENCE OF PREVENTIVE REGIMENS

Fig 1.

CONTRAST VOLUME

RAOIOLOGIC PROCEDURE

Risk factors for eM-AN.

terization. 130,144 The larger and stiffer guidewires and catheters for percutaneous transluminal angioplasty may also increase the risk of angiographyrelated atheroembolism.I09.127 In this regard, five reports of atherosclerotic renal artery angioplasty noted cholesterol emboli occurring' 'in the hospital" in 0.6% to 6% of cases, with an overall incidence of 16 of 1,014 attempted dilatations. 145 149 In a large review of noncoronary angioplasty (4,662 renal and peripheral cases), Becker et al 150 cited a 4.8% incidence of "thrombosis/embolism of any vesseL" SUMMARY AND AREAS FOR FUTURE INVESTIGATION

In summary, CM-AN and atheroembolism are important potential complications of intravascular contrast media administration. The risk of CM-AN may be enhanced by a number of factors, including CRI, diabetes mellitus, volume of contrast media administered, HOCM (in CRI), absence of prophylactic intervention, and possibly the specific radiologic procedure performed. 22 It is reasonable to assume that the degree of risk for CM-AN in a given patient is ultimately determined by an interplay of both the number and magnitude of risk factors present (Fig 1). In an attempt to determine the risk for CMAN when angiography is performed to diagnose renovascular disease in patients with varying degrees of CRI, several important questions remain unanswered. First, it remains unknown what the incidence of CM-AN would be in high-risk pa-

tients who are aggressively hydrated and studied using small volumes of LOCM, made possible by digital technology, and whether this approach would result in a lower incidence of CM-AN than previously observed. The clinical course of CM-AN also requires further elucidation. For the majority of patients affected by CM-AN, the clinical course is characterized by a brief and asymptomatic increase in the serum creatinine value. What remains unclear is why some patients progress to more clinically serious forms of acute renal failure and whether there are clinical or laboratory data that could allow the clinician to prospectively identify those patients with CM-AN who will develop a more serious outcome. Also unclear at the present time is whether a specific prophylactic regimen is most effective and whether diabetic azotemic patients should receive different prophylactic interventions than nondiabetic azotemic patients. 90 It is uncertain whether the reduced nephrotoxicity of LOCM agents is equal with all currently available formulations and if newer, second-generation LOCM agents (nonionic dimers, which are iso-osmolar with plasma)151.152 confer yet even more protection from nephrotoxicity in high-risk patients. Furthermore, is the observed nephrotoxic benefit of LOCM only apparent above a "critical" level of CRI or if a specific volume of contrast media is exceeded? Does the reduction of nephrotoxicity associated with LOCM use result in consistent clinical benefit and reduced costs? Finally, can the selective application of LOCM result in fewer cases of severe forms (ie, requiring dialysis) of contrast nephrotoxicity? With regard to atheroembolism, the true incidence of this complication after angiography and the procedural risk factors remain poorly defined. Knowledge of these factors and whether modification of angiographic catheters and techniques will have any impact on the occurrence of this potentially devastating complication will ultimately help clinicians better weigh the risks of invasive investigation of renovascular disease. Until these questions can be satisfactorily answered, it is difficult to recommend with certainty how rigorously clinicians should pursue digital angiography in azotemic patients who are suspected to have renal ischemic disease. Although anecdotal and unpublished reports sug-

723

RUDNICK ET AL

gest that the majority of such patients can be safely studied with modem digital angiographic techniques and LOCM, prospective and rigorously designed studies are still needed to definitively determine the risks involved with such an approach.

REFERENCES 1. Jacobsen HR: Ischemic renal disease: An overlooked clinical entity? Kidney Int 34:729-743, 1988 2. Scobie IE, Maher ER, Hamilton G, Dick R, Sweny P, Moorhead JF: Atherosclerotic renovascular disease causing renal failure-A case for treatment. Clin Nephrol 31:119122, 1989 3. Mailloux LU, Bellucci AG, Mossey RT, Napolitano RT, Moore T, Wilkes BM, Bluestone PA: Predictors of survival in patients undergoing dialysis. Am J Med 84:855-862, 1988 4. Hansen KJ, Tribble RW, Reavis SW, Canzanello VJ, Craven TE, Plonk GW, Dean RH: Renal duplex sonography: Evaluation of clinical utility. J Vasc Surg 12:227-236, 1990 5. Kent KC, Edelman RR, Kim D, Steinman TI, Porter DH, Skillman JJ: Magnetic resonance imaging: A reliable test for the evaluation of proximal atherosclerotic renal arterial stenosis. J Vasc Surg 13:311-318, 1991 6. Nally JV, Jr, Black HR: State-of-the-art review: Captopril renography - Pathophysiological considerations and clinical observations. Semin Nucl Med 22:85-97, 1992 7. Berns AS: Nephrotoxicity of contrast media. Kidney Int 36:730-740, 1989 8. Coggins CH, Fang LS-T: Acute renal failure with antibiotics, anesthetic agents and radiographic contrast agents, in Brenner BM, Lazarus JM (eds): Acute Renal Failure (ed 2). New York, NY, Churchill Livingstone, 1988, pp 295-352 9. Berns JS, Rudnick MR: Radiocontrast media associated nephrotoxicity. Kidney 24:1-5, 1992 10. Diaz-Buxo JA, Wagoner RD, Hattery RR, Palumbo PJ: Acute renal failure after excretory urography in diabetic patients. Ann Intern Med 83:155-158, 1975 11. Teruel JL, Marcen R, Onaindia JM, Seitano A, Quereda C, Ortuno J: Renal function impairment caused by intravenous urography. Arch Intern Med 141:1271-1274, 1981 12. Fang LS-T, Sirota RA, Ebert TH, Lichtenstein NS: Low fractional excretion of sodium with contrast media-induced acute renal failure. Arch Intern Med 140:531-533, 1980 13. Byrd L, Sherman RL: Radiocontrast-induced acute renal failure: A clinical and pathophysiologic review. Medicine 58:270-279, 1979 14. VanZee BE, Hoy WE, Talley TE, Jaenike JR: Renal injury associated with intravenous pyelography in nondiabetic and diabetic patients. Ann Intern Med 89:51-54, 1978 15. Carvallo A, Rakowski TA, Argy WP, Jr, Schreiner GE: Acute renal failure following drip infusion pyelography. Am J Med 65:38-45, 1978 16. Manske CL, Sprafka 1M, Strony JT, Wang Y: Contrast nephropathy in azotemic diabetic patients undergoing coronary angiography. Am J Med 89:615-620, 1990 17. Harkonen S, Kjellstrand CM: Exacerbation of diabetic renal failure following intravenous pyelography. Am J Med 63:939-946, 1977

18. Shafi T, Chou S-Y, Porush JG, Shapiro WB: Infusion intravenous pyelography and renal function: Effects in patients with chronic renal insufficiency. Arch Intern Med 138:1218-1221, 1978 19. Harris KG, Smith TP, Cragg AH, Lemke JH: Nephrotoxicity from contrast material in renal insufficiency: Ionic versus nonionic agents. Radiology 179:849-852, 1991 20. Taliercio CP, Vlietstra RE, Ilstrup DM, Burnett JC, Menke KK, Stensrud SL, Holmes DR, Jr: A randomized comparison of the nephrotoxicity of iopamidol and diatrizoate in high risk patients undergoing cardiac angiography. J Am Coli Cardiol 17:384-390, 1991 21. Barrett BJ, Parfrey PS, Vavasour HM, McDonald J, Kent G, Hefferton D, O'Dea F, Stone E, Reddy R, McManamon PJ: Contrast nephropathy in patients with impaired renal function: High versus low osmolar media. Kidney Int 41:1274-1279, 1992 22. Moore RD, Steinberg EP, Powe NR, Brinker JA, Fishman EK, Graziano S, Gopalan R: Nephrotoxicity of highosmolality versus low-osmolality contrast media: Randomized clinical trial. Radiology 182:649-655, 1992 23. Levy EM, Viscoli CM, Horwitz RI: Unexpected high mortality in contrast nephropathy. J Am Soc NephroI4:319, 1993 (abstr) 24. Mudge GH: Nephrotoxicity of urographic radiocontrast drugs. Kidney Int 18:540-552, 1980 25. Harkonen S, Kjellstrand C: Contrast nephropathy. Am J Nephrol 1:69-77, 1981 26. Anderson RI, Linas SL, Berns AS, Henrich WL, Miller TR, Gabow PA, Schrier RW: Nonologuric acute renal failure. N Engl J Med 296:1134-1137, 1977 27. Weinrauch LA, Healy RW, Leland OS, Goldstein HH, Kassissieh SD, Libertino JA, Takcas FJ, D'Elia JA: Coronary angiography and acute renal failure in diabetic azotemia nephropathy. Ann Intern Med 86:56-59, 1977 28. Taliercio CP, Vlietstra MB, Fisher LD, Burnett JC: Risks for renal dysfunction with cardiac angiography. Ann Intern Med 104:501-504, 1986 29. Anto HR, Chou S-Y, Porush JC, Shapiro WB: Infusion intravenous pyelography and renal function: Effects of hypertonic mannitol in patients with chronic renal insufficiency. Arch Intern Med 141:1652-1656, 1981 30. Older RA, Korobkin M, Cleeve DM, Schaaf R, Thompson W: Contrast-induced acute renal failure: Persistent nephrogram as clue to early detection. Am J Roentgenol 134:339-342, 1980 31. Lang EK, Foreman J, Schlegel JU, Leslie C, List A, McCormick P: The incidence of contrast medium-induced acute tubular necrosis following arteriography: A preliminary report. Radiology 138:203-206, 1981 32. Love L, Lind JA, Jr, Olson MC: Persistent CT nephrogram: Significance in the diagnosis of contrast nephropathy. Radiology 172:125-129, 1989 33. Hou SH, Bushinsky DA, Wish JB, Cohen JJ, Harrington JT: Hospital-acquired renal insufficiency: A prospective study. Am J Med 74:243-248, 1983 34. Shusterman N, Strom BL, Murray TG, Morrison G, West SL, Maislin G: Risk factors and outcome of hospitalacquired acute renal failure. Clinical epidemiologic study. Am J Med 83:65-71, 1987 35. Kumar S, Hull JD, Lathi S, Cohen AJ, Pletka PG:

724

CONTRAST NEPHROTOXITY AND ATHEROEMBOLISM

Low incidence of renal failure after angiography. Arch Intern Med 141:1268-1270, 1981 36. D'Elia lA, Gleason RE, Alday M, Malarick C, Godley K, Warram 1, Kaldany A, Weinrauch LA: Nephrotoxicity from angiographic contrast material: A prospective study. Am 1 Med 72:719-724, 1982 37. Cramer BC, Parfrey PS, Hutchinson TA, Baran D, Melanson DM, Ethier RE, Seely IF: Renal function following infusion of radiologic contrast material: A prospective controlled study. Arch Intern Med 145:87-89, 1985 38. Moore RD, Steinberg EP, Powe NR, White RI, lr, Brinker lA, Fishman EK, Zinreich SJ, Smith CR: Frequency and determinants of adverse reactions induced by high-osmolality contrast media. Radiology 170:727-732, 1989 39. Davidson Cl, Hlatky M, Morris KG, Pieper K, Skelton TN, Schwab SI, Bashore TM: Cardiovascular and renal toxicity of a nonionic radiographic contrast agent after cardiac catheterization: A prospective trial. Ann Intern Med 110: 119124, 1989 40. Schwab SI, Hlatky MA, Pieper KS, Davidson Cl, Morris KG, Skelton TN, Bashore TM: Contrast nephrotoxicity: A randomized controlled trial of a nonionic and an ionic radiographic contrast agent. N Engl 1 Med 320: 149-153, 1989 41. Rich MW, Crecelius CA: Incidence, risk factors , and clinical course of acute renal insufficiency after cardiac catheterization in patients 70 years of age or older. Arch Intern Med 150:1237-1242, 1990 42. Lautin EM, Freeman Nl, Schoenfeld AH, Bakal CW, Hararniti N, Friedman AC, Lautin lL, Braha S, Kadish EG, Sprayregen S, Belizon I: Radiocontrast-associated renal dysfunction: A comparison of lower-osmolality and conventional high-osmolality contrast media. Am 1 RadioI157:59-65, 1991 43. Rudnick MR, Goldfarb S, Ludbrook P, Halpern E, Murphy M: Nephrotoxicity r,)lIowing cardiac angiography: A double-blind multicenter trial of ionic and nonionic contrast media in 1194 patients. 1 Am Soc NephroI2:668, 1991 (abstr) 44. Parfrey PS, Griffiths SM, Barrett Bl, Paul MD, Genge M, Withers 1, Farid N, McManamon PI: Contrast materialinduced renal failure in patients with diabetes mellitus, renal insufficiency, or both. N Engl 1 Med 320:143-149, 1989 45. Mason RA, Arbeit LA, Giron F: Renal dysfunction after arteriography. lAMA 253 :1001-1004, 1985 46. Nunez BD, Allon M: Effect of cardiac catheterization on renal function. Clin Nephrol 34:263-266, 1990 47. Katholi RE, Taylor GJ, Woods WT, Womack KA, Katholi CR, McCann WP, Moses HW, Dove IT, Mikell FL, Woodruff RC, Miller BD, Schneider JA: Nephrotoxicity of nonionic low-osmolality versus ionic high-osmolality contrast media: A prospective double-blind randomized comparison in human beings. Radiology 186:183-187, 1993 48. Lautin EM, Freeman NJ, Schoenfeld AH, Bakal CW, Haramati N, Friedman AC, Lautin lL, Braha S, Kadish EG, Sprayregen S, Belizon I: Radiocontrast-associated renal dysfunction: Incidence and risk factors. Am 1 Roentgenol 157:49-58, 1991 49. Gomes AS, Baker JD, Martin-Paradero V, Dixon SM, Takiff H, Machleder HI, Moore WS: Acute renal failure after major arteriography. Am J Roentgenol 145:1249-1253, 1985 50. Harkonen S, Kjellstrand CM: Intravenous pyelography in nonuremic diabetic patients. Nephron 24:268-270, 1979 51. Cigarroa RG, Lange RA, Williams RH, Hillis LD:

Dosing of contrast material to prevent contrast nephropathy in patients with renal disease. Am 1 Med 86:649-652, 1989 52. Martin-Paradero V, Dixon SM, Baker ID, Takiff H, Gomes AS, Busuttil RW, Moore WS: Risk of renal failure after major angiography. Arch Surg 118:1417-1420, 1983 53. Swartz RD, Rubin IE, Leeming BW, Silva P: Renal failure following major angiography. Am 1 Med 65:31-37, 1978 54. Smolens P:The kidney in dysproteinemic states. AKF Nephrol Lett 4:27-42, 1987 55. Defronzo RA, Humphrey RL, Wright JR, Cooke CR: Acute renal failure in multiple myeloma. Medicine 54:209223, 1975 56. Alexanian R, Barlogie B, Dixon D: Renal failure in multiple myeloma. Pathogenesis and prognostic implications. Arch Intern Med 150:1693-1695, 1990 57. Huang ZQ, Kirk KA, Connell KG, Sanders PW: Bence 10nes proteins bind to a common peptide segment of TarnrnHorsfall glycoprotein to promote heterotypic aggregation. J Clin Invest 92:2975-2983, 1993 58. Sanders PW, Booker BB : Pathobiology of cast nephropathy from human Bence 10nes proteins. J C1in Invest 89:630-639, 1992 59. Lasser EC, Lang IH, Zawadzki ZA: Contrast mediamyeloma protein precipitates in urography. lAMA 198:945947, 1966 60. Schwartz RH, Berdon WE, Wagner HE: Tarnrn-Horsfall urinary microprotein precipitation by urographic contrast agents. Am 1 Roentgenol 100:698-701, 1970 61. McCarthy CS, Becker lA: Multiple myeloma and contrast media. Radiology 183:519-521, 1992 62. Kyle RA: Multiple myeloma. Review of 869 cases. Mayo Clin Proc 50:29-40, 1975 63. Cohen DJ, Sherman WH, Osserman EF, Appel GB: Acute renal failure in patients with multiple myeloma. Am 1 Med 76:247-256 1984 64. McClennan BL: Low-osmolality contrast media: Premises and promises. Radiology 162: 1-8, 1987 65. Spataro RF: New contrast agents for urography. Radiol Clin North Am 22:365-380, 1984 66. McClennan BL, Stolberg HO: Intravascular contrast media. Ionic versus nonionic: Current status. Radiol Clin North Am 29:437-454, 1991 67. Russel SB, Bioi LI, Sherwood T: Monomereldimere contrast media in the renal circulation: Experimental angiography. Br 1 Radiol 47:268-271, 1974 68. Morris TW, Katzberg RW, Fisher HW: A comparison of the hemodynamic responses to metrizarnide and meglumine/sodium diatrizoate in canine renal angiography. Invest Radiol 13:74-78, 1978 69. Lund G, Rysavy 1, Salmonowitz E. Cragg A. Vlodaver Z, Bendell W. Castaneda-Zuniga W. Amplatz K: Nephrotoxicity of contrast media assessed by occlusion arteriography. Radiology 152:615-619, 1984 70. Tornquist C. Almen T, Golman K. Holtas S: Renal function following nephroangiography with metrizamide and iohexol. Effects on renal blood flow, glomerular permeability and filtration rate and diuresis in dogs. Acta Radiol Diagn 26:483-489. 1985 71. Katzberg RW. Morris TW, Lasser EC. DiMarco PL. Merguerian PA, Ventura lA. Pabico RC. McKenna BA:

RUDNICK ET AL

Acute systemic and renal hemodynamic effects of meglumine/sodium diatrizoate 76% and iopamidol in euvolemic and dehydrated dogs. Invest Radiol 21:793-797, 1986 72. Deray G, Baumelou B, Martinez F, Brillet G, Jacobs C: Renal vasoconstriction after low and high osmolar contrast agents in ischemic and nonischemic canine kidneys. Clin NephroI36:93-96, 1991 73. Holtas S, Tejler L: Proteinuria following nephroangiography. IV. Comparison in dogs between ionic and nonionic contrast media. Acta Radiol Diagn 20:13-18, 1979 74. Thomsen HS, Hemmingsen L, Golman K, Skaarup P, Larsen S: Low sodium diet, indomethacin, and contrast media. A comparison between renal effects of diatrizoate and iohexol in rats. Acta Radiol 31:613-618, 1990 75. Thomsen HS, Dorph S, Mygind T, Hemmingsen L, Holith J, Larsen S, Nielsen H, Rygaard H, Skaarup P: Urine profiles following intravenous diatrizoate, iohexol, or ioxilan in rats. Invest Radiol 23:S168-S170, 1988 (suppl 1) 76. Deray G, Dubois M, Martinez F, Baumelou B, Beaufils H, Bourbouze R, Baumelou A, Jacobs C: Renal effects of radiocontrast agents in rats: A new model of acute renal failure. Am J Nephrol 10:507-513, 1990 77. Golman K, Almen T: Contrast media-induced nephrotoxicity. Survey and present state. Invest Radiol 20:S92-S97, 1985 (suppl) 78. Messana JM, Cielinski DA, Nguyen VD, Humes HD: Comparison of the toxicity of the radiocontrast agents iopamidol and diatrizoate to rabbit renal proximal tubule cells in vitro. J Pharmacol Exp Ther 244:1139-1144, 1988 79. Cedgard S, Herlitz H, Geterud K, Attman P-O, Aurell M: Acute renal insufficiency after administration of low-osmolar contrast media. Lancet 2:1281, 1986 80. Evans JR, Shankel SW, Cutler RE: Low osmolar contrast agents and nephrotoxicity. Ann Intern Med 107:116, 1987 81. Aron NB, Feinfeld DA, Peters AT, Lynn RI: Acute renal failure associated with ioxaglate, a low-osmolality radiocontrast agent. Am J Kidney Dis 13:189-193, 1989 82. Gomes AS, Lois JF, Baker JD, McGlade CT, Bunnell DH, Hartzman S: Acute renal dysfunction in high-risk patients after angiography: Comparison of ionic and nonionic contrast media. Radiology 170:65-68, 1989 83. Deray G, Bellin M-F, Boulechfar H, Baumelou B, Koskas F, Baumelou A, Grellet J, Jacobs C: Nephrotoxicity of contrast media in high-risk patients with renal insufficiency: Comparison of low and high-osmolar contrast agents. Am J Nephrol 11:309-312, 1991 84. Barrett BJ, Carlisle EJ: Metaanalysis of the relative nephrotoxicity of high and low-osmolality iodinated contrast media. Radiology 188: 171-178, 1993 85. Rudnick MR, Goldfarb S, Murphy MJ: Mannitol and other prophylactic regimens in contrast media-induced acute renal failure. Coronary Artery Dis 2:1047-1052, 1991 86. Vari RD, Natarajan LP, Whitescarver SA, Jackson BA, Ott CE: Induction, prevention and mechanisms of contrast media-induced acute renal failure. Kidney Int 33:699-707, 1988 87. Old CW, Duarte CM, Lehmer LM, Henry AR, Sinnott RC: A prospective evaluation of mannitol in the prevention of radiocontrast acute renal failure. Clin Res 29:472A, 1981 (abstr)

725 88. Vosnides GR, Kalogeropoulos V, Spanos H, Papadakis G, Papachristoforou K, Grigoropoulos L, Edipidis K, Moutsouris D, Haddad M, Billis AG: Radiocontrast-induced deterioration of renal function in patients with chronic renal failure. Abstracts of the Eighth International Congress of Nephrology. Athens, Greece, University Studio Publishing, 1981, p 306 (abstr) 89. Solomon R, D'Elia J, Mann D: Prevention of contrastinduced acute renal failure (CIARF) in a high risk group. J Am Soc Nephrol 3:731, 1992 (abstr) 90. Weisberg LS, Kurnik PB, Kurnik BRC: Renal vasodilator drugs and the risk of radiocontrast nephropathy (RCN). J Am Soc Nephrol 3:731, 1992 (abstr) 91. Eisenberg RL, Bank WO, Hedgock MW: Renal failure after major angiography can be avoided with hydration. Am J Radiol 136:859-861, 1981 92. Brown RS, Ransil B, Clark BA: Prehydration protects against contrast nephropathy in high risk patients undergoing cardiac catheterization. J Am Soc Nephroll:330, 1990 (abstr) 93. Heyman SN, Brezis M, Greenfeld Z, Rosen S: Protective role of furosemide and saline in radiocontrast-induced acute renal failure in the rat. Am J Kidney Dis 14:377-385, 1989 94. Oguagha C, Porush JG, Chou SY, Anto H, Shapiro WB, Faubert PF: Prevention of acute renal failure (ARF) following infusion intravenous pyelography (IVP) in patients with chronic renal insufficiency (CRI) by furosemide (F). Abstracts of the Eight International Congress of Nephrology. Athens, Greece, University Studio Publishing, 1981, p 290 (abstr) 95. Beronaide VC: Prevention of acute renal failure secondary to radiocontrast agents. Abstracts of the Eight International Congress of Nephrology. Athens, Greece, University Studio Publishing, 1991, p 380 (abstr) 96. Weinstein J-M, Heyman S, Brezis M: Potential deleterious effect of furosemide in radiocontrast nephropathy. Nephron 62:413-415, 1992 97. Neumayer HH, Junge W, Kufner A, Wenning A: Prevention of radiocontrast media-induced (CM) nephrotoxicity by the calcium antagonist (CA) nitrendipine: A prospective randomized clinical trial. Kidney Int 37:260, 1990 (abstr) 98. Wilfling M, Kampf D, Jun MS, Junge W: Nitrendipine (N) and nephrotoxicity of nonionic contrast media: A randomized controlled clinical trial. J Am Soc Nephrol 2:671, 1991 (abstr) 99. Pourrat JP, Douste-Blazy P: Renal side effect of nifedipine. Clin Cardiol 7:29-30, 1984 100. Deray G, Martinez R, Cacoub P, Baumelou B, Baumelou A, Jacobs C: A role for adenosine calcium and ischemia in radiocontrast-induced intrarenal vasoconstriction. Am J Nephrol 10:316-322, 1990 101. Erley CM, Schlepckow S, Koehler J, Duda SH, Huppert PE, Osswald H, Risler T: Theophylline prevents contrast media (CM) induced renal failure. J Am Soc Nephrol 3:723, 1992 (abstr) 102. Arend LJ, Bakris GL, Burnett JC, Megerian C, Speilman WS: Role for intrarenal adenosine in the renal hemodynamic response to contrast media. J Lab Clin Med 110:406411, 1987 103. Erley CM, Duda SK, Schlepckow S, Koehler J, Huppert PE, Strohmaier WL, Bohle A, Risler T, Osswald H:

726

CONTRAST NEPHROTOXITY AND ATHEROEMBOLISM

Adenosine antagonist theophylline prevents the reduction of glomerular filtration rate after contrast media application. Kidney Int 45:1425-1431, 1994 104. Margulies KB, McKinley LJ, Allgren RL, Stanson AW, Burnett JC: Intra-arterial atrial natriuretic factor (ANF) attenuates radiocontrast-induced nephropathy in humans. J Am Soc Nephrol 2:666, 1991 (abstr) 105. Kassirer JP: Atheroembolic renal disease. N Engl J Med 280:812-818, 1969 106. Smith MC, Ghose MK, Henry AR: The clinical spectrum of renal cholesterol embolization. Am J Med 71:174180, 1981 107. Fine MJ, Kapoor W, Falanga V: Cholesterol crystal embolization: A review of 221 cases in the English literature. Angiology 38:769-784, 1987 108. Meyrier A, Buchet P, Simon P, Fernet M, Rainfray M, Callard P: Atheromatous renal disease. Am J Med 85: 139146, 1988 109. Colt HG, Begg RJ, Saporito J, Cooper WM, Shapiro AP: Cholesterol emboli after cardiac catheterization: Eight cases and a review of the literature. Medicine 67:389-700, 1988 110. Mannesse CK, Blankestijn PJ, Man I'nt Veld AJ, Schalekamp MADH: Renal failure and cholesterol crystal embolization: A report of a surviving case and a review of the literature. Clin Nephrol 36:240-245, 1991 Ill. Rosman HS, Davis TP, Reddy D, Goldstein S: Cholesterol embolization: Clinical findings and implications. J Am Coli Cardiol 15:1296-1299, 1990 112. Coburn JW, Agre KL: Renal thromboembolism, atheroembolism, and other acute diseases of the renal arteries, in Schrier RW, Gottschalk CW (eds): Diseases of the Kidney (ed 5). Boston, MA, Little, Brown, 1993, pp 2119-2135 113. Fisher ER, Hellstrom HR, Myers JD: Disseminated atheromatous emboli. Am J Med 29: 176-180, 1960 114. Thurlbeck WM, Castleman B: Atheromatous emboli to kidneys after aortic surgery. N Engl J Med 257:444-447, 1957 115. Sayre GP, Campbell DC: Multiple peripheral emboli in atherosclerosis of the aorta. Arch Intern Med 103:799-806, 1959 116. Gore F, Collins DP: Spontaneous atheromatous embolization: Review of the literature and report of 16 additional cases. Am J Clin Pathol 33:416-426, 1960 117. Om A, Ellahham S, DiSciascio G: Cholesterol embolism: An underdiagnosed clinical entity. Am Heart J 124:1321-1326, 1992 118. Jones DB, Iannacone PM: Atheromatous emboli in renal biopsies: An ultrastructural study. Am J Pathol 78:261276, 1975 119. Williams HH, Wall BM, Cooke CR: Reversible nephrotic range proteinuria and renal failure in atheroembolic renal disease. Am J Med Sci 299:58-61, 1990 120. Falanga V, Fine MJ, Kapoor WJ: The cutaneous manifestations of cholesterol crystal embolization. Arch Dermatol 122:1194-1198, 1986 121. O'Keefe ST, Woods B, Breslin DJ, Tsapatsaris NP: Blue toe syndrome: Causes and management. Arch Intern Med 152:2197-2202, 1992 122. Kasinath BS, Corwin HL, Bidani AK, Korbet SM, Schwartz MM: Eosinophilia in the diagnosis of atheroembolic renal disease. Am J Nephrol 7:173-177, 1987

123. Wilson DM, Salazer TL, Farkouh ME: Eosinophiluria in atheroembolic renal disease. Am J Med 91:186189, 1991 124. Dalakos TG, Streeten DHP, Jones D, Obeid A: "Malignant" hypertension resulting from atheromatous embolization predominantly of one kidney. Am J Med 57:135-138, 1974 125. Gaines PA, Cumberland DC, Kennedy A, Welsh CL, Moorhead P, Rutley MS: Cholesterol embolization: A lethal complication of vascular catheterization. Lancet 1: 168-170, 1988 126. Bruns FJ, Segal DJ, Adler S: Control of cholesterol embolization by discontinuation of anticoagulant therapy. Am J Med Sci 275:105-107, 1978 127. Tilley WS, Harston WE, Siami G, Stone WJ: Renal failure due to cholesterol emboli following PTCA. Am Heart J 110:1301-1302, 1985 128. McGowan JA, Greenberg A: Cholesterol atheroembolic renal disease: Report of 3 cases with emphasis on diagnosis by skin biopsy and extended survival. Am J Nephrol 6:135-139, 1986 129. Siemons L, Vander Heuvel P, Parizel G, Buyssens N, Debroe ME, Cuykens JJ: Peritoneal dialysis in acute renal failure due to cholesterol embolization: Two cases of recovery of renal function and extended survival. Clin Nephrol 28:205-208, 1987 130. Case Records of MGH (Case 38-1993). N Engl J Med 329:948-955, 1993 131. Cappielo RA, Espinoza LR, Adelman H, Aguilar J, Vasey FB, Germain BF: Cholesterol embolism: A pseudovasculitic syndrome. Semin Arthritis Rheum 18:240-241, 1989 132. Varanas UR, Moorthy AV, Beirne GS: Spontaneous atheroembolic disease as a cause of renal failure in the elderly. J Am Geriatr Soc 27:407-409, 1979 133. Preston RA, Stemmer CL, Materson BJ, Perez-Stable E, Pardo V: Renal biopsy in patients 65 years of age or older: An analysis of the results of 334 biopsies. J Am Geriatr Soc 38:669-674, 1990 134. Cross SS: How common is cholesterol embolism. J Clin Pathol 44:859-861, 1991 135. Harrington JT, Sommers SC, Kassirer JP: Atheromatous emboli with progressive renal failure: Renal arteriography as probable inciting factor. Ann Intern Med 68:152-160, 1968 136. Ramirez G, O'Neill WM, Lambert R, Bloomer HA: Cholesterol embolization, a complication of angiography. Arch Intern Med 138:1430-1432, 1978 137. Block PC, Elmer D, Fallon JT: Release of atherosclerotic debris after transluminal angiop1asty. Circulation 65:950-952, 1982 138. Drost H, Buis B, Haan D, Hillers JA: Cholesterol embolism as a complication of left heart catheterization: Report of seven cases. Br Heart J 52:339-342, 1984 139. Ong HT, Elmsley WG, Friedlander DH: Cholesterol atheroembolism: An increasingly frequent complication of cardiac catheterization. Med J Aust 154:412-414, 1991 140. Glassock RJ, Ritz E, Bommer J, Andrassy K, Waldherr R: Acute renal failure, hypertension, and skin necrosis in a patient with streptokinose therapy. Am J NephroI4:193200, 1984 141. Gupta BK, Spinowtiz BS, Charytan C, Wahl SJ: Cholesterol crystal embolization-associated renal failure after

RUDNICK ET AL

therapy with recombinant tissue-type plasminogen activator. Am J Nephrol 21:659-662, 1993 142. Wingo JP, Nix ML, Greenfield LJ, Barnes RW: The blue toe syndrome: Hemodynamics and therapeutic correlates of outcome. J Vase Surg 3:475-480, 1986 143. Grossman W: Complications of cardiac catheterization: Incidence, causes and prevention, in Grossman W (ed): Cardiac Catheterization and Angiography (ed 3). Philadelphia, PA, Lea & Febiger, 1986, pp 30-42 144. Engster GS, Reisig AH, Ugaldea CT: Percutaneous left brachial catheterization using 5-French preformed (Judkins) catheters. Cathet Cardiovasc Diagn 12:274-276, 1986 145. Sos TA, Saddekini S, Pickering TG, Laragh JH: Technical aspects of percutaneous transluminal angioplasty in renovascular disease. Nephron 44:45-50, 1986 (suppl I) 146. Martin LG, Casarella WJ, Alspaugh JP, Chuang VP: Renal artery angioplasty: Increased technical success and decreased complications in the second 100 patients. Radiology 159:631-634, 1986

727 147. Hayes JM, Risius B, Novick AC, Geisinger M, Zelch M, Gifford RW, Vidt DG, Olin JW: Experience with percutaneous transluminal angioplasty for renal artery stenosis at the Cleveland Clinic. J Urol 139:488-492, 1988 148. Geyskes GG: Treatment of renovascular hypertension with percutaneous transluminal renal angioplasty. Am J Kidney Dis 12:253-265, 1988 149. Martin LG, Casarella WJ, Gaylord GM: Azotemia caused by renal artery stenosis: Treatment by percutaneous angioplasty. Am J Radiol 150:839-844, 1988 150. Becker GJ, Katzen BT, Dake MD: Noncoronary angioplasty. Radiology 170:921-940, 1989 151. Gavant ML, Siegle RL: Iodixanol in excretory urography: Initial clinical experience with a nonionic dimeric (ratio 6:1) contrast medium. Radiology 183:515-518, 1992 152. Singh K, Sundgren R, Bolstad B, Bjork L, Lie M: Iodixanol in abdominal digital subtraction angiography. A randomized, double-blind, parallel trial with iodixanol and iohexol. Acta Radiol 34:242-245, 1993