Dye-Induced Nephropathy By Samuel N. Heyman and Seymour Rosen The expanding use of imaging and interventional studies with iodinated radiologic contrast agents underscores the potential risk for dye nephropathy. Currently, dye-induced nephropathy is one of the leading causes of iatrogenic acute kidney failure, accounting for about 10% of renal failure in intensive care units. In this review, the patho- physiology of radiocontrast nephropathy is discussed, with a special emphasis on the importance of medullary hypoxic damage. The risk factors and clinical course of dye nephropathy, as well as its prevention or potential therapeutic interventions, are discussed in this perspective. © 2003 Elsevier Inc. All rights reserved. HE EXPANDING USE of imaging and inter- renal dysfunction should be considered including Tventional procedures with iodinated radio- nephrotoxic injury produced by other agents, sep- logic contrast agents underscores the potential risk sis, rhabdomyolysis, cholesterol emboli after arte- for dye (radiocontrast) nephropathy. In the late rial studies, shock, and other ischemic insults. 1960s, this iatrogenic disease entity was consid- This review focuses on the pathophysiology of ered rare and exotic. Its incidence, however, radiocontrast nephropathy, with a special emphasis quickly surged to involve some 40% of patients on tubular hypoxic damage. In this perspective we undergoing dye studies in the early 1980s, rapidly analyze the mechanisms by which recognized risk leading to the recognition of high-risk groups, such factors might predispose to renal dysfunction after as diabetic patients and individuals with preexist- contrast studies, and critically evaluate the preven- ing renal failure, low cardiac output, or dehydra- tive/therapeutic strategies currently applied or in- tion. Subsequently, the incidence of dye nephrop- vestigated. athy gradually declined to less than 3% of contrast PATHOPHYSIOLOGIC BACKGROUND studies, predominantly because of patient selec- tion, because of the recognition of the importance Although recognized for some 40 years, the of hydration status, and because of the introduction pathophysiology of contrast nephropathy remains a of the less-nephrotoxic low osmolar and nonionic controversial issue. It is classified as acute tubular agents. Nevertheless, dye-induced nephropathy re- necrosis or toxic nephropathy but, in fact, very mains one of the leading causes of iatrogenic acute little is known about its true renal morphology in kidney failure, accounting for about 10% of cases humans. Proximal tubular vacuolization has been of acute renal failure in intensive care units. encountered in renal biopsy examinations, but this Among high-risk patients its incidence exceeds change does not correlate with renal failure. In- 20%, despite adherence to well-accepted protective deed, this alteration is present after dye adminis- measures, providing a formidable challenge to fur- tration under experimental settings, irrespective of ther improve preventive strategies. kidney function. Urinary markers of tubular injury Dye nephropathy is defined as a decline in glo- appear inconsistently, or are absent in humans with merular filtration rate (GFR) after the intravascular contrast nephropathy. Many toxic nephropathies are believed to be administration of iodinated contrast agents. Kidney mediated primarily through well-characterized di- dysfunction is manifested with an increasing rect tubular-cell toxicity, such as heavy metals, plasma creatinine level that peaks at 2 to 5 days, cisplatin, or aminoglycosides in experimental and and usually returns to baseline values by 5 to 10 days. Dye-associated renal failure usually is nono- liguric and renal sediment is unremarkable in most From the Department of Medicine, Hadassah Hospital, Mt. cases. Fractional sodium excretion is often low, Scopus, and the Hebrew University Medical School, Jerusalem, Israel; and the Department of Pathology, Beth Israel Deacon- suggesting prerenal failure. Contrast nephropathy ess Medical Center, and Harvard Medical School, Boston, MA. usually is self-limited, but some patients may run a Address reprint requests to Samuel N. Heyman, MD, Depart- protracted course and require renal replacement ment of Medicine, Hadassah University Hospital, Mount Sco- therapy, associated with increased morbidity and pus, PO Box 24035, Jerusalem 91240. E-mail: heyman@ cc.huji.ac.il mortality, and prolonged hospitalization. The clin- © 2003 Elsevier Inc. All rights reserved. ical diagnosis usually is evident under most cir- 0270-9295/03/2305-0009$30.00/0 cumstances, but other potential causes of acute doi:10.1016/S0270-9295(03)00092-5 Seminars in Nephrology, Vol 23, No 5 (September), 2003: pp 477-485 477 478 HEYMAN AND ROSEN clinical settings. Renal handling of the nephrotoxin oxygen balance is manifested by high levels of predominantly determines the distribution pattern cytochrome AA3 in its redox state, and of unsat- of tubular damage. The injury is dose dependent, urated hemoglobin, detected by blood oxygen level and the contribution of perturbations is relatively dependent (BOLD) magnetic resonance imaging2 marginal, with the exception of the hydration state. in humans. On the other hand, data regarding direct tubular Efficient mechanisms closely match medullary toxicity of radiologic dyes is characterized poorly, oxygen supply and demand by the determination of and is occasionally (but not necessarily) attributed regional blood flow and metabolic activity. The to hypertonicity. Contrast agents, once filtered latter effect is mediated by the control of GFR and through the glomerulus, are not reabsorbed or me- proximal tubular reabsorption (both governing sol- tabolized by tubular cells. Furthermore, although ute delivery to the distal nephron) and by the the dose of radiocontrast has been recognized as an regulation of distal tubular reabsorption. Locally independent risk factor for renal dysfunction, dye produced prostaglandins and nitric oxide, and the nephropathy rarely is encountered in the absence generation of adenosine from the breakdown of of predisposing factors. Whereas the incidence of adenosine triphosphate, are major participants in dye nephropathy in the aged population (a predis- these mechanisms. The location of mediator pro- posing factor by itself) was only 1.3%, in the duction and the distribution and density of its re- absence of other risk factors it exceeded 60% in the ceptors are important in maintaining medullary presence of 3 or more confounding conditions.1 oxygenation. For instance, adenosine, released dur- These data suggest that factors other than direct ing adenosine triphosphate consumption, exerts tubular toxicity predominantly are responsible for cortical vasoconstriction and inhibits transport ac- dye nephropathy. We present evidence indicating tivity in mTALs through A1 receptors, and induces that among high-risk individuals, altered renal mi- medullary vasodilation through A2 receptors. crocirculation and medullary tubular hypoxic dam- Comparably, endothelin-1 exerts cortical vasocon- age play a pivotal role in the pathogenesis of dye striction through ET-A receptors, but enhances nephropathy. medullary blood flow activating ET-B receptors. In this perspective, corticomedullary redistribution of RENAL MEDULLARY OXYGENATION blood flow and the activation of the tubuloglo- Renal parenchymal oxygen supply is not ho- merular feedback mechanism may be regarded as mogenous: although the renal cortex is well oxy- measures that maintain medullary oxygenation and genated, a sharp decline in tissue PO2 is noted at the prevent tubular hypoxic damage (see reference 3 corticomedullary junction, reaching 20 to 30 mm for a detailed bibliography). Hg under normal physiologic conditions. Medul- lary hypoxia is the price paid for the renal diluting/ RADIOCONTRAST AND MEDULLARY concentrating capacity, attributed to the unique OXYGENATION architecture of the countercurrent system. Some The administration of a radiocontrast agent re- 10% only of renal blood flow and oxygen supply sults in a marked decline of outer-medullary oxy- are directed to the renal medulla through vascular genation. Using oxygen microelectrodes, we and bundles (vasa recta), originating from efferent ar- others found that renal parenchymal PO2 decreases, terioles of juxtamedullary nephrons. Oxygen coun- both in the cortex and in the medulla. This effect is tercurrent diffusion from descending to ascending most pronounced and dramatic in the outer me- vasa recta further compromises medullary oxygen dulla, where low ambient PO2 declines further to supply to some 8 mL/min/100 g tissue. This lim- values as low as 8 mm Hg after the injection of ited oxygen delivery is marginally sufficient for the ionic high osmolar dye, as well as with nonionic metabolic needs for tubular transport, predomi- low osmolar agents. This dye-induced decline in nantly performed by medullary thick ascending medullary oxygenation can be restored by the in- limbs (mTALs) and S3 (straight) segments of the hibition of mTAL reabsorptive activity with the proximal tubule. Consequently, oxygen extraction loop diuretic furosemide (see reference 3 for a by the renal medulla is near-maximal, reaching detailed bibliography). 79% of the regional oxygen supply, with only a Hypoxia-induced factor 1 recently has been de- small oxygen reserve left. This critical medullary tected within the medulla and medullary rays DYE-INDUCED NEPHROPATHY 479 shortly after the administration of contrast (C. aggregation