Hazards of Contrast-Induced Acute Kidney Injury in Elderly Women

Abstract

Evaluation of: Sidhu RB, Brown JR, Robb JF et al.: Interaction of gender and age on post cardiac catheterization contrast-induced acute kidney injury. Am. J. Cardiol. 102(11), 1482–1486 (2008). A total of 13,127 consecutive patients undergoing coronary angiography with complete data were grouped by age and gender into four age categories (<50, 51–64, 65–79 and >80 years). Rates of postcatheterization contrast-induced acute kidney injury were higher for women compared with men in the 65–79 years (14.5 vs 11.0%; p < 0.001) and over 80 years (18.7 vs 15.1%; p = 0.048) age groups.

A recent analysis by Sidhu and colleagues has renewed awareness of contrast-induced acute kidney injury (CI-AKI) as a common complication after exposure to radiopaque contrast material [1]. CI-AKI, previously termed contrast nephropathy, occurs after intravascular iodinated contrast enters the kidney and provokes sustained intrarenal vasoconstriction, outer medullary and tubular ischemia, followed by cellular injury propagated by oxidative damage to renal tubular cells [2]. It is now understood that when this process occurs, the contrast is retained in the kidney in the peritubular space and is allowed to further cellular damage owing to the direct cytotoxicity of the iodinated, carbon-based molecules [3]. Recent observations suggest that contrast may dwell within the renal parenchyma for days after contrast exposure and, hence, create a prolonged risk of acute kidney injury after the initial contrast exposure [2]. Since most x-ray-based techniques rely on iodinated contrast, including conventional angiography and computed tomography, the use of intravascular contrast is expected to continue rising as developed nations care for an increasingly elderly population. A reduced nephron mass as a result of chronic kidney disease (CKD) and senescence is recognized to be the most common risk condition for CI-AKI [4]. Additional risk factors, such as diabetes, heart failure and anemia, work to increase the baseline risk in addition to a critical reduced renal filtration rate [3]. Estimating formulas based on age, gender, race and serum creatinine have been refined to yield the estimated glomerular filtration rate (eGFR), which is standardized to 1.73 m² body surface area. As a general rule, a normal eGFR for young adults is approximately 130 ml/min/1.73 m² and over the course of normal aging until death, the eGFR is reduced by 50%; thus, a normal nonagenarian could expect to have an eGFR of 65 ml/min/1.73 m² [5]. Most studies agree that when the eGFR falls below 60 ml/min/1.73 m², there has been a critical loss of nephrons as a result of CKD risk factors, and there is increasing vulnerability to the remaining nephron units (remnant nephrons) to acute kidney damage. The number of nephron units is thought to be related to birthweight, particularly in men, while women – on average – have 15% less nephron units from birth than men of similar size, hence, over the course of normal aging, women may run a course much closer to the critical residual nephron mass at which susceptibility to CI-AKI occurs [6]. This is important as CI-AKI is a clinical condition upon which the hazard for symptomatic outcomes is increased, including major adverse cardiac and renal events, rehospitalization and death.

Results

In the observational study published in the 1 December, 2008, issue of the American Journal of Cardiology, Sidhu and coworkers presented gender-specific rates of CI-AKI from the Dartmouth Dynamic Registry from 1998 to 2006 in 13,127 patients undergoing diagnostic catheterization with or without coronary intervention, which had baseline and at least one follow-up serum creatinine [1]. The baseline characteristics by age and gender draw attention to differing rates of patients, with eGFR less than 60 ml/min/1.73 m² (56% of women ≥ 80 years compared with 11% of women < 50 years). Across every age group, a relative approximate 20% more women than men had an eGFR less than 60 ml/min/1.73 m². Thus, in the highest risk group – women aged over 80 years – 56% had an eGFR less than 60 ml/min/1.73 m² before contrast exposure, and this translated into the highest rate of CI-AKI – 18.7%. Another important observation from the demographics is the surge of adiposity in the younger age groups with 52% of women aged below 50 years compared with 17% of those aged 80 years or above being obese. Since obesity is the major determinant of Type 2 diabetes and is directly linked to CKD, we can expect much higher rates of baseline renal impairment in future cohorts of women as they enter the ninth decade where the cardiovascular disease is 86% (Figure 1) [7].

Figure 1.

Current prevalence of cardiovascular disease in the USA by age and gender.

In the present study, the rates of major cardiac and renal events were low in all groups as the majority (∼70%) of procedures were elective. Women below the age of 50 years had less than 1% rates of all cardiac and renal events compared with those aged 80 years or above, where the rates of cardiac events were 3%, stroke 0.7%, renal failure requiring dialysis 0.4% and all-cause mortality of 5%. Unlike many prior studies, this report did not demonstrate a relationship between CI-AKI and cardiorenal events, possibly because the follow-up was limited to the hospitalization and the majority of elective cases are usually discharged the same or the next day after the procedure. Another explanation is that incomplete and variable measurement of serum creatinine during the follow-up may have created variation that reduced the observed power to find the association.

Implications of coronary computed angiography

Since the introduction of 4-slice spiral computed tomographic systems in 2000, with rapid and revolutionary technological advances in the spatial and temporal resolution of multidetector row computed tomography, the application of non-invasive coronary computed tomography angiography (CCTA) in clinical practice has exploded, replacing invasive coronary angiography in clinical situations where the pretest probability of coronary disease is low or intermediate. In addition, since women more frequently present with atypical symptoms, more associated symptoms and greater functional disability often resulting in challenging assessment with other noninvasive modalities, such as stress testing [8], CCTA may result in rapid diagnosis and management. However, the implications of CI-AKI, particularly in older women, must be considered. The rate of CI-AKI has been reported to be from less than 5% in patients undergoing CCTA (creatine rise ≥ 0.3 mg/dl) [9]. Although this rate is much lower than that of coronary angiography (owing to greater admixture of contrast with the blood pool in the venous phase compared with the arterial phase, and absence of superimposed atheroembolism as common owing to arterial catheter exchanges with cardiac catheterization), this rate is probably lower in published studies since many CCTA centers exclude patients with CKD. Iso-osmolar contrast use in CCTA may offer an optimal CCTA imaging profile, with lesser renal toxicity and fewer hemodynamic effects [10]. As with invasive coronary angiography, in patients with known or at risk for CI-AKI, adequate preprocedure hydration and other preventive measures may result in lowering the risk of CI-AKI.

Future perspective

Both the aging populations and obesity pandemics in Westernized countries portend increasing numbers of women who will be at risk for CI-AKI when intravenous contrast will be administered. There has been little advancement in the development of a nontoxic contrast agent for x-ray-based imaging – hence, iodinated contrast will be used for the foreseeable future. There are no currently approved diagnostic tests or preventive therapies for CI-AKI. We expect the future clinical development of neutrophil gelatinase-associated lipocalin as an acute marker of contrast-induced renal tubular injury [11]. This marker rises much earlier than serum creatinine and should give enough advanced warning to initiate more intensive intravenous hydration, resulting in increased urine flow rates and reductions in the retention of contrast in the urinary and peritubular spaces. The two leading preventive approaches include intravenous rolofylline and oral deferiprone. Rolofylline is an adenosine A₁-receptor antagonist, which is designed to blunt the degree of vasoconstriction caused by intravenous contrast and, hence, works to prevent the initiation of the injury sequence [12]. Deferiprone is a labile iron chelator that removes catalytic iron from the renal tubular cells, which are undergoing ischemic injury, and prevents the participation of iron in the generation of oxygen free radicals, which cause oxidative damage to the surrounding viable cells and nephron units [13]. Thus, for the expected increasing proportion of elderly women undergoing intravascular contrast procedures, there is future hope for a prompt diagnosis (neutrophil gelatinase-associated lipocalin) of CI-AKI and a two-pronged prophylactic approach (rolofylline and deferiprone) to reduce this common complication.

Executive summary

• Contrast-induced acute kidney injury (CI-AKI) is most common in elderly women who have a reduced number of functioning nephrons within the kidney as a result of age and gender. The remaining nephrons, which function at a higher workload, are vulnerable to ischemic injury as iodinated contrast evokes vasoconstriction within the kidneys.

• Cardiac computed tomography is a new alternative to conventional coronary angiography; however, it still exposes patients to iodinated contrast and probably poses a lower risk of CI-AKI.

• Neutrophil gelatinase-associated lipocalin is a normally produced protein by the kidney that elevates in response to CI-AKI.

• Deferiprone is a labile iron chelator that may remove locally produced iron from renal tubular cells and reduce oxidative damage due to iodinated contrast.