A ray of light in the dark: alternative approaches to the assessment and treatment of ischemic nephropathy

Abstract

Atherosclerotic renal arterial stenosis (ARAS) is a common complication in elderly patients with chronic kidney disease (CKD). It has been reported that 5–22% of elderly CKD patients are affected by ARAS [1]. ARAS often causes severe renovascular hypertension that is difficult to treat with antihypertensive combination regimens. As angiotensin is generally recognized to be responsible for renovascular hypertension, a recent report has suggested that treatment with angiotensinconverting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) is beneficial for RAS patients by leading to lower cardiovascular event rates and reducing the requirement for dialysis [2]. However, these benefits come with considerable risk for hospitalization for rapidly progressive renal dysfunction in some ARAS population by excessive reduction of glomerular filtration pressure [2, 3]. Moreover, ARAS is associated with a high annual death rate of 16%, mainly due to cardiovascular events [4], and is a predictor for death independent of other conventional cardiovascular risk factors [5, 6]. ARAS is a clinical condition that is distressing to nephrologists or interventional cardiologists engaged in treatment, because the benefits of percutaneous transluminal renal angioplasty (PTRA) and stenting of the renal arteries in ARAS patients has been a topic of debate. A meta-analysis of three randomized trials [7–9] comparing conventional medication with PTRA revealed that PTRAwas not therapeutically beneficial to blood pressure control in ARAS patients, even though it had a significant effect in reducing the dosage of medication [10]. In focusing on renal deterioration, two large trials showed that renal arterial stenting had no benefit over medical therapy in outcomes relating to blood pressure, preservation of renal function and mortality [11, 12]. Thus, there is yet no evidence from clinical trials that revascularization reduces the incidence of end-stage renal disease in patients with ARAS. A possible reason for these negative findings is that some of the subjects in the trials had no room for renal improvement by PTRA at the time of entry. Although insufficient efficacy of revascularization on renal outcome in ARAS patients has been evidenced in several clinical trials, there may be hope that revascularization improves renal function in some populations of ARAS patients. Development of an examination to evaluate renal function is needed to determine which ARAS patients might benefit from revascularization and subsequent follow-up management until therapeutic intervention. The severity of RAS is assumed to be a predictor for ischemic nephropathy, but it has been documented that severity of RAS only weakly relates to the presence of ischemic nephropathy, as reported in a previous study showing that the severity of proximal renal artery lesions was often unassociated with renal dysfunction in ARAS patients [13]. Thus, other feasible mechanisms beyond hemodynamic decrement seem to influence the pathogenesis of RAS-mediated parenchymal damage, and this should be considered in deciding when and to whom therapeutic intervention should be applied. Lerman et al. [14–22] at the Mayo Clinic, Rochester, MN, have consistently and intensively investigated the efficient evaluation and treatment for post-stenotic kidneys in ARAS by using immunological approaches. These investigators have recently demonstrated the significance of elevated inflammatory cytokines/chemokines, including interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-6, and of CD68+ macrophage expansion for the evaluation of severity of damage to the human post-stenotic kidney with ARAS [16, 19]. Lerman et al. also showed a strong association between reduction of these elevated cytokines/chemokines in stenotic kidneys and renal functional recovery after revascularization in an experimental swine model of ARAS [15]. Therefore, it is anticipated that treatments to modulate pro-inflammatory cytokines/chemokines in post-stenotic kidneys can attenuate renal dysfunction in post-stenotic kidneys and improve renal prognosis after revascularization in the ARAS population. IN F O C U S