Purpose of review Obesity is established as an important contributor of increased diabetes mellitus, hypertension, and cardiovascular disease, all of which can promote chronic kidney disease (CKD). Recently, there is a growing appreciation that, even in the absence of these risks, obesity itself significantly increases CKD and accelerates its progression. Recent findings Experimental and clinical studies reveal that adipose tissue, especially visceral fat, elaborates bioactive substances that contribute to the pathophysiologic renal hemodynamic and structural changes leading to obesity-related nephropathy. Adipocytes contain all the components of the renin–angiotensin–aldosterone system, plasminogen activator inhibitor, as well as adipocyte-specific metabolites such as free fatty acids, leptin, and adiponectin, which affect renal function and structure. In addition, fat is infiltrated by macrophages that can alter their phenotype and foster a proinflammatory milieu, which advances pathophysiologic changes in the kidney associated with obesity. Summary Obesity is an independent risk factor for development and progression of renal damage. Although the current therapies aimed at slowing progressive renal damage include reduction in weight and rely on inhibition of the renin–angiotensin system, the approach will likely be supplemented by interventions aimed at obesity-specific targets including adipocyte-driven cytokines and inflammatory factors.

Objective—: Angiotensin II is a major determinant of atherosclerosis. Although macrophages are the most abundant cells in atherosclerotic plaques and express angiotensin II type 1 receptor (AT1), the pathophysiologic role of macrophage AT1 in atherogenesis remains uncertain. We examined the contribution of macrophage AT1 to accelerated atherosclerosis in an angiotensin II-responsive setting induced by uninephrectomy (UNx). Methods and Results—: AT1 ^−/− or AT1 ^+/+ marrow from apolipoprotein E deficient (apoE ^−/− ) mice was transplanted into recipient apoE ^−/− mice with subsequent UNx or sham operation: apoE ^−/− /AT1 ^+/+ →apoE ^−/− +sham; apoE ^−/− /AT1 ^+/+ →apoE ^−/− +UNx; apoE ^−/− /AT1 ^−/− →apoE ^−/− +sham; apoE ^−/− /AT1 ^−/− →apoE ^−/− +UNx. No differences in body weight, blood pressure, lipid profile, and serum creatinine were observed between the 2 UNx groups. ApoE ^−/− /AT1 ^+/+ →apoE ^−/− +UNx had significantly more atherosclerosis (16907±21473 versus 116071±8180 μm ² , P <0.05). By contrast, loss of macrophage AT1 which reduced local AT1 expression, prevented any effect of UNx on atherosclerosis (77174±9947 versus 75714±11333 μm ² , P =NS). Although UNx did not affect total macrophage content in the atheroma, lesions in apoE ^−/− /AT1 ^−/− →apoE ^−/− +UNx had fewer classically activated macrophage phenotype (M1) and more alternatively activated phenotype (M2). Further, UNx did not affect plaque necrosis or apoptosis in apoE ^−/− /AT1 ^−/− →apoE ^−/− whereas it significantly increased both (by 2- and 6-fold, respectively) in apoE ^−/− /AT1 ^+/+ →apoE ^−/− mice. Instead, apoE ^−/− /AT1 ^−/− →apoE ^−/− had 5-fold–increase in macrophage-associated apoptotic bodies, indicating enhanced efferocytosis. In vitro studies confirmed blunted susceptibility to apoptosis, especially in M2 macrophages, and a more efficient phagocytic function of AT1 ^−/− macrophages versus AT1 ^+/+ . Conclusion—: AT1 receptor of bone marrow-derived macrophages worsens the extent and complexity of renal injury-induced atherosclerosis by shifting the macrophage phenotype to more M1 and less M2 through mechanisms that include increased apoptosis and impaired efferocytosis.

Accelerated atherosclerosis and increased cardiovascular events are not only more common in chronic kidney disease (CKD) but are more resistant to therapeutic interventions effective in the general population. The oral charcoal adsorbent, AST-120, currently used to delay start of dialysis, reduces circulating and tissue uremic toxins, which may contribute to vasculopathy, including atherosclerosis. We, therefore, investigated whether AST-120 affects CKD-induced atherosclerosis. Apolipoprotein E-deficient mice, a model of atherosclerosis, underwent uninephrectomy, subtotal nephrectomy or sham operation at 8 weeks of age and were treated with AST-120 after renal ablation. Atherosclerosis and its characteristics were assessed at 25 weeks of age. Uninephrectomy and subtotal nephrectomised mice had significantly increased acceleration of atherosclerosis. AST-120 treatment dramatically reduced the atherosclerotic burden in mice with kidney damage, while there was no beneficial effect in sham-operated mice. The benefit was independent of blood pressure, serum total cholesterol or creatinine clearance. AST-120 significantly decreased necrotic areas and lessened aortic deposition of the uremic toxin indoxyl sulfate without affecting lesional macrophage or collagen content. Furthermore, AST-120 lessened aortic expression of monocyte chemoattractant protein-1, tumor necrosis factor-α and interleukin-1β messenger RNA. AST-120 lessens the extent of atherosclerosis induced by kidney injury and alters lesion characteristics in apolipoprotein E-deficient mice, resulting in plaques with a more stable phenotype with less necrosis and reduced inflammation.

Purpose of review Patients with chronic kidney disease (CKD) have the highest risk for atherosclerotic cardiovascular disease (CVD). Current interventions have been insufficiently effective in lessening excess incidence and mortality from CVD in patients with CKD versus other high-risk groups. This review focuses on traditional and CKD-related risks as well as key mechanisms of macrophage foam cell formation that underlie the excess CVD in the setting of CKD. Recent findings Hyperlipidemia, particularly increased low-density lipoprotein (LDL) cholesterol, is the key factor in atherogenesis in the general population, but has not been found to be the overriding risk for greater CVD in CKD, especially as renal damage progresses. Although higher incidence of CVD in CKD is not due to higher serum lipids per se, CKD is associated with abnormal lipid metabolism that is proatherogenic. CKD-related risks, including inflammation and disturbances in mineral metabolism, have been implicated. In addition, perturbations of the macrophage, a cell that is central in atherogenesis, may be important. Summary The mechanisms underlying the heightened risk for CVD in CKD have been the focus of intense study and may relate to the combined effects of traditional and CKD-specific risks involving inflammation and lipid metabolism, especially perturbation of macrophage cholesterol homeostasis.