Sundararaman Swaminathan

The Role of Iron in Diabetes and Its Complications

The central importance of iron in the pathophysiology of disease is derived from the ease with which iron is reversibly oxidized and reduced. This property, while essential for its metabolic functions, makes iron potentially hazardous because of its ability to participate in the generation of powerful oxidant species such as hydroxyl radical (1). Oxygen normally accepts four electrons and is converted directly to water. However, partial reduction of oxygen can and does occur in biological systems. Thus, the sequential reduction of oxygen along the univalent pathway leads to the generation of superoxide anion, hydrogen peroxide, hydroxyl radical, and water (1,2). Superoxide and hydrogen peroxide appear to be the primary generated species. These species may then play a role in the generation of additional and more reactive oxidants, including the highly reactive hydroxyl radical (or a related highly oxidizing species) in which iron salts play a catalytic role in a reaction. This reaction is commonly referred to as the metal catalyzed Haber-Weiss reaction (1): \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \[\frac{\mathrm{Fe}^{3{+}}{+}\mathrm{O}\_{{\dot{2}}}^{{\mbox{--}}} \mathrm{Fe}^{2{+}}{+}\mathrm{O}\_{2}\ \mathrm{Fe}^{2{+}}{+}\mathrm{H}\_{2}\mathrm{O}\_{2} \mathrm{Fe}^{3{+}}{+}{\cdot}\mathrm{OH}{+}\mathrm{OH}{-}}{\mathrm{O}\_{{\dot{2}}}^{{\mbox{--}}}{+}\mathrm{H}\_{2}\mathrm{O}\_{2} \mathrm{O}\_{2}{+}{\cdot}\mathrm{OH}{+}\mathrm{OH}{-}}\] \end{document} Because iron participates in the formation of reactive oxygen species, organisms take great care in the handling of iron. Indeed, iron sequestration in transport and storage proteins may contribute to antioxidant defenses. It is now well established that oxidants can cause the release of catalytic iron (1); thus, a vicious cycle is initiated that leads to the formation of more reactive oxygen species. In this review, we discuss the role tissue iron and elevated body iron stores play in causing type 2 diabetes and the pathogenesis of its important complications, particularly diabetic nephropathy and cardiovascular disease (CVD). In addition, we emphasize that iron overload is not a prerequisite for iron to mediate either diabetes or its complications. Important in its pathophysiology is the availability of so-called catalytic iron or iron that is available to …

Changing Incidence of Glomerular Disease in Olmsted County, Minnesota: A 30-Year Renal Biopsy Study

Membranous nephropathy (MN) is considered the most common cause of nephrotic syndrome in white adults, but recent studies have shown an increasing incidence of focal segmental glomerulosclerosis (FSGS). These studies are difficult to interpret because the majority of cases came from urban tertiary referral centers. For validating these findings in the general population, trends in the incidence of various forms of glomerular disease (glomerulonephritis [GN]) among the residents of Olmsted County, MN were studied. Biopsy data of local patients who had a diagnosis of a nondiabetic glomerular disease from 1974 through 2003 were reviewed. Biopsies were categorized as (1) FSGS, (2) MN, (3) minimal change, (4) lupus nephritis, (5) membranoproliferative GN (MPGN), (6) IgA nephropathy (IgAN), (7) crescentic/necrotizing GN, and (8) other. Time trends in the annual age- and gender-adjusted (2000 US population) incidence rate per 100,000 Olmsted County population were estimated. A total of 195 biopsies were analyzed. Overall, IgAN was present in 22%, FSGS was present in 17%, and MN was present in 10%. Between 1974 to 1983 and 1994 to 2003, the incidence of any type of GN among Olmsted County residents increased more than two-fold (P < 0.001), FSGS by 13-fold (P < 0.001), and IgAN by three-fold (P = 0.002). Increases in MN were nonsignificant (2.5-fold; P = 0.13). Currently (1994 to 2003), the most frequent type of GN is IgAN (25%), followed by FSGS (20%) and MN (11%), with annual incidence rates of 2.1, 1.8, and 1.0 per 100,000/yr, respectively. This study confirms that the incidence of GN is growing overall, particularly for FSGS, which is the leading cause of nephrotic syndrome in white adults.

New Insights into Nephrogenic Systemic Fibrosis

Nephrogenic systemic fibrosis is a new disorder reported almost exclusively in patients who have renal insufficiency and are exposed to contrast media formulated with gadolinium. High morbidity and mortality are associated with this severely disabling and painful condition. The acute phase begins upon exposure to gadolinium contrast media, characterized by a systemic inflammatory response involving iron mobilization, and then as a progressive, chronic phase in which fibrosis develops. Proposed is a unifying model of cumulative risk factors in which the interplay of systemic inflammation and stimulated hematopoietic environment associated with hyperparathyroidism and erythropoietin may tie to a common pathogenic mechanism of fibrogenesis. Because there are no uniformly effective interventions to treat nephrogenic systemic fibrosis other than successful renal transplantation, prevention by avoiding gadolinium contrast media in patients with chronic kidney disease is vital. On the basis of suspected pathogenesis, it is also reasonable to limit erythropoietin and iron therapy to dosages ensuring recommended targets and adequately control hyperparathyroidism. Herein is reviewed what is currently known about this subject.

Cardiac and vascular metal deposition with high mortality in nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis is a severe disabling disease that can follow gadolinium-based contrast exposure. In this study we analyzed the clinical and laboratory records of patients with nephrogenic systemic fibrosis who had a history of exposure to gadolinium-based contrast media and identified their cardiac and vascular events. At autopsy, we found that the heart, blood vessels, and skin of three patients who died of cardiac and/or vascular complications had appreciable amounts of gadolinium, iron, and aluminum as measured by inductively coupled plasma-mass spectrometry and confirmed by x-ray fluorescence. Of the 32 patients with nephrogenic systemic fibrosis studied, 10 died at a median of 112 days after diagnosis. Cardiovascular events contributed to the mortality of 9 patients and included congestive heart failure, recurrent arrhythmias, hypotension, stroke, limb ischemia, posterior ischemic optic neuropathy and sudden death. Our results show that increased cardiac and vascular complications along with short survival in nephrogenic systemic fibrosis are associated with metal accumulation in the heart, blood vessels, and skin of these patients.

Inflammation in AKI: Current Understanding, Key Questions, and Knowledge Gaps

Inflammation is a complex biologic response that is essential for eliminating microbial pathogens and repairing tissue after injury. AKI associates with intrarenal and systemic inflammation; thus, improved understanding of the cellular and molecular mechanisms underlying the inflammatory response has high potential for identifying effective therapies to prevent or ameliorate AKI. In the past decade, much knowledge has been generated about the fundamental mechanisms of inflammation. Experimental work in small animal models has revealed many details of the inflammatory response that occurs within the kidney after typical causes of AKI, including insights into the molecular signals released by dying cells, the role of pattern recognition receptors, the diverse subtypes of resident and recruited immune cells, and the phased transition from destructive to reparative inflammation. Although this expansion of the basic knowledge base has increased the number of mechanistically relevant targets of intervention, progress in developing therapies that improve AKI outcomes by modulation of inflammation remains slow. In this article, we summarize the most important recent developments in understanding the inflammatory mechanisms of AKI, highlight key limitations of the commonly used animal models and clinical trial designs that may prevent successful clinical application, and suggest priority approaches for research toward clinical translation in this area.

Novel inflammatory mechanisms of accelerated atherosclerosis in kidney disease

A substantial body of evidence has accumulated linking an increased incidence of cardiovascular disease in patients with acute kidney injury (AKI), chronic kidney disease (CKD), and end-stage renal disease (ESRD). A multitude of novel risk factors related to decreased kidney function might interact with the renal and systemic immune systems involved in renal injury and repair to participate in accelerated atherogenesis (Immune inflammation-Renal injury-Atherosclerosis--the IRA Paradigm). In this review, we will discuss several of these novel risk factors and present the potential for the role of the immune-inflammatory system in accelerated atherosclerosis of kidney disease.

First responders: understanding monocyte-lineage traffic in the acutely injured kidney

Interstitial monocytic infiltration of the kidney occurs within hours of acute kidney injury and is an important determinant of functional decline and fibrosis. Li et al. used several surface markers to distinguish between dendritic cells and inflammatory monocytes following acute kidney injury and to identify two chemokine receptors that regulate monocyte traffic. This Commentary examines the degree to which monocyte-lineage diversity, trafficking, and contribution to renal injury have been teased out to date.

Acute interstitial nephritis due to deferasirox: a case report

Deferasirox is a new oral iron chelator used to treat transfusional iron overload. Pre-marketing clinical trials revealed little organ-specific toxicity. Increases in serum creatinine were noted in one-third of patients but were mild and non-progressive. We describe a 62-year-old man with myelodysplastic syndrome who developed a progressive decline in renal function after starting deferasirox. A kidney biopsy showed acute interstitial nephritis with increased eosinophils, suggesting drug hypersensitivity. Deferasirox was discontinued and renal function returned to baseline. This is the first pathological description of deferasirox-related acute kidney injury in humans, which differs from tubular vacuolization observed in animals.

Hepcidin Mitigates Renal Ischemia-Reperfusion Injury by Modulating Systemic Iron Homeostasis

Iron-mediated oxidative stress is implicated in the pathogenesis of renal ischemia-reperfusion injury. Hepcidin is an endogenous acute phase hepatic hormone that prevents iron export from cells by inducing degradation of the only known iron export protein, ferroportin. In this study, we used a mouse model to investigate the effect of renal ischemia-reperfusion injury on systemic iron homeostasis and determine if dynamic modulation of iron homeostasis with hepcidin has therapeutic benefit in the treatment of AKI. Renal ischemia-reperfusion injury induced hepatosplenic iron export through increased ferroportin expression, which resulted in hepatosplenic iron depletion and an increase in serum and kidney nonheme iron levels. Exogenous hepcidin treatment prevented renal ischemia-reperfusion-induced changes in iron homeostasis. Hepcidin also decreased kidney ferroportin expression and increased the expression of cytoprotective H-ferritin. Hepcidin-induced restoration of iron homeostasis was accompanied by a significant reduction in ischemia-reperfusion-induced tubular injury, apoptosis, renal oxidative stress, and inflammatory cell infiltration. Hepcidin -: deficient mice demonstrated increased susceptibility to ischemia-reperfusion injury compared with wild-type mice. Reconstituting hepcidin-deficient mice with exogenous hepcidin induced hepatic iron sequestration, attenuated the reduction in renal H-ferritin and reduced renal oxidative stress, apoptosis, inflammation, and tubular injury. Hepcidin-mediated protection was associated with reduced serum IL-6 levels. In summary, renal ischemia-reperfusion injury results in profound alterations in systemic iron homeostasis. Hepcidin treatment restores iron homeostasis and reduces inflammation to mediate protection in renal ischemia-reperfusion injury, suggesting that hepcidin-ferroportin pathway holds promise as a novel therapeutic target in the treatment of AKI.

Novel approaches targeted toward oxidative stress for the treatment of chronic kidney disease.

Purpose of reviewChronic kidney disease is a worldwide health problem that affects about 10% of the adult population. No major advances have been made in the treatment of this common disease, which leads to end-stage kidney disease and is associated with cardiovascular events and high economic costs. We review new approaches that are currently being explored to halt progression of kidney disease. Recent findingsRedox balance plays a significant pathogenic role in the progression of kidney disease through regulation of signaling pathways, gene expression, cell proliferation, and fibrosis. In this review we define the term reactive oxygen metabolites, or oxidants, and discuss novel treatment modalities for diabetic and nondiabetic chronic kidney disease. Our emphasis here is on human studies and those agents that may have a direct or indirect link to oxidative stress and catalytic (labile) iron. SummaryWe believe that intercepting these pathways with one or more drugs may provide novel therapeutic modalities for halting progression of chronic kidney disease.