Abstract

Loss of blood associated with hemodialysis procedures and laboratory testing, together with impaired iron absorption due to elevation of hepcidin, invariably cause iron deficiency in end-stage renal disease patients. For this reason, nearly all ESRD patients require intravenous iron to replete iron stores. Unfortunately, intravenously administered iron is often used routinely with inadequate attention to the body iron stores or severity of systemic inflammation. This has led to an epidemic of iron overload in the ESRD population. Only a minute amount (3-4 mg) of the total body iron (3-4 g in an adult man) resides in the plasma bound to transferrin, which serves as a safe vehicle for iron transport in the circulation. IV iron products are generally administered as bolus injections of 100 to 1000 mg, which far exceeds the available pool of free transferrin and represents a huge quantity compared to the intestinal iron absorption of 1 to 2 mg/day in the course of 3 to 4 meals. Administration of these products results in increased plasma level of catalytically active non-transferrin bound iron and the rise in the biomarkers of oxidative stress and inflammation. IV iron bypasses the biological safeguards for the transport and handling of iron and helps to intensify chronic kidney disease-associated oxidative stress and inflammation. As briefly described in this review, indiscriminate use of IV iron can accelerate cardiovascular disease, promote microbial infections, aggravate viral hepatitis, and worsen diabetes and diabetic complications in such patients. For these reasons IV iron should be used judiciously in this vulnerable population.

Background

Nearly all hemodialysis patients require IV iron to replete iron stores. Unfortunately, IV iron preparations are often used routinely with inadequate attention to the body iron stores or severity of systemic inflammation.1,2 Implementation of the bundled reimbursement policy has resulted in further increase in the use of IV iron preparations; between April 2012 and April 2013, 67-70% of the U.S. end-stage renal disease population on dialysis was reported to have used IV iron during each month.3

Iron bound to transferrin in the plasma, to ferritin in the storage sites, or to various metalloproteins and enzymes in various tissues, is kept in a safe and catalytically inactive state. However, improperly liganded ferrous iron reacts with H2O2,which is abundantly generated by mitochondria and inflammatory cells. This leads to formation of hydroxyl radical (OH), which is the most reactive and cytotoxic free radical known (H2O2+Fe2+ =OH+OH+ Fe3+), and conversion of Fe2 to ferric iron (Fe3+). Fe3+ is then transformed back to Fe2+ by superoxide (Fe3+ + O2•- = Fe2+ + O2), which is produced by mitochondria and mono-oxygenases and by reducing molecules such as ascorbic acid. This leads to sustained production of •OH which causes cytotoxicity and tissue damage by attacking and denaturing lipids, proteins, DNA, and other molecules.

Only a minute amount (3-4 mg) of the total body iron (3-4 g in an adult man) resides in the plasma bound to transferrin which serves as the vehicle for transport of iron between the sites of absorption, storage, and consumption. IV iron products are generally administered as bolus injections of 100 to 1000 mg, which far exceeds the available pool of free transferrin and represents a huge quantity compared to the natural iron absorption of 1 to 2 mg/day in the course of 3 to 4 meals. In fact, administration of these products results in an increased plasma level of catalytically active non-transferrin bound iron and the biomarkers of oxidative stress and inflammation in ESRD patients. It should be noted that increased plasma hepcidin and tissue ferritin levels, which suppress intestinal absorption, limit mobilization of iron stores, and lower plasma iron level in patients with systemic inflammation, represent a protective response. The rise in hepcidin and ferritin in such patients helps to limit iron-mediated oxidative stress and tissue injury and to deprive invading microbes from access to iron, which is essential for their growth and virulence. While absorption of orally administered iron is inhibited by increased hepcidin, intravenously administered iron bypasses these biological safeguards and helps to intensify the underlying oxidative stress and inflammation or infection in such patients. The proteases and lysosome-secreted hydrogen ions released during inflammation lead to the disassociation of iron from its binding proteins, thus enabling iron to catalyze reactive oxygen species (ROS) formation, resulting in tissue damage. For these reasons, cautions should be used in administering IV iron in CKD patients with evidence of severe inflammation. Some of the adverse effects of indiscriminate use of IV iron preparations are briefly described below.

Cardiovascular consequences: There is considerable evidence supporting the role of excessive use of IV iron in the pathogenesis of cardiovascular disease, which is the leading cause of premature death in ESRD patients (reviewed in reference #4). In this context, IV iron administration results in increased production of ROS and marked reduction of endothelium-dependent vasorelaxation in humans. In addition, pharmacologically relevant concentrations of IV iron products inhibit proliferation, promote apoptosis, and induce monocyte adhesion in cultured human endothelial cells and markedly reduce acetylcholine-induced vasorelaxation in isolated artery rings. Moreover, carotid artery media-intima thickness, which is a clinical measure of arteriosclerosis and atherosclerosis, is directly related to the cumulative annual dose of IV iron in ESRD patients. Likewise, IV iron has been suggested to be a factor in the development of vascular calcification.5 Taken together, these observations provide compelling evidence for the role of IV iron in the pathogenesis of endothelial dysfunction, and development and progression of atherosclerosis and arteriosclerosis in CKD.

Immunological consequences: Advanced CKD results in profound immunological disorders, including immune activation and immune deficiency. The CKD-associated immune deficiency leads to the high incidence and severity of infections and poor response to vaccination, whereas immune activation causes systemic inflammation and contributes to oxidative stress, cardiovascular disease, anemia cachexia, and other complications. As described in a recent review,4 high doses of IV iron compounds impair phagocytic and microbial killing capability of polymorphonuclear (PMN) leukocytes and lower antibody response to hepatitis B vaccination in the ESRD population. In addition, incubation in media containing therapeutic concentration of IV iron preparations diminishes helper lymphocyte survival in vitro. These events can contribute to the CKD-associated immune deficiency. On the other hand, by facilitating formation of pro-inflammatory M1 macrophages and catalyzing generation of ROS that can activate nuclear factor kappa-light-chain-enhancer protein complex (NFkB), iron loading promotes inflammation.

Increased risk of infections: Infections are a common cause of death in the ESRD population. This is, in part, due to the CKD-associated immune deficiency. As noted above, excessive use of IV iron preparations contribute to immune deficiency by depleting helper T cell population, impairing phagocytic ability of PMNs, and limiting antibody production. In addition, because iron is essential for bacterial multiplication and virulence,iron overload due to high doses of IV iron may increase the risk and severity of infections. In fact, in a recent retrospective study of a large cohort of a U.S. dialysis population, Brookhart et al. found a significant association between bolus dosing of iron preparations and the incidence of infection-related mortality and hospitalization.6

Liver disease: Liver is the major site of iron storage, and hepatic tissue iron content closely correlates with total body iron stores. As described in a recent review, several carefully conducted studies have documented marked increase in hepatic iron content (approaching those found in patients with hemosiderosis and hemochromatosis) in hemodialysis patients receiving IV iron therapy.4 The prevalence of hepatitis B and C in patients with ESRD is high and patients with ESRD are at risk of drug-induced hepatotoxicity due to the use of multiple pharmaceutical agents. Elevated iron content of the liver tissue has been suggested to amplify the damaging effects of hepatotoxic agents, and viral hepatitis, and may modify the response to interferon therapy.7 In addition, the stainable iron level in hepatocytes and portal tract cells is a predictor of progression and clinical and histological outcomes in advanced chronic hepatitis C.8 Therefore, use of IV iron preparations should be considered with greater caution in ESRD patients with viral hepatitis and those receiving drugs with hepatotoxic properties.9

Impact of iron overload on diabetes progression and its complications

Type 2 diabetes is the leading cause of CKD worldwide. Iron overload plays an important role in the pathogenesis and progression of diabetes and its complications.10 Iron overload increases the risk of type 2 diabetes by reducing insulin production and inducing insulin resistance. Iron overload causes insulin deficiency by promoting pancreatic beta cell apoptosis via iron-induced oxidative stress. Beta cells are exquisitely sensitive to oxidative injury due to their strict reliance on mitochondrial glucose metabolism and their limited antioxidant defense capacity. This is compounded by the high capacity of beta cells to take up iron via divalent metal transporters, which heightens their susceptibility to iron toxicity. The role of iron in the pathogenesis of diabetes is supported by the fact that the reduction in body iron pool with bloodletting or blood donation improves insulin sensitivity in type 2 diabetics.10 Glycated proteins play a major part in the pathogenesis of renal and vascular complications of diabetes. Unbound iron increases and chelation therapy reduces hyperglycemia-induced protein glycation.11 Moreover, glycated proteins bind iron-forming complexes in which the proteins remain catalytically active.12 Thus, iron facilitates formation of glycated proteins, and glycated proteins sustain catalytic activity of iron, events that promote and amplify oxidative stress, inflammation and hence renal and cardiovascular complications in diabetic patients. In fact, plasma non-transferrin-bound iron concentration is commonly elevated in diabetic patients and has been implicated in the pathogenesis of vascular complications.13 Therefore, it is important to avoid excessive use of IV iron preparations in ESRD patients with type 2 diabetes to prevent iron-mediated depletion of the residual beta cells, exacerbation of the insulin resistance, and the cardiovascular complications.

Summary

In conclusion, because IV iron bypasses the internal checks and balances associated with oral iron, the indiscriminate use of IV iron can accelerate cardiovascular disease, promote microbial infections, aggravate viral hepatitis, and worsen diabetes and diabetic complications in ESRD/CKD patients. For these reasons, IV iron should be used judiciously in this vulnerable population.

References

1. Vaziri ND. Epidemic of iron overload in dialysis population caused by intravenous iron products: a plea for moderation. The American Journal of Medicine. Oct 2012;125(10):951-952.

2. Rostoker G, Griuncelli M, Loridon C, et al. Hemodialysis-associated hemosiderosis in the era of erythropoiesis-stimulating agents: a MRI study. The American Journal of Medicine. Oct 2012;125(10):991-999 e991.

3. US-DOPPS Practice Monitor, June 2013. http://dopps.org/DPM. Accessed August 15, 2013.

4. Vaziri ND. Understanding iron: promoting its safe use in patients with chronic kidney failure treated by hemodialysis. American Journal of Kidney Diseases. Jun 2013;61(6):992-1000.

5. Neven E, De Schutter TM, Behets GJ, Gupta A., D’Haese PC. Iron and vascular calcification. Is there a link? Nephrology Dialysis Transplantation. 2011;26(4):1137-1145.

6. Brookhart MA, Freburger JK, Ellis AR, Wang L, Winkelmayer WC, Kshirsagar AV. Infection risk with bolus versus maintenance iron supplementation in hemodialysis patients. Journal of the American Society of Nephrology, Jun 2013;24(7):1151-1158.

7. Bonkovsky HL, Banner BF, Lambrecht RW, Rubin RB. Iron in liver diseases other than hemochromatosis. Seminars in Liver Disease. Feb 1996;16(1):65-82.

8. Lambrecht RW, Sterling RK, Naishadham D, Stoddard AM, Rogers T, Morishima C, Morgan TR, Bonkovsky HL. Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C. Gastroenterology. May 2011;140(5):1490-1500 e1493.

9. Shan Y, Lambrecht RW, Bonkovsky HL. Association of hepatitis C virus infection with serum iron status: analysis of data from the third National Health and Nutrition Examination Survey. Clinical Infectious Diseases. Mar 15 2005;40(6):834-841.

10. Fernandez-Real JM, Penarroja G, Castro A, Garcia-Bragado F, Hernandez-Aguado I, Ricart W. Blood letting in high-ferritin type 2 diabetes: effects on insulin sensitivity and beta-cell function. Diabetes. Apr 2002;51(4):1000-1004.

11. Redmon JB, Pyzdrowski KL, Robertson RP. No effect of deferoxamine therapy on glucose homeostasis and insulin secretion in individuals with NIDDM and elevated serum ferritin. Diabetes. Apr 1993;42(4):544-549.

12. Qian M, Liu M, Eaton JW. Transition metals bind to glycated proteins forming redox active “glycochelates”: Implications for the pathogenesis of certain diabetic complications. Biochemical and biophysical research communications. Sep 18 1998;250(2):385-389.

13. Shah SV, Baliga R, Rajapurkar M, Fonseca VA. Oxidants in chronic kidney disease. Journal of the American Society of Nephrology. Jan 2007;18(1):16-28.