Oxidative Stress in Chronic Kidney Disease

Oxidative stress results from the imbalance of reactive oxygen species (ROS) and defense mechanisms, which results in cell damage. In addition, the presence of inflammation is a well-documented factor influencing the development of oxidative stress in dialysis patients (Samouilidou, Grapsa, Kakavas, Lagouranis, & Agrogiannis, 2003). Renal sources for ROS are activated macrophages, vascular cells, and various glomerular cells. ROS may affect cells of the host organism, especially at sites of inflammation, in addition to playing a role in the defense system against other agents. This effect plays a role in a variety of renal diseases such as glomerulonephritis and tubulointerstitial nephritis, which can contribute to proteinuria and other conditions (Ichikawa, Kiyama, & Yoshioka, 1994; Klahr, 1997). ROS are also thought to contribute to the pathogenesis of ischemia reperfusion injury in the kidney (Dobashi, Ghosh, Orak, Singh, & Singh, 2000). This suggests that the kidney may be particularly susceptible to oxidative stress.

Additional uremia-related metabolic aberrations such as IV iron exposure, biocompatibility changes associated with dialysis, and hyperhomocystinemia may also contribute to increased oxidative stress. Renal anemia is another contributor to oxidative stress in patients with chronic renal failure undergoing hemodialysis (HD). Glutathione peroxidase has been identified as the prominent, highly effective radical-eliminating system in erythrocytes (Klemm et al., 2001). When this is inhibited, there is significant delay in the erythrocyte elimination of free radicals, illustrating a defect in the antioxidant forces outside the glutathione peroxidase system. The optimized correction of renal anemia may represent an effective means of strengthening antioxidant capacity and may be effective in reducing cardiovascular risk potential (Siems et al., 2001).

Albumin is the major plasma protein target of oxidant stress in patients with chronic renal failure (CRF) or HD. Himmelfarb and McMonagle (2001) demonstrated significant differences in the oxidation of plasma albumin as determined by plasma carbonyl formation using The Western blot immunoassay and enzyme-linked immunosorbent assay (ELISA) techniques in CKD patients compared to healthy volunteers. Danielski et al. confirmed this finding by demonstrating that patients with hypoalbuminemia on HD had significantly accelerated cardiovascular disease (CVD) compared to normoalbuminemic individuals on HD (2003).

Consequences for the vascular system include endothelial dysfunction and alterations of cellular turnover. This supports the hypothesis that oxidative stress is interrelated to inflammation since different oxidant free radicals are generated by phagocytic cells in response to inflammatory stimuli. The endothelium is a source and a target of oxidants and participates in the acute inflammatory response (Locatelli et al., 2003; Himmelfarb, Stenvinkel, Ikizler, & Hakim, 2002).

There is evidence that oxidative stress can cause hypertension, and hypertension can cause oxidative stress (Vaziri, 2004). Oxidative stress contributes to hypertension, endothelial dysfunction, and brain disorders in animals with CRF. This is partly due to the up-regulation of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase and the down-regulation of superoxide dismutase (SOD). Hypertension, on the other hand, activates nuclear factor kappa B and mitigates tubulointerstitial inflammation in animals. This illustrates that oxidative stress, hypertension, and inflammation are closely interrelated and contribute to a vicious cycle that can lead to progressive deterioration of hypertension and target organ damage (Vasiri, 2004). In addition, several studies support the hypothesis that uremia is associated strongly with oxidative stress. Treatment with HD or peritoneal dialysis for more than 2 years, as well as loss or deficiency of antioxidant activity such as Vitamin E deficiency enhances even further oxidation and reduction of antioxidant levels in patients receiving these treatments. Decreased potential for oxygen-radical-scavenger activity becomes pronounced after 7 years of HD treatment (Koken, Serteser, Kahraman, Gokce, & Demir, 2004).

Mortality rates in the ESRD population are estimated to be 30 times higher than the general population due to accelerated cardiovascular risk (Wart, 2005). Several factors have been implicated in this process including diabetes, high cholesterol, and hypertension as well as non-traditional/unique risk factors such as elevated homocysteine levels, anemia, hyperphosphatemia, accumulation of uremic toxins, chronic inflammation, thrombogenic and metabolic disturbances, and electrolyte imbalances (Wratten, Galaris, Tetta, & Sevanian, 2002; Pupim, Himmelfarb, McMonagle, Shyr, & Ikizler, 2004). Two separate studies, have documented the 30-fold increase in CVD. The Chronic Kidney Disease and the Risk of Death, Cardiovascular Events, and Hospitalization study, referred to as the Kaiser study, studied over a million adult patients with chronic kidney disease in San Francisco, California (McCullough, 2004). Results showed that as kidney function drops, the risk of death, cardiovascular events such as heart attacks and strokes, and hospitalization increases. In fact, when the glomerular filtration rate (GFR) is less than 15 ml/minute, the risk of death is 600% higher – CVD prevalence is 343% greater, and hospitalizations increase by 315%. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT) study, in which over 14,500 patients with heart attacks were studied (Pfeffer et al., 2003), death rates ranged from 14.1% in patients with GFR of >75, compared with 45.5% in patients whose GFR was less than 45 ml/min. Researchers from this study attributed the increased risk of death from CVD, in part, to complications of kidney disease, including anemia, oxidative stress, abnormal calcium and phosphorus regulation, and inflammation (Wart, 2005). These studies and other evidence support the theory that increased oxidative stress in patients with CKD may be one of the primary reasons for increased inflammation, immuno-suppression, and increased risk of CVD and related death.

Treatment
Treatment of oxidative stress includes antioxidant therapy, primarily Vitamin E and Vitamin C. There are a few studies that were able to show some beneficial effects of these therapies, but it remains highly controversial. Interestingly, the effects were equivocal in non-renal patients. Only one cross-sectional study evaluated the association between oxidative stress markers and CVD in patients with CRF and found a positive association between serum malondialdehyde and prevalent CVD in patients on HD (Massy & Nguyen-Khoa, 2002). Additionally, limited data regarding interventional trials with antioxidant therapies aimed at reducing CVD is available. In fact, only the Secondary Prevention with Antioxidants of Cardiovascular Disease in ESRD (SPACE) trial was able to demonstrate a reduction of CV events as an endpoint in patients on dialysis with established CVD. In this study, the patients received 800 IU of Vitamin E per day; however, the study was small and of limited duration (Boaz et al., 2000).

Recently, some studies have been done with protandim. This substance is composed of five botanical ingredients with an extensive history of use and is currently marketed and sold as a nutraceutical. Protandim stimulates the body to increase production of two enzymes, superoxidase (SOD) and catalase (CAT), which act as catalytic antioxidants that boost the body’s first line of defense in destroying the harmful free radicals. It has been found to lower subjects’ levels to oxidative stress similar to that of a newborn or young child (McCord & Edeas, 2005). It is not clear whether protandim has the same effect in those with chronic diseases, although separate studies have shown to increase CAT in an animal model and to increase SOD in a diabetic animal model. Oxidative stress and aging was measured in this study by evaluating lipid peroxidation, which was determined by measuring thiobartituric acid reactive substances (TBARS) (McCord & Edeas, 2005). Additional studies in animal models by both Wallace and Brownlee (2005) suggest similar findings in both CKD and diabetic CKD models. There is no doubt that correcting the oxidant/antioxidant imbalance in patients with CRF is an important approach to consider for reducing the risk of developing cardiovascular disorders and perhaps the key to understanding the pathophysiology of uremic CVD.

While it is important to consider oxidative stress as a potentially important source of patient morbidity and mortality, the limited data available at this time provides no clear-cut evidence of the clinical benefit of antioxidant maneuvers aimed at reducing CVD either in CRF patients or the general population (Massy & Nguyen-Khoa, 2002). This illustrates the need for further well-designed, randomized controlled clinical trials with antioxidants to establish evidence-based recommendations for clinical application.

References
Boaz, M., Smetana, S., Weintstein, T., Matas, Z., Gafter, U., Iaina, A., et al. (2000). Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease: Randomized placebo-controlled trial. Lancet, 356(9237), 1213-1218.

Danielski, M., Ikizler, T.A., McMonagle, E., Kane, J.C., Pupim, L.B., Morrow. J., et al. (2003). Linkage of hypoalbuminemia, inflammation, and oxidative stress in patients receiving maintenance hemodialysis therapy. American Journal of Kidney Diseases, 42(2), 286-294.

Dobashi, K., Ghosh, B., Orak, J.K., Singh, I., & Singh, A.K. (2000). Kidney ischemia-reperfusion: Modulation of antioxidant defenses. Molecular Cell Biochemistry, 205, 1-11.

Himmelfarb, J., & McMonagle, E. (2001). Albumin is the major plasma protein target of oxidant stress in uremia. Kidney International, 60(1), 358-363.

Himmelfarb, J., Stenvinkel, P., Ikizler, T.A., & Hakim, R.M. (2002). The elephant in uremia: Oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney International, 62(5), 1524-1538.

Ichikawa, I., Kiyama, S., & Yoshioka, T. (1994). Renal antioxidant enzymes: Their regulation and function. Kidney International, 45, 1-9.

Klahr, S. (1997). Oxygen radicals and renal diseases. Minerals Electrolytes and Metabolism, 23, 140-3.

Klemm, A., Voigt, C., Friedrich, M., Funfstuck, R., Sperschneider, H., Jager, E.G., et al. (2001). Determination of erythrocyte antioxidant capacity in hemodialysis patients using electron paramagnetic resonance. Nephrology Dialysis Transplantation, 16(11), 2166-71.

Koken, T., Serteser, M., Kahraman, A., Gokce, C., & Demir, S. (2004). Changes in serum markers of oxidative stress with varying periods of hemodialysis. Nephrology, 9(2), 77-82.

Locatelli, F., Canaud, B., Eckardt, K., Stenvinkel, P., Wanner, C., Zoccali, C. (2003). Oxidative stress in end stage renal disease: An emerging threat to patient outcome. Nephrology Dialysis Transplantation, 18, 1272-1280.

Massy, Z.A., & Nguyen-Khoa, T. (2002). Oxidative stress and chronic renal failure: Markers and management. Journal of Nephrology, 15(4), 336-341.

McCord, J.M., & Edeas, M.A. (2005). SOD, oxidative stress, and human pathologies: A brief history and a future vision. Biomedical Pharmacotherapy, 59(4), 139-42.

McCullough, P.A. (2004). Cardiovascular disease in chronic kidney disease from a cardiologist’s perspective. Current Opinion in Nephrology and Hypertension, 13(6), 591-600.

Pfeffer, M.A., McMurray, J.J.V., Velazquez, E.J., Rouleau, J.-L., Kober, L., Maggioni, A.P., et al. (2003). Valsartan, Captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. New England Journal of Medicine, 349(20), 1893-1906.

Pupim, L.B., Himmelfarb, J., McMonagle, E., Shyr, Y., & Ikizler, TA. (2004). Influence of initiation of maintenance hemodialysis on biomarkers of inflammation and oxidative stress. Kidney International, 65(6), 2371-2379.

Samouilidou, E.C., Grapsa, E.J., Kakavas, I., Lagouranis, A., & Agrogiannis, B. (2003). Oxidative stress markers and C-reactive protein in end stage renal failure patients on dialysis. International Urology and Nephrology, 35(3), 393-397.

Siems, W., Quast, S., Carluccio, F., Wiswedel, I., Hirsch, D., Augustin, W., et al. (2001). Oxidative stress in chronic renal failure as a cardiovascular risk factor. Clinical Nephrology, 58(Suppl. 1), S12-19.

Vaziri, N.D. (2004). Roles of oxidative stress and antioxidant therapy in chronic kidney disease and hypertension. Current Opinion in Nephrology and Hypertension, 13(1), 93-99.

Wallace, D., & Brownlee, M. (2005). Oxidative Stress, Aging and Botanicals. Presented June 3, 2005, by Health Web.

Wart, P.J. (2005). Kidney disease increases CVD risk. (Newsletter). Nashville, TN: Wellsource, Vanderbilt University.

Wratten, M.L., Galaris, D., Tetta, C., & Sevanian, A. (2002). Evolution of oxidative stress and inflammation during hemodialysis and their contribution to cardiovascular disease. Antioxidant Redox Signal, 4(6), 935-944.

Additional Readings
Agarwal, R. (2003). Proinflammatory effects of oxidative stress in chronic kidney disease: Role of additional angiotensin II blockade. American Journal of Physiology – Renal Physiology, 284, 863-69.

Dursun, E., Ozben, T., Suleymanlar, G., Dursun, B., & Yakupoglu, G. (2002). Effect of hemodialysis on the oxidative stress and antioxidants. Clinical Chemical Laboratory Medicine, 40(10), 1009-1013.

Galle, J. (2001). Oxidative stress in chronic renal failure. Nephrology Dialysis Transplantation, 16, 2135-37.

Himmelfarb, J., & Hakim, R.M. (2003). Oxidative stress in uremia. Current Opinions in Nephrology and Hypertension, 12(6), 593-598.

Himmelfarb, J. (2004). Linking oxidative stress and inflammation in kidney disease: Which is the chicken and which is the egg? Seminars in Dialysis, 17(6), 449-454.

Himmelfarb, J., & Gordon, C.S. (2004). Antioxidant therapy in uremia: Evidence-based medicine? Seminars in Dialysis, 17(5), 327-332.

Lucchi, L., Bergamini, S., Iannone, A., Perrone, S., Stipo, L., Olmeda, F., et al. (2005). Erythrocyte susceptibility to oxidative stress in chronic renal failure patients under different substitutive treatments. Artificial Organs, 29(1), 67.

Oberg, B.P., McMenamin, E., Lucas, F.L., McMonagle, E., Morrow, J., Ikizler, T.A., et al. (2004). Increased prevalence of oxidant stress and inflammation n patients with moderate to severe chronic kidney disease. Kidney International, 65(3), 1009-1016.