Treatment Of Oxidative Stress in Kidney Transplantation

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Part Ⅱ：Oxidative Stress in Kidney Transplantation Causes, Consequences, and Potential Treatment

Mohsen Nafar, Zahra Sahraei, Jamshid Salamzadeh, Shiva Samavat, Nosartolah D Vaziri

Oxidative stress is a major mediator of adverse outcomes throughout the course of transplantation. Transplanted kidneys are prone to oxidative stress-mediated injury by pre-transplant and post-transplant conditions that cause reperfusion injury or imbalance between oxidants and antioxidants. Besides adversely affecting the allograft, oxidative stress and its constant companion, inflammation, causes cardiovascular disease, cancer, metabolic syndrome, and other disorders in transplant recipients. The presence and severity of oxidative stress can be assessed by various biomarkers produced from the interaction of reactive oxygen species with lipids, proteins, nucleic acids, nitric oxide, glutathione, etc. In addition, the expression and activities of redox-sensitive molecules such as antioxidant enzymes can serve as biomarkers of oxidative stress. Via activation of nuclear factor kappa B, oxidative stress promotes inflammation which, in turn, amplifies oxidative stress through reactive oxygen species generation by activated immune cells. Therefore, inflammation markers are indirect indicators of oxidative stress. Many treatment options have been evaluated in studies conducted at different stages of transplantation in humans and animals. These studies have provided useful strategies for use in donors or in organ preservation solutions. However, strategies tested for use in the post-transplant phase have been largely inconclusive and controversial. A number of therapeutic options have been exclusively examined in animal models and only a few have been tested in humans. Most of the clinical investigations have been of short duration and have provided no insight into their impact on the long-term survival of transplant patients. Effective treatment of oxidative stress in the transplant population remains elusive and awaits future exploration

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Newer Biomarkers

Severe reperfusion injury is a risk factor for delayed graft function. Nuclear magnetic resonance spectroscopy-based metabolomics are used to establish reperfusion-specific metabolic markers of oxidative stress both in the blood and in kidney tissue. Some of the immunosuppressant drugs can also alter urine metabolomic patterns by inducing oxidative stress, which can be detected by nuclear magnetic resonance spectroscopy.⁶⁴ These markers have been shown to be related to the pathologic changes of the allograft and could be used as a predicting factor in the diagnosis of delayed graft function.65 While the application of omics technologies can identify novel and promising biomarker candidates for the early assessment of reperfusion injury, the clinical utility of these markers requires validation in clinical trials.66 The plasma level of polyunsaturated fatty acids, as a marker of adaptation to ischemia, falls with cold ischemia and the level of allantoin, a marker of oxidative stress, rises after reperfusion and correlates with cold ischemia time.65 Low serum level of sulfatide, a major component of lipoproteins, is correlated with a high incidence of cardiovascular diseases in hemodialysis patients. After transplantation, there is a slow and gradual increase in sulfatide level towards normal values over the first post-transplant year, suggesting a close correlation between serum sulfatide and kidney function. This rise in sulfatide level parallels the decline in MDA, improvement in platelet function, and cardiovascular disease risk reduction.67 Accumulation of advanced glycation end products such as N epsilon-carboxymethyl lysine in chronic kidney failure induces oxidative stress and inflammation. Carboxymethyllysine homeostasis is regulated by megalin-mediated endocytosis and lysosomal degradation in proximal tubules. Accumulation of glycation end products in endothelium contributes to cardiovascular complications. In biopsy specimens of chronic allograft nephropathy cases, tubular deposition of carboxymethyl lysine was inversely associated with the degree of tubular atrophy and interstitial fibrosis, a phenomenon which might be due to reduced megalin and megalin-mediated proximal tubular epithelial uptake. In contrast, glomerular carboxymethyl lysine deposition was positively associated with transplant dysfunction. Furthermore, glomerular deposition of carboxymethyl lysine could play a pathophysiological role in chronic allograft injury, and as such, it may be a reliable marker of oxidative stress.68 In patients with allograft nephropathy (CAN), impaired tissue oxygenation and oxidative stress are causally related. To assess tissue oxygen bioavailability, blood oxygen level-dependent magnetic resonance imaging is used in which deoxyhemoglobin is utilized as an endogenous contrast agent. Using this technique, a significant increase in medullary and cortical oxygen bioavailability has been detected in allografts with CAN pointing to reduced oxygen uptake. This was associated with a significant increase in serum and urine hydrogen peroxide and serum heat shock protein 27 levels, denoting an increased burden of oxidative stress in patients with CAN. Taken together these observations illustrate the association between intrarenal oxygenation and oxidative stress in CAN.69 Galectin-3 is a lectin with a variety of functions such as promoting neutrophil adhesion, inducing oxidative stress, mastocyte migration and degranulation, and producing pro-inflammatory cytokines. A lesser amount of reactive oxygen species was detected in galectin-3 knockout mice than the wild type mice in response to reperfusion injury; therefore, galactin-3 may be used as a marker of free radical injury.70

TREATMENT

Treatment Options in Oxidative Stress

Oxygen-free radicals are generated during the reperfusion of ischemic organs. Experimental studies have demonstrated that the damage produced by reperfusion can be prevented by a free radical scavenger. Transplant recipients have elevated levels of oxidative stress, which has prompted the idea that supplementary antioxidants may be beneficial.

Ischemia Times and Donor’s Condition

Some of the detrimental donor-related or transplantation-related factors like factors related to brain death (eg, hemodynamic instability, systemic release of cytokines, and reperfusion injury, and ischemia times during surgery) are known to enhance immunogenicity and reactive oxygen species production. In donors with cardiac death, where there is a relatively higher incidence of graft dysfunction than donors with brain death, an important option to reduce ischemia-induced injuries is shortening of both cold and warm ischemia times by proper perfusion of the organ after cardiac death and extracorporeal membrane oxygenation.71 Even in donation after cardiac death, successful kidney transplantation has been performed by using a noninvasive load-distributing-band chest compression device to maintain adequate perfusion.59,72 Data suggest that a cold ischemia time shorter than 18 hours does not significantly affect graft survival.73 Dopamine stimulates HO-1, which helps to attenuate oxidative stress and protect the organ from reperfusion injury and inflammation. Catecholamine treatment in the brain-dead organ donors lowers the risk of rejection and results in better long-term graft survival by modulating cytokine production and preventing cold-induced damage and free radical production.74 In animal studies of autotransplant kidneys, sildenafil application before ischemia, resulted in higher levels of NO and renal vascular flow and also lower post-transplant reperfusion- and warm-ischemia damage; hence, it can be used as a preventive option. 75,76 Also, long-term sildenafil administration in hypertensive rats attenuates endothelial dysfunction and reduces renal oxidative stress and renal macrophage accumulation.77 Furthermore, pretreatment of rat donors with allopurinol attenuates ischemia-induced damages and leads to lower serum creatinine values and better survival and renal histology after transplantation.78

Vitamins

By scavenging reactive oxygen species, antioxidant compounds can attenuate oxidative stress and lipid peroxidation. Several animal and human studies have suggested that antioxidant vitamins such as vitamin C (ascorbic acid) and vitamin E (α-tocopherol) might reduce oxidative stress caused by reperfusion injury and calcineurin inhibitor nephrotoxicity. Five patients supplemented with vitamin C (500 mg per day), vitamin E (500 mg per day), or both in the first 3 months after kidney transplantation exhibited more than 20% reduction in serum creatinine levels. Interestingly, serum creatinine level was increased by more than 50% by discontinuing the vitamins. The role of vitamins is more important especially in grafts donated from deceased donors.79 In a model of dog autotransplantation, ascorbic acid administration 3 days after transplantation led to higher levels of antioxidant enzymes (SOD and glutathione peroxidase) which may play a role in attenuating reperfusion injury.73 Intravenous administration of multivitamins 1 hour before kidney transplantation in a pig model was shown to diminish plasma MDA 2 hours after the procedure.80 Even after a single dose of vitamin C (2 g), lipid peroxidation was reduced after transplantation.81 On the other hand, in a randomized placebo-controlled trial, the effect of 400 IU/d of vitamin E, 500 mg/d of vitamin C, and 6 mg/d of β-carotene was evaluated for 6 months in 10 kidney transplant recipients treated with cyclosporine A as a part of their immunosuppressive therapy. The trough level of cyclosporine decreased by 24% and the glomerular filtration rate improved by 12% without any changes in markers of oxidative stress (MDA) or plasma antioxidant enzymes.82 Niacin, an antioxidant and anti-inflammatory agent attenuates oxidative stress, inflammation, proteinuria, and hypertension in rats with chronic kidney failure.83 Niacin also improves lipid metabolism in rat models of chronic kidney disease.84 Melatonin is another potent antioxidant and anti-inflammatory product. Its production is impaired in chronic kidney failure which may in part contribute to the associated oxidative stress. Melatonin administration has been shown to reduce oxidative stress (MDA levels) and renal inflammation in rats with renal mass reduction.85 Free radicals are well-known risk factors of cardiovascular disease in kidney transplant recipients and CKD patients. The progression of atherosclerosis is mediated by increased lipid and lipoprotein oxidation and endothelial damage and dysfunction. Different results were reported by the two randomized clinical trials evaluating the effect of oral vitamin E supplementation on clinical endpoints in patients with mild-to-moderate renal insufficiency and for hemodialysis patients. Daily supplementation with 400 IU of vitamin E for 4.5 years in patients with renal insufficiency showed no significant change in the rate of mortality related to myocardial infarction, stroke, or cardiovascular. In contrast, a 50% risk reduction in cardiovascular events was seen with 800 IU vitamin E daily supplement in transplant recipients.86 Thiamine deficiency is a potential risk factor for delayed graft function in transplanted patients. Acute tubular necrosis caused by reperfusion injury plays a major role in the pathogenesis of delayed graft function, and thiamine supplementation may attenuate reperfusion injury.87 Management of hyperhomocysteinemia by folic acid and vitamin B12 in kidney transplant recipients may result in cardiovascular protection and better graft function by improving endothelial function, limiting oxidative stress, and reducing prothrombotic status.88 There is a decline in CRP levels 3 months after treating hyperhomocysteinemia with these agents.89 Folic acid supplementation has been shown to attenuate carotid intima-media thickness after kidney transplantation.90 Folic acid supplementation for 12 weeks as well as vitamin B6 supplementation for 6 months has been shown to significantly lower homocysteine levels in transplanted patients with stable graft function.91,92 Coenzyme Q10 is a lipid-soluble substance that is present in most eukaryotic cells and plays an essential role in the mitochondrial electron transport chain. In a study of 11 transplanted patients, treatment with Coenzyme Q10 for 4 weeks resulted in a significant attenuation of oxidative stress as assessed by measurements of MDA, SOD, glutathione peroxidase, and the basic parameters of lipid metabolism.93

Anticoagulation Treatment

Coagulation is a key phenomenon in organs from deceased donors and a significant cause of reperfusion injury. Inhibition of thrombin is an effective therapy against reperfusion injury and results in reduced chronic graft fibrosis, with a significantly positive effect on graft survival. In a study conducted in pigs, treatment with melagatran (a thrombin inhibitor) before warm ischemia or in the preservation solution demonstrated improved graft survival and reduced renal fibrosis.94

Antihypertensive Agents and Statins

Carvedilol is an antihypertensive drug with potent anti-oxidant properties. Treatment with carvedilol (30 minutes before surgery and 12 hours after reperfusion) in the rat transplant model has been reported to significantly lower plasma creatinine levels after reperfusion injury, suggesting improvement in kidney function. Histopathological analysis revealed decreased reperfusion injury-induced damage in the kidney.95 In a study of a small cohort of patients with chronic graft rejection, treatment with carvedilol improved lipid profile and reduced lipid oxidation, but it did not alter the course of the chronic rejection.96 In addition, carvedilol has been shown to attenuate cyclosporine-induced oxidative stress.97,98 Nebivolol is a β1-receptor blocker that raises NO availability and exerts antioxidant, anti-apoptotic, and anti-inflammatory effects. Nebivolol administration for 15 days before ischemia-reperfusion in rats has been reported to improve kidney function and attenuate inflammation and apoptosis after renal reperfusion injury.99 Administration of angiotensin II type 1 receptor antagonist, losartan, in transplant patients significantly reduces the plasma TGF-β and uric acid levels and lowers proteinuria.100 Treatment with the angiotensin II type 1 receptor antagonist, irbesartan, 1 day before and for 21 days after transplantation, concurrently with cyclosporine, has been shown to improve markers of oxidative stress in rats. 101 Likewise, the angiotensin-converting enzyme inhibitor, ramipril, attenuates cyclosporine-induced oxidative stress in human kidney transplant recipients.102 Addition of diazoxide to a rat kidney preservation solution has been reported to significantly attenuate the rise in MDA level, enhance SOD activity, reduce oxidative stress-mediated injury, and decrease cell apoptosis in the kidneys during hypothermic preservation.103 Treatment with nicorandil (a potassium channel opener and vasodilator drug used to treat angina pectoris) has been shown to dose-dependently reduce the urinary β2-microglobulin level and lower the severity of acute tubular damage in a rat model of reperfusion injury.104 Statins inhibit the synthesis of isoprenoids which are involved intra-cellular trafficking of proteins and cell signaling, events that are critical in immune cell activation. Consequently, they can exert anti-inflammatory effects and attenuate oxidative stress by limiting activation of nicotinamide adenine dinucleotide phosphate oxidase and production of reactive oxygen species. Via these pleiotropic effects, statins may attenuate the progression of chronic allograft nephropathy. In this context, statins have been shown to increase the level of the potent antioxidant enzyme, glutathione peroxidase, in transplanted patients during the first 6 months after transplantation without affecting serum creatinine or glomerular filtration rate.105 In addition, several large randomized trials have shown that statins modulate cell proliferation and inflammation and that long-term (2 years) statin therapy following kidney transplantation can slow down the rate of decline in kidney function.106

N-Acetylcysteine and Glutathione System

N - a c e t y l c y s t e I n e t r e a t m e n t h a s b e e n reported to lower markers of oxidative stress without significantly affecting histopathological lesions following reperfusion injury in rats.107 N-acetylcysteine also attenuates lipid peroxidation and increases glutathione levels after induction of ischemia-reperfusion in rats.75 Co-administration of N-acetylcysteine and NO donor (sodium nitroprusside and phosphoramidon) has been found to lessen renal reperfusion injury in donor kidneys destined for transplantation.76 N-acetylcysteine improves early outcomes of deceased donor kidney transplantation by attenuating oxidative stress.24 Treatment with N-acetylcysteine, which serves as a precursor for the production of reduced glutathione, showed no significant change in the plasma redox parameters of transplant patients with stable kidney function. However, N-acetylcysteine administration improved the estimated glomerular filtration rate and increased high-density lipoprotein cholesterol, which positively correlated with the glutathione peroxidase activity.106 In addition, cyclosporine-induced nephrotoxicity is significantly ameliorated by N-acetylcysteine. 108

Selenium

As an essential constituent of glutathione peroxidase and related enzymes, selenium plays a major role in redox reactions. In fact, selenium supplementation for 3 months in transplant recipient patients has been shown to normalize glutathione system and low-density lipoprotein cholesterol level.60

Insulin

Ischemia-reperfusion and hyperglycemia are the main inducers of oxidative stress and have a major role in the pathophysiology of tissue injury in transplant recipients. In cadaveric kidney allograft recipients treated with intravenous insulin to maintain blood glucose below10 mmol/L, plasma total radical-trapping antioxidant values were significantly higher than the control group at days 1 and 4 after transplantation.109

Apotransferrin

Redox-active iron is released into the circulation in response to renal ischemia-reperfusion. By avidly binding the elemental iron, apo transferrin lowers the circulating redox-active iron and protects against renal reperfusion injury via inhibition of oxidative stress and inflammation. Apotransferrin could be used in the treatment of acute kidney failure, as seen after transplantation of ischemia-induced organ damage.110

Preservation Solution

Adding antioxidants to preservation solutions may be a proper strategy to protect organs from oxidative stress and minimize cold storage-induced organ damage. Preservation of kidney tissue before transplantation has a major role in the outcome of organs. Histidine-tryptophan-ketoglutarate (HTK) solution results in better survival, lower rate of initial nonfunctioning, and decreased free radicals. 111 Addition of selenium to the preservation solution protects kidneys against oxidative stress during warm and cold ischemia.112 Life is an artificial preservative solution that contains nutrients, growth factors, and a nonprotein oxygen and nutrient carrier. This solution lowers both warm and cold renal ischemia-reperfusion in comparison with the University of Wisconsin (UW) solution as assessed by the release of lactate dehydrogenase.113 Adding selected flavonoids to UW or Euro-Collins solution attenuates coldstorage-induced injury demonstrated by less lipid peroxidation.114 Lidoflazine, the calcium entry blocker, improves the preservation properties of the UW solution in a rat model. 115 Adding selenium to the reperfusion solution (HTK, custodial) leads to decreased MDA concentration within 2 hours after transplantation.116 Addition of p38 mitogen-activated protein kinase inhibitors to UW solution in pig renal preservation solution resulted in lesser TNF-α levels and lesser apoptosis.117 Also, adding mito-quinone, a mitochondria-targeted antioxidant, to UW preservation solution decreases oxidant production by about 2-fold, completely prevents mitochondrial dysfunction, and significantly improves cell viability and/or renal morphology.118 These represent potentially helpful strategies to improve transplantation outcomes. Comparing UW and HTK preservation solution, kidneys preserved by HTK produce the highest ROS values.119 However, perfusion with HTK prior to storage in UW may improve the results which are reflected by the reduction of free radicals.111 In rats the capacity of intravenous infusion of DHL-HisZn, a new α-lipoic acid derivative, in inhibiting reactive oxygen species generation and preventing renal reperfusion injury was examined. Pretreatment with DHL-HisZn before ischemia-reperfusion induction, decreased reperfusion-induced tissue injuries, serum creatinine, blood urea, and MDA levels in the kidneys of rats with renal reperfusion injury.120 Inhibition of thrombin during preservation of graft in pig autotransplant model preserved kidney function, protecting against chronic inflammation and oxidative stress. Thus, anticoagulants could be a critical treatment for improving kidney quality for transplantation.121 When L-carnitine is added to Belzer solution for preserving kidney, less reperfusion injury and oxidative stress injury is detected. Furthermore, decreased lipid peroxidation, inducible nitric oxide synthase expression, and free radical generation are observed.122,123

Nitric Oxide System

Depletion of NOS cofactor, tetrahydrobiopterin, and accumulation of NOS inhibitor, asymmetrical dimethylarginine, or uncoupling of the normal homodimeric state of endothelial NOS results in conversion of NOS isoforms from the NO-producing to superoxide-producing enzymes. Accordingly, the effect of the NOS cofactor tetrahydrobiopterin was evaluated on early rejection in a rat kidney transplantation model. In allograft models, tetrahydrobiopterin precursor (sepiapterin) led to a noticeable decrease in superoxide production and was accompanied by a reduction in peri-arterial macrophage infiltration and an increase in NO production, but these effects were not observed in the isografts transplantation.124 In a randomized double-blind study, L-arginine (the substrate for NO production by NOS) supplementation improved kidney function in kidney transplant recipients.125

Other Agents

L-carnitine is an endogenous mitochondrial membrane compound, which could effectively protect reperfusion injury in the kidney. In fact, the addition of L-carnitine to the culture medium12 hours before reperfusion injury has been shown to inhibit hydrogen peroxide-induced injuries, intracellular reactive oxygen species generation, and lipid peroxidation in a concentration-dependent manner in the cultured human proximal tubular epithelial cell line. This effect was mediated by promoting endogenous antioxidant molecules such as glutathione peroxidase, catalase, and SOD. In addition, L-carnitine reduced DNA fragmentation and caspase-3 activity.126 Taurine is a potent free radical scavenger that attenuates oxygen-free radical-induced damage and thereby can be potentially useful in a variety of kidney diseases. This organic acid can prevent FK506-induced kidney toxicity by attenuating the production of reactive oxygen species, in vitro.127 Administration of taurine to donors before nephrectomy has been shown to protect the kidney grafts from injury and improve graft function by limiting oxidative stress in the rat transplantation model.128 A non-enzymatic, reactive oxygen species-related pathway has been suggested to produce 8-is prostaglandin F2α, which is an indicator of oxidative stress. Nonselective (acetylsalicylic acid) or selective cycloxygenase-1 inhibitor has been shown to completely abolish the 8-is prostaglandin F2α and prostaglandin F2α production during reperfusion injury in kidneys. Also, it is assumed that fish oil could decrease or suppress oxidative stress and prostaglandin F2 production and as such could be useful in attenuating reperfusion injury. To test this hypothesis in a randomized trial, 22 kidney transplant patients were given either fish oil dietary supplementation, 6 g/d (720 mg of docosahexaenoic acid and 1080 mg of eicosapentaenoic acid) or placebo for 6 months. Contrary to expectations, omega-3 fatty acids supplementation raised plasma 8-isoprostane levels, whereas placebo treatment lowered it.129 However, long-term omega-3 supplementation has been shown to attenuate upregulation of pro-oxidant, pro-inflammatory, and profibrotic pathways and decrease tubulointerstitial fibrosis in rats with CKD induced by subtotal nephrectomy.130 Comparison of the antioxidant capacity of anesthetic induction agents, propofol and thiopentone, has shown that propofol counteracts oxidative stress more efficiently by decreasing the formation of a major F(2)-isoprostane in transplant patients.131 Pre-transplantation treatment with rabbit antirat thymocyte immunoglobulin in a rat model of reperfusion injury has been shown to reduce the infiltration of macrophages, CD4+ and CD8+ T cells, and leukocyte function-associated antigen- 1-positive cells in the allograft after cold ischemia. However, pretreatment with rabbit anti-rat thymocyte immunoglobulin had no effect on either granulocyte infiltration severity of oxidative stress.23 The dietary supplementation with a carotenoid, astaxanthin, has shown promising results as an antioxidant and anti-inflammatory agent against cardiovascular disease in kidney transplant recipients. In a study of 66 kidney transplant recipients enrolled to receive either 12 mg/d of astaxanthin or placebo for 1 year, the group given astaxanthin showed lower plasma isoprostanes reflecting its efficacy as an antioxidant agent.132 Tempol, a superoxide dismutase mimetic compound has been shown to reduce plasma MDA levels and enhance SOD activity of the kidney tissue in rats with subtotal nephrectomy. However, it failed to suppress oxidative stress and actually accelerated the deterioration of kidney function and structure.133 This was attributed to increased production of hydrogen peroxide which is a potent activator of nuclear factor kappa B, which is the master regulator of genes encoding numerous pro-inflammatory cytokines and pro-apoptotic factors.

Plants

Nigella sativa is an annual flowering plant, native to south and southwest Asia, whose protective effect against ischemia-reperfusion damage to various organs has been previously documented. Co-administration of Nigella sativa with induction of reperfusion injury in a rat model was effective in reducing blood urea and creatinine levels and decreasing the tubular necrosis score. Nigella sativa treatment markedly reduced oxidative stress index and total oxidant status levels and increased total antioxidant capacity in both kidney tissue and blood.134 Ligustrazine, the key component of the Chinese herb chuanxiong, has been reported to protect the murine kidneys from warm reperfusion injury.135 Administration of ligustrazine in the study animals significantly reduced myeloperoxidase activity, lowered MDA level, and raised SOD activity.135

Diet

A Mediterranean-type diet seems to enhance the body’s capacity to contain reactive oxygen species.136 In fact, a prospective study of 160 adult kidney allograft recipients showed that the Mediterranean diet reduced the risk of metabolic syndrome after a 1 year of follow-up. 137

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CONCLUSIONS

Oxidative stress is a common cause of allograft damage after transplantation; patients with reperfusion injuries, which can induce oxidative stress, are prone to acute allograft rejection, delayed graft function, chronic allograft nephropathy, and endothelial dysfunction. Chronic kidney failure, inflammation, diabetes mellitus, reperfusion injury, and immunosuppressive agents are among many risk factors of oxidative stress. There are various markers in blood, urine, and kidney tissue that can be used as indicators of oxidative stress status. Due to the fact that oxidative stress can affect the short-term and long-term survival of both graft and patient, different prophylactic and therapeutic approaches have been employed to reduce oxidative stress, ranging from decreasing ischemic time to changes in the composition of preservation solution and use of a variety of free radical scavengers.

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