Organ Transplantation

Organ Transplantation

Contributor(s): Dr. Shayna Sandhaus, PhD

1 Overview

Summary and Quick Facts

  • Modern medicine’s ability to transplant a healthy organ from a donor into a sick recipient and save their life is nothing short of amazing. The technology of transplantation continues to improve rapidly, and organ transplant recipients now have better outcomes than ever before.
  • This protocol will help you understand what to expect after transplantation. Learn about the importance of keeping the immune system in balance to avoid rejection, while fending off infections.
  • Supplementation with B-vitamins like B6, B12, and L-methylfolate can help control levels of an amino acid called homocysteine. High homocysteine levels have been associated with worse outcomes in transplant recipients.

Why are Transplanted Organs Rejected?

Organ transplantation involves surgically replacing a failing organ with a healthy donor organ. Transplants offer a great solution for many patients with organ failure and can improve their lifespan and quality of life. However, donor organs are often rejected by the host's (recipient's) immune system. The immune system recognizes that the new tissue is foreign, causing an inflammatory attack on the new tissue which if not stopped results in failure of the transplanted organ.

Multiple inflammatory cytokines stimulate cytotoxic T cells to attack the transplanted organ while simultaneously inhibiting the action of protective T regulatory cells. Conventional treatments help suppress the immune system and protect the transplanted organ; however, they often have severe side effects. Importantly, certain immunosuppressive drugs also reduce the amount of T regulatory cells in circulation, preventing the immune system from developing tolerance to the new organ.

Natural interventions such as curcumin and omega-3 fatty acids may help lessen the inflammatory immune response and promote more successful transplant tolerance.

What Conventional Medical Treatments Help Prevent Organ Transplant Rejection?

  • Immunosuppressive drugs (eg, calcineurin inhibitors [eg, cyclosporine])

What Natural Interventions May Be Beneficial for Organ Transplantation?

  • Curcumin. Curcumin, a component of the spice turmeric, is a potent anti-inflammatory agent. Numerous studies demonstrate curcumin's ability to inhibit inflammatory cytokines involved in transplant rejection. An animal study showed mice that had heart transplants survived significantly longer when treated with an immunosuppressive drug in combination with curcumin than the drug alone.
  • Omega-3 fatty acids. Omega-3 fatty acids found in fish oil, known for their anti-inflammatory properties, also suppress cytokines involved in transplant rejection. Many studies demonstrate their beneficial effects, including a study where kidney transplant patients supplemented with fish oil experienced better recovery of renal function after a rejection episode than control patients.
  • Resveratrol. Resveratrol has been shown to inhibit the activity of multiple inflammatory cytokines. Animals who received a genetically incompatible liver transplant had reduced levels of cytotoxic T cells and survived significantly longer when supplemented with resveratrol.
  • Quercetin. Quercetin is known to modulate the action of several inflammatory cytokines. In combination with vitamin E, quercetin has been shown in vitro to combat the hepatotoxic effects of cyclosporine, a common immunosuppressive drug. Quercetin also inhibited T-cell proliferation, suggesting it may be effective in reducing transplant rejection.
  • Vitamin D. Researchers investigating the importance of vitamin D on transplant success found heart transplant patients with the lowest blood levels of the active form of vitamin D (1,25-dihydroxy vitamin D) were over 8 times as likely to die one year post transplant than those with the highest levels.
  • Grape seed extract. The ratio of protective T regulatory cells to Th17 cells, T cells that are particularly aggressive, is associated with the likelihood of transplant tolerance. Grape seed extract has been shown to alter the ratio favorably and modulate immune response.
  • Higher homocysteine levels have been shown to be associated with increased mortality after transplantation. Several natural interventions can lower homocysteine levels, including B complex vitamins (vitamins B6, B12, and folate) and N-acetylcysteine.
  • Polyphenols. Polyphenols, such as those found in green and black tea, cocoa, and pomegranate, have cardioprotective effects that may be beneficial after organ transplantation.
  • Other natural interventions that may benefit transplant patients include coenzyme Q10, vitamins C and E, L-arginine, probiotics, and magnesium.

2 Introduction

The increased frequency of organ transplant operations over the decades has given rise to some startling statistics; five-year survival of transplanted tissue is only 50% for lung transplants, 67% for liver transplants and not much better for other organs.1 These bleak statistics are attributable to the destruction of transplanted tissue by the host's (tissue recipient's) immune system, which ultimately leads to the rejection of the transplanted organ.

Despite the widespread use of immunosuppressive drugs and advancements in medical technology, the immune system remains a formidable factor in successful organ transplantation.2

Certain aspects of the immune system are responsible for suppressing inflammation and inhibiting transplant rejection. Important inhibitory components of the immune system are Treg, (or T regulatory cells). The inflammatory cytokines IL-1β, IL-2, IL-6, IL-15, IL-21 and tumor necrosis factor-alpha (TNF-α), by inhibiting the function of Treg cells and promoting the activation of cytotoxic T cells, are responsible for the intensity of the attack against the transplanted tissue by the host's immune system.3

New findings demonstrate that calcineurin inhibitors (CNIs), immunosuppressive drugs widely prescribed to transplant patients, fail to address an important underlying cause of transplant rejection—insufficient levels of protective Treg cells.

Several nutrients have been shown in peer-reviewed studies to target the specific inflammatory cytokines that are dually responsible for the stimulation of aggressive T cells and the suppression of protective Treg cells.

3 Immunological Response to Foreign Tissue

Transplanted tissue contains molecular components of the donor’s immune system, known as the major histocompatibility complex (MHC), coupled with antigen presenting cells (APCs), which interact with the host’s immune system. Donor APCs, with the help of MHCs, present peptides (sections of proteins) derived from the transplanted tissue to specialized receptors, called CB8 receptors, on certain T cells (white blood cells involved in cellular immunity) of the host. The host’s T cells recognize that the peptide is foreign and begin traveling through the body in search of cells that contain this peptide.

The host’s T cells are now “activated” and programmed to destroy the cells of the transplanted tissue. As the activated T cells travel, they secrete inflammatory cytokines that serve to recruit and activate additional T cells to help destroy the foreign cells. Importantly, these cytokines stimulate a particularly aggressive class of T cells, called Th17 cells, as well. This process culminates in the initiation of an inflammatory storm that triggers the host’s immune system to mount a full-fledged assault against the transplanted tissue.

4 Inflammatory Cytokines and Treg Cells: Pivotal Roles in Tissue Tolerance

The immune system is more than a “seek-and-destroy” mechanism. Certain aspects of the immune system are responsible for suppressing inflammation and inhibiting the tissue destruction caused by activated T cells. These inhibitory components of the immune system are known as T regulatory, or Treg cells. Treg cells are the counterbalance to aggressive, activated T cells. Without Treg cells, our immune system would constantly attack our own tissue. In fact, the role of Treg cells in suppressing autoimmune diseases (eg, diseases in which the immune system attacks the body’s own tissue, like rheumatoid arthritis, lupus, Crohn’s disease, psoriasis, etc.) has been well documented.4

Treg cells are critical to the tolerance of an allograft (genetically non-identical transplant [All human transplants are allografts, unless the organ is taken from an identical twin]). The more Treg cells present in circulation, the weaker the attack against the transplanted tissue.5 Ironically, the same inflammatory cytokines that stimulate aggressive T cells also suppress Treg cells, promoting the attack against the transplanted tissue from two angles.

Treg cells and T cells originate in the thymus, a specialized organ located just behind the sternum, between the lungs. Here, non-functional progenitor cells develop (differentiate) into either the immunomodulatory Treg cells, or the aggressive cytotoxic T cells, depending on cytokine exposure.

Exposure to high levels of the inflammatory cytokines Il-1β, IL-6, or IL-21 causes progenitor cells to develop into aggressive T cells, while exposure to sufficient levels of a highly specialized anti-inflammatory cytokine, called transforming growth factor-β (TGF-β), induces differentiation into Treg cells. Significantly, it has been shown that high levels of IL-6 inhibit the ability of TGF-β to effectively induce differentiation of progenitor cells to Treg cells, leading to an increase in the number of allograft-destroying cytotoxic T cells.3,6

The roles of the inflammatory cytokines IL-1β, IL-2, IL-6, IL-15, IL-21 and TNF-α in transplant rejection have been well-studied. By inhibiting the function of Treg cells and promoting the activation of T cells, these cytokines are responsible for the intensity of the attack against the transplanted tissue by the host’s immune system.3

One of the most effective strategies for modulating an over-aggressive immune response against transplanted tissue is to target the specific inflammatory cytokines that are dually responsible for the stimulation of aggressive T cells and the suppression of protective Treg cells.

What You Have Learned So Far

  • Organ transplantation involves surgically replacing a failing organ with a healthy organ from a donor.
  • The donated organ does not contain the same DNA as the recipient of the transplant. Therefore, the recipient’s immune system recognizes that the donated organ is foreign and tries to eliminate it, leading to transplant rejection.
  • Multiple inflammatory cytokines, like IL-1β, IL-2, IL-6, IL-15, IL-21 and TNF-α, stimulate cytotoxic T cells to attack the transplanted organ.
  • T regulatory cells, or Treg cells, help to calm the attack against the transplanted tissue by suppressing the activity of cytotoxic T cells.
  • The same inflammatory cytokines that stimulate the aggressive cytotoxic T cells also inhibit the action of the protective Treg cells, contributing to transplant rejection from two angles.
  • Targeting specific inflammatory cytokines responsible for stimulating cytotoxic T cells and suppressing Treg cells is a rational approach to reducing the over-aggressive immune response to transplanted tissue.

5 Natural Compounds That Target Pro-Inflammatory Cytokines Involved in Transplant Immunology

Curcumin

Studies of curcumin, a principle component of the Indian spice turmeric, have identified it as a potent anti-inflammatory agent.7 In particular, numerous studies have revealed the ability of curcumin to target several cytokines involved in transplant rejection, including IL-1, IL-2, IL-6, IL-21 and TNF-α.8-11

An experimental study found that curcumin, in combination with cyclosporine, significantly improved survival time in animals that received a cardiac transplant from donors with incompatible genotypes. Animals treated with curcumin and cyclosporine survived for an average of 28.5–35.6 days after receiving a transplant, compared to untreated animals, which survived an average of only 9.1 days. The effect of the combination of curcumin and cyclosporine was greater than the effect of either one alone. The authors concluded that curcumin is efficacious as a novel adjuvant for immune system modulation both in vivo and in vitro.12

To more closely examine the immunomodulatory effects of the spice, researchers analyzed the effects of curcumin on lymphocytes of renal transplant patients who were experiencing transplant rejection. They found that the use of curcumin dose-dependently decreased interferon-alpha (an inflammatory cytokine) induction in cultures from patients experiencing acute rejection (38.3%‒18.3%) and those experiencing chronic rejection (40.6%‒12.9%), when compared with corresponding untreated cultures. Furthermore, the team also noted that curcumin was able to inhibit activation of nuclear factor kappaβ (NF-kappaβ), an inflammatory transcription factor, and inhibit proliferation of T cells, having a synergistic effect when combined with cyclosporine. The researchers concluded that curcumin was a pharmacologically safe adjuvant to be used with cyclosporine, and can effectively suppress inflammatory cytokine induction after renal transplant.13

Curcumin has also been shown to combat acute renal failure and related oxidative stress caused by chronic administration of cyclosporine in an animal model. Researchers administered a dose of curcumin, equivalent to roughly 145 mg for a 60 kg human, to animals, along with cyclosporine for 21 days. It was shown that curcumin markedly reduced elevated levels of thiobarbituric acid reactive substances (markers of oxidative stress), significantly attenuated renal dysfunction, increased levels of the antioxidant enzymes superoxide dismutase and catalase, and normalized altered renal morphology in cyclosporine treated animals.14

Fish Oil

Omega-3 fatty acids, also known for their potent anti-inflammatory properties, are capable of suppressing the inflammatory cytokines IL-1, IL-2, IL-6, IL-15 and TNF-α.15-18

Researchers examined the endothelial function, as measured by endothelium-dependent vasodilation, of seven cardiac transplant patients who consumed 5,000 mg of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) daily for three weeks and compared the results to those of seven cardiac transplant control patients who did not receive fish oil. The researchers found that endothelium-dependent vasodilation was significantly improved in the fish oil group (+14% to +15%), while it worsened in the control group over the study period (-1% to -9%).19

In another study, researchers examined the effect of 6 grams of fish oil taken daily for one month in 40 cyclosporine treated patients who had received a transplanted kidney. It was found that fish oil-treated patients showed a significantly better recovery of renal function after a histologically confirmed rejection episode compared to control. The researchers went on to conclude that “dietary supplements with fish oil favorably influence renal function in the recovery phase following a rejection episode in cyclosporine-treated renal transplant recipients.20

To evaluate the perioperative safety of fish oil in a transplant population, researchers evaluated hemodynamic, biochemistry, and hematological parameters in kidney recipients who received intravenous fish oil for five days postoperatively. The researchers concluded that “administration of [omega-3 fatty acids] is safe in organ donors and in kidney recipients.”21

In 2008, researchers found that dietary fish oil significantly reduced the severity of rejection to transplanted small bowel tissue in an animal model. They also found that fish oil favorably altered the expression of several genes involved in allograft rejection, and reduced the rate of apoptosis of graft cells. They went on to conclude that “omega-3 polyunsaturated fatty acids can suppress the rejection to mucosal cells of allograft at the time of chronic rejection in small intestinal transplantation, which may be significant in increasing the surviving rate of allograft, delaying the chronic dysfunction, and prolonging the lifetime of both allograft and acceptor.22

Additionally, fish oil was shown to stimulate production of the very important anti-inflammatory cytokine TGF-β and decrease the level of circulating cytotoxic T cells in pregnant women receiving 500 mg DHA and 150 mg EPA daily. Fish oil supplementation was associated with reduced production of multiple inflammatory cytokines.23

Resveratrol

Studies conducted on resveratrol provide strong evidence that suggests it can help quell the cytokine storm and prolong the survival of transplanted tissue. Resveratrol has been shown to attenuate the action of the cytokines IL-1β, IL-2, IL-6 and TNF-α.24-27

Resveratrol, at a dose equivalent to 967 mg for a 60 kg human, was shown to significantly increase survival time of animals that received a genetically incompatible liver transplant. Furthermore, resveratrol also reduced levels of cytotoxic T cells.28

In a skin graft model, used to study transplant rejection, rats supplemented with relatively small doses of resveratrol, equivalent to approximately 5 mg for a 60 kg human, had notable prolongation of the time period before their skin grafts were rejected. Only ~20% of the allografts in the control group survived greater than nine days post-operation, compared to 100% of the grafts in the group receiving resveratrol. Researchers noted that resveratrol significantly reduced infiltration of T cells and necrosis in graft tissue.29

Green and Black Tea Polyphenols

Compounds in green and black tea have been identified as particularly powerful anti-inflammatory agents.30 Studies have shown that components of tea are potent inhibitors of IL-1β, Il-2, IL-6, and TNF-α.31-34

Cardiovascular health is a major concern for transplant recipients, especially because cyclosporine, an immunosuppressive drug widely used after organ transplantation, is known to impair endothelial function.35

Black tea consumption was shown to dramatically improve endothelial function, as measured by flow-mediated vasodilation and brachial artery diameter, in a study of renal transplant patients aged 25–50 years. The researchers went on to conclude that “based on our study, short-term consumption of black tea may improve endothelial function and endothelium-dependent arterial vasodilation in renal transplant recipients.36

Quercetin

The flavonoid quercetin is found in significant quantities in apples, onions, grapes and citrus fruits. Quercetin is known to modulate the action of several inflammatory cytokines that are of particular concern to transplant recipients, including IL-1β, IL-2, IL-6, IL-15, and TNF-α.37-41

Quercetin, in combination with vitamin E, has also been shown in vitro to combat the hepatotoxic effects of cyclosporine. Researchers found that the combination attenuated cyclosporine-induced oxidative stress by restoring the activity of the antioxidative enzymes glutathione peroxidase and catalase. They concluded that “our data demonstrates that vitamin E and quercetin play a protective role against the imbalance elicited by cyclosporine between the production of free radicals and antioxidant defense systems, and suggests that a combination of these two antioxidants may find clinical application where cellular damage is a consequence of reactive oxygen species.42

Considering the cytokine suppressive effects of quercetin, a team of researchers evaluated the impact of quercetin on the proliferation of T cells. The team found that quercetin significantly inhibited T-cell proliferation, suggesting it may be effective in reducing transplant rejection. They concluded “these results suggest the potential use of these select phytochemicals for treating autoimmune and transplant patients...”43

Vitamin D

Published studies have revealed an astonishing number of benefits attributable to vitamin D. Among these benefits, modulating the activity of multiple inflammatory cytokines is especially important in the context of organ transplantation.

Researchers discovered that vitamin D was able to prevent a cyclosporine mediated increase in the inflammatory cytokines IL-1β, IL-6, and TNF-α in an animal model.44 Vitamin D, in combination with cyclosporine, significantly reduced production of IL-2 and the proliferation of T cells, and vastly prolonged allograft survival in an animal model of liver transplantation. The authors of this study went on to conclude that vitamin D is effective as an adjunct to immunosuppressive therapy for the prevention and treatment of liver graft rejection.45

A very important 2009 study shed light on just how critical vitamin D supplementation is for transplant recipients. Researchers examined the relationship between blood levels of the active form of vitamin D (1,25-dihydroxy vitamin D) and one-year mortality rates of heart transplant patients.

They found that “one-year mortality was 3.7 per 100 person-years in the tertile with the highest [1,25-dihydroxy vitamin D] concentrations, 13.2 per 100 person-years in the intermediate tertile and 32.1 per 100 person-years in the tertile with the lowest [1,25-dihydroxy vitamin D] concentrations.”

This means that the mortality rate was over eight times higher at one-year post-transplant in the group with the lowest one-third blood levels of active vitamin D compared to the group with the highest one-third levels of active vitamin D. The researchers also found that higher blood levels of vitamin D were associated with lower levels of the inflammatory marker C-reactive protein, as well as the cytokine TNF-α.46

6 The Th17:Treg Ratio: A Limitation of Immunosuppressive Pharmaceutical Drugs

The ratio of a particularly aggressive sub-class of T cells, called Th17 cells, to Treg cells is highly reflective of the tendency of the immune system to react aggressively towards transplanted tissue.

It is known that Treg cells have anti-inflammatory properties and cause quiescence of an over-aggressive immune response and prolongation of transplant function. Furthermore, Th17 cells are pro-inflammatory and can exacerbate the immune response in transplant rejection.6,47,48

In October, 2010, researchers confirmed that decreasing the Th17:Treg resulted in increased allograft survival in an animal model. The team administered TGF-β directly to mice that had received transplants of pancreatic islet cells. Administering TGF-β resulted in a decrease in IL-6 activity and number of Th17 cells in circulation, and an increase in circulating Treg cells, prolonging allograft survival time. The researchers concluded that targeting IL-6 activity and lowering the Th17:Treg ratio "provides a promising approach for inducing transplant tolerance..."49

Incorporating this recent understanding of immune tolerance and inflammatory pathology, researchers examined the impact of calcineurin inhibitors (CNIs) on the level of allograft protecting Treg cells circulating in 32 liver transplant recipients. Their study revealed that CNIs significantly reduced the level of Treg cells in circulation, compared to healthy control patients not receiving a CNI. The data led the team to conclude that CNIs hampered progression towards a tolerance inducing Th17:Treg profile.50

These new findings demonstrate that the most commonly prescribed immunosuppressive drugs in transplant patients fail to address an important underlying cause of transplant rejection—insufficient levels of protective Treg cells.

Grape Seed Extract Favorably Alters the Th17:Treg Ratio

An October 2010 study revealed that a proanthocyanidin-rich grape seed extract is highly effective in reducing the ratio of Th17:Treg and modulating an over-aggressive immune response. Researchers observed that grape seed extract favorably altered the Th17:Treg ratio in both animal (murine) and human cell lines.51

In taking their research a step further, the scientists examined the effect of grape seed extract on the clinical symptoms of mice with collagen-induced arthritis, a model highly sensitive to the Th17:Treg ratio. They found that grape seed extract effectively attenuated clinical symptoms, confirming that the extract was a potent immunomodulator. The authors concluded that “by potently regulating inflammatory T-cell differentiation, grape seed extract may serve as a possible novel therapeutic agent for inflammatory and autoimmune diseases.”

Another study showed that dietary supplementation with blueberry extract (also high in proanthocyanidins) was highly effective in prolonging the survival of transplanted dopamine neurons, which are exceptionally delicate, in an animal model of Parkinson’s disease. Researchers also noted the mice receiving blueberry extract exhibited better mobility and coordination than did the control group, which was not receiving blueberry extract.52

7 Targeting Residual Effects of Organ Transplantation and Side Effects of Immunosuppressive Pharmaceutical Drugs

Avoiding tissue rejection is not the only challenge facing transplant recipients. Many other complications frequently arise as a result of receiving a transplant and taking immunosuppressive drugs.

In nearly all transplant cases, the vasculature of the transplanted organ functions less optimally than that of the host’s native tissue. This often leads to cardiovascular complications, such as blood clots and hypertension.53,54 It is vitally important that the health and function of the endothelial cells (cells that line the inside of blood vessels) in recipients of an organ transplant be maintained.

Controlling Homocysteine

Maintaining a low level of homocysteine is very important for transplant patients. Homocysteine is an amino acid derivative that damages endothelial cells and contributes to the pathogenesis of atherosclerosis.

A study published in October 2010 found that higher homocysteine was a predictor of death from any cause in 378 renal transplant recipients, even after the researchers adjusted for multiple confounding factors. Subjects with the lowest one-third homocysteine level (<13.1 µmol/L) were much more likely to be alive 3,000 days post-transplant than those with the highest one-third homocysteine levels (>18.5 µmol/L). Researchers also noted subjects taking a CNI had higher levels of homocysteine than subjects not taking a CNI (mean 16.3 µol/L vs. 14.3 µmol/L), suggesting CNIs, like cyclosporine, might raise homocysteine.55

Fortunately, there are several nutraceutical ingredients that have been shown to effectively control homocysteine in transplant patients.

B6, B12 and 5-Methyltetrahydrofolate

In evaluating 98 renal transplant patients, researchers found that, not only were high levels of homocysteine correlated with chronic allograft dysfunction, but intake of vitamin B6, as well as higher blood levels of the active form of folate, 5-methyltetrahydrofolate, were associated with lower levels of homocysteine and improved vascular health. The researchers noted that “increased folate and vitamin B6 intakes seem to reduce homocysteine concentrations among transplant patients…and could contribute to reducing the risk of chronic allograft dysfunction.56

In 56 renal transplant recipients, the combination of 50 mg B6, 400 mcg B12 and 5 mg folic acid daily, for six months, was found to significantly reduce levels of homocysteine (from 21.8 µmol/L to 9.3 µmol/L vs. no change in the placebo group) and carotid intima-media thickness, a marker of atherosclerosis (from 0.95 mm to 0.64 mm, average 32% reduction) while the placebo group showed a marked increase in carotid intima-media thickness (from 0.71 mm to 0.87 mm) over the trial period.57

A study of 730 renal transplant patients provided unique insight into the importance of vitamin B12 and active folate in this population. Researchers in this study noted that higher levels of plasma B12 and active folate are likely associated with a survival advantage seen in kidney transplant patients who have a genetic predisposition to having higher levels of these vitamins in circulation.58

N-Acetyl Cysteine

The antioxidant N-acetyl cysteine (NAC), especially in combination with B vitamins, has been shown to lower homocysteine levels and improve endothelial function.59

In 12 children who received liver transplants, intravenous infusions of NAC (70 mg/kg), in combination with prostaglandin-E1, were administered daily for six days starting immediately post-operation. The combination reduced the severity of rejection episodes within the first three months after the transplant, compared to a control group who did not receive infusions.60

Intravenous NAC (5 grams over four hours) was shown to dramatically reduce levels of homocysteine (from 15.5 µmol/L to 3.36 µmol/L) in 11 renal transplant patients with healthy levels of B12 and folate. The team reported no adverse effects attributable to NAC. This study highlights both the safety and efficacy of NAC in renal transplant patients.61

An animal model of cyclosporine-induced kidney toxicity found that NAC was protective against the nephrotoxic effects of cyclosporine. Animals receiving cyclosporine alone showed significant increases in oxidative stress, as measured by levels of the reactive species nitric oxide and malondialdehyde, significant decreases in superoxide dismutase and glutathione peroxidase activity and notable kidney morphological changes, while animals receiving NAC with cyclosporine did not manifest these changes.62

In an in vitro study conducted on cells taken from lung transplant recipients, NAC was able to reduce the genetic expression of the inflammatory cytokine TNF-α, which contributes to transplant rejection. The authors concluded that “the therapeutic use of antioxidant compounds could, therefore, be of interest in conditions such as lung transplantation, in which oxidative stress and inflammation can contribute significantly to the loss of allograft function.63

Cocoa and Pomegranate Polyphenols

Researchers, in double-blind placebo-controlled fashion, examined the impact of polyphenols derived from cocoa on the vascular health of 22 heart transplant recipients. Researchers evaluated endothelial function, as measured by endothelium-dependent coronary vasomotion and coronary artery diameter, two hours after subjects consumed 40 grams of dark chocolate, providing 15.6 mg of polyphenols. Cocoa polyphenols were found to significantly increase coronary artery diameter (from 2.36 to 2.51 mm) and improve coronary vasomotion (+4.5% vs. -4.3% in the placebo group). Furthermore, researchers also saw a significant reduction in platelet adhesion in the polyphenol group (from 4.9% to 3.8%) compared to no change in the placebo group, indicating a decreased risk of blood clot formation and hypertension.64

Polyphenols from pomegranate, also known to support endothelial function,65 were administered to animals at a dose equivalent to ~500 mg for a 60 kg human for 21 days. Researchers found that pomegranate polyphenols significantly reduced cyclosporine-induced hepatic oxidative stress, as measured by levels of thiobarbituric acid reactive substances and activity of the antioxidative enzymes glutathione-S-transferase, superoxide dismutase and catalase. The team concluded that “the results of this study indicate that [pomegranate polyphenols] might play an important role in protecting [against] cyclosporine-induced oxidative damage in the liver.66

Coenzyme Q10

Daily supplementation with 90 mg of coenzyme Q10 (CoQ10) for four weeks resulted in significant improvements in cardiovascular health, as measured by HDL, LDL and total cholesterol levels, in 11 renal transplant patients. Furthermore, the researchers found that CoQ10 did not adversely affect blood levels of cyclosporine, highlighting the safety of CoQ10 in transplant patients taking cyclosporine.67 This data suggest CoQ10 could safely combat the side effects of cyclosporine, which is known to cause oxidative damage and unfavorably alter cholesterol levels.68

Vitamins C and E

A double-blind trial examining the effect of supplementation with a combination of 500 mg vitamin C and 400 IU vitamin E, twice daily, showed that the vitamins slowed the progression of coronary arteriosclerosis in heart transplant patients. Over a period of one year, patients receiving vitamins C and E (n=19) experienced no increase in average intima-media index, while patients receiving a placebo (n=21) saw an 8% increase.69

In a randomized placebo-controlled fashion, researchers studied the effects of 2,000 mg of vitamin C on the vascular function of 13 renal transplant patients. They found that vitamin C significantly improved endothelium-dependent dilation (from 1.6% to 4.5%) and enhanced the antioxidant capacity of the subject’s blood, as measured by the time required to oxidize lipids in vitro.70

Cyclosporine is a widely prescribed immunosuppressive drug known to cause oxidative damage, and is associated with an unhealthy lipid profile.68 Vitamin E was effective in reducing cyclosporine-induced mitochondrial damage to porcine renal endothelial cells71 and, in combination with quercetin, was shown to be protective against hepatotoxicity caused by cyclosporine, as measured by the level of thiobarbituric acid-reacting substances, and activity of glutathione peroxidase and catalase, in an animal model.42

It is important to note that, in at least one study, the combination of vitamins C and E was shown to reduce blood levels of cyclosporine by roughly 30% in heart transplant recipients who were taking 500 mg vitamin C twice daily and 400 IU vitamin E twice daily. These researchers went on to state that “although more detailed pharmacokinetic analysis is necessary to clarify the exact mechanism of this interaction, physicians who take care of transplant recipients should be aware that more frequent cyclosporine concentration monitoring is warranted after initiating these anti-oxidant agents.72

L-Arginine

The amino acid L-arginine has been shown in multiple studies to improve the function of endothelial cells.73,74

A 2010 study of 22 heart transplant patients found that supplemental L-arginine, 6 grams twice daily, improved endothelial function, as measured by the nitric oxide/endothelin ratio, and increased sub-maximal exercise capacity, as measured by a 6-minute walk test (distance walked increased from 525 m to 580 m). Significantly, the researchers also noted that supplemental L-arginine improved subjects’ overall quality-of-life score, as measured by standardized questionnaire.75

Probiotics

A study of 777 liver transplant recipients found that surgical site infection occurred in 37.8% of patients. These infections resulted in, on average, roughly 24 additional days of hospital stay, $159,967 in extra expenses, and a 10% increase in mortality.76 Furthermore, post-operative infections have been associated with a significantly higher incidence of graft loss due to rejection.77

A randomized placebo-controlled trial of 95 liver transplant recipients examined the effects of probiotics (10 billion colony forming units [CFUs]), in combination with fiber, on post-operative infection rates. The researchers found that infection occurred in only 13% of the patients receiving probiotics and fiber versus 48% of patients in the control group.78

In order to duplicate these impressive results, the same lead researcher conducted another similar study shortly thereafter. This time the team studied the effect of probiotics, in combination with fiber, against fiber alone, on post-operative infection rates in 66 liver transplant recipients. The group receiving the combination of probiotics and fiber had an infection rate of only 3%, while, in the group receiving solely fiber, post-operative infection occurred in 48% of the patients.79

Magnesium

Magnesium wasting is common in transplant patients, especially those who receive a transplanted kidney.80 Low levels of magnesium have been shown to potentiate the toxic effects of cyclosporine and reduce allograft survival.81

In a study of 14 hypomagnesemic renal transplant patients, magnesium supplementation at a dose of 400 to 1,200 mg daily, for three months, was shown to significantly improve total and LDL cholesterol levels, glucose metabolism, and restore levels of magnesium. The researchers concluded that magnesium replenishment was effective for combating magnesium wasting and important for maintaining the health of renal transplant patients.82

What You Need To Know

  • The over-aggressive immune response against transplanted tissue results in very poor 5-year survival rates for transplanted organs.
  • Targeting specific inflammatory cytokines, like IL-1β, IL-2, IL-6, IL-15, IL-21 and TNF-α, which impair the activity of protective Treg cells and stimulate cytotoxic T cells, is a rational approach to calming the over-aggressive immune response and supporting healthy function of transplanted tissue.
  • Several nutrients target these inflammatory cytokines and favorably alter the ratio of highly aggressive Th17 cells to transplant-protecting Treg cells.
  • The most widely prescribed immunosuppressive drugs to transplant patients, calcineurin inhibitors, fail to promote the activity of protective Treg cells and have been shown to be highly toxic.
  • Many nutrients safely address the residual effects of organ transplantation such as infection, poor endothelial function and aggressive atherosclerosis, and combat side effects of immunosuppressive drugs.

8 Summary

Organ transplantation offers individuals with critically injured or failing organs a means to improve the quality of their lives and extend their lifespan. However, receiving a transplanted organ comes with many challenges.

Because a donated organ does not contain the DNA of the tissue recipient, the immune system of the host recognizes the transplanted organ as pathological and attempts to eliminate it. This ongoing battle between the donated tissue and the host’s immune system ultimately results in the destruction of the transplanted tissue. Thus, recipients of a transplant must take side-effect laden immunosuppressive drugs in order to preserve the transplanted organ for as long as possible.

Life Extension has identified multiple nutraceuticals which, based on peer-reviewed scientific evidence, target specific aspects of the immune response involved in tissue rejection, as well as help combat side effects of immunosuppressive drugs.

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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