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group_1_presentation_1_-_kidney_transplant_rejection [2016/01/29 23:52] dheriaj |
group_1_presentation_1_-_kidney_transplant_rejection [2018/01/25 15:18] (current) |
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| ==== Renal Replacement Therapy ==== | ==== Renal Replacement Therapy ==== | ||
| Individuals with end-stage kidney failure will require renal replacement therapy. There are two primary treatments for renal replacement therapy: dialysis and renal transplants<sup>[15]</sup>. Dialysis is a treatment that removes wastes and excess fluids from your blood. There are two types of dialysis treatments: hemodialysis, which cleans the blood through an artificial kidney hooked up to a machine, and peritoneal dialysis, which removes waste products and excess fluids by using the body's peritoneal as a filter. On the other hand, a kidney transplant is an operation to replace a damaged kidney with a donated kidney. The best and most effective replacement therapy would be kidney transplants<sup>[15]</sup>. | Individuals with end-stage kidney failure will require renal replacement therapy. There are two primary treatments for renal replacement therapy: dialysis and renal transplants<sup>[15]</sup>. Dialysis is a treatment that removes wastes and excess fluids from your blood. There are two types of dialysis treatments: hemodialysis, which cleans the blood through an artificial kidney hooked up to a machine, and peritoneal dialysis, which removes waste products and excess fluids by using the body's peritoneal as a filter. On the other hand, a kidney transplant is an operation to replace a damaged kidney with a donated kidney. The best and most effective replacement therapy would be kidney transplants<sup>[15]</sup>. | ||
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| ===== Kidney Transplantation ===== | ===== Kidney Transplantation ===== | ||
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| === Disadvantages === | === Disadvantages === | ||
| There are some contraindications with a renal transplant; these include: pulmonary, cardiac and hepatic insufficiency, history of metastatic cancer, and morbid obesity. Emotional and psychological well-being of the recipient is also taken into consideration prior to a transplant. Currently, there are more than 3,000 Canadians waiting for a kidney transplant<sup>[13]</sup>. Difficulties finding a match, and the long waiting lists are two primary concerns with regards to kidney transplants. Canada's transplant system puts "geography in front of needs" of patients, putting the more vulnerable patients at risk. In fact, it can four to six years on average for an individual to be matched with a kidney in Ontario and British Colombia <sup>[12]</sup>. The possibility of rejection post-transplant is also a concern, however, rejection is less of a problem nowadays due to immunosuppressant medications. | There are some contraindications with a renal transplant; these include: pulmonary, cardiac and hepatic insufficiency, history of metastatic cancer, and morbid obesity. Emotional and psychological well-being of the recipient is also taken into consideration prior to a transplant. Currently, there are more than 3,000 Canadians waiting for a kidney transplant<sup>[13]</sup>. Difficulties finding a match, and the long waiting lists are two primary concerns with regards to kidney transplants. Canada's transplant system puts "geography in front of needs" of patients, putting the more vulnerable patients at risk. In fact, it can four to six years on average for an individual to be matched with a kidney in Ontario and British Colombia <sup>[12]</sup>. The possibility of rejection post-transplant is also a concern, however, rejection is less of a problem nowadays due to immunosuppressant medications. | ||
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| ===== Kidney Transplant Rejection ===== | ===== Kidney Transplant Rejection ===== | ||
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| ==== Minimizing Risks of Rejection ==== | ==== Minimizing Risks of Rejection ==== | ||
| Human Leukocyte Antigen (HLA) is the human version of the commonly studied Major Histocompatibility Complex (HMC), highly involved in immunological reactions. This HLA molecule is expressed on the surface of all cells in the human body, presenting randomly generated peptides from the interior[20]. This allows for the immune system to monitor whether cells are healthy or infected, as well as whether an immune response needs to be mounted. To prevent the immune system from recognizing the newly transplanted graft as foreign, the donor and recipient both have their HLA genes checked using high-resolution DNA typing techniques[20]. The HLA system has loci across chromosome 6, expressing 3 classes of HLA[20]. When matching HLA between the donor and recipient, HLA –A, –B, and –DR are checked for similarities[20]. There are a vast number of alleles for these genes (>800 type –A and –B, >400 type –DR), adding to the complexity of matching donors and recipients appropriately to minimize risk of rejection[20]. | Human Leukocyte Antigen (HLA) is the human version of the commonly studied Major Histocompatibility Complex (HMC), highly involved in immunological reactions. This HLA molecule is expressed on the surface of all cells in the human body, presenting randomly generated peptides from the interior[20]. This allows for the immune system to monitor whether cells are healthy or infected, as well as whether an immune response needs to be mounted. To prevent the immune system from recognizing the newly transplanted graft as foreign, the donor and recipient both have their HLA genes checked using high-resolution DNA typing techniques[20]. The HLA system has loci across chromosome 6, expressing 3 classes of HLA[20]. When matching HLA between the donor and recipient, HLA –A, –B, and –DR are checked for similarities[20]. There are a vast number of alleles for these genes (>800 type –A and –B, >400 type –DR), adding to the complexity of matching donors and recipients appropriately to minimize risk of rejection[20]. | ||
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| + | <style float-right> | ||
| + | {{:chromosome_6.jpg|}} | ||
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| + | ''Figure 6: Chromsome 6 Expresses 3 Classes of HLA'' | ||
| + | </style> | ||
| Internationally, HLA matching between donors and recipients differ by the acceptability of mismatches[20]. Countries with organ transplant systems regulate the amount of HLA mismatch they deem is acceptable in order for the transplant to be viable[20]. In the United States, because the majority of organ donors belong to Caucasian ancestry, the HLA alleles are skewed towards certain populations[20]. This puts recipients of differing ancestral backgrounds at a disadvantage when an organ transplant is vital for their health, such as in the case of end-stage renal diseases[20]. | Internationally, HLA matching between donors and recipients differ by the acceptability of mismatches[20]. Countries with organ transplant systems regulate the amount of HLA mismatch they deem is acceptable in order for the transplant to be viable[20]. In the United States, because the majority of organ donors belong to Caucasian ancestry, the HLA alleles are skewed towards certain populations[20]. This puts recipients of differing ancestral backgrounds at a disadvantage when an organ transplant is vital for their health, such as in the case of end-stage renal diseases[20]. | ||
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| ==== Allorecognition ==== | ==== Allorecognition ==== | ||
| - | In many cases of renal transplantation, the recipient’s immune system is able to recognize that the transplanted kidney is a foreign organ, by a process termed allorecognition. This allows the immune system to prime T-cells to recognize and launch an immune response against the new organ. There are 3 main ways via which allorecognition occurs: | + | In many cases of renal transplantation, the recipient’s immune system is able to recognize that the transplanted kidney is a foreign organ, by a process termed allorecognition. This allows the immune system to prime T-cells to recognize and launch an immune response against the new organ [3]. There are 3 main ways via which allorecognition occurs: |
| - | - Direct allorecognition occurs when donor dendritic cells (or other antigen-presenting cells) from the graft present a graft peptide to T-cells of the recipient’s immune system. This usually results in immediate rejection, but the response becomes less likely to occur over time due to the decrease in donor dendritic cell count. | + | - Direct allorecognition occurs when donor dendritic cells (or other antigen-presenting cells) from the graft present a graft peptide to T-cells of the recipient’s immune system. This usually results in immediate rejection, but the response becomes less likely to occur over time due to the decrease in donor dendritic cell count [3]. |
| - | - Indirect allorecognition occurs when recipient antigen-presenting cells display a graft antigen to the recipient T-cells. This is the most common occurrence that is responsible for chronic rejections. | + | - Indirect allorecognition occurs when recipient antigen-presenting cells display a graft antigen to the recipient T-cells. This is the most common occurrence that is responsible for chronic rejections [3]. |
| - | - Semi-direct allorecognition occurs when recipient antigen-presenting cells “capture” donor MHC complexes with an antigen from the graft and presenting it to T-cells of the recipient’s immune system. The function of semi-direct allorecognition has not yet been elucidated. | + | - Semi-direct allorecognition occurs when recipient antigen-presenting cells “capture” donor MHC complexes with an antigen from the graft and presenting it to T-cells of the recipient’s immune system. The function of semi-direct allorecognition has not yet been elucidated [3]. |
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| + | <style float-left> | ||
| + | {{:allorecognition.jpg?300x200}} | ||
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| + | ''Figure 7: Allorecognition in Renal Transplants'' | ||
| + | </style> | ||
| ==== Types of Rejection ==== | ==== Types of Rejection ==== | ||
| - | Before performing a kidney transplantation, physicians ensure that the donor kidney is a match to the recipient. Often times, even when an HLA antigen match has occurred, the recipient’s immune system may still detect the donor organ has foreign; triggering a severe immune response. There are three types of rejection: | + | Before performing a kidney transplantation, physicians ensure that the donor kidney is a match to the recipient [20]. Often times, even when an HLA antigen match has occurred, the recipient’s immune system may still detect the donor organ has foreign; triggering a severe immune response. There are three types of rejection: |
| - | * **Hyper Acute Rejection:** This is the most rapidly elicited form of kidney transplant rejection. Hyper acute rejection occurs a few minutes after the transplant has taken place and is the result of mismatched ABO blood types; triggering a humoral immune response. For example, this would occur if the recipient had type A blood and the donor had type B blood. In this case, the donor organ tissue must be removed right away to prevent death of the recipient. | + | * **Hyper Acute Rejection:** This is the most rapidly elicited form of kidney transplant rejection. Hyper acute rejection occurs a few minutes after the transplant has taken place and is the result of mismatched ABO blood types; triggering a humoral immune response. For example, this would occur if the recipient had type A blood and the donor had type B blood. In this case, the donor organ tissue must be removed right away to prevent death of the recipient [3]. |
| - | * **Acute Rejection**: Acute rejection takes at least a week to occur and is modulated by cytotoxic T cells; signifying the involvement of the immune system. In this case, the recipient has circulating antibodies in their blood before the transplant occurs. The T cells produce cytokines that then recruit other inflammatory mediators leading to the eventual death of the kidney tissue. | + | * **Acute Rejection**: Acute rejection takes at least a week to occur and is modulated by cytotoxic T cells; signifying the involvement of the immune system. In this case, the recipient has circulating antibodies in their blood before the transplant occurs. The T cells produce cytokines that then recruit other inflammatory mediators leading to the eventual death of the kidney tissue [3]. |
| - | * **Chronic Rejection:** Chronic rejection describes long-term dysfunction of the donated organ. In most patients, chronic rejection takes several months to elicit. It is the most prevalent cause of renal dysfunction, usually characterized by a gradual loss of kidney function, coupled with hypertension and excess protein in the urine. Chronic rejection initially develops in tissue grafts that are prone to continuous damage as a result of indirect recognition of alloantigens. In this case, the immune modulators destroy the endothelium of blood vessels, depleting the donor organ tissue of blood. | + | * **Chronic Rejection:** Chronic rejection describes long-term dysfunction of the donated organ [3]. In most patients, chronic rejection takes several months to elicit. It is the most prevalent cause of renal dysfunction, usually characterized by a gradual loss of kidney function, coupled with hypertension and excess protein in the urine. Chronic rejection initially develops in tissue grafts that are prone to continuous damage as a result of indirect recognition of alloantigens [3]. In this case, the immune modulators destroy the endothelium of blood vessels, depleting the donor organ tissue of blood. |
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| ==== Mechanisms of Rejection ==== | ==== Mechanisms of Rejection ==== | ||
| - | Overall, allorecognition leads to the priming of T-cells, activating them to respond to the presenting antigen. In most cases, dendritic cells or other antigen-presenting cells are exposed to these peptides first, resulting in their activation and migration to the thymus. In the thymus, the antigen is presenting via MHC to T-cells, allowing for their maturation and ability to launch an immune response. Recently, it has been elucidated that T-cells do not necessarily need to become activated at the Thymus, but can also be activated directly at the graft via interactions with the endothelial cell lining of the transplant. The microenvironment where T-cells become activated leads to the differentiation of T-cells, varying in their cytokine signatures and functionalities (CD8+ T-cells versus CD4+ T-cells). This differentiation depends on the expression of a master transcription factor, determining the final subset of cytotoxic T-cells (CD8+) and T-helper cells (CD4+). During renal transplants, there are many factors that can affect the microenvironment post-transplant: | + | Overall, allorecognition leads to the priming of T-cells, activating them to respond to the presenting antigen. In most cases, dendritic cells or other antigen-presenting cells are exposed to these peptides first, resulting in their activation and migration to the thymus. In the thymus, the antigen is presenting via MHC to T-cells, allowing for their maturation and ability to launch an immune response [20]. Recently, it has been elucidated that T-cells do not necessarily need to become activated at the Thymus, but can also be activated directly at the graft via interactions with the endothelial cell lining of the transplant [20]. The microenvironment where T-cells become activated leads to the differentiation of T-cells, varying in their cytokine signatures and functionalities (CD8+ T-cells versus CD4+ T-cells). This differentiation depends on the expression of a master transcription factor, determining the final subset of cytotoxic T-cells (CD8+) and T-helper cells (CD4+). During renal transplants, there are many factors that can affect the microenvironment post-transplant [20]: |
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| + | <style float-right> | ||
| + | {{:rejection_mech.png?300x200}} | ||
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| + | ''Figure 8: Mechanisms of Rejection'' | ||
| + | </style> | ||
| * Immune status of the recipient at the time of transplant | * Immune status of the recipient at the time of transplant | ||
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| * Current immunosuppressive regime | * Current immunosuppressive regime | ||
| - | CD8+ T-cells, also known as cytotoxic T-cells, are typically activated after forming a three-cell cluster between itself, a CD4+ T-cell, and an antigen-presenting cell. It can directly destroy graft cells by expressing perforin to disrupt their membrane and injecting granzyme in to the cell to destroy crucial proteins via the release of cytotoxic granules. FasL released by the cytotoxic T-cell can bind to FasR on the target cell, resulting in the triggering of apoptosis of the graft cell by triggering various cascades. CD4+ T-cells release cytokines that result in inflammation, and can attract other immune cells towards the location of the graft. Recent studies indicate that CD4+ T-cells can result in graft rejection by themselves, although the exact mechanism is not clear. | + | CD8+ T-cells, also known as cytotoxic T-cells, are typically activated after forming a three-cell cluster between itself, a CD4+ T-cell, and an antigen-presenting cell [20]. It can directly destroy graft cells by expressing perforin to disrupt their membrane and injecting granzyme in to the cell to destroy crucial proteins via the release of cytotoxic granules. FasL released by the cytotoxic T-cell can bind to FasR on the target cell, resulting in the triggering of apoptosis of the graft cell by triggering various cascades [20]. CD4+ T-cells release cytokines that result in inflammation, and can attract other immune cells towards the location of the graft. Recent studies indicate that CD4+ T-cells can result in graft rejection by themselves, although the exact mechanism is not clear [20]. |
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| Due to the prolonged half-life, multiple drug interactions are quite possible. Concomitant use with strong CYP3A4/P-gp inducers or inhibitors fluctuates the sirolimus concentrations. When cyclosporine is used simultaneously with mTOR inhibitors, there is an increase in the maximum concentration of the drug (Cmax) and area-under-the-curve (AUC) for both compounds. Thus, if both drugs are to be administered, it is recommended to have a 4 hour gap between the administration of cyclosporine and mTOR inhibitors. | Due to the prolonged half-life, multiple drug interactions are quite possible. Concomitant use with strong CYP3A4/P-gp inducers or inhibitors fluctuates the sirolimus concentrations. When cyclosporine is used simultaneously with mTOR inhibitors, there is an increase in the maximum concentration of the drug (Cmax) and area-under-the-curve (AUC) for both compounds. Thus, if both drugs are to be administered, it is recommended to have a 4 hour gap between the administration of cyclosporine and mTOR inhibitors. | ||
| Adverse effects from the use of mTOR inhibitors include hyperlipidemia, thrombocytopenia, anemia, pneumonitis, oral ulcers, and diarrhea. These agents can also hinder the healing process of wounds and dehiscence production of lymphoceles. When used concomitantly with calcineurin inhibitors, sirolimus heightens the nephrotoxicity of calcineurin <sup>[1]</sup>. | Adverse effects from the use of mTOR inhibitors include hyperlipidemia, thrombocytopenia, anemia, pneumonitis, oral ulcers, and diarrhea. These agents can also hinder the healing process of wounds and dehiscence production of lymphoceles. When used concomitantly with calcineurin inhibitors, sirolimus heightens the nephrotoxicity of calcineurin <sup>[1]</sup>. | ||
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| ==== Calcineurin Inhibitors ==== | ==== Calcineurin Inhibitors ==== | ||
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| <style float-right> | <style float-right> | ||
| - | {{:fungi.png|}} | + | {{:fungi.png?200x220}} |
| - | ''Figure 6: Cyclosporine from a Fungal Origin'' | + | ''Figure 9: Cyclosporine from a Fungal Origin'' |
| </style> | </style> | ||
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| Tacrolimus prevents the production of IL-2 through calcineurin inhibition by binding to the tacrolimus binding protein (TBP). This macrolide antibiotic is active against T-helper cells. The tacrolimus FKBP12 active complex inhibits calcineurin with a stronger potency than the corresponding cyclosporine complex. This drug is used particularly for maintenance immunosuppression and during the refractory rejection under cyclosporine-based therapy (known as rescue therapy). Adverse effects are similar to the calcineurin inhibitor, cyclosporine, but with a lower occurrence of hypertension, hyperlipidemia, hirsutism, gum hyperplasia and skin changes. However, it is reported that Tacrolimus has a lower occurrence of acute-rejections and less-pronounced adverse effects. In addition, Tacrolimus can cause reverse alopecia <sup>[13]</sup>. | Tacrolimus prevents the production of IL-2 through calcineurin inhibition by binding to the tacrolimus binding protein (TBP). This macrolide antibiotic is active against T-helper cells. The tacrolimus FKBP12 active complex inhibits calcineurin with a stronger potency than the corresponding cyclosporine complex. This drug is used particularly for maintenance immunosuppression and during the refractory rejection under cyclosporine-based therapy (known as rescue therapy). Adverse effects are similar to the calcineurin inhibitor, cyclosporine, but with a lower occurrence of hypertension, hyperlipidemia, hirsutism, gum hyperplasia and skin changes. However, it is reported that Tacrolimus has a lower occurrence of acute-rejections and less-pronounced adverse effects. In addition, Tacrolimus can cause reverse alopecia <sup>[13]</sup>. | ||
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| ==== Future Treatments ==== | ==== Future Treatments ==== | ||
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| <style float-left> | <style float-left> | ||
| - | {{:3d2.png|}} | + | {{:3d2.png?371x265}} |
| - | ''Figure 7: 3D Print Technology for Customizing Organs'' | + | ''Figure 10: 3D Print Technology for Customizing Organs'' |
| </style> | </style> | ||
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| 3D-Prints is a relatively new application that is being used to print many organs such as the heart, kidneys and other crucial organs <sup>[18]</sup>. | 3D-Prints is a relatively new application that is being used to print many organs such as the heart, kidneys and other crucial organs <sup>[18]</sup>. | ||
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| ====== References ====== | ====== References ====== | ||
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| [20] Wood, K. J., & Goto, R. (2012). Mechanisms of rejection: current perspectives. Transplantation, 93(1), 1-10. | [20] Wood, K. J., & Goto, R. (2012). Mechanisms of rejection: current perspectives. Transplantation, 93(1), 1-10. | ||
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