KIDNEY TRANSPLANTATION

Submitted by, Mrs Bibi Baby 2 nd year MSc Nursing PION.

KIDNEY TRANSPLANTATION HISTORICAL REVIEW OF KIDNEY TRANSPLANTATION The first cadaveric kidney transplantation in the United States was performed on June 17, 1950, on Ruth Tucker, a 44-year-old woman with polycystic kidney disease, at Little Company of Mary Hospital in Evergreen Park, Illinois. Although the donated kidney was rejected ten months later because no immunosuppressive therapy was available at the time. The development of effective anti-rejection drugs was years away. The intervening time gave Tucker's remaining kidney time to recover and she lived another five years. The Herrick twin brothers were the subjects of the world's first successful kidney transplant, The first kidney transplants between living patients were undertaken in 1954 in Boston and Paris. The Boston transplantation, performed on December 23, 1954, at Brigham Hospital was performed by Joseph Murray, J. Hartwell Harrison, John P. Merrill and others. The procedure was done between identical twins to eliminate any problems of an immune reaction. For this and later work, Dr. Murray received the Nobel Prize for Medicine in 1990. The recipient died eight years after the transplantation. The first kidney transplantation in the United Kingdom did not occur until 1960, when Michael Woodruff performed one between identical twins in Edinburgh. Until the routine use of medications to prevent and treat acute rejection, introduced in 1964, deceased donor transplantation was not performed. The kidney was the easiest organ to transplant: tissue typing was simple, the organ was relatively easy to remove and implant, live donors could be used without difficulty, and in the event of failure, kidney dialysis was available from the 1940s. Tissue typing was essential to the success: early attempts in the 1950s on sufferers from Bright's disease had been very unsuccessful. The major barrier to organ transplantation between genetically non-identical patients lay in the recipient's immune system, which would treat a transplanted kidney as a "non-self" and immediately or chronically, reject it. Thus, having medications to suppress the immune system was essential. However, suppressing an individual's immune system places that individual at greater risk of infection and cancer (particularly skin cancer and lymphoma), in addition to the side effects of the medications.

DEFINITION OF KIDNEY TRANSPLANTATION Kidney transplantation or renal transplantation is the organ transplant of a kidney into a patient with end-stage renal disease. A kidney transplant is a surgical procedure in which a kidney is removed from one person (donor) and placed into the body of a person suffering from renal failure (recipient), in whom the transplanted kidney can perform all the functions which the patient's own kidneys are not able to perform. INDICATIONS OF KIDNEY TRANSPLANTATION
1. End -stage renal disease (ESRD), Common diseases leading to ESRD include

malignant hypertension.

infections. diabetes mellitus.

focal segmental glomerulosclerosis.

2. Genetic causes include polycystic kidney disease.

3. A number of inborn errors of metabolism.

4. Autoimmune conditions such as lupus and Goodpasture's syndrome. 5. Diabetes .

CONTRAINDICATIONS OF KIDNEY TRANSPLANTATION

Certain infections, such as TB or bone infections. Recent history of cancer. Infections such as hepatitis. Smoking, alcohol or drug abuse, or other risky lifestyle habits. Serious cardiac or peripheral vascular disease. Hepatic insufficiency. Moderate heart disease and/or vascular disease which includes documentation of poor cardiac function evidenced by an ejection fraction < 50% and/or coronary lesions that

have not been successfully revascularized and/or cerebrovascular disease or ischemic ulcers.

Severe obesity (BMI of greater then 35). History of noncompliance to medical therapy. Active infections. HIV Positive. Active substance abuse. Active psychiatric disorder which remains untreated or is untreatable.

SOURCES OF KIDNEY: DONORS

Kidneys are obtained from 4 sources:-

1. Cadaver donors : A cadaver kidney is removed from an individual who has been declared as brain-dead from non-kidney related causes, such as an accident or a stroke. Since a cadaver kidney is from a person not related to the patient, the kidney has less possibility of close antigen matching and thus less chances of success. The age range of most suitable kidney donors is from 2-70 years. The age of the most suitable kidney is less important than the quality of kidney function. The donar muist be free of active I V drug abuse, severe hypertension, long standing diabetes mellitus, malignancies, sepsis, and communicable disease , including hepatitis B and C, syphilis, TB. The kidneys are removed and preserved. They can be preserved for up to 72 hours, but most transplant surgeons prefer to transplant kidneys before cold ischemic time reaches 24 hours.

2. Living related donors: Very close relatives-parents, siblings (brothers & sisters), children, grandparents may donate a kidney to a near relative. This is because a normal individual has two kidneys and can live safely in good health with one kidney. Kidney donation does not alter the physical capacity or life-style or longevity of life of such a donor.

3.Emotionally related recipient donor mother kidney donor: In the situation where cadaver donor transplant is not available & living related donors are found unfit, emotionally related kidney donors like spouse (husband/wife) cousins, uncles, aunts, in-laws may donate a kidney and they are called emotionally related kidney donors.

4.Unrelated kidney donors: When cadaver donors, living related donors, emotionally related donors are not available or are found unfit, then unrelated donor kidney transplantation can be considered. Patients should understand that the chances of rejection are higher ; costly medicines like Cyclosporin-A, ATG, etc. have to be taken for better function of the transplanted kidney. IMMUNOLOGY OF GRAFT REJECTIONS The mechanism of immune recognition and response to an allograft is helpful to better understand the patient who has undergone kidney transplantation. The degree of immune response to a graft depends partly on the degree of genetic disparity between the grafted organ and the host. Types of grafts: Xenografts, which are grafts between members of different species, have the most disparity and elicit the maximal immune response, undergoing rapid rejection. Autografts, which are grafts from one part of the body to another (eg, skin grafts), are not foreign tissue and, therefore, do not elicit rejection. Isografts, which are grafts between genetically identical individuals (eg, monozygotic twins), also undergo no rejection. Allografts are grafts between members of the same species that differ genetically. This is the most common form of transplantation. The degree to which allografts undergo rejection depends partly on the degree of similarity or histocompatibility between the donor and the recipient The degree and type of response also vary with the type of the transplant. The kidneys are highly vascular organs and lead to a vigorous cell mediated response in the host. Immunology

The immune response to a transplanted organ consists of both cellular (lymphocyte mediated) and humoral (antibody mediated) mechanisms. Although other cell types are also involved, the T cells are central in the rejection of grafts.

Immunology The immune response to a transplanted organ consists of both cellular (lymphocyte mediated) and humoral (antibody mediated) mechanisms. Although other cell types are also involved, the T cells are central in the rejection of grafts. 1. Major histocompatibility complex(MHC) Cells in the tissues and mammals , birds, and bony fish express MHC surface molecules, which are crucial for immune system to be able to recognize and respond to a foreign antigen. In humans , these MHC molecules are located on the short arm chromosomes 6 and encode for proteins termed the HLAs. MHC molecules serve two basic functions: they identify self from nonself and coordinate the T-cell receptor(TCR) recognition of the antigen-MHC complex. The MHC molecules are divided into two groups: Class I and Class II. MHC class I molecules appear on the surface of all cells and are known as MHC class II molecules appear on antigen presenting cells(APCs) and are

HLA-A, B ,C. termed HLA-DR,DP,DQ. One MHC haplotype is inherited from each parent as a locus containing each of the six genetically linked HLA molecules. In kidney transplantation , only the HLA-A,B,DR are determined due to their immunogenicity.

 A zero antigen mismatched kidney has no mismatches in either locus for HLAA,B,DR, although mismatches may be present at HLA-C,DP,DQ or at other minor antigens. Although advances in immunosuppression have narrowed advantages for well- matched transplants, a 2- haplotype- identical transplant from a family member or a zero antigen mismatched deceased donor transplant confers a graft survival benefit compared to transplants with lesser degrees of matching.

2. Antigen-presenting cells. APCs are distributed in a ubiquitous manner in body tissues and allow T cells to recognize foreign antigens. Monocytes, macrophages, dendritic cells and acitivated B cells can serve as APCs. Either by phagocytosis or through surface immunoglobulin(Ig)(B cells), APCs capture foreign antigens, degrade and process them into peptides, and express these foreign peptides on MHC class II surface molecules. Through TCR interactions and various downstream events, the T cell is then able to coordinate an immune response to this foreign antigen. 3. T cells T cells are processed in the thymus and are central to cellular immunity and allograft recognition and rejection. These properties make them a common target of drugs designed to prevent rejection. Central to immune response is the ability of the T cell to recognize foreign antigen through a surface TCR. These receptors recognizes antigens through either indirect or direct pathways. The indirect pathway involves TCR recognition of a foreign antigens that is presented by a self MHC molecule located on an APC surface.

 The direct pathway refers to the ability of some T cells populations to recognize foreign MHC that is not presented with self MHC on an APC. There are two major classes of T cells: T helper cells T helper cells which express CD4 surface molecules(CD4+). CD4+ cells recognize MHC class II molecules on the surface of APCs. CD4+ cells are activated after recognition of a foreign antigen(e.g. foreign MHC from a kidney tansplant). They initiate an immune response to foreign peptides by secreting cytokines important in B cell proliferation and activation and cytotoxic T-cell activation. 4. T cell and APC interactions. T-cells and APCs have a number of important interactions central to allograft recognition and rejection. Signal 1 is the term for initial binding of the T cell to the APC through interactions between the TCR/CD3 complex and foreign peptide expressed in MHC. Signal 1 is a calcium- dependent process and results in calcineurin activation. Although signal 1 alone will cause anergy, the addition of signal 2 , also known as costimulation, will lead to an immune response. The best understood costimulation signal is between CD28 on the T- cell surface and 7 on the APC surface. CD 28/B7 activation leads to intracellular signaling, interleukin 2(IL-2) production, and T-cell activation. While CD28 is antigen-4 (CTLA-4) immunoglobulin is expressed only on activated T cells. Cytotoxic T cells Cytotoxic Tcells which express CD8 surface molecules(CD8+). CD8+ cells are restricted to recognition of MHC class I. CD8+ T cells kill each bearing foreign antigen through the use of cytotoxic molecules such as perforins, granzymes and fas , which triggers apoptosis in the targeted cell.

 CTLA-4 binds preferentially to B7 and eventually inactivates the immune response, thereby providing potent negative feed back. Another costimulatory molecule, CD40, is found on APCs and activated B cells, and binds to CD 40 ligand(CD40L) on T cells. The CD40/CD40L pathway is important in Ig production and class switching by B cells. 5. B cells B cells develop at multiple sites of the body, including the liver, spleen and lymphnodes. In response to T-cell signals for activation and proliferation, they produce Igs. A nave B cell produces IgM and ,after class switching, is able to produce IgG, IgA. Depending on their class , antibodies mediate opsonization for phagocytosis or antibody- dependent cellular cytotoxicity, and can fix complement. B cells and antibodies are important in the process of hyper acute rejection( immediate allograft destruction due to performed antibodies), and donor specific antibodies have been implicated in both antibody- mediated (humoral) rejection and chronic allograft nephropathy(CAN). Mechanisms of graft rejection Genetic background The antigens responsible for rejection of genetically disparate tissues are called histocompatibility antigens; they are products of histocompatibility genes. Histocompatibility antigens are encoded on more than 40 loci, but the loci responsible for the most vigorous allograft rejection reactions are located on the major histocompatibility complex (MHC).

In humans, the MHC is called the human leukocyte antigen (HLA) system and is located on the short arm of chromosome 6, near the complement genes. Other antigens cause only weaker reactions, but combinations of several minor antigens can elicit strong rejection responses. The MHC genes are codominantly expressed, which means

that each individual expresses these genes from both the alleles on the cell surface. Furthermore, they are inherited as haplotypes or 2 half sets (one from each parent). This makes a person half identical to each of his or her parents with respect to the MHC complex. This also leads to a 25% chance that an individual might have a sibling who is HLA identical.

The MHC molecules are divided into 2 classes. The class I molecules are normally expressed on all nucleated cells, whereas the class II molecules are expressed only on the professional antigen-presenting cells (APCs), such as dendritic cells, activated macrophages, and B cells. The physiological function of the MHC molecules is to present antigenic peptides to T cells, since the T lymphocytes only recognize antigen when presented in a complex with an MHC molecule. The class I molecules are responsible for presenting antigenic peptides from within the cell (eg, antigens from the intracellular viruses, tumor antigens, self-antigens) to CD8 T cells. The class II molecules present extracellular antigens such as extracellular bacteria to CD4 T cells.

Immunology of graft rejections

The immune response to a transplanted organ consists of both cellular (lymphocyte mediated) and humoral (antibody mediated) mechanisms. Although other cell types are also involved, the T cells are central in the rejection of grafts. The rejection reaction consists of the sensitization stage and the effector stage.

Sensitization stage In this stage, the CD4 and CD8 T cells, via their T-cell receptors, recognize the alloantigens expressed on the cells of the foreign graft. Two signals are needed for recognition of an antigen; the first is provided by the interaction of the T cell receptor with the antigen presented by MHC molecules, the second by a costimulatory receptor/ligand interaction on the T cell/APC surface. Of the numerous costimulatory

pathways, the interaction of CD28 on the T cell surface with its APC surface ligands, known as CD80 or CD86. In addition, cytotoxic T lymphocyteassociated antigen-4 (CTLA4) also binds to these ligands and provides an inhibitory signal. Other costimulatory molecules include the CD40 and its ligand CD40L (CD154).

Typically, helices of the MHC molecules form the peptide-binding groove and are occupied by peptides derived from normal cellular proteins. Thymic or central tolerance mechanisms (clonal deletion) and peripheral tolerance mechanisms (eg, anergy) ensure that these self-peptide MHC complexes are not recognized by the T cells, thereby preventing autoimmune responses.

At least 2 distinct, but not necessarily mutually exclusive, pathways of allorecognition exist, the direct and indirect pathways. Each leads to the generation of different sets of allospecific T cell clones.

Direct pathway In the direct pathway, host T cells recognize intact allo-MHC molecules on the surface of the donor or stimulator cell. Mechanistically, host T cells see allo-MHC molecule + allo-peptide as being equivalent in shape to self-MHC + foreign peptide and, hence, recognize the donor tissue as foreign. This pathway is presumably the dominant pathway involved in the early alloimmune response.

The transplanted organ carries a variable number of passenger APCs in the form of interstitial dendritic cells. Such APCs have a high density of allo-MHC molecules, and are capable of directly stimulating the recipient's T cells. The relative number of T cells that proliferate on contact with allogeneic or donor cells is extraordinarily high as compared with the number of clones that target antigen presented by self-APC. Thus, this pathway is important in acute allorejection.

Indirect pathway

In the indirect pathway, T cells recognize processed alloantigen presented as peptides by self-APCs. Secondary responses such as those that occur in chronic or late acute rejection are associated with T cell proliferative responses to a more variable repertoire, including peptides that were previously immunologically silent. Such a change in the pattern of T cell responses has been termed epitope switching or spreading.

A link between self-MHC + allopeptide-primed T cells and the development of acute vascular type rejection has been demonstrated to be mediated in part by accelerated alloantibody production. In addition, chronic allograft vasculopathy may be mediated by T cells primed by the indirect pathway.

Molecular mechanisms of T cell activation

During T cell activation, membrane-bound inositol phospholipid is hydrolyzed into diacylglycerol (DAG) and IP3. This increases the cytoplasmic calcium. The elevation in calcium promotes the formation of calcium-calmodulin complexes that activate a number of kinases as well as protein phosphatase IIB or calcineurin. Calcineurin dephosphorylates cytoplasmic nuclear factor of activated T cells (NFAT), permitting its translocation to the nucleus, where it binds to the IL-2 promoter sequence and then stimulates transcription of IL-2 mRNA. Numerous other intracellular events, including protein kinase C (PKC) activation by DAG and activation of nuclear factor kappa B (NFkB) also occur at the molecular level. Effector stage

Alloantigen-dependent and independent factors contribute to the effector mechanisms. Initially, nonimmunologic "injury responses" (ischemia) induce a nonspecific inflammatory response. Because of this, antigen presentation to T cells is increased as the expression of adhesion molecules, class II MHC, chemokines, and cytokines is upregulated. It also promotes the shedding of intact, soluble MHC molecules that may activate the indirect allorecognition pathway. After activation, CD4-positive T cells initiate macrophage-mediated delayed type hypersensitivity (DTH) responses and provide help to B cells for antibody production.

Various T cells and T cell-derived cytokines such as IL-2 and IFN- are upregulated early after transplantation. Later, -chemokines like RANTES (regulated upon activation, normal T cell expressed and secreted), IP-10, and MCP-1 are expressed, and this promotes intense macrophage infiltration of the allograft. IL-6, TNF-, inducible nitric oxide synthase (iNOS) and growth factors, also play a role in this process. The growth factors, including TGF- and endothelin, cause smooth muscle proliferation, intimal thickening, interstitial fibrosis, and, in the case of the kidney, glomerulosclerosis.

Endothelial cells activated by T cellderived cytokines and macrophages express class II MHC, adhesion molecules, and costimulatory molecules. These can present antigen and thereby recruit more T cells, amplifying the rejection process. CD8positive T cells mediate cell-mediated cytotoxicity reactions either by delivering a "lethal hit" or, alternatively, by inducing apoptosis.

Apoptosis

The final common pathway for the cytolytic processes is triggering of apoptosis in the target cell. After activation of the CTLs, they form cytotoxic granules that contain perforin and granzymes. At the time of target cell identification and engagement, these granules fuse with the effector cell membrane and extrude the

content into the immunological synapse. By a yet unknown mechanism, the granzymes are inserted into the target cell cytoplasm where granzyme B can trigger apoptosis through several different mechanisms, including direct cleavage of procaspase-3 and indirect activation of procaspase-9. This has been shown to play the dominant role in apoptosis induction in allograft rejection.

Alternatively, CD8-positive CTLs can also use the Fas-dependent pathway to induce cytolysis and apoptosis. The Fas pathway is also important in limiting T cell proliferation in response to antigenic stimulation; this is known as fratricide between activated CTLs. Cell-mediated cytotoxicity has been shown to play an important role in acute, although not chronic, allograft rejection.

Role of natural killer cells

The natural killer (NK) cells are important in transplantation because of their ability to distinguish allogenic cells from self and their potent cytolytic effector mechanisms.[4] These cells can mount a maximal effector response without any prior immune sensitization. Unlike T and B cells, NK cells are activated by the absence of MHC molecules on the surface of target cells (missing self hypothesis). The recognition is mediated by various NK inhibitory receptors triggered by specific alleles of MHC class I antigens on cell surfaces.

In addition, they also possess stimulatory receptors, which are triggered by antigens on nonself cells. These effector responses include both cytokine release and direct toxicity mediated through perforin, granzymes, Fas ligand (FasL), and TNFrelated apoptosis-inducing ligand (TRAIL). Through this double negative mode of activation, they are thought to play a role in the rejection of both bone marrow and transplantable lymphomas in animal models.

NK cells also provide help to CD28-positive host T cells, thereby promoting allograft rejection.Their importance in the field of bone marrow transplants has been recognized for years. In humans, their graft-versus-host alloresponse has been used for its potent graft-versus-leukemia effect and has contributed to an increase in the rate of sustained remission in patient with acute myelogenous leukemia.

NK cells are now being recognized as active participants in the acute and chronic rejection of solid tissue grafts. Recent studies have indicated that NK cells are present and activated following infiltration into solid organ allografts. They may regulate cardiac allograft outcomes. Studies have also shown that humans with killer cell immunoglobulin-like receptors that are inhibited by donor MHC have a decreased risk of liver transplant rejection. In cases of renal transplantation, these cells are not suppressed by the current immunosuppressive regimens.

Role of innate immunity

Although T cells have a critical role in acute rejection, the up-regulation of proinflammatory mediators in the allograft is now recognized to occur before the T cell response; this early inflammation following engraftment is due to the innate response to tissue injury independent of the adaptive immune system. Several recent studies have examined the role of Toll-like receptor (TLR) agonists and TLR signals in allorecognition and rejection.

These innate mechanisms alone do not appear sufficient to lead to graft rejection itself. However, they are important for optimal adaptive immune responses to the graft and may play a major role in resistance to tolerance induction. The development of methods to blunt innate immune responses, which has potential implications for a wide variety of diseases, is likely to have a significant impact on transplantation, as well.

RENAL PRESERVATIONS The removal, storage, and transplantation of a solid organ from a donor profoundly alters the homeostasis of the interior milieu of the organ. These effects manifest in the degree to which the return of normal organ function is delayed or prevented after transplantation is completed. The injury an organ sustains during recovery, preservation, and transplantation occurs primarily as a result of ischemia and hypothermia. Techniques for organ preservation serve to minimize this damage to promote optimal graft survival and function. Preservation solutions Various flush solutions are used for organ preservation. Each substantially differs in their composition, but the purposes of each are similar: to prevent cellular edema, to delay cell destruction, and to maximize organ function after perfusion is reestablished. Euro-Collins solution Euro-Collins solution was developed as a modification of the original Collins solution and contained high concentrations of potassium (110 mM), phosphate (60 mM), and glucose (180 mM). Organ preservation improved with the use of Euro-Collins solution. When it was

used for kidney preservation, delayed renal function after implantation was significantly reduced.

Bretschneider histidine tryptophan ketoglutarate solution

Bretschneider histidine tryptophan ketoglutarate (HTK) solution was found to be effective in liver and kidney preservation. Its contents include histidine (200 mM), mannitol (30 mM), tryptophan and alpha-ketoglutaric acid. It also contains low concentrations of sodium, potassium, and magnesium. Histidine serves as a buffer, and tryptophan, histidine, and mannitol act as oxygen free-radical scavengers. The solution improved renal function after transplantation compared with Euro-Collins solution. University of Wisconsin solution University of Wisconsin (UW) solution was developed for liver, kidney, and pancreas preservation. It has been considered the standard for renal and hepatic preservation, effectively extending the ischemic time for kidneys and livers and allowing them to be transported considerable distances to waiting recipients. The solution has an osmolality of 320 mmol/kg and pH 7.4 at room temperature and is composed of the following:

Potassium 135 mmol/L Sodium 35 mmol/L Magnesium 5 mmol/L Lactobionate 100 mmol/L Phosphate 25 mmol/L Sulphate 5 mmol/L Raffinose 30 mmol/L Adenosine 5 mmol/L Allopurinol 1 mmol/L Glutathione 3 mmol/L Insulin 100 U/L Dexamethasone 8 mg/L Hydroxyethyl starch (HES) 50 g/L

Bactrim 0.5 ml/L

The lactobionate is the major effective component of the solution. Its insoluble nature maintains the colloid oncotic pressure of the solution, delaying or preventing equilibration of the solution across the cell membrane, and thus delaying the development of cellular edema. The lowered concentration of potassium improves the flushing efficiency of the solution by removing the vasoconstrictive effect of the high potassium solution. Glutathione is unstable in solution and effective as an oxygen free-radical scavenger only if it is added immediately before use. Adenosine and allopurinol help in this function.

Techniques of Organ Preservation

Because most transplanted organs are from deceased donors, the organ must inevitably be stored after its removal from the donor until it can be transplanted into a suitable recipient. The donor and recipient are often in different locations, and time is needed to transport the donor organ to the hospital where the recipient is being prepared for transplantation. Effective, safe, and reliable methods are needed to preserve the organ ex vivo until transplantation can be performed. Acceptable preservation times vary with the organ. The stored for 40-50 hours, but earlier transplantation is preferred. kidney can safely be

Hypothermic preservation
Hypothermia is the preferred technique of organ preservation because it is simple, does not require sophisticated expensive equipment, and allows ease of transport. Hypothermia is beneficial because it slows metabolism. With hypothermia, the degradative reactions are considerably slowed but not halted. A 10 C decrease in temperature slows the metabolic rate approximately by a factor of 2. Cooling an organ from 37 C to approximately 0 C slows metabolism by a factor of 12-13. Hypothermia alone is not sufficient for adequate preservation because of the time necessary for optimal use of deceased donor organs. Therefore, the organ must also be flushed with an appropriate preservation solution.

Two techniques of hypothermic preservation are used: simple cold storage and continuous hypothermic perfusion. With simple cold storage, the organ is flushed with cold preservative solution and placed in a sterile bag immersed in the solution. The sterile bag is placed inside another bag that contains crushed ice. Advantages of simple cold storage include universal availability and ease of transport. With continuous hypothermic perfusion, which Belzer developed in 1967, a machine is used to continuously pump perfusion fluid through the organ. In this way, oxygen and substrates are continuously delivered to the organ, which maintains ion-pump activity and metabolism, including the synthesis of ATP and other molecules. For kidneys, machine perfusion offers superior results compared with simple cold storage. With simple cold storage, approximately 25-30% of transplanted kidneys have delayed graft function, but with machine perfusion, the rate can be less than 10%. The perfusate is similar to the UW solution, except for the impermeant. For continuous perfusion, gluconate is used in place of lactobionic acid. Ethical issues in transplantation 1. It is the right of individuals to donate as well as to receive an organ . 2. Commercially motivated renal transplantation is unacceptable, has been widely prohibited by law, and the International Society of Transplantation strongly opposes its practice. 3. Given the increasing success of living donor transplants as judged by graft and patient survival, and given the scarcity of cadaveric organs, living-donor transplants should be encouraged. 4. The altruistic living donor must give informed consent, which can only be obtained if he has a proper understanding of the risk involved (e.g., pain, hernia (5%), infection (2%), pneumothorax (5%) and death [1:3000]) . 5. A patient should be treated as an end and not as a means. Respect for dignity, integrity and authenticity of the person is a basic human right . 6. Acceptance of living unrelated donors should be done only after the local ethical committee has given permission or, as required by the country, permission by the Courts .

7. In the last instance, what is and what is not ethical should be determined by the balance between clinical utilitarian demand (saving lives in a cost-effective way) and respect for an individuals right to donate or not to donate an organ in life or after death. Pre operative management before the kidney transplantation procedure: 1. Emotional and physical preparation of the patient for surgery. 2. Informed consent for transplantation and availability of potential donars. 3. The need of immunosuppressive drugs and measures to prevent infection must be reviewed. 4. Dialysis may be required before surgery for any significant abnormality such as fluid overload and hyperkalemia. 5. Inform the patients about the need for dialysis for days or weeks because the kidney there is a chance the kidney may not function immediately.
6. The vascular access must be patent extremity must be labeled dialysis access. No

procedures to prevent use of affected extremity for BP measurements, blood drawing or I V infusions. Investigations to be done before kidney transplantation.
1. Tissue and blood typing to help make sure that the body will not reject the donated

kidney Blood Type matching The first test establishes blood type. There are four blood types A, B, AB and 0. Everyone fits into one of these inherited groups. The recipient and donor must have either the same blood type or compatible ones. The list below shows compatible types.

If blood type is A, donor blood type must be A or O If blood type is B, donor blood type must be B or O If blood type is AB (universal recipient), donor blood type must be A, B, AB or O If blood type is O (universal donor), donor blood type must be O

The AB blood type, called the universal recipient, is the easiest to match because the individual accepts all blood types. Blood type 0, called the universal donor, is the hardest to match. Although people with blood type O can donate to all types, they can only receive kidneys from blood type 0 donors. For example, if a patient with blood type O were transplanted with a kidney from an A donor, the body would recognize the donor kidney as foreign and destroy it. The Rh type (+, -) is not a factor in donor matching. Tissue Typing This involves matching of a type of white blood cell called "lymphocytes". These cells (in fact, all body cells) have special markers called antigens on their surfaces. It is now known that a special group of these antigens, called HLA (Human Leukocyte Antigens) are important in transplantation. The closer the match of antigens between patient and donor, the better the chance of a successful transplant. Since these antigens are inherited from parents, each child inherits half of their antigens from each parent. Therefore, if a parent is the prospective donor for the child, they will share at least one half of the antigens. For siblings (brothers and sisters) of a recipient, the chances of a match are: 25% will have full match, 50% will have a half match, 25% will be completely mismatched.
2. Heart tests such as an EKG, echocardiogram, or cardiac catheterization.

3. Blood investigations hepatitis B,C,HIV, Creatinine levels, blood urea nitrogen, RBS,FBS,PPBS, PT,PTT, INR. 4. Chest X-Ray 5. Tests to look for early cancer. KIDNEY TRANSPLANTATION PROCEDURE . In most cases the barely functioning existing kidneys are not removed, as this has been shown to increase the rates of surgical morbidities. Therefore, the kidney is usually placed in a location different from the original kidney, often in the iliac fossa, so it is often necessary to use a different blood supply:

The renal artery of the kidney, previously branching from the abdominal aorta in the donor, is often connected to the external iliac artery in the recipient.

The renal vein of the new kidney, previously draining to the inferior vena cava in the donor, is often connected to the external iliac vein in the recipient.

Kidney transplant surgery usually lasts three to five hours. The damaged kidneys are usually left in place, with the new kidney being placed in the lower abdomen. The artery and vein of the new kidney will be attached to an artery and vein in the lower part of the abdomen, just above one of the legs. The new kidney's ureter, the tube that links the kidney to the bladder, will be connected to the bladder. The transplanted kidney may function immediately. In some cases the kidney begins to work only after a week or so. Soreness or pain around the surgery site is common.. The recovery time in the hospital is usually about seven days. Kidney-pancreas transplant
The kidney is transplanted together with the pancreas. This is done in patients with diabetes mellitus type 1, in whom the diabetes is due to destruction of the beta cells of the pancreas and in whom the diabetes has caused renal failure (diabetic nephropathy).

Typical Postoperative Orders for the Kidney Transplant Patient :

Fluid: 0.45% normal saline cc: cc replacement per hour up to 500 cc/hour. Vital signs and pulse oximetry: Every 1 hour times 12; every 2 hours times 12, then every hour if stable. Incentive spirometer : Every 2 to 4 hours. Intake and output: Hourly first 12 hours then every 2 hours. Foley irrigation PRN if clots are present. CVP every hour times four, then every 2 hours times four, then every 4 hours. Glucometer: If diabetic, check every 6 hours. Diet: Clear liquids post operative day 1; advance as tolerated. Diabetic diet if diabetic. Labs: CBC, chemistry, glucose, phosphorus, magnesium, calcium. Postoperative day 3, immunosuppressive drug levels. Analgesia: Morphine 1-10 mg every hour for the first 48 hours then oxycodon (Percocet[R]) or propoxyphene (Darvocet[R]) 1 to 2 tablets every 4 to 6 hours PO. Compression device until ambulatory.

POST TRANSPLANT CARE Typical hospital stay for a transplant recipient is about five days. Both kidney donors and recipients will experience some discomfort in the area of the incision after surgery. Central venous pressure will be measured through a central line and should be maintained at 10 mmHg; systolic blood pressure should be maintained above 120 mmHg. To minimize inflammation and maximize postoperative diuresis, steroids such as methylprednisolone (Solumedrol[R]) (up to 1 gram). Diuretics such as mannitol (Osmitrol[R]) (up to 12.5 grams) and furosemide (Lasix[R]) (up to 200 mg) are administered to the patient intravenously in the operating room. A calcium channel blocker such as verapamil (Calan[R]) (5 mg) also may be administered directly into the renal artery to reduce capillary spasm and improve renal blood flow. Caution should be exercised with using verapamil for patients who have a history of taking beta blocker antihypertensive medications

 Pain management in the transplant patient consists of morphine administered intravenously every 2 to 3 hours for the first 24 to 48 hours . Pain should be assessed using the self-reporting pain visual analog scale and compared with vital signs. A regimen of immunosuppressive, or anti-rejection, medication is prescribed to prevent the body's immune system from rejecting the new kidney. Common immunosuppressants include cyclosporine, prednisone, tacrolimus, mycophenolate mofetil, sirolimus, baxsiliximab, daclizumab, and azathioprine. The kidney recipient will be required to take a course of immunosuppressant drugs for the lifespan of the new kidney. Intravenous antibodies may also be administered after transplant surgery and during rejection episodes. Because the patient's immune system is suppressed, he or she is at an increased risk for infection. The incision area should be kept clean, and the transplant recipient should avoid contact with people who have colds, viruses, or similar illnesses. If the patient has pets, he or she should not handle animal waste. Fluid Replacement: Intravenous fluid replacement must be adequate to keep the patient euvolemic or mildly hypervolemic, as assessed through repeated CVP measurements. The choice of intravenous fluid will depend upon the transplant center's protocol but is usually 0.45% normal saline, which closely resembles the sodium content of a newly transplanted diuresing kidney (60 to 80 mEq/L) . Urine output must be monitored and recorded hourly, with output replaced on an hourly milliliter-for-milliliter basis. If the patient is hypovolemic or an attempt is being made to increase urine output, 0.9% normal saline can he administered intravenously as fluid boluses of 250 to 500 ml over 1 hour. The transplant team will provide detailed instructions on what should be avoided posttransplant. After recovery, the patient will still have to be vigilant about exposure to viruses and other environmental dangers. Transplant recipients may need to adjust their dietary habits. Certain immunosuppressive medications cause increased appetite or sodium and protein retention, and the patient may have to adjust his or her intake of calories, salt, and protein to compensate. Early Postoperative Bleeding; The following signs of postoperative bleeding should be reported to the surgeon immediately .

* Dressing over the transplant incision is soaked with blood. * Blood is oozing from an incision that has been closed with surgical glue. * Drains are filled with blood on an hourly basis. * The hematocrit decreases. * There is a palpable or a visible distention over the incision site (known as a perinephric hematoma). * The patient exhibits signs and symptoms of blood loss such as tachycardia, hypotension, decreased level of consciousness, and/or decreased urine output. POSSIBLE COMPLICATIONS POST-TRANSPLANT 1. Rejection The body resists the presence of foreign cells or tissue of a donor kidney in much the same way that it fights off bacteria and viruses which cause illness. The rejection process occurs when the patients white blood cells reduce or stop the function of the transplanted kidney. Some patients experience a rejection episode in the first few weeks after their operation. Symptoms of rejection may include fever, decreased urine output, fluid retention and increase in weight, tenderness over the kidney and elevated blood pressure. Most rejection episodes can be reversed with drug treatment. There are three types of rejection: a) Hyperacute Rejection - Hyperacute rejection occurs within minutes to hours after the release of the vascular clamps to the transplanted kidney. In spite of aggressive treatment with anti-rejection medications, hyperacute rejection often leads to graft loss. Even with sophisticated cross-matching procedures, a hyperacute rejection episode still may occur in approximately 5% of patients. b) Acute Rejection - Acute rejection occurs days to weeks after the transplant and is manifested by signs and symptoms such as fever, chills, myalgias, and arthralgias.

Approximately 90% of acute rejection episodes are cell mediated and are reversed pharmacologically with relative ease.

c) Chronic Rejection - occurs slowly over a long period of time and there may be no obvious symptoms. Chronic rejection leads to late graft loss, occurs insidiously over months to years, and results in progressive loss of renal function. Chronic rejection can be due to noncompliance with immunosuppressive medications, the age of the transplant, and/or use of medications/herbal supplements that decrease immunosuppression medication levels. In kidney recipients, chronic rejection (called chronic allograft nephropathy) manifests as fibrosis and glomerulopathy. The following factors increase the risk of chronic rejection:

Previous episode of acute rejection. Inadequate immunosuppression. Initial delayed graft function. Donor-related factors (eg, old age, hypertension). Reperfusion injury to organ. Long cold ischemia time. Recipient-related factors (eg, diabetes, hypertension, hyperlipidemia). Posttransplant infection (eg, cytomegalovirus [CMV]).

2. Infection Because the drugs used to prevent and control rejection also weaken the bodys defences, patients are more prone to infection after transplant. Risk of infection commonly in the wound site, mouth, urinary tract and lungs is highest in the first few months after transplant because drug dosage is highest. This is the reason for strict infection control in the transplant ward. Whilst some infections can be very serious, most are controlled by antibiotics and/or reducing doses of anti-rejection drugs. 3. Cardio vascular disease Transplant recipients have an increased incidence of atherosclerotic vascular disease. Cardiovascular disease is the leading cause of death after renal transplantation. Hypertension, hyperlipidemia, diabetes mellitus, smoking, rejection, infections and increased homocysteine levels can all contribute to cardiovascular disease.

Immunosupressants can worsen hypertension and hyperlipidemia levels. It is important that the patient be taught to control risk factors. 4. Malignancies The over all incidence of malignancies in kidney transplantation is about 6% which is 100 times greater than in the general population. The primary cause if this increased is the immunosuppressive theraphy. The malignancies include cancer of the skin, lips, kidney, hepatobiliary system, vulva and perineum: lymphomas and Kaposi sarcoma and other sarcomas. 5. Recurrence of original renal disease Recurrence of the original disease that destroyed the native kidneys occurs in some kidney transplant recipients. It is most common with certain types of Glomerulonephritis, IgA nephropathy, diabetic nephropathy and focal segmental sclerosis. Disease recurrence can result in the loss of a functioning kidney transplant. Patients must be adviced before transplantation if they have a disease known to recur. 6. Corticosteroid related complications Aseptic necrosis of hips, knees and other joints can result from chronic corticosteroids theraphy and renal osteodystrophy. Other significant problems related to corticosteroids include peptic ulcer disease, glucose intolerance and diabetes, cataracts, hyperlipidemia, and an increased incidence of infections and malignancies. vigilant monitoring fro side effects of corticosteroids and early treatment is essential.

Advantages of transplantation over dialysis .

1. There is no dependence on the machine thrice a week for the rest of one's life. 2. There are hardly any restrictions in the diet and fluid intake after a successful transplant. 3. The physical sense of well-being is so much better that one can go back to work in a style similar to that before the illness. 4. Usually the anaemia (and feeling of tiredness) seen in patients with renal failure is reversed after a successful transplant, since the kidney is functioning to maintain normal red cell production. For patients on dialysis, correction of anaemia requires life-long use of

erythropoietin injections which are extremely expensive. 5. A woman may be able to conceive a child after having a successful transplant. (women on dialysis usually do not ovulate and therefore are unable to become pregnant.) 6. Men who may be having sexual problems such as inability to maintain an erection may find this problem eliminated once they receive a successful transplant.

Journal abstract Malignancy After Renal Transplantation: The Role of Immunosuppression Abstract Outcomes of kidney transplantation, in terms of graft and patient survival, have improved over the past few decades, partly as a result of the introduction of new immunosuppressive drugs. Many immunosuppressive agents are associated with an increased risk of cardiovascular events and an increased risk of cancer, however, which can compromise patient survival. Cancer is more common among solid-organ transplant recipients than it is in the general population or in patients on dialysis. In fact, malignancy is the third most common cause of death in renal transplant recipients. Immunosuppressive treatments used in renal transplant recipients can cause malignancy by supporting oncogenesis caused by certain viruses or by impairing immune surveillance thereby enabling faster tumor growth Immunosuppressive drugs associated with an increased risk of malignancy after transplantation are also discussed, as are immunosuppressive drugs that seem to have antioncogenic properties.

CONCLUSION

Major progress have been made in organ transplantation since the kidney transplantation was performed in 1954 in boston between identical twins. The advance made in organ procurement and preservation, surgical techniques, tissue typing and matching, understanding of immune system, immunosuppressants theraphy, and prevention of and treatment for graft rejection have dramatically increased the success of organ transplantation.

BIBLIOGRAPHY
1) Suzanne C, Brend G. Medical surgical nursing. 10th edition. Philadelphia:

Lippincott William & Wilkins; 2004

2) Lewis, Heitkemper, Dirksen, OBrien, Bucher. Medical surgical nursing. 7th

edition. Missouri: Elsevier; 2008

3) Ignatavicius D, Workman L, Mishler A. Medical surgical nursing. 2nd edition.

Philadelphia: W.B Saunders company; 2000

4) A Alcaraz, K Budde, U Humke, G Karam, M Lucan. guidelines on renal

transplantation. 1 st edition: Elsevier; 2008.

5) Robert W Schrier. Manual of Nephrology. 7th edition.: Lippincott Williams and wilkins

publishers;2011.
6) Renal transplantation. Available at: http://www.medscape.org/viewarticle/727252