Transplant 101

1. Transplant 101

2. Transplant 101: Overview Transplant as treatment for ESRD The pretransplant evaluation Contraindications to transplantation Deciding on a donor Deceased United Network for Organ Sharing (UNOS) and organ allocation Living Determining a suitable candidate Donor evaluation Matching donor and recipient Kidney transplantation has become a very successful and routine treatment for ESRD. Patients who receive kidney transplants have a higher quality of life, less costly therapy, and less risk of death than those on dialysis. This success has led to a demand for organs that cannot be met by the limited number of available deceased donors. The United Network for Organ Sharing (UNOS) has attempted to develop a fair allocation system for placing patients on waiting lists for kidney transplantation. An increase in the number of available organs would allow patients to receive kidney transplants earlier in the course of their disease. Kidney transplantation has become a very successful and routine treatment for ESRD. Patients who receive kidney transplants have a higher quality of life, less costly therapy, and less risk of death than those on dialysis. This success has led to a demand for organs that cannot be met by the limited number of available deceased donors. The United Network for Organ Sharing (UNOS) has attempted to develop a fair allocation system for placing patients on waiting lists for kidney transplantation. An increase in the number of available organs would allow patients to receive kidney transplants earlier in the course of their disease.

3. History of Kidney Transplantation Initial experiments date back to World War II AZA debuted in 1960s Transplant outcomes improved CsA introduced in the early 1980s 1-year graft survival rate exceeds 80% Now, transplant patients have survival advantages over those remaining on dialysis Despite initial experiments dating back to World War II, kidney transplantation did not emerge as a truly viable means of treating ESRD until the introduction of AZA in the early 1960s. CsA followed 20 years later, ushering in the current era of solid-organ transplantation with 1-year graft survival rates exceeding 80%. Experience gathered in the past two decades documents even greater survival advantages for transplant recipients over those remaining on dialysis. Despite initial experiments dating back to World War II, kidney transplantation did not emerge as a truly viable means of treating ESRD until the introduction of AZA in the early 1960s. CsA followed 20 years later, ushering in the current era of solid-organ transplantation with 1-year graft survival rates exceeding 80%. Experience gathered in the past two decades documents even greater survival advantages for transplant recipients over those remaining on dialysis.

4. Treatment Modalities for ESRD Patients (2002) This improvement in transplantation survival rates has proven timely as the number of patients experiencing ESRD continues to swell. As of 2002, 431,284 patients were diagnosed with ESRD, with slightly less than one third having a kidney transplant as treatment. USRDS 2004 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. 2004.This improvement in transplantation survival rates has proven timely as the number of patients experiencing ESRD continues to swell. As of 2002, 431,284 patients were diagnosed with ESRD, with slightly less than one third having a kidney transplant as treatment. USRDS 2004 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. 2004.

5. Transplant-Related Quality-of-Life Benefits Relatively unrestricted diet Freedom to travel Ability to become pregnant and bear children Can engage in training for athletic competition Lifestyle free of dialysis constraints In addition, kidney transplantation offers quality-of-life benefits that cannot be obtained through dialysis. These include the opportunity to: • Eat a relatively unrestricted diet • Travel without need for dialysis • Become pregnant and bear children • Engage in strenuous training for athletic competition • Enjoy a life free of the limitations imposed by dialysis  In addition, kidney transplantation offers quality-of-life benefits that cannot be obtained through dialysis. These include the opportunity to: • Eat a relatively unrestricted diet • Travel without need for dialysis • Become pregnant and bear children • Engage in strenuous training for athletic competition • Enjoy a life free of the limitations imposed by dialysis  

6. ESRD Survival by Treatment Modality Transplantation carries a significant survival advantage over dialysis, and the advantage becomes greater over time. This chart may slightly overstate the survival advantage for transplantation, since the dialysis population contains a number of patients with risk factors that disqualify them from placement on the transplant waiting list. Still, transplantation significantly reduces the risk of death, even for dialysis patients on the transplant waiting list. National Kidney Foundation. Available at: http://www.kidney.org. Transplantation carries a significant survival advantage over dialysis, and the advantage becomes greater over time. This chart may slightly overstate the survival advantage for transplantation, since the dialysis population contains a number of patients with risk factors that disqualify them from placement on the transplant waiting list. Still, transplantation significantly reduces the risk of death, even for dialysis patients on the transplant waiting list. National Kidney Foundation. Available at: http://www.kidney.org.

7. Treatment Modality in ESRD Patients Alive Beyond 10 Years The data in this figure show that more than two thirds of ESRD patients surviving at least 10 years have functioning kidney allografts. USRDS 2000 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. 2000.The data in this figure show that more than two thirds of ESRD patients surviving at least 10 years have functioning kidney allografts. USRDS 2000 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. 2000.

8. Graft Survival in 2405 Paired-Kidney Transplants: Short vs Long ESRD Time Time on dialysis can strongly affect the eventual survival of a kidney allograft. In this paired-kidney analysis, graft survival rates at 5 and 10 years were significantly worse for recipients who had spent >24 months on dialysis (58% and 29%, respectively) than for recipients who were on dialysis for <6 months prior to transplantation (78% and 63%, respectively). Meier-Kriesche HU, et al. Transplantation. 2002;74:1377-1381.Time on dialysis can strongly affect the eventual survival of a kidney allograft. In this paired-kidney analysis, graft survival rates at 5 and 10 years were significantly worse for recipients who had spent >24 months on dialysis (58% and 29%, respectively) than for recipients who were on dialysis for <6 months prior to transplantation (78% and 63%, respectively). Meier-Kriesche HU, et al. Transplantation. 2002;74:1377-1381.

9. Survival Benefit of Transplant vs Remaining on Waiting List This figure illustrates the survival advantage of transplantation for patients healthy enough to qualify for the deceased-donor waiting list. Taking the risk of death over time for wait-listed patients as the reference value (horizontal line, RR=1.0), the dotted and dashed lines show the survival advantage provided by an “ideal” kidney transplant and by transplantation with a “marginal” donor organ. Transplant carries a higher risk of death in the immediate posttransplant period only. Ojo AO, et al. J Am Soc Nephrol. 2001;12:589-597.This figure illustrates the survival advantage of transplantation for patients healthy enough to qualify for the deceased-donor waiting list. Taking the risk of death over time for wait-listed patients as the reference value (horizontal line, RR=1.0), the dotted and dashed lines show the survival advantage provided by an “ideal” kidney transplant and by transplantation with a “marginal” donor organ. Transplant carries a higher risk of death in the immediate posttransplant period only. Ojo AO, et al. J Am Soc Nephrol. 2001;12:589-597.

10. Contraindications to Transplantation Active malignancy or metastatic cancer Immunosuppression can enable tumor growth Cirrhosis Unless simultaneous liver transplant is planned Severe myocardial dysfunction or peripheral vascular disease Unless due to potentially reversible ischemia, which should be corrected prior to transplant Other severe, irreversible extrarenal disease Active mental illness If patient cannot give informed consent or comply with drug regimens The following conditions are considered contraindications to transplantation: • Active malignancy—Immunosuppression can enable tumor growth. • Cirrhosis—Unless a liver transplant is undertaken at the same time, patients with cirrhosis are typically not considered for kidney transplantation. • Severe myocardial dysfunction or peripheral vascular disease—Because of their limited life expectancy and the severe shortage of donor organs, these individuals make poor transplant candidates, unless the cardiac dysfunction is due to potentially reversible ischemia. • Other severe, irreversible disease—In such cases, kidney transplantation may provide little benefit. • Active mental illnesses. Kasiske BL, et al. Am J Transplant. 2001;1(suppl 2):1-95. Siddqi N, et al. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2005:169-192. The following conditions are considered contraindications to transplantation: • Active malignancy—Immunosuppression can enable tumor growth. • Cirrhosis—Unless a liver transplant is undertaken at the same time, patients with cirrhosis are typically not considered for kidney transplantation. • Severe myocardial dysfunction or peripheral vascular disease—Because of their limited life expectancy and the severe shortage of donor organs, these individuals make poor transplant candidates, unless the cardiac dysfunction is due to potentially reversible ischemia. • Other severe, irreversible disease—In such cases, kidney transplantation may provide little benefit. • Active mental illnesses. Kasiske BL, et al. Am J Transplant. 2001;1(suppl 2):1-95. Siddqi N, et al. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2005:169-192.

11. Contraindications to Transplantation (cont’d) Chronic infection or untreated current infection Irreversible limited rehabilitative potential Persistent nonadherence to treatment Active substance abuse Must be treated prior to transplant; drug screening may be required as proof of drug-free status Primary oxalosis Unless combined liver/kidney transplant is an option Other contraindications to transplantation include: • Chronic infection—Patients suffering from an infection should not undergo kidney transplantation, because of the required immunosuppression. • Irreversible limited rehabilitative potential—This may limit the benefit the patient can derive from transplantation. • Persistent nonadherence to treatment—This too may limit the potential benefit from transplantation. • Active substance abuse—Patients with substance abuse problems must be referred for treatment before being considered for kidney transplantation. • Primary oxalosis—The underlying liver abnormality is likely to degrade the kidney graft unless the patient also receives a liver transplant. Kasiske BL, et al. Am J Transplant. 2001;1(suppl 2):1-95. Siddqi N, et al. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2005:169-192. Other contraindications to transplantation include: • Chronic infection—Patients suffering from an infection should not undergo kidney transplantation, because of the required immunosuppression. • Irreversible limited rehabilitative potential—This may limit the benefit the patient can derive from transplantation. • Persistent nonadherence to treatment—This too may limit the potential benefit from transplantation. • Active substance abuse—Patients with substance abuse problems must be referred for treatment before being considered for kidney transplantation. • Primary oxalosis—The underlying liver abnormality is likely to degrade the kidney graft unless the patient also receives a liver transplant. Kasiske BL, et al. Am J Transplant. 2001;1(suppl 2):1-95. Siddqi N, et al. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2005:169-192.

12. Referring Patients to the Transplant Center The referring nephrologist is responsible for coordinating all pretransplant care Point person in coordinating care with transplant center, specialists (eg, cardiology) Encouraging patients to learn about transplantation helps improve outcomes Transplantation can be preemptive Identify potential donors Patient can be listed when GFR <20 mL/min As the referring nephrologist, you can teach your patients about options for renal replacement therapy, and help prepare those who choose transplantation. After the transplant, once the patient’s condition has stabilized, you are also likely to provide most follow-up care. As renal function declines, patients can be placed on a waiting list for kidney transplantation when GFR falls below 20 mL/min. Recent data indicate that transplantation as early as possible yields the best outcomes. In some cases, it may be possible for a transplant to occur before institution of chronic dialysis (preemptive transplantation). It’s important to begin discussing options with your patients while they still have them (late stage 3 or early stage 4 CKD). There is no medical reason a preemptive transplant cannot take place when a living donor is available. Meier-Kriesche HU, et al. Transplantation. 2002;74:1377-1381 As the referring nephrologist, you can teach your patients about options for renal replacement therapy, and help prepare those who choose transplantation. After the transplant, once the patient’s condition has stabilized, you are also likely to provide most follow-up care. As renal function declines, patients can be placed on a waiting list for kidney transplantation when GFR falls below 20 mL/min. Recent data indicate that transplantation as early as possible yields the best outcomes. In some cases, it may be possible for a transplant to occur before institution of chronic dialysis (preemptive transplantation). It’s important to begin discussing options with your patients while they still have them (late stage 3 or early stage 4 CKD). There is no medical reason a preemptive transplant cannot take place when a living donor is available. Meier-Kriesche HU, et al. Transplantation. 2002;74:1377-1381

13. Kidney Transplant Evaluation Process Patients may find the prospect of kidney transplantation a bit frightening. The better they understand the process, the more likely they are to have a successful outcome. It is especially important that patients understand the active role they will have to take in caring for themselves posttransplant, particularly with regard to immunosuppression. Upon referral to the transplant center, your patient will be evaluated to determine whether a transplant is the best treatment option. This evaluation will include a discussion of the risks and benefits of transplantation, and identify any barriers to transplantation. If a barrier (such as ischemic heart disease, substance abuse, or a history of noncompliance with dialysis or other medical regimens) is identified, your patient will most likely be referred to a specialist, such as a cardiologist or substance abuse center, for further evaluation. Kasiske BL, et al. Am J Transplant. 2001;1(suppl 2):1-95. Patients may find the prospect of kidney transplantation a bit frightening. The better they understand the process, the more likely they are to have a successful outcome. It is especially important that patients understand the active role they will have to take in caring for themselves posttransplant, particularly with regard to immunosuppression. Upon referral to the transplant center, your patient will be evaluated to determine whether a transplant is the best treatment option. This evaluation will include a discussion of the risks and benefits of transplantation, and identify any barriers to transplantation. If a barrier (such as ischemic heart disease, substance abuse, or a history of noncompliance with dialysis or other medical regimens) is identified, your patient will most likely be referred to a specialist, such as a cardiologist or substance abuse center, for further evaluation. Kasiske BL, et al. Am J Transplant. 2001;1(suppl 2):1-95.

14. Pretransplant Recipient Evaluation Full medical history and physical exam CBC and chemistry panel PT and PTT Blood type HBV and HBC serology HIV screen CMV test Pelvic exam and Pap smear Chest X-ray ECG HLA tissue typing and cytotoxic antibodies VDRL screen Following the initial evaluation, the transplant candidate will have to go through a lengthy workup to determine his or her overall health status. Additional tests will also be conducted to find donor organs that will be the most immunologically compatible with the patient. Routine pretransplant evaluations are listed on this slide. Kasiske BL, et al. Am J Transplant. 2001;1(suppl 2):1-95. Following the initial evaluation, the transplant candidate will have to go through a lengthy workup to determine his or her overall health status. Additional tests will also be conducted to find donor organs that will be the most immunologically compatible with the patient. Routine pretransplant evaluations are listed on this slide. Kasiske BL, et al. Am J Transplant. 2001;1(suppl 2):1-95.

15. Pretransplant Recipient Evaluation Voiding cystourethrogram Pharmacologic or exercise stress test ECG Coronary angiogram Mammogram Noninvasive vascular study Abdominal ultrasound Upper GI series and upper endoscopy Barium enema and lower endoscopy PSA test Immunoelectrophoresis EBV screen VZV test HSV titer Toxoplasmosis titer Lipid profile PPD tuberculin test Different transplant centers may require a different battery of tests. Contact the center to which you refer your patients to learn which procedures your patients will undergo. This way, you can accurately inform your patients about the evaluation process. Elective pretransplant tests are listed on this slide. Siddqi N, et al. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2005:169-192. Different transplant centers may require a different battery of tests. Contact the center to which you refer your patients to learn which procedures your patients will undergo. This way, you can accurately inform your patients about the evaluation process. Elective pretransplant tests are listed on this slide. Siddqi N, et al. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2005:169-192.

16. Reasons for Exclusion From Transplant Eligibility Approximately one third of patients initially referred for transplantation are considered ineligible. Medical contraindication is the main reason for ineligibility. Exclusion criteria differ between transplant centers, so become familiar with your transplant center’s regulations. New standards from the Centers for Medicare and Medicaid Services (CMS) mandate that transplant centers make exclusion criteria widely available to patients and referring physicians. Holley JL, et al. Am J Kidney Dis. 1998;32:567-574.Approximately one third of patients initially referred for transplantation are considered ineligible. Medical contraindication is the main reason for ineligibility. Exclusion criteria differ between transplant centers, so become familiar with your transplant center’s regulations. New standards from the Centers for Medicare and Medicaid Services (CMS) mandate that transplant centers make exclusion criteria widely available to patients and referring physicians. Holley JL, et al. Am J Kidney Dis. 1998;32:567-574.

17. Conditions Requiring Therapy Prior to Transplantation Active infection Hepatitis Diabetic foot infections Tuberculosis Cardiovascular disease Angiography and revascularization as necessary Peptic ulcer disease Cerebrovascular disease Substance abuse Occasionally, pretransplant workups may reveal previously undiagnosed health issues. These emerging health issues do not necessarily preclude transplant but may require intervention before a transplant can be considered. At the transplant center’s discretion, a patient with such a condition may be placed on the UNOS waiting list, but he or she will not accrue points for waiting until the condition is treated. Conditions requiring therapy prior to transplantation are shown on this slide. Kasiske BL, et al. Am J Transplant. 2001;1(suppl 2):1-95. Occasionally, pretransplant workups may reveal previously undiagnosed health issues. These emerging health issues do not necessarily preclude transplant but may require intervention before a transplant can be considered. At the transplant center’s discretion, a patient with such a condition may be placed on the UNOS waiting list, but he or she will not accrue points for waiting until the condition is treated. Conditions requiring therapy prior to transplantation are shown on this slide. Kasiske BL, et al. Am J Transplant. 2001;1(suppl 2):1-95.

18. Malignancy and Transplantation Standard waiting time is 2 years for most cancers Liver cancer—kidney transplant not recommended without liver transplant Multiple myeloma—transplant not recommended 2- to 5-year wait recommended Malignant melanoma (2 years if in situ) Breast cancer Cervical/uterine cancer (longer wait may reduce recurrence) Because some cancers recur more frequently in transplant patients than in the general population, patients with a history of malignancy should not undergo transplantation until adequate time has elapsed to ensure the malignancy has not recurred. Siddqi N, et al. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2005:169-192. Kiberd BA, et al. Am J Transplant. 2003;3:619-625. Because some cancers recur more frequently in transplant patients than in the general population, patients with a history of malignancy should not undergo transplantation until adequate time has elapsed to ensure the malignancy has not recurred. Siddqi N, et al. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2005:169-192. Kiberd BA, et al. Am J Transplant. 2003;3:619-625.

19. Advantages and Disadvantages of Living-Donor Transplantation Several advantages and disadvantages of living-donor transplantation have been identified and are listed in this table. Kendrick E, et al. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2005:135-168. Several advantages and disadvantages of living-donor transplantation have been identified and are listed in this table. Kendrick E, et al. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2005:135-168.

20. Living and Deceased Kidney Donors, 1993-2002 Many transplant centers consider living donors to be the best option for kidney transplant candidates, due in part to the increasing length of the wait for a deceased-donor organ. As shown in this figure, there has been steady growth in the number of living donors over the past decade, while availability of deceased-donor kidneys has remained relatively static. 2003 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1993-2002.Many transplant centers consider living donors to be the best option for kidney transplant candidates, due in part to the increasing length of the wait for a deceased-donor organ. As shown in this figure, there has been steady growth in the number of living donors over the past decade, while availability of deceased-donor kidneys has remained relatively static. 2003 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1993-2002.

21. Living Donor Evaluation Donor’s risk must be considered separately from recipient’s need for transplant Donor must be informed of the risks ABO blood-type compatibility, tissue type, and crossmatch are initial screening steps With multiple suitable donors, the transplant center will help determine the best donor For a younger recipient who may require a second transplant, a parent may be selected over a sibling, whose kidney may be needed in the future Because donor nephrectomy is an elective operation removing an organ from an otherwise-healthy individual, risks are closely monitored. Sometimes the transplant center will have the donor and recipient evaluated by separate teams, to ensure the donor’s risk is considered separately from the recipient’s need for a transplant. Initial steps taken to screen for donor suitability include a discussion of the risks and benefits involved with donation, ABO blood-type compatibilities, HLA tissue typing, and HLA antibody crossmatch. If multiple family members have blood types and tissue crossmatches suitable for donation, the transplant center will work with the family to determine which potential donor should be selected. If no willing family member is ABO blood-type or tissue-type compatible, an emotionally related donor such as a spouse or friend would be the next likely donor candidate. Kasiske BL, et al. J Am Soc Nephrol. 1996;7:2288-2313.Because donor nephrectomy is an elective operation removing an organ from an otherwise-healthy individual, risks are closely monitored. Sometimes the transplant center will have the donor and recipient evaluated by separate teams, to ensure the donor’s risk is considered separately from the recipient’s need for a transplant. Initial steps taken to screen for donor suitability include a discussion of the risks and benefits involved with donation, ABO blood-type compatibilities, HLA tissue typing, and HLA antibody crossmatch. If multiple family members have blood types and tissue crossmatches suitable for donation, the transplant center will work with the family to determine which potential donor should be selected. If no willing family member is ABO blood-type or tissue-type compatible, an emotionally related donor such as a spouse or friend would be the next likely donor candidate. Kasiske BL, et al. J Am Soc Nephrol. 1996;7:2288-2313.

22. Living Donor Evaluation (cont’d) Medical history and physical exam Comprehensive lab screening Blood count/chemistry panel HBV, HCV, HIV, and CMV tests Glucose tolerance test Urinalysis 24-hour protein and creatinine Cardiovascular workup Chest X-ray ECG Exercise treadmill for donors older than age 50 Helical CT urogram Psychosocial evaluation Repeat crossmatch before transplant The designated donor candidate will undergo a detailed physical and mental/emotional assessment. The American Society of Transplant Physicians has developed an algorithm for the evaluation of potential donors. This slide has been designed to simplify, not replace, that information. Again, this evaluation process will vary by transplant center, and the transplant physician’s discretion will play a significant role in donor selection. Kasiske BL, et al. J Am Soc Nephrol. 1996;7:2288-2313. The designated donor candidate will undergo a detailed physical and mental/emotional assessment. The American Society of Transplant Physicians has developed an algorithm for the evaluation of potential donors. This slide has been designed to simplify, not replace, that information. Again, this evaluation process will vary by transplant center, and the transplant physician’s discretion will play a significant role in donor selection. Kasiske BL, et al. J Am Soc Nephrol. 1996;7:2288-2313.

23. Contraindications to Kidney Donation Age <18 years or >65-70 years Hypertension >140/90 mm Hg or need for medication Diabetes Proteinuria >250 mg/24 hours GFR <80 mL/min Microscopic hematuria Multiple renal vessels Significant medical illness History of thrombosis or thromboembolism Strong family history of renal disease, diabetes, or hypertension Psychiatric conditions or substance abuse Pregnancy Potential contraindications to kidney donation are listed in this slide. Kasiske BL, et al. J Am Soc Nephrol. 1996;7:2288-2313. Potential contraindications to kidney donation are listed in this slide. Kasiske BL, et al. J Am Soc Nephrol. 1996;7:2288-2313.

24. Donor/Recipient Matching Three factors are involved in tissue matching and antibody production Human leukocyte antigen (HLA) antibodies Crossmatch Panel-reactive antibody (PRA) Beyond blood type, there are three factors involved in tissue matching and antibody production—HLA antibodies, crossmatch, and PRA. How well the donor and recipient match can affect the risk of acute rejection, the amount of immunosuppressive drugs needed to prevent rejection, and, ultimately, the outcome of the transplant.  Beyond blood type, there are three factors involved in tissue matching and antibody production—HLA antibodies, crossmatch, and PRA. How well the donor and recipient match can affect the risk of acute rejection, the amount of immunosuppressive drugs needed to prevent rejection, and, ultimately, the outcome of the transplant.  

25. HLA Matching Three groups of HLA proteins (HLA-A, HLA-B, HLA-DR) Many different specific HLA proteins in each group, each with a numerical designation One HLA in each group (haplotype) is inherited from each parent 4 different combinations from 2 parents 25% chance of siblings being haploidentical 25% chance of siblings sharing no haplotype 50% chance of siblings sharing 1 haplotype HLA matching involves three groups of proteins located on the surface of the white blood cells and some other tissues, HLA-A, HLA-B, and HLA-DR. There are many different specific HLA proteins in each group; each has its own numerical designation. One HLA in each group (or haplotype) is inherited from each parent, with 4 different combinations. There is a 25% chance that siblings will have identical haplotypes, a 25% chance of no shared haplotype, and a 50% chance of 1 shared haplotype. HLA matching involves three groups of proteins located on the surface of the white blood cells and some other tissues, HLA-A, HLA-B, and HLA-DR. There are many different specific HLA proteins in each group; each has its own numerical designation. One HLA in each group (or haplotype) is inherited from each parent, with 4 different combinations. There is a 25% chance that siblings will have identical haplotypes, a 25% chance of no shared haplotype, and a 50% chance of 1 shared haplotype.

26. Crossmatch Crossmatch tests whether the recipient has antibodies to the potential donor Negative crossmatch is desired Positive crossmatch increases risk of rejection Antibodies can develop, so repeat crossmatch testing is required immediately before transplant The crossmatch tests whether the recipient has anti-HLA antibodies to the potential donor. These antibodies are the result of previous blood transfusions, pregnancies, or solid-organ transplants. A negative crossmatch is desired, as a positive crossmatch increases the risk of rejection. Antibodies can develop at any time, so repeat crossmatch testing is required immediately before the transplant is performed. Over the past decade, crossmatch techniques have become much more advanced, and they are now able to detect even small quantities of reactive antibody.  The crossmatch tests whether the recipient has anti-HLA antibodies to the potential donor. These antibodies are the result of previous blood transfusions, pregnancies, or solid-organ transplants. A negative crossmatch is desired, as a positive crossmatch increases the risk of rejection. Antibodies can develop at any time, so repeat crossmatch testing is required immediately before the transplant is performed. Over the past decade, crossmatch techniques have become much more advanced, and they are now able to detect even small quantities of reactive antibody.  

27. Panel-Reactive Antibody (PRA) PRA is the amount of HLA antibody present in the recipient’s serum (expressed as a percentage) Determined by testing the recipient’s serum against a panel of cells from 60 people with different HLA proteins HLA antibodies can change, especially in response to blood transfusion, prior transplant, or pregnancy Higher % PRA makes finding a donor more difficult PRA is expressed as a percentage and represents the amount of HLA antibody present in the recipient’s serum. To determine a recipient’s PRA, a serum sample is tested against a panel of cells from 60 different people with different HLA proteins. If a potential recipient demonstrates antibodies reactive with 40 of the donors, the PRA is 67%. This number predicts the likelihood of a positive crossmatch: a donor with a PRA of 67% will likely have a positive crossmatch with two thirds of potential donors, making finding a suitable kidney difficult. Fortunately, most transplant candidates on the waiting list have low PRA levels. PRA is determined each month, and it is based on tests against sera collected from dialysis patients on the kidney transplant waiting list.PRA is expressed as a percentage and represents the amount of HLA antibody present in the recipient’s serum. To determine a recipient’s PRA, a serum sample is tested against a panel of cells from 60 different people with different HLA proteins. If a potential recipient demonstrates antibodies reactive with 40 of the donors, the PRA is 67%. This number predicts the likelihood of a positive crossmatch: a donor with a PRA of 67% will likely have a positive crossmatch with two thirds of potential donors, making finding a suitable kidney difficult. Fortunately, most transplant candidates on the waiting list have low PRA levels. PRA is determined each month, and it is based on tests against sera collected from dialysis patients on the kidney transplant waiting list.

28. Open Nephrectomy Advantages Long-term safety record Simpler equipment requirements Minimal potential abdominal complications Shorter operative time Minimal warm ischemia time Excellent early graft function Disadvantages Postoperative pain Recovery time prior to return to work (6-8 weeks) Long surgical scar with potential for hernia Abdominal wall asymmetry possible At one point, all donor kidneys were removed through a fairly large flank incision. In such cases, the surgeon will often use an extrapleural and extraperitoneal approach just above or below the twelfth rib. Then, the kidney is carefully dissected to preserve renal arteries, veins, and the periureteral blood supply. More recently, a laparoscopic procedure has been developed. About half of all transplant centers offer laparoscopic donor nephrectomy. However, even at centers with laparoscopic capability, donor anatomy and preference sometimes influence the choice of surgical approach. Kendrick E, et al. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2005:135-168.At one point, all donor kidneys were removed through a fairly large flank incision. In such cases, the surgeon will often use an extrapleural and extraperitoneal approach just above or below the twelfth rib. Then, the kidney is carefully dissected to preserve renal arteries, veins, and the periureteral blood supply. More recently, a laparoscopic procedure has been developed. About half of all transplant centers offer laparoscopic donor nephrectomy. However, even at centers with laparoscopic capability, donor anatomy and preference sometimes influence the choice of surgical approach. Kendrick E, et al. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2005:135-168.

29. Laparoscopic Nephrectomy Advantages Less postoperative pain Minimal surgical scarring Rapid return to work (~4 weeks) Shorter hospital stay Magnified view of renal vessels Disadvantages Impaired early graft function Pneumoperitoneum may compromise renal blood flow Longer operative time Tendency to have shorter renal vessels and multiple arteries Graft loss/damage during “learning curve” Added expense Slight increase in donor mortality In a laparoscopic nephrectomy, the donor is placed in the flank position, and the abdomen is insufflated with carbon dioxide. A miniature video camera and instruments are inserted into three or four small incisions in the abdominal wall. The surgeon is able to observe the instruments on a video screen and can thus identify and isolate the renal artery and vein. The perinephric tissues and ureter are manipulated into a plastic sack. A vascular stapler is then used to divide the renal vessels, and the kidney and plastic sack are removed from the abdomen through a small incision below the umbilicus. It is generally thought that the laparoscopic approach allows much faster recovery from the operative procedure. Kendrick E, et al. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2005:135-168. In a laparoscopic nephrectomy, the donor is placed in the flank position, and the abdomen is insufflated with carbon dioxide. A miniature video camera and instruments are inserted into three or four small incisions in the abdominal wall. The surgeon is able to observe the instruments on a video screen and can thus identify and isolate the renal artery and vein. The perinephric tissues and ureter are manipulated into a plastic sack. A vascular stapler is then used to divide the renal vessels, and the kidney and plastic sack are removed from the abdomen through a small incision below the umbilicus. It is generally thought that the laparoscopic approach allows much faster recovery from the operative procedure. Kendrick E, et al. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2005:135-168.

30. Waiting List for a Deceased-Donor Kidney When a living donor cannot be identified Wait can exceed 5 years for blood types O and B Administered by UNOS Patient can be listed when GFR <20 mL/min Transplant center will list the patient after evaluation Patients should ask the transplant center if their names are on the list When a patient reaches ESRD (GFR <20 mL/min) and has been evaluated by the transplant center, he or she may be added to the waiting list administered by UNOS if a living donor cannot be identified. UNOS is based in Richmond, Virginia. It is authorized by the National Organ Transplant Act to oversee organ allocation on a national basis. The patient’s ABO blood type and tissue type are included in his or her file. UNOS allocates kidneys via computerized matching, in accordance with a points system. Unlike with other organs, severity of disease does not figure into the kidney allocation process. Evaluation by a transplant center does not ensure that the patient has been placed on the waiting list. Instruct your patients to specifically ask whether their names and data have been submitted to UNOS. When a patient reaches ESRD (GFR <20 mL/min) and has been evaluated by the transplant center, he or she may be added to the waiting list administered by UNOS if a living donor cannot be identified. UNOS is based in Richmond, Virginia. It is authorized by the National Organ Transplant Act to oversee organ allocation on a national basis. The patient’s ABO blood type and tissue type are included in his or her file. UNOS allocates kidneys via computerized matching, in accordance with a points system. Unlike with other organs, severity of disease does not figure into the kidney allocation process. Evaluation by a transplant center does not ensure that the patient has been placed on the waiting list. Instruct your patients to specifically ask whether their names and data have been submitted to UNOS.

31. Deceased-Donor Kidney Allocation UNOS allocates kidneys in this order: Perfect HLA match, national basis Locally, within recovering hospital’s OPO To patients with PRA >80% In “payback” OPOs, then regionally, then nationally To patients age <18 years In payback OPOs, then regionally, then nationally To patients with PRA 21% to 79% In payback OPOs, then regionally, then nationally To patients with PRA 0% to 20% In payback OPOs, then regionally, then nationally Within above categories, per points system When an organ is procured, the computer will search nationally for a recipient who matches the donor at all identified HLA loci. If a match is found, it will be delivered to the patient’s transplant center and the patient will be notified. Approximately 15% of transplanted kidneys are allocated on the basis of a “perfect” match. If there is no perfect HLA match for an available kidney, the kidney is allocated to a patient in the local area of the organ procurement organization (OPO). If a suitable local patient cannot be matched with the kidney, the kidney is allocated according to an algorithm that takes into account PRA status, patient age, geographic factors, and the UNOS points system. United Network for Organ Sharing. Available at: http://www.unos.org. When an organ is procured, the computer will search nationally for a recipient who matches the donor at all identified HLA loci. If a match is found, it will be delivered to the patient’s transplant center and the patient will be notified. Approximately 15% of transplanted kidneys are allocated on the basis of a “perfect” match. If there is no perfect HLA match for an available kidney, the kidney is allocated to a patient in the local area of the organ procurement organization (OPO). If a suitable local patient cannot be matched with the kidney, the kidney is allocated according to an algorithm that takes into account PRA status, patient age, geographic factors, and the UNOS points system. United Network for Organ Sharing. Available at: http://www.unos.org.

32. Accruing Points on the UNOS List Points are awarded in accordance with this formula: Time on waiting list Quality of antigen mismatch—HLA-DR antigens only (no points for HLA-A or HLA-B matches) PRA—points are assigned if PRA level is >80% with a negative preliminary donor/patient crossmatch Pediatric patients (age <18) awarded add’l points Donation status—individuals who have donated a vital organ in the US receive preference Medical urgency NOT a factor in points system except by local agreement Points are awarded according to the criteria on this slide. In some OPOs, and only with the agreement of all transplant centers in that OPO, medical urgency may be considered in the allocation of available deceased-donor kidneys. United Network for Organ Sharing. Available at: http://www.unos.org.Points are awarded according to the criteria on this slide. In some OPOs, and only with the agreement of all transplant centers in that OPO, medical urgency may be considered in the allocation of available deceased-donor kidneys. United Network for Organ Sharing. Available at: http://www.unos.org.

33. Interim Medical Examinations During wait for a deceased-donor, routine medical evaluations should be conducted Lipid panels Diabetes screening Cancer screening Pap smears and mammograms for women Digital rectal exam or PSA test for men Cardiovascular examination as indicated The community nephrologist should advise the transplant center of changes in health that preclude transplantation Patients who require medical intervention may remain on the UNOS list, but do not accrue “time of waiting” points While waiting for a kidney to become available, your patient should continue to undergo routine medical evaluations, such as lipid panels, diabetes screening, cancer screening (Pap smears and mammograms for women; digital rectal exam or PSA test for men), and cardiovascular examination if indicated. One of the most distressing events in ESRD care occurs when a kidney becomes available, but because of deterioration in medical status, the patient is unable to undergo the transplant. This often occurs because of miscommunication between the referring nephrologist and the transplant center. It is imperative that the “waiting list” identify ESRD patients who are ready for transplantation when a kidney becomes available. To meet this end, transplant centers must be kept up to date about changes in a candidate’s health status. As the referring nephrologist, you should advise the transplant center of any changes in the patient’s health status that would preclude transplant. The patient will not be removed from the waiting list, but he or she will not accrue additional “time of waiting” points until the medical status is upgraded. While waiting for a kidney to become available, your patient should continue to undergo routine medical evaluations, such as lipid panels, diabetes screening, cancer screening (Pap smears and mammograms for women; digital rectal exam or PSA test for men), and cardiovascular examination if indicated. One of the most distressing events in ESRD care occurs when a kidney becomes available, but because of deterioration in medical status, the patient is unable to undergo the transplant. This often occurs because of miscommunication between the referring nephrologist and the transplant center. It is imperative that the “waiting list” identify ESRD patients who are ready for transplantation when a kidney becomes available. To meet this end, transplant centers must be kept up to date about changes in a candidate’s health status. As the referring nephrologist, you should advise the transplant center of any changes in the patient’s health status that would preclude transplant. The patient will not be removed from the waiting list, but he or she will not accrue additional “time of waiting” points until the medical status is upgraded.

34. Expanded-Criteria Donor (ECD) Kidneys From “marginal” donors whose age (>50 years) or medical status would once have precluded donation More likely to fail, but make transplantation more widely available ~15% of deceased-donor kidneys are ECD Offered only to patients who consent in advance to accept ECD organs The shortage of kidneys for transplantation has led to a broadening of what are considered “acceptable” donors. Although ECD kidneys are more likely to fail, compared with standard kidneys, they still provide significant advantages over remaining on dialysis.The shortage of kidneys for transplantation has led to a broadening of what are considered “acceptable” donors. Although ECD kidneys are more likely to fail, compared with standard kidneys, they still provide significant advantages over remaining on dialysis.

35. Accepting an ECD Kidney Decision: present benefits of ECD kidney vs future “standard” kidney ECD kidneys more attractive due to: Increasing waiting times for standard kidneys Aging donor population, increasing ECD availability Clinical improvements may narrow gap between ECD and standard kidney outcomes Placement on ECD waiting list does not preclude eligibility for standard kidney Deciding whether or not to accept an ECD kidney depends largely on how much longer a given individual expects to have to wait for a “standard” kidney. The patient and the physician must determine whether the poorer outcomes and costs of continued dialysis outweigh the benefits that a later transplant with a “standard” kidney would provide. As waiting times grow longer, ECD kidneys become more attractive, especially for older patients (who have a reduced chance of surviving to receive a standard kidney). It is important to note that placement on the ECD waiting list does not reduce the patient’s eligibility to receive a standard kidney should one become available. Schnitzler MA, et al. Transplantation. 2003;75:1940-1945. Deciding whether or not to accept an ECD kidney depends largely on how much longer a given individual expects to have to wait for a “standard” kidney. The patient and the physician must determine whether the poorer outcomes and costs of continued dialysis outweigh the benefits that a later transplant with a “standard” kidney would provide. As waiting times grow longer, ECD kidneys become more attractive, especially for older patients (who have a reduced chance of surviving to receive a standard kidney). It is important to note that placement on the ECD waiting list does not reduce the patient’s eligibility to receive a standard kidney should one become available. Schnitzler MA, et al. Transplantation. 2003;75:1940-1945.

36. Conclusion Community nephrologists play a key role in the transplant process Identification of patients who will benefit from transplant Referral to the transplant center Coordination of specialists in pretransplant evaluation Continuation of care while waiting for transplant Notifying transplant center of health status changes Long-term care posttransplant When a patient is confronted with renal failure, the nephrologist plays a critical role in determining the optimal treatment for that patient. If both the nephrologist and the patient agree that kidney transplantation is an option, the nephrologist will continue to be involved in the patient’s care through the referral to the transplant center, evaluation, pretransplant care, and posttransplant care. When a patient is confronted with renal failure, the nephrologist plays a critical role in determining the optimal treatment for that patient. If both the nephrologist and the patient agree that kidney transplantation is an option, the nephrologist will continue to be involved in the patient’s care through the referral to the transplant center, evaluation, pretransplant care, and posttransplant care.