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Kidney Transplantation

The burden of end-stage renal disease.

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End-stage renal disease (ESRD) is a chronic, progressive illness with a high mortality rate.1 The number of U.S. residents who have been diagnosed with ESRD has increased steadily with the aging of the population. In 1980, 59,172 people had been diagnosed with ESRD; in 2010, that number had soared to 584,544.1 The average annual Medicare cost to treat ESRD also has increased. In 1991, the average annual cost per person was $35,943; in 2010, it was $75,043.1

A person who is receiving dialysis therapy has an average life expectancy of 7.1 years.1 This increases to 18.5 years if a kidney transplant is received.1 In addition to longevity of life, a person who undergoes kidney transplantation generally experiences an improvement in physical and emotional well-being, a reduction in fatigue, an increased ability to return to work, and improved satisfaction with life.

Pretransplant Considerations

Early referral is important for successful transplantation and long-term survival. Each transplant center has specific criteria that recipients must meet in order to qualify for a transplanted organ. A pre-emptive transplant is performed when the estimated glomerular filtration rate (eGFR) is 20 mL/min or less and the patient has not started dialysis therapy. A referral for transplant can also be made after dialysis therapy has been initiated. A transplant recipient may receive a kidney from a donor who is living or deceased.

Evaluation for Transplant

A person's overall health status and length of time on dialysis are important factors in successful transplantation. Prior to receiving a transplanted kidney, it is important for the patient to have well-controlled blood pressure, well-controlled blood glucose levels, a stable hemoglobin level, and a healthy nutritional status. Potential recipients are screened for dental disease, ischemic heart disease, cerebrovascular disease, obesity, pulmonary disease, and psychosocial stability.2,3 A dental exam, electrocardiogram and/or echocardiogram, chest x-ray and colonoscopy are required by many transplant centers. Women require a pelvic exam, a Papanicolaou test and mammography. Men require a prostate evaluation.

Standard blood tests include a complete blood cell count, comprehensive metabolic panel, blood and tissue typing, anticoagulation studies, a hepatitis panel, HIV testing, herpes simplex virus and cytomegalovirus titers.2,3

Other requirements vary among transplant centers. Some require patients who smoke cigarettes to have been abstinent for a certain period of time. Others have specifications for body mass index. For patients with a drug or alcohol addiction, completion of a rehabilitation program may be required before being approved as a transplant candidate.

It is also important for a transplant recipient to have health insurance coverage or another source of funds available to cover the cost of transplant surgery, postoperative care and immunosuppressant medications required for the rest of his or her life.

Securing an Organ

Since the first kidney was successfully transplanted in 1954, the demand for kidneys has exceeded the number of kidneys available for transplant.4 The National Organ Transplant Act of 1984 was passed to address the organ shortage and assure fair distribution of organs in the United States.4 This act made the sale of human organs illegal and led to the development of the National Organ Procurement and Transplant Network (OPTN). This network is operated by the United Network for Organ Sharing (UNOS), a private nonprofit organization.4,6

Organs from deceased donors are allocated based on medical urgency, the degree and quality of tissue match, blood type compatibility, length of time on the waiting list, age and organ size, immune status, and recipient's proximity to the transplant center.4-6

OPTN has designated 11 donor regions in the United States. Available organs are offered first to local recipients, then to regional recipients, then to national recipients.4,6 Today, 233 medical centers provide kidney transplantation in this country.4 At the end of 2011, 86,547 people were on the waiting list for a kidney transplant. During 2011, 10,399 people received transplants from deceased donors, 4,922 people received transplants from living donors, and 5,139 people died while on the waiting list.4

Post-Transplant Considerations

Rejection of the transplanted kidney or allograft can lead to organ failure. A person who has received a transplant is monitored closely after surgery and after discharge from the transplant center. Three types of rejection can occur: hyperacute rejection, which occurs minutes to hours after transplantation; acute rejection, which occurs days to weeks after transplantation; and chronic rejection, which occurs slowly over months to years after transplantation.5

Immunosuppressant Medications

Several medications are used to prevent allograft rejection. Most transplant center protocols use a combination of three classes of medications: corticosteroids, antimetabolites and calcineurin inhibitors (CNIs) or m-TOR kinase inhibitors.7,8

Prednisone is the most commonly used corticosteroid. This class of medication inhibits T-cell and macrophage activation.7,8  Common adverse side effects include increased risk of infection, growth impairment, osteonecrosis, impaired wound healing, cataract formation, hyperlipidemia, glucose intolerance, and psychologic abnormalities.7,8

Mycophenolate mofetil (CellCept, Myfortic) and azathioprine (Imuran) are the most commonly used antimetabolites. This class of medication blocks de novo purine synthesis, inhibits DNA and RNA synthesis, and controls T- and B-cell lymphocyte and monocyte proliferation.7,8 Common adverse side effects include gastrointestinal symptoms such as nausea, vomiting, reflux and diarrhea. Hematologic abnormalities such as leukopenia and anemia may also occur.7,8

Tacrolimus (Prograf) and cyclosporine (Gengraf, Neoral, Sandimmune) are the most commonly used CNIs. This class of medications restricts T-cell activation by inhibiting calcineurin, impairing nuclear proteins and limiting the expression of critical cytokine genes including interlukin-2, interlukin-4, interferon-gamma and tumor necrosis factor-alpha.7,8

The CNIs are metabolized by the cytochrome P 450 and CYP3A4 enzyme and have multiple drug-drug interactions. 7 Care should be used when prescribing medications for patients who are taking CNIs. Drugs that increase the serum level of CNIs include calcium channel blockers, amiodarone (Pacerone), HIV protease inhibitors, antifungal agents, erythromycin-based antibiotics, lovastatin (Mevacor) and fluvoxamine (Luvox). Grapefruit juice also increases the serum level of CNIs.7,8

Drugs that decrease the serum level of CNIs include antitubercular agents and anticonvulsants. St. John's wort also decreases serum CNI levels.7,8 Serum trough levels of CNIs are regularly monitored because elevated levels can cause nephrotoxicity and allograft failure. Common adverse side effects include hypertension, electrolyte abnormalities such as hyperkalemia and hypomagnesemia; digestive system effects such as nausea, vomiting, diarrhea, and colelithiasis; and dermatologic abnormalities such as hypertrichosis, thickening of the skin, alopecia and gingival hyperplasia.7,8    

Sirolimus (Rapamune), a macrolide antibiotic compound, is also used for immunosuppression. This medication inhibits mTOR kinase, an enzyme used for RNA transcription and cell cycle progression.7,8  Sirolimus is metabolized by CYP3A4 in the liver and interacts with calcium channel blockers, antifungal agents, antitubercular agents and anticonvulsants.7,8 The most common adverse side effects are hypertension, dyslipidemia, electrolyte imbalances, thrombosis, impaired wound healing, pneumonitis and hematologic abnormalities.7,8

Post-Transplant Care

The most common causes of mortality in the months and years following kidney transplantation are cardiovascular disease, cancer, and infection.7,9 Transplant recipients require monitoring and treatment for hypertension, dyslipidemia, atherosclerosis, glucose intolerance and osteoporosis.7

Immunosuppression increases the risk for life-threatening infections. Transplant recipients are at risk for bacterial and viral infections and are generally placed on prophylactic antibiotic and antiviral therapy for several weeks after surgery. Patients should receive influenza, pneumococcus, varicella and hepatitis B vaccines prior to transplantation and all recommended non-live virus vaccines after transplant.7,9 Immunosuppression increases the risk of malignant tumor growth. A full physical examination with screening of heart, breasts, lungs, colon, prostate and skin should be performed annually - and more frequently if abnormalities are found after transplant.

Advances in ESRD Treatment

Currently, researchers are examining the potential use of stem cells and regenerative medicine to reduce the high number of deaths that occur annually due to a shortage of kidneys available for transplant. The kidney is a complex organ comprised of a variation of cell types that perform different functions. Researchers are studying the ability of stem cells to repair damaged cells to slow or halt kidney disease progression. 10,11 The process of seeding cells into discarded animal or human kidney scaffolds for organ regeneration is also being studied.12

Practice Implications

Patients with ESRD who receive a kidney transplant experience an improved quality of life and a lower risk of mortality. Referring patients with chronic kidney disease to a nephrology provider when they have an eGFR of 30 mL/min or less provides an opportunity for close monitoring of kidney function and an early referral for kidney transplantation.

References

1. United States Renal Data System, USRDS 2012 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. http://www.usrds.org/adr.aspx

2. Kasiske BL, Connaire JJ. Selection of prospective kidney transplant recipients.  In: Greenberg A. Primer on Kidney Diseases. 5th ed. Philadelphia, PA: Saunders Elsevier; 2009: 525-541.

3. Kendrick E. Evaluation of the transplant recipient. In: Danovich GM. Handbook of Kidney Transplantation.3rd ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2001: 130-145.

4. United Network for Organ Sharing. Donation and Transplantation. http://www.unos.org/donation/index.php

5. Helderman JH, Goral S. Transplantation immunobiology. In Danovich GM. Handbook of Kidney Transplantation. 3rd ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2001: 17-33.

6. Katznelson S, et al. Histocompatibility testing, crossmatching, and allocation of cadaveric kidney transplants. In Danovich GM. Handbook of Kidney Transplantation. 3rd ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2001: 39-61.

7. Mannon RB. Post-transplantation monitoring and outcomes. In: Greenberg A. Primer on Kidney Diseases. 5th ed. Philadelphia, PA: Saunders Elsevier; 2009: 534-542.

8. Danovich GM. Immunosuppressive medications and protocols for kidney transplantation. In: Danovich GM. Handbook of Kidney Transplantation. 3rd ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2001: 62-110.

9. Bottomley MJ, Harden PN. Update on the long-term complications of renal transplantation. Brit Med Bull. 2013;106:117-134.

10. Morigi M, Benigni A. Mesenchymal stem cells and kidney repair. Nephrol Dial Transplant. 2013;28(4):788-793.

11. Sedrakyan S, et al. Stem cells as a therapeutic approach to chronic kidney diseases. Curr Urol Rep. 2012;13(1):47-54.

12. Orlando G, et al. Discarded human kidneys as a source of ECM scaffold for kidney regeneration technologies. Biomaterials. 2013;34(24):5915-5925.

Valerie L. Lee is a family nurse practitioner who specializes in nephrology at St. Luke's Clinic in Boise, Idaho. She has completed a disclosure statement and reports no relationships related to this article.

                                   




     

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