eMedicine Specialties > Transplantation > Surgery

Renal Transplantation (Urology)

Bradley H Collins, MD, Associate Professor, Department of Surgery, Division of Transplantation, Surgical Director of Kidney Transplantation, Surgical Director of Pancreas Transplantation, OPTN/UNOS Program Director of Kidney Transplantation and Pancreas Transplantation, Duke University Medical Center
Thomas D Johnston, MD, Director, Renal and Pediatric Transplantation, Associate Professor, Department of Surgery, University of Kentucky

Updated: Oct 22, 2009

History

Organ transplantation has a long history, beginning with skin autografting in India during the 6^th century BCE. These techniques were adopted by Western medical practitioners during the early Renaissance period and were described in a text on the restoration of the nose, lips, and ears by Gaspare Tagliacozzi (1545-1599). In 1906, Mathieu Jaboulay performed xenotransplantation in humans. He transplanted the kidneys of pigs and goats into the arms of patients with renal failure. Reportedly, these xenografts functioned for as long as one hour. In 1911, Dr. L. J. Hammond of Philadelphia performed the first human-to-human kidney transplant and enjoyed transient success. The work of Jaboulay, Hammond, and others in the early 1900s was performed long before the human immune system was characterized.

Jaboulay's student Alexis Carrel made many significant contributions to the field of organ transplantation. While in Chicago, he developed techniques that improved the vascular anastomosis and introduced cooling as a method of organ preservation. After moving to the Rockefeller Institute in New York, Carrel realized that he could successfully perform renal autografts in dogs; however, kidney allografts between dogs invariably failed. This observation suggested that the failures were not due to technical factors but rather an intrinsic difference between dogs. Carrel hypothesized that the “principle of immunity" might explain his observations.

In 1942, Thomas Gibson and Peter Medawar published their early experience with skin allografts used for the treatment of burns sustained by aviators in World War II. They noted that a recipient's second set of skin grafts, obtained from a donor, were destroyed more rapidly than the first set, obtained from the same donor. The results of Medawar's elegant animal experiments were later developed into the immunologic concept of self and nonself.

Dr. Joseph Murray performed the first successful human kidney transplant in 1954 in Boston. The transplant was performed between identical twin brothers, with the healthy twin serving as a living donor. The recipient lived for eight years before succumbing to recurrent kidney disease. Although this and subsequent identical twin transplants did not address the problem of rejection, they did serve as a proof of concept. For his work in the field of organ transplantation, Murray was awarded the Nobel Prize in Medicine in 1990.

Prior to the advent of immunosuppression, kidney transplantation was limited to HLA-identical siblings and was not applicable to the vast majority of patients with end-stage renal disease. In 1963, the introduction of azathioprine and steroid combination therapy produced encouraging results and became the mainstay of immunosuppression. The results of transplantation had improved; however, acute rejection and complications associated with steroid therapy persisted.

The introduction of cyclosporine in 1983 was one of the most pivotal events in the history of organ transplantation, as it significantly improved the outcomes of all solid organ transplants by reducing the risk of rejection. Further innovations, including anti–T-cell antibodies (both monoclonal and polyclonal preparations), as well as other maintenance immunosuppressants (eg, tacrolimus, mycophenolate, sirolimus), have made a significant impact on both patient and graft survival. Currently, one-year patient and graft survival rates exceed 90% in most transplant centers.

Indications and Contraindications

Indications for Renal Transplantation

Contraindications to Renal Transplantation

• Metastatic cancer
• Ongoing or recurring infections that are not effectively treated.
• Serious cardiac or peripheral vascular disease
• Hepatic insufficiency
• Serious conditions that are unlikely to improve because of kidney transplant, as the patient’s life expectancy can be finitely measured
• Demonstrated and repeated episodes of medical noncompliance
• Inability to adequately perform rehabilitation following transplantation.
• AIDS (CDC definition of CD4 count <200 cells/mm³) unless the following: CD4 count >200 cells/mm³ for >6 mo, undetectable HIV-I RNA, on stable antiretroviral therapy >3 mo, and no major infectious/neoplastic complications

Patient Evaluation

The pretransplant evaluation must address potential contraindications, should include baseline immunologic studies, and should assess the patient's likelihood of success with transplantation.

Basic pretransplant studies

The need for dialysis or a creatinine clearance of <20 mL/min is generally an accepted definition of chronic renal failure. A documented creatinine clearance ≤20 mL/min is necessary to qualify for listing for transplantation in the United States. Typically, basic pretransplant studies are required, including the following:

• Echocardiogram and a stress study
• Chest radiograph
• Pulmonary studies
• Colonoscopy or barium enema (dependent on patient age)
• Mammography, pap smear, prostate-specific antigen (PSA) test, as indicated (dependent on patient age)
• Noninvasive vascular studies
• Abdominal and renal ultrasound
• Serologic tests for HIV, hepatitis B and hepatitis C, cytomegalovirus (CMV), and other viral infections
• Studies of bladder capacity and function (potentially indicated)

Organ Donation

Kidneys are recovered from either living donors or deceased (brain dead) donors. Living donation typically occurs between individuals who share an emotional bond but are not necessarily related. Good Samaritan living donors are anonymous donors who wish to donate their kidney to an individual that he or she doesn’t know. The incidence of living unrelated transplants (those performed between individuals not related by blood) is increasing.² These living unrelated transplants generally have excellent outcomes that are superior to the best-matched deceased donor transplants, although the results are slightly inferior to HLA–identical and haploidentical living donor transplants.

Living donor transplantation

Living donation is a scheduled event that offers the advantage of optimal preparation for the recipient and donor. This situation allows for control of logistics that minimize the organ preservation time. The total ischemia time from removal of the kidney from the donor to the restoration of blood flow in the recipient can be less than 1 hour. With this short preservation time, very low rates of initial poor function of the graft are observed, with most grafts producing high volumes of urine within a few hours with a concomitant clearance of creatinine within the first day.

Previously, living donation required a flank incision, often with rib resection. However, the introduction of laparoscopic and laparoscopy-assisted techniques has proven to be a major improvement to living donation.⁴ Paralleling those advantages noted with other laparoscopic procedures, laparoscopic donor nephrectomy reduces donor postoperative hospital stays by several days and recovery time in motivated patients by several weeks.

In the authors' experience, donors share the advantages noted in other programs,⁵ with diminished need for pain medication, earlier discharge (typically the morning of postoperative day 1), and more rapid functional recovery when compared with open donor nephrectomy. Early experience has shown a considerable increase in the willingness to donate. Transplant programs have noted increases in their overall kidney transplant volumes because potential donors face less postoperative morbidity and fewer economic disincentives when this technique is used.²

Laparoscopic donor nephrectomy poses a number of surgical challenges. The pneumoperitoneum required for laparoscopic surgery may decrease venous return and compromise graft perfusion. However, with skillful anesthesia, this can be overcome. Careful laparoscopic surgery is required to recover grafts with adequate vessel length and with a well-preserved blood supply to the ureter. Given careful recovery, the authors have not found multiple renal arteries to be a contraindication to recovery except in the rare case in which 4 or more approximately equal-sized arteries are present. The left kidney is preferred because of implantation advantages associated with a longer renal vein; however, the right kidney is preferable in some donors because of anatomic issues.

The authors' preferred implantation approach is direct end-to-side anastomosis of the renal artery to the external iliac artery. However, different approaches are available to the surgeon, including various patch techniques, use of vascular autograft and allograft, and the use of recipient hypogastric or epigastric arteries.

End-to-side anastomosis between the donor main renal artery just above its bifurcation and the recipient external iliac artery.

Transplantation Technique

Gibson incision

Various approaches to kidney transplantation have been used. The Gibson incision is the most common method; it involves a curvilinear incision in a lower quadrant of the abdomen, with division of the muscles of the abdominal wall and dissection of the retroperitoneal space to expose the iliac vessels and the bladder. The external iliac artery and vein are the preferred targets, though the common iliacs may be also used. The inferior vena cava and aorta are accessible via the right-sided approach. Occasionally, a midline incision is utilized. This approach is useful when a recipient has prior transplants in both lower quadrants or a large kidney is placed in a small recipient. The anastomoses are typically performed with permanent vascular sutures (5-0, 6-0, or 7-0; as mandated by operative conditions).

Ureteroneocystostomy

The ureter is anastomosed to the bladder by formation of a ureteroneocystostomy. This procedure may involve bringing the ureter through a tunnel in the bladder submucosa (Leadbetter-Politano), or it may involve creating an anastomosis between the tip of the ureter and the bladder mucosa, then partially covering this with bladder muscularis (Lich).

The decision to use a ureteral stent to facilitate performing the ureteroneocystostomy and reducing the risk of obstruction in the early postoperative period is highly individualized. Some surgeons routinely place stents and some avoid them. The authors typically perform Lich ureteroneocystostomies and insert stents when the ureter or bladder tissue appears marginal. Arranging for cystoscopic stent removal within a few weeks of transplantation is important because a forgotten stent can cause hematuria and become a nidus for stone formation and infection.

Ureteroureterostomy

In rare clinical situations, anastomosis of the ureter to the bladder is not possible. If the donor ureter is devascularized during recovery and must be cut to a length that is too short to reach the bladder, then other options must be considered. Rarely, it is impossible to sufficiently mobilize the bladder for the standard anastomosis. Anastomosis of the donor ureter to the native ureter is a viable option.

Postoperative Management

Postoperative management includes conduction of the procedure and the administration of immunosuppression. The operation involves management of a dynamic fluid balance of a new kidney that is capable of responding to the high urea nitrogen load with an osmotic diuresis but is less capable of concentrating urine or reabsorbing sodium. With improving renal function, fluid balance must be maintained, hypertension management may need modification, and electrolyte abnormalities may require correction.

Current immunosuppressive therapy can be divided into 2 phases: induction and maintenance. For some patients, a state of immunosuppression is induced just prior to the operation. This induction phase is continued during and following transplantation and is divided into antibody and nonantibody regimens. The typical antibody-based induction immunosuppression uses either monoclonal or polyclonal antibody preparations directed at T lymphocytes in combination with calcineurin inhibitors (CNIs; eg, cyclosporine, tacrolimus), antiproliferative agents (eg, azathioprine, mycophenolate), and corticosteroids. Maintenance therapy includes various combinations of a calcineurin inhibitor, an antiproliferative agent, and prednisone.

The choice of induction strategy depends on several factors. Some centers routinely use antibody induction. In centers that do not routinely use antibody induction, most agree that antibody induction should be used in immunologically higher risk transplant cases (eg, retransplants, especially when the first kidney was lost to acute or chronic rejection; African American patients; patients with evidence of significant prior sensitization to human leukocyte antigens as evidenced by a high panel-reactive antibody titer).

Calcineurin inhibitors have been the mainstay of clinical immunosuppression since cyclosporine was introduced in the early 1980s. Calcineurin inhibitors were the first agents to target proliferating T lymphocytes by blocking the elaboration of cytokines (eg, interleukin 2) essential for T-cell proliferation. Both cyclosporine and tacrolimus are naturally occurring products and have significant toxicities. Most notably, these agents have a significant dose-related nephrotoxicity.

The fact that the agents that revolutionized kidney transplantation have significant nephrotoxicity is ironic. This nephrotoxicity, combined with erratic absorption and complex pharmacokinetics, necessitates ongoing monitoring of drug levels to maintain therapeutic levels while avoiding toxicities. While most centers follow drug trough levels, some have used pharmacokinetic modeling to good effect.⁶ Both cyclosporine and tacrolimus are metabolized in the liver by the cytochrome P450 system. Drugs that alter cytochrome P450 metabolism can result in higher blood levels (ie, fluconazole, verapamil) or lower drug levels (ie, rifampin, phenytoin sodium).

The adverse consequences (eg, hypertension, renal impairment) of long-term cyclosporine use for solid organ transplant rejection have prompted exploration of various treatment regimens. Gallagher et al studied long-term graft survival by comparing 3 immunosuppressive regimens in 489 patients with a median follow-up of 20.6 y. The regimens included azathioprine and prednisolone (AP), long-term cyclosporine alone (Cy), or cyclosporine initiation followed by withdrawal at 3 months and azathioprine and prednisolone replacement (WDL).⁷

Mean graft survival (censoring deaths) was superior in the WDL group (14.8 y) compared with the AP group (12.4 y; P = .01) and the Cy group (12.5 y; P = .01). Without censoring deaths, graft survival was superior in the WDL group (9.5 y) compared with the AP group (6.7 y; P = .04) and the Cy group (8.5 y; P = .06). Patient survival did not differ between the 3 groups. Renal function was superior in the AP group at 1, 10, and 15 years posttransplantation and in the WDL group at 1, 5, 10, 15, and 20 years compared with the Cy group.⁷

A new strategy for immunosuppression involves the use of sirolimus (Rapamune), an immunosuppressive drug that targets T cells at a different site in the activation pathway.⁸ Sirolimus can be used in conjunction with reduced doses of calcineurin inhibitors or as a replacement for calcineurin inhibitors in low immunologic risk transplant recipients. Sirolimus lacks the nephrotoxicity of calcineurin inhibitors.⁹ Sirolimus does, however, reduce wound healing and may cause significant myelosuppression.⁹ Patients at high immunologic risk must be maintained on a combination regimen of sirolimus, cyclosporine, and corticosteroids for the first year following transplantation; high-risk patients are defined as transplant recipients who are African American, repeat renal transplant recipients who lost a previous kidney transplant for immunologic reasons, or patients with high panel-reactive antibody values.

Mycophenolic acid reversibly inhibits de novo synthesis of purines during S phase. Because the salvage pathway of purines synthesis is less active in lymphocytes than in other tissues, lymphocytes depend more on this pathway. Mycophenolate is far more selective than its predecessor, azathioprine, and inhibits proliferation of both B and T cells. Used in conjunction with other agents, usually calcineurin inhibitors, mycophenolate significantly reduces the incidence of acute cellular rejection. Mycophenolate can be administered as either a mofetil ester or a sodium salt in enteric coated form. This agent also reportedly reduces interstitial fibrosis associated with chronic rejection in animal models. This agent's principal toxicities occur in the gastrointestinal tract and principally manifest as nausea and diarrhea. This toxicity may limit the use of mycophenolate, but patients who can tolerate it may experience significant reductions in allograft rejection.

Steroids play an important role in induction and maintenance of immunosuppression and in the treatment of rejection. Unfortunately, steroids are associated with many complications of immunosuppression, including bone disease, hypertension, peptic ulcer disease, glucose intolerance, growth retardation, infection, obesity, and lipid abnormalities. Efforts to reduce steroid exposure have taken 2 forms: steroid avoidance and steroid minimization. Steroids have been completely avoided in a limited number of carefully selected cases, albeit with some increase in the rejection rate.

Steroid doses have been reduced and rapidly tapered without significant increased rejection risk.¹⁰ Steroid reduction has been associated with decreases in hypertension, diabetes, and other adverse events associated with steroid therapy. Patients with stable graft function and no significant rejection episodes can often be weaned off steroids within the first 3-12 months and maintained on either combination therapy with a calcineurin inhibitor and an antiproliferative agent or, occasionally, monotherapy consisting of a calcineurin inhibitor alone.¹¹

Complications

Numerous complications are associated with kidney transplantation.

• The incidence of delayed graft function (as defined by the need for dialysis after transplantation) varies based on donor, recipient, and transplant characteristics. Delayed graft function is rare with living donor grafts, probably because of the short cold ischemia time (CIT). For deceased donor kidneys, cold ischemia time remains the best predictor of delayed graft function. While most delayed-graft-function kidneys eventually function, they do have a somewhat diminished lifespan compared with kidneys that function immediately.¹² Delayed allograft function is associated with increased hospital stays and increased perioperative expense.
• Renal artery thrombosis occurs in about 1% of transplants, usually from small-caliber arteries. Nephrectomy is generally required if thrombectomy is unsuccessful. Arterial stenosis occurs in 2-10% of cases, may occur within months or years following transplantation, and is associated with the abrupt onset of hypertension. It can be suspected based on Doppler ultrasound findings. Confirmation generally requires angiography to confirm the presence of the stenosis and exclude proximal vascular disease. One author has found carbon dioxide angiography useful, especially in the setting of renal insufficiency, as it permits the avoidance of nephrotoxic contrast.¹³ Management of arterial stenoses has increasingly turned to percutaneous techniques, including angioplasty and stent placement.
• Venous thrombosis occurs in 0.5-4% of cases. Thrombosis of the main renal vein has been treated successfully in rare instances with thrombolytic agents, though the graft has typically infarcted by the time the thrombosis is detected. Graft infarction may occur with patent main arteries and veins, and nephrectomy is generally required. Graft thrombosis associated with sepsis carries a significant recipient mortality rate. Prompt nephrectomy is indicated.
• With exception of infection, ureteral obstruction is the most common urinary tract problem associated with transplantation. It may occur early or late. Early obstruction may result from clot, edema, or technical problems associated with the ureteroneocystostomy. When Foley catheter placement and expectant management does not resolve the problem, surgical revision of the ureteroneocystostomy over a stent may be required. Late obstruction, when not caused by external compression (eg, lymphocele, pregnancy), is associated most typically with fibrosis or nephrolithiasis. Management is typically by radiologic or cystoscopic stent placement and stricture dilatation.
• Urine can leak at any level of the urinary tract, from the renal pelvis to the urethra. Suspect urine leak when a patient with good or improving graft function develops a fluid leak from the wound or abdominal pain or perineal swelling, typically within a month of transplantation. Fluid leaking from the wound can be collected and assayed for creatinine. Nuclear renal scan is probably the most sensitive test for urine leak. Small bladder leaks often can be managed by bladder decompression with a Foley catheter. Larger and more proximal leaks typically require exploration and repair.
• Leakage from perivascular lymphatic vessels can lead to significant collections of lymph between the lower pole of the transplanted kidney and the bladder. A lymphocele can manifest as swelling, pain, and impaired renal function within the first year following transplantation. Ultrasonography or CT scanning demonstrates the collection well and is used to facilitate treatment planning. Aspiration occasionally resolves the problem, but prolonged catheter drainage is associated with a significant risk of infection. Sclerotherapy with 10% povidone-iodine solution may be successful in small unloculated collections, but lymphocele has a high rate of recurrence. Some early success has been observed on instilling fibrin glue that contains gentamicin and iodine solution. However, the current standard of care is internal drainage of the lymphocele into the abdominal cavity. This is increasingly performed laparoscopically.
• The risk of opportunistic infections is increased following transplantation.¹⁴ These infections are typically caused by commonly encountered pathogens including cytomegalovirus, BK virus, fungi, Pneumocystis (carinii) jiroveci, and Legionella species.¹⁵
• With improved immunosuppression, acute rejection has become less of a problem following transplantation. In the first year following transplantation, acute rejection is observed in approximately 15-25% of patients. Rejection is usually asymptomatic, although it sometimes presents with fever and pain at the graft site. Rejection usually presents as an unexplained rise in serum creatinine levels and can be confirmed with biopsy. Typical biopsy findings of acute cellular rejection include a lymphoplasmacytic infiltration of the renal interstitial areas with occasional penetration of the tubular epithelium by these cells. Most rejection episodes can be treated successfully with a short course of increased steroids. Failure to respond to steroid therapy for a particularly aggressive appearance determined by biopsy may prompt a change of treatment strategy (eg, antilymphocyte antibody agents).
• Chronic rejection appears to have both immunologic and nonimmunologic components. As a broad classification for progressive graft failure, risk factors include initial poor function of the graft and a history of acute rejection episodes. Chronic rejection is not treatable.
• Posttransplant diabetes, hypertension, and hyperlipidemia are all complications of immunosuppressive agents.

Prognosis

Prognosis following kidney transplantation is generally excellent, with 1-year graft survival rates of 80-95%. Many factors influence the anticipated outcome. Human leukocyte antigen–identical living-related transplants have the best overall graft survival rate, while complete mismatch cadaver donor transplants have the worst graft survival rate. Complete mismatch living donor transplants have outcomes equivalent to zero mismatch cadaver donor transplants.

Other factors affect the outcomes following kidney transplantation. The kidney's preservation time can affect outcome. Prolonged cold ischemia time can result in delayed graft function immediately after transplantation and may result in a somewhat shorter lifespan for the transplant. Older age in the donor can adversely affect both immediate graft function and long-term outcomes. In general, both delayed graft function after transplantation and early rejection episodes adversely affect the long-term outcome of the transplant.

Although advances in immunosuppression have led to significant decreases in the incidence and severity of posttransplant acute rejection, these decreases have not led to corresponding increases in graft and patient survival. The most likely explanation for this discrepancy is that the current most common cause of kidney graft loss is death of the recipient with a functioning graft.

To achieve significant improvements in graft and patient survival, patients' comorbidities must be addressed more effectively. Cardiac disease, which is chief among these comorbidities, can be exacerbated by complications of immunosuppression. Special attention should be paid to cardiac risk factors following transplantation, including hypertension, hyperlipidemia, and diabetes.

For further information, see Mayo Clinic - Kidney Transplant Information. For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Kidney Transplant.

Recent Advances

As the number of patients listed for kidney transplantation continues to increase, transplant professionals continue to search for methods to increase the donor pool.¹⁶

Transplanting across a positive crossmatch

A significant number of patients have preformed antibodies to potential living donors. These antibodies develop as the result of exposure to foreign antigens by blood transfusions, prior transplantation, or pregnancy. These recipients have positive crossmatches against identified living donors. Many transplant centers have protocols that enable these sensitized patients to receive kidneys from living donors against whom they have a positive crossmatch. This usually involves several pretransplant pheresis sessions to remove the offending antibodies and intravenous immunoglobulin to inhibit the return of antibodies. The living donor transplant is then performed when the crossmatch converts to negative. Postoperatively, the recipient usually receives additional pheresis treatments and immunoglobulin infusions.¹⁶

Donor exchange

Another option for patients with a positive crossmatch with a potential donor is to enroll in a donor exchange program. Incompatible donor-recipient pairs are screened against other incompatible pairs to determine whether the donors could donate to another recipient. The most equitable method involves 2 recipients exchanging or swapping their donors, with both recipients receiving the kidneys of equal quality. More complicated metrics have been proposed and performed.¹⁷

Multimedia

Media file 1: End-to-side anastomosis between the donor main renal artery just above its bifurcation and the recipient external iliac artery.

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Keywords

renal transplantation, organ transplant, kidney transplant, chronic renal failure, CRF, end stage renal disease, ESRD, deceased donor, cadaveric donor, living kidney donor, extended criteria donor

Contributor Information and Disclosures

Author

Bradley H Collins, MD, Associate Professor, Department of Surgery, Division of Transplantation, Surgical Director of Kidney Transplantation, Surgical Director of Pancreas Transplantation, OPTN/UNOS Program Director of Kidney Transplantation and Pancreas Transplantation, Duke University Medical Center
Bradley H Collins, MD is a member of the following medical societies: American College of Surgeons, American Society of Transplant Surgeons, and Society of University Surgeons
Disclosure: Nothing to disclose.

Coauthor(s)

Thomas D Johnston, MD, Director, Renal and Pediatric Transplantation, Associate Professor, Department of Surgery, University of Kentucky
Thomas D Johnston, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Surgeons, American Society of Transplant Surgeons, Association for Academic Surgery, International College of Surgeons US Section, and Kentucky Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Edward David Kim, MD, FACS, Professor of Surgery, Division of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center
Edward David Kim, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society for Reproductive Medicine, American Society of Andrology, American Urological Association, and Tennessee Medical Association
Disclosure: Lilly Consulting fee Consulting; Astellas Consulting fee Speaking and teaching; Indevus Consulting fee Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Chief Editor

Sanjay Kulkarni, MD, FACS, Director, Kidney and Pancreas Transplantation and Assistant Professor of Surgery, Department of Surgery, Yale University School of Medicine
Sanjay Kulkarni, MD, FACS is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Surgeons, American Society of Transplant Surgeons, and Association for Academic Surgery
Disclosure: Nothing to disclose.

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