In 1911, Hammond and Sutton of Philadelphia performed the first human-to-human kidney transplant with transient success. Since then the techniques and indications have evolved. The first wholly successful human transplant took place on December 23, 1954, in Boston, Massachusetts. Surgeon Joseph Murray performed a kidney transplant between identical twin brothers. Although this and subsequent twin transplants did little to solve the problem of rejection, these procedures contributed to proving the value of the procedure and to the solution of many technical problems. In 1963, the introduction of azathioprine and steroid combination therapy produced encouraging results and became the mainstay of immunosuppression until the introduction of cyclosporine in 1983. Cyclosporine, in turn, substantially improved outcomes of cadaver kidney transplants. Further innovations include anti-T-cell antibodies, both monoclonal and polyclonal, and other agents (e.g.: tacrolimus, mycophenolate, sirolimus). Kidney transplantation greatly improves the quality of life for chronic renal failure patients.
Renal transplantation is the treatment of choice for patients with chronic renal failure from most causes. This recommendation is born of its success from several points of view. With recent 1-year graft survival rates approaching 90% and average graft lifetimes in excess of 10 years, this procedure is a cost-effective alternative to dialysis. Recent studies show that renal transplantation prolongs patient lifespan relative to dialysis. Increasingly, patients on dialysis are being referred for transplant evaluation. Because of this, the average patient’s waiting time for a cadaver kidney transplantation has increased significantly over the past several years. A resurgence of interest in living donation, associated with the introduction of the laparoscopic living donor nephrectomy in 1994, has led to significantly increased numbers of living donor transplants, with associated reductions in waiting time and improved short-term outcomes.
The most common causes are diabetes, hypertension, glomerulonephritis, and polycystic kidney disease. In carefully selected patients, virtually all causes of chronic renal failure can be treated with transplantation. Some conditions are likely to recur in the transplanted kidney, including immunoglobulin A (IgA) nephropathy, certain glomerulonephritides, oxalosis, and diabetes. Generally, the rate of recurrence is slow enough to justify transplantation.
In some patients, kidney transplantation alone is not optimal treatment. Combined kidney and pancreas transplantation is the treatment of choice for patients who have type 1 diabetes and renal failure. This can pose a dilemma when the patient has potential living donor candidates. At present, pancreas graft survival is slightly worse in pancreas-after-kidney transplants, but this may be offset in some cases by the reduced waiting time that living donor transplantation affords.
The treatment of oxalosis is controversial; in some cases, renal transplantation in conjunction with pyridoxine therapy can produce good results, but combined liver and kidney transplantation is generally preferred. Hemolytic uremic syndrome, which is not an uncommon cause of renal failure in children, may recur following transplantation in response to cyclosporine-based or tacrolimus-based immunosuppression. Renal tumors (e.g.: Wilms tumor in children, renal cell carcinoma in adults) can be treated with transplantation. A 2-year disease-free interval before transplantation is strongly advised.
These include cardiopulmonary insufficiency, morbid obesity, peripheral and cerebrovascular disease, tobacco abuse, hepatic insufficiency, and other less common factors that increase the risk associated with major surgical procedures. Adverse effects of immunosuppressive drugs may exacerbate atherosclerosis, hypertension, diabetes, and lipid disorders and may thus increase cardiac risk in patients following transplantation. Currently, the most common cause of renal graft failure is patient death from cardiac disease, not direct failure of the graft.
Grafting of a new kidney will not work without immunosuppression. Infection and malignancy are the primary medical conditions that are contraindications to immunosuppression. Acute infections should be fully resolved at the time of transplantation. In general, one should wait approximately 5 years following successful treatment of breast cancer, colorectal cancer, melanoma, diffuse bladder carcinoma, and non-in situ ovarian cancer. This is estimated to reduce the risk of recurrence from about 50% if the transplant is performed within 2 years to about 35% if performed between 2 and 5 years and to about 10% if performed after 5 years. Some tumors may require shorter waiting times. One year is reasonable for isolated nodules of prostatic carcinoma and focal bladder carcinoma. Two years is adequate for in situ uterine carcinoma, some renal tumors (e.g.: clear cell, Wilms, urothelioma), and basal or squamous cell skin carcinoma.
HIV is currently an absolute contraindication in most programs. However, transplantation has been performed successfully in patients with well-maintained CD4 counts. Poor social support, substance abuse, and intractable financial problems can compromise postoperative management and immunosuppression, contraindicating transplantation.
The risk of recurrent disease is not a contraindication to renal transplantation. In about 3% of transplants, evidence of recurrence is observed by 2 years, and it is observed in about 20% by 8 years. Glomerulonephritides (e.g.: mesangiocapillary glomerulonephritis type 1, IgA nephropathy) are most likely to recur; however, loss of the kidney generally occurs late, and, thus, these diseases are not contraindications to transplantation. Focal and segmental glomerulosclerosis is associated with a highly variable rate of recurrence in the first allograft; however, if the first allograft is lost to recurrent disease, the risk of recurrence in the second allograft is approximately 85%.
Similarly, patients with diabetes mellitus have poorer outcomes following transplantation than do patients without diabetes; nearly all patients demonstrate histologic evidence of diabetic nephropathy within 4 years. However, the improved quality of life for patients with diabetes following transplantation justifies its use as the treatment of choice for these patients if they also have end-stage kidney disease. Increasingly, the treatment of choice for patients with type 1 diabetes and renal failure is combined kidney and pancreas transplantation or pancreas transplantation after kidney transplantation. This latter option is particularly attractive when the patient can be transplanted first with a kidney from a living donor.
Hereditary oxalosis is associated with a high rate of recurrence after kidney transplantation and graft failure. The optimal management remains controversial, but it may involve (1) intensive preoperative dialysis to reduce the oxalate burden and (2) combined liver and kidney transplantation.
The need for dialysis or a creatinine clearance of less than 20 mL/min is generally an accepted definition of chronic renal failure. Typically, basic pretransplant studies are required, including the following: Echocardiogram and a stress study, Chest radiograph, Pulmonary studies, Colonoscopy or barium enema, Noninvasive vascular studies, Abdominal and renal ultrasound, Serologic tests for HIV, hepatitis, cytomegalovirus (CMV), and other viral infections, Studies of bladder capacity and function (usually indicated).
Immunologic studies should include human leukocyte antigen (HLA) typing and measurement of the panel reactive antibody (PRA) titer. The panel reactive antibody titer approximates the likelihood that a randomly chosen kidney donor has a positive cytotoxic lymphocyte crossmatch with the potential recipient. This is used, in part, to determine the patient’s position on the waiting list.
Evaluation of potential living donors may involve some of the studies detailed above. This is subject to great variation between programs; however, assessment of renal function, general health, an imagining study of the renal vasculature, human leukocyte antigen typing, and crossmatching are essential in all cases. The authors have found that spiral CT scans allow evaluation of the renal vasculature as well as parenchymal abnormalities. All donors should be in good health and should not have conditions that may compromise their renal function in the future.
Kidney allografts are procured from both living donors and cadaver donors. Living donation typically occurs among persons who know each other; however, some charitable donations (i.e.: donor offers a kidney to the recipient best able to use it or in greatest need) are documented. Transplants performed among persons not related by blood, which are called living unrelated transplants, are increasing. These living unrelated transplants generally have good outcomes and are superior to all but the best-matched cadaver transplants, although the results are slightly poorer than human leukocyte antigen-identical and haploidentical (half identical) living donor transplants.
While living donation typically occurs among persons who know each other, cadaver donation is generally anonymous. Allocation of cadaver donor grafts is based on a waiting list system, with special priorities given to human leukocyte antigen zero mismatch pairings because of their documented improved graft survival rate, to pediatric recipients to minimize the impact of chronic renal failure on growth, and to patients with a high panel reactive antibody titer to increase their probability of transplantation.
Using present technologies for organ preservation, most cadaver kidney grafts come from cadavers whose brains are dead but whose hearts are beating. Increasingly, donation after cardiac death (DCD), particularly in the controlled setting of withdrawal of support in the intensive care unit, is being realized as a source of kidney allografts. Outcomes for allografts obtained in this fashion can be equivalent to those obtained following brain death, especially if the DCD kidneys are preserved by pulsatile perfusion.
Absolute contraindications to cadaver donation include some active infections, including HIV, and extracranial malignancy. Relative contraindications include poor renal function in the donor, positive hepatitis serology findings, advanced donor age (especially if paired with hypertension or diabetes), and other factors likely to compromise long-term graft function.
Various approaches to kidney transplantation have been used. The most common method involves a curvilinear incision in a lower quadrant of the abdomen (i.e.: Gibson incision), with division of the muscles of the abdominal wall and dissection of the preperitoneal space to expose the iliac vessels and the bladder. Then, the donor kidney’s renal vessels are connected to the iliac vessels, typically with end- to-side anastomoses of a fine (i.e.: 5-0, 6-0) permanent vascular suture.
The ureter is introduced into the bladder by creating 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. Lich ureteroneocystostomies and insert stents can be done 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.
Postoperative management includes management of the operative procedure itself and immunosuppression. Managing the operative procedure itself involves management of a dynamic fluid balance with 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, which requires isotonic fluid replacement, often in the 250- to 500-mL/h range. 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. The induction phase of immunosuppression occurs during and immediately 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 calcineurin inhibitors (CNIs; e.g.: cyclosporine, tacrolimus), antiproliferative agents (e.g.: azathioprine, mycophenolate), and steroids. Both nonantibody induction therapy and most forms of maintenance therapy dispense with the antibodies but use calcineurin inhibitors, antiproliferative agents, and steroids in various combinations. 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 (e.g.: retransplants), especially when the first kidney was lost to acute or chronic rejection, in African American patients, and in 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 (e.g.: interleukin 2) essential for T-cell proliferation. Both cyclosporine and tacrolimus are naturally occurring products and have significant toxicities. Most notably, these 2 agents have a significant dose- related nephrotoxicity. The fact that 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. Both cyclosporine and tacrolimus are metabolized in the liver by the cytochrome P 450 system; drugs that alter cytochrome P 450 metabolism can result in higher blood levels (i.e.: fluconazole, verapamil) or lower drug levels (i.e.: rifampin, phenytoin sodium [Dilantin]).
A new strategy for immunosuppression involves the use of sirolimus, which is a new immunosuppressive drug that targets T cells at a different site in the activation pathway. Sirolimus can be used in conjunction with reduced doses of calcineurin inhibitors or as a replacement for calcineurin inhibitors. Sirolimus lacks the nephrotoxicity of calcineurin inhibitors. Sirolimus does, however, reduce wound healing and may cause significant myelosuppression.
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. 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. However, steroid doses have been reduced and rapidly tapered without significant increased rejection risk. 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 monotherapy using a calcineurin inhibitor alone.
Early or late complications associated with renal transplantation may occur. Early postoperative complications include the following:
Delayed graft function (DGF) varies based on donor, recipient, and transplant characteristics. Vascular- related and ureter-related complications are possible. Renal artery thrombosis occurs in about 1% of transplants, usually from small-caliber arteries. Nephrectomy is generally indicated, especially if the thrombosis occurs in the perioperative period. 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. 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, although the graft has typically infarcted by the time the thrombosis is detected. Graft infarction may occur with patent main arteries and veins; nephrectomy is generally required. Graft thrombosis associated with sepsis carries a significant recipient mortality rate. Prompt nephrectomy is indicated.
Ureteral obstruction is the most common urinary tract problem associated with transplantation. It may occur early or late. Early obstruction may result from distal obstruction, 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 (e.g.: 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. Leakage from perivascular lymphatic vessels can lead to significant collections of lymph between the lower pole of the transplanted kidney and the bladder. Lymphocele can manifest as swelling, pain, and impaired renal function within the first year following transplantation. The risk of opportunistic infections is increased. These infections are typically caused by commonly encountered bacteria, including cytomegalovirus, BK virus, fungi, Pneumocystis carinii, and Legionella species.
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 (e.g.: antilymphocyte antibody agents).
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. Surprisingly, 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 (i.e.: cold ischemia 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. Therefore, special attention should be paid to cardiac risk factors following transplantation, including hypertension, hyperlipidemia, and diabetes.
Many of the medical/legal pitfalls (or risks) in general surgery are applicable to transplantation surgery. Specifically, obtaining informed consent for the surgical procedure is paramount. One difference in transplantation surgery is the popularity of enrolling patients into clinical studies. If this is arranged, specific consent forms need to be obtained and filled out by the patient. Also, Institutional Review Board (IRB) approval may be required. Transplantation must be performed in a timely manner to enhance the viability of the donor organ. Delays can increase the risk of complications and rejection.
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