KIDNEY TRANSPLANTATION: An Overview
By – Dr. Hemal Shah
Kidney transplantation in the last 65 years has enjoyed remarkable progress with the development of novel immunosuppressants, antirejection therapy and various surgical procedures. This has resulted into huge success in the field of renal transplantation.
The first clinical cadaver renal transplant was performed in 1933 by the Ukrainian surgeon Voronoy, with unsuccessful results secondary to the immunologic barrier. In the 1950’s these obstacles were circumvented by performing the procedure between identical twins. The era of modern renal transplantation began with the introduction of azathioprine to suppress the human immune system. With the demonstration of the synergistic effect of glucocorticoids, renal transplantation was established as a viable option for the treatment of ESRD. This was followed soon by the development of polyclonal antilymphocyte agents such as ALG which contributed significantly to the treatment of acute rejection (AR). Immunosuppression remained relatively constant for the next 15 years until the 80’s, and the introduction of cyclosporine A (CyA). At that time, it was the most specific immunosuppressive agent known. It resulted in significant improval in graft and patient survival rates, not only after kidney transplantation, but after all organ transplants, thus allowing for a dramatic increase in extrarenal transplants.
INDICATIONS AND PREOPERATIVE EVALUATION:
For the majority of people with ESRD, transplantation results in superior survival, improved quality of life and lower costs as compared with chronic dialysis. There are very few absolute contraindications and so most patients with ESRD should be considered as potential candidates. The subsequent lifelong immunosuppression is associated with considerable morbidity. Therefore, evaluation of a potential recipient must focus on identifying risk factors that could be minimized or may even contraindicate a transplant.
The preoperative evaluation can be divided into four phases: medical, surgical, immunologic, and psychosocial. The medical evaluation begins with a complete history and physical examination. Any history of congestive heart failure, angina, myocardial infarction or stroke should be elicited. Patients with symptoms suggestive of cardiovascular disease or significant risk factors (e.g. diabetes, age over 50, previous MI) should undergo further cardiac evaluation. Echocardiography should be performed if patients have evidence of valvular disease or a history of congestive heart failure, to determine left ventricular ejection fraction. Any problems identified should be treated appropriately (medically or surgically); patients whose cardiovascular problems are too severe should not undergo transplantation. Patients with suspected cerebrovascular disease should undergo evaluation with carotid duplex Doppler studies.
Untreated malignancy and active infection are absolute contraindications to transplantation because of the requisite lifelong immunosuppression. Following curative treatment of malignancy, an interval of 2 to 5 years is recommended prior to transplantation. This recommendation is influenced by the type of malignancy, with longer observation periods for neoplasms such as melanoma or breast cancer and shorter periods for carcinoma in situ or low grade malignancies such as basal cell carcinoma of the skin. Chronic infections such as osteomyelitis or endocarditis must be fully treated. Other areas of the medical evaluation should concentrate on gastrointestinal problems such as peptic ulcer disease, symptomatic cholelithiasis, and hepatitis. Patients with ulcers should receive appropriate treatment followed by endoscopic evaluation to document resolution. Cholelithiasis should be treated by cholecystectomy prior to the transplant. Patients who are hepatitis C positive, but have no evidence of active hepatic inflammation, are acceptable transplant candidates. Whether patients with hepatitis B should be transplanted is controversial. There is an increased risk in these patients of developing chronic active hepatitis and cirrhosis after receiving immunosuppression, but many have excellent long-term survival rates and improved quality of life compared with those on chronic dialysis. Therefore, many centers feel that chronic hepatitis B infection, in the absence of cirrhosis or active viral replication, is not a contraindication to transplantation.
The surgical evaluation should concentrate on identifying vascular or urologic abnormalities that may affect transplantation. Evidence of vascular disease that is revealed by the history (claudication or rest pain) or the physical examination (diminished or absent pulse, bruit) should be evaluated further by Doppler studies or angiography. Urologic evaluation should rule out chronic infection in the native kidney, which may require nephrectomy pretransplant. Other indications for nephrectomy include huge polycystic kidneys, significant reflux, or uncontrollable renal vascular hypertension. Children especially require a complete GU tract examination to evaluate reflux and bladder outlet obstruction.
An assessment of the patient’s immunologic status involves determining blood type, tissue type (HLA A,B,DR antigens), and presence of any cytotoxic antibodies against HLA antigens (because of prior transplants, blood transfusions, or pregnancies).
A psychosocial evaluation is necessary to ensure that patients understand the nature of the transplant procedure, with its attendant risk. They must be capable of following the medical regimen following the transplant. Patients who have not been compliant with their medical regimen in the past must demonstrate a willingness and capability to do so, before they undergo the transplant.
Finally, it is important to remember that patients may be on the cadaver organ waiting list for prolonged periods. Regular reevaluation is necessary to search for any progression of underlying or new disease that may require attention or may contraindicate transplantation.
Living donors are preferred over cadaver donors. Recipients of living donor organs enjoy improved long-term success, avoid a prolonged wait and are able to plan the timing of their transplant in advance. Moreover, they have a significantly decreased incidence of ATN, increased potential for HLA matching and the opportunity to initiate and optimize immunosuppression therapy preoperatively. All of these advantages contribute to a lower incidence of early acute rejection and to improved graft and patient survival rates. While there is significant benefit for the recipient, there is no physical benefit for the living donor, only potential for harm. Therefore, it is paramount that the risks of donation are acceptably low, that the donor is fully aware of the potential risks, and has freely given informed consent. Laboratory evaluation of the donor should include basic blood tests (e.g. CBC, electrolytes, glucose, viral serology), assessment of renal function (serum creatinine, creatinine clearance, urinalysis) and an anatomic evaluation of the kidneys (IVP, angiogram). With appropriate preoperative screening, the risk of a lethal complication as a result of donation is estimated to be less than 0.05%. The incidence of postoperative complications was roughly 8% in one large series; most of these were relatively minor. Living unrelated donors are being used with increasing frequency, with excellent results, comparable to living related (non-HLA identical) donors.
In the absence of living donors, transplant candidates are placed on the cadaver organ waiting list. Determining the appropriateness of a given cadaver donor depends on that donor’s medical history (e.g. age, diabetes, increased blood pressure, any known kidney abnormality or previous malignancy) and pre-donation renal function. The serum creatinine is the most useful measurement of renal function. It is important to determine the admission creatinine, its trend over the duration of hospitalization, as well as the reversibility of any elevation with appropriate measures such as hydration. With marginal renal donors (e.g. those with hypertension or diabetes, or those over age 65 but with normal serum creatinine), the kidneys should be biopsied at the time of procurement. As long as less than 10% of examined glomeruli are sclerotic, long-term success rates are good.
Compatible blood group; similar to blood donation.
Recipient workup; these tests are done to ascertain the fitness of the patient for the transplant and care required after transplant
Fitness to undergo major surgery will include an age appropriate cardiac workup like ECG/ ECHO/ stress test / and coronary angiogram in select cases.
A detailed liver work in also required in select cases.
Donor workup; these are test of the donor so that she or he can go through surgery without problem and the kidney given to patient is of good quality.
All routine test like CBC/ renal profile/ liver function tests / cardiac workup for fitness of surgery/ viral markers- HIV/ HCV/HbsAg.
USG abdomen / renal scan / CT-IVP and CT angiogram for determining the renal function of both kidneys.
Immunological workup. This help us decide about the possibility of rejection etc.
Lymphocyte cross match HLA; this test is to be done in India in presence of the nephrologist.
Legal work up
Establishment of blood relation; Birth certificate stating the names Government issued photo identification [ passport] having the name and recent photographs Certificates confirming residency
The surgical technique for renal transplantation has changed very little from the original pelvic operation described in 1951. The most common approach today is the standard pelvic operation, with retroperitoneal placement of the kidney allowing easy access for percutaneous renal biopsy. Usually, the right iliac fossa is chosen because of the more superficial location of the iliac vein on this side. However, the left iliac fossa should be used if the patient may be a candidate for a future pancreas transplant, if it is a second transplant, or if there is significant arterial disease on the right side.
With the standard approach, the dissection is extraperitoneal. The iliac vessels are identified and assessed for suitability for anastomosis. The internal iliac artery can be used as the inflow vessel, with an end-to-end anastomosis, or the external iliac artery can be used with an end-to-side anastomosis. To minimize the risk of lymphocele formation, only a modest length of artery is dissected free and lymphatics overlying the artery are ligated. The donor renal vein is anastomosed end-to-side to the external iliac vein.
After the vascular anastomosis is completed and the kidney perfused, urinary continuity can be restored by a number of methods. The most common techniques are a posterior Leadbetter-Politano, anterior multi-stitch (Litch) or an anterior single-stitch. Results with the three methods are similar. Regardless of the technique used, the anastomosis must be tension-free and protected by at least a 1 centimeter submucosal tunnel to provide protection against reflux during voiding.
The initial postoperative care is not unlike that of other surgical patients. Fluid and electrolyte status, vital signs, CVP, and urine output are carefully monitored. Special issues include immunosuppression and monitoring for transplant-related surgical and medical complications unique to these patients.
6.1 Surgical complications
As with other surgical cases, postoperative hemorrhage, wound infection and seroma may be seen. Unique complications can be categorized as vascular, urologic or lymphatic.
Vascular complications can involve the donor vessels (renal artery thrombosis, renal vein thrombosis), the recipient vessels (iliac artery thrombosis, psuedo aneurysms, deep venous thrombosis) or both. Renal artery thrombosis usually occurs early posttransplant, often resulting in graft loss. Most commonly, it occurs secondary to a technical problem such as intimal dissection, kinking or torsion of the vessels. Other causes include hyperacute rejection, unresponsive acute rejection, and a hyper-coaguable state. Presentation is with a sudden cessation of urine output. Diagnosis is easily made with color flow Doppler studies. While urgent thrombectomy is indicated, the majorities of grafts are non-salvageable and require removal. Stenosis of the renal artery, a late complication, presents with evidence of graft dysfunction or hypertension. Doppler studies constitute a good screening exam with high sensitivity (87.5%) and specificity (100%). First-line treatment is with interventional radiologic techniques, while surgery is reserved for those not responding.
Arterial complications that affect the recipient vessels are much less common, but can be equally devastating. Early events such as iliac artery thrombosis can be limb threatening, while late complications such as pseudoaneurysms or fistula can lead to significant hemorrhage.
Renal vein thrombosis is not as common as its arterial counterpart, but again graft loss is the usual end result. Causes include angulation or kinking of the vein, compression by hematoma or lymphocele, anastomotic stenosis and extension of an underlying DVT. Doppler studies are again the best diagnostic test. Urgent thrombectomy is rarely successful and nephrectomy is usually required.
Venous thromboembolic complications that affect the recipient vessels (DVT and PE) are not uncommon.
Urinary tract complications, manifesting as leakage or obstruction, generally occur in 2% to 10% of cases. The underlying cause is often related to poor blood supply and ischemia of the transplant ureter. Leakage most commonly occurs from the anastomotic site. Causes other than ischemia include undue tension created by a short ureter or direct surgical injury. Presentation is usually early (before the 5th posttransplant week); symptoms include fever, pain, swelling at the graft site, increased creatinine level, decreased urine output, and cutaneous urinary drainage. Diagnosis can be confirmed with hippurate renal scan. Early surgical exploration with ureteral re-implantation is usually indicated, though small leaks may be managed by percutaneous nephrostomy and stent placement with good results.
6.2. Medical complications
Medical problems unique to transplant recipients are related to infections and graft dysfunction secondary to rejection or drug toxicity.
There are four types of clinical rejection: hyperacute, accelerated, acute, and chronic. Only the first three are seen in the early posttransplant period; the last (CR) remains the most frequent cause of graft failure. Hyperacute and accelerated rejection occur very early posttransplant and reflect host anti-donor presensitization; with current crossmatch techniques, these events are relatively rare. Acute rejection, however, is not uncommon, affecting at least one-third of recipients on standard CyA-based immunosuppression. It is most prevalent in the first few months posttransplant, and is unusual after the first year.
With current immunosuppression, symptoms such as fever, graft tenderness, malaise, and oliguria are unusual with acute rejection. The most common manifestation is an asymptomatic rise in the serum creatinine. The previously discussed technical problems, as well as medical causes such as dehydration, infection and CyA induced nephrotoxicity, must be ruled out. Physical examination, routine biochemistry tests, CyA blood level determination and a Doppler ultrasound will usually rule in or out these possibilities. The diagnosis of AR is ultimately best established with a renal biopsy. Treatment is then initiated based on the severity of rejection, degree of dysfunction, and previously administered immunosuppression. Options include a course of high-dose steroids or antilymphocyte preparations (ATG or OKT3).
Induction and maintenance immunosuppression varies from center to center. At the present time, most transplant centers use a combination of tacrolimus (Tac), prednisone and mycophenolate mofetil (MMF) for maintenance, with or without a polyclonal (ATG),InterluekinII blocker or monoclonal (OKT3) antilymphocyte agent for induction therapy.
The introduction and widespread use of CyA in the early 1980s substantially improved transplant outcome. Microemulsion cyclosporine is actually not a new drug, but rather an old drug in a new package. The active drug remains cyclosporine A. The newer formulation has superior oral bioavailability, compared with the older formulation especially in patients who were poor absorbers of CyA . Whether or not this improved pharmacokinetic profile correlates with an improved clinical outcome is currently being studied.
Tacrolimus, (FK506) a metabolite of a soil fungus found in Japan, works in a similar manner to CyA, but is much more potent on a molar basis.
Mycophenolate mofetil (MMF) was approved by the FDA for the prevention of acute renal rejection in May 1995. It is a semi-synthetic derivative of mycophenolate acid (MPA), the active immunosuppressive compound. MPA is a reversible inhibitor of an enzyme that is crucial for the de-novo synthesis of purines. The net result is a selective and reversible antiproliferative effect on T and B lymphocytes.
Sirolimus, a macrolid antibiotic, is structurally similar to tacrolimus. It is 50 times more potent than, and synergistic with, CyA.
RESULTS OF RENAL TRANSPLANTATION:
Outcome after kidney transplantation has steadily improved over the past five decades, thanks to improvement in immunosuppression, antirejection therapy, organ retrieval techniques, perioperative care, and treatment of posttransplant infectious complications.
Most centers now report patient survival rates exceeding 95% during the first posttransplant year for all recipients. Living donors have a clear advantage over cadaver donors; reported 5-year patient survival rates after living and cadaver transplants are approximately 90% and 80%, respectively. Compared with dialysis, the survival advantage after a transplant is probably greatest for diabetics. Without a transplant, overall survival in this group is 26% at 5 years.