Renal Transplantation

Authored by Dixon Kaufman, MD, Director of Pancreas Transplantation, Associate Professor, Department of Surgery, Division of Transplantation, Northwestern University Medical School

Coauthored by Alan Koffron, MD, Director, Living-Donor Transplantation, Assistant Professor of Surgery, Department of Surgery, Division of Transplantation, Northwestern University Medical School

Dixon Kaufman, MD, is a member of the following medical societies: American Association for the Study of Liver Diseases, American Association of Immunologists, American College of Surgeons, American Diabetes Association, American Medical Association, American Society of Transplant Surgeons, Association for Academic Surgery, Central Surgical Association, Illinois State Medical Society, National Kidney Foundation, Phi Beta Kappa, Society for Surgery of the Alimentary Tract, and Society of University Surgeons

Edited by Laura Lyngby Mulloy, DO, Chair, Associate Professor, Department of Internal Medicine, Division of Nephrology, Hypertension and Transplantation, Medical College of Georgia; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; George R Aronoff, MD, Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine; Michael E Zevitz, MD, Consulting Faculty, Clinical Assistant Professor, Department of Medicine, Finch University of Health Science, Chicago Medical School; and Vecihi Batuman, MD, FACP, Chief of Renal-Hypertension, New Orleans VA Medical Center, Professor, Department of Internal Medicine, Section of Nephrology, Tulane University School of Medicine

eMedicine Journal, December 26 2001, Volume 2, Number 12

INTRODUCTION

Background: Kidney transplantation should be strongly considered for all patients who are medically suitable with chronic and end-stage renal disease (ESRD). A successful kidney transplant offers enhanced quality and duration of life and is more effective (medically and economically) than chronic dialysis therapy. Transplantation is the renal replacement modality of choice for patients with diabetic nephropathy and pediatric patients.

Currently in the US, more than 80,000 persons are living with a functioning kidney transplant. This number represents 27% of the nearly 300,000 persons enrolled in the US ESRD program.

In 1973, Congress enacted Medicare entitlement for ESRD treatment to provide equal access to dialysis and transplantation for all patients with ESRD in the Social Security system by removing the financial barrier to care. Currently, the main obstacle is donor organ shortage.

Pathophysiology: An increasing rise in ESRD coupled with a lack of donor organs has resulted in an average waiting time of more than 2 years for a cadaveric renal transplant.

Frequency:

• In the US: The overall rate of ESRD is approximately 735/1,000,000. As the end-stage population continues to increase, projections estimate that the current population of 372,407 will exceed 660,000 by the year 2010.

Mortality/Morbidity: The 1-year life expectancy after kidney transplantation is 95-98%. The standardized mortality rate for patients on dialysis who are awaiting kidney transplantation is 6.3/100 patient-years. The standardized mortality rate with each treatment per 100 patient-years is as follows:

• Dialysis - 6.3

• Cadaveric transplant - 3.8

• Living donor transplant - 2.0

Age: The proportion of patients either waiting for a kidney transplant or receiving a kidney transplant according to age is as follows:

Age (Years)	Wait List (%)	Transplant (%)
0-19	2.8	3.7
20-39	31.2	33.6
40-59	15.0	13.0
60-70	39.5	37.2

(From Wolfe et al, NEJM 341: 1725, 1999.)

CLINICAL

History: Candidates for renal transplantation undergo an extensive evaluation to identify factors that may have an adverse effect on outcome. Virtually all transplant programs have a formal committee that meets regularly to discuss the results of evaluation and select medically suitable candidates to place on the waiting list. Most programs perform the evaluation in the outpatient setting and possess a relatively uniform approach to the diagnosis and treatment of the pertinent medical and psychosocial issues affecting candidacy.

• Preexisting morbidities of the transplant candidate with renal disease

• Hematologic abnormalities, such as anemia and platelet-hemostatic dysfunction

• Upper and lower gastrointestinal track abnormalities, such as gastritis, peptic ulcer disease, diverticulosis, diverticulitis, spontaneous colonic perforation, and prolonged adynamic ileus (pseudoobstruction)

• Hepatic abnormalities, such as viral hepatitis B and C

• The cardiovascular system is profoundly affected in patients with chronic or end-stage renal failure. The increased mortality is related to hypertension, atherosclerotic heart disease with myocardial infarction, congestive heart failure, and left ventricular hypertrophy.

• Bone and joint disease is common because of low calcium levels, high phosphorus concentrations, and elevated serum parathyroid hormone (PTH) levels.

Causes:

• A diverse array of diseases destroys renal function in all age groups. The most common etiologies of renal disease leading to kidney transplantation are the following:

• Diabetes – 31%

• Chronic glomerulonephritis – 28%

• Polycystic kidney disease – 12%

• Nephrosclerosis (hypertensive) – 9%

• Systemic lupus erythematosus (SLE) – 3%

• Interstitial nephritis – 3%

• Understanding the etiology of renal disease is important because the primary renal pathology may influence the outcome based on the propensity for recurrence of disease and the association of comorbidities.

WORKUP

Lab Studies:

• Pretransplant recipient laboratory evaluation: Emphasize identifying and treating all coexisting medical problems that may increase the morbidity and mortality rates of the surgical procedure and adversely impact the posttransplant course. In addition to a thorough medical evaluation, evaluate the social issues of the patient to determine conditions that may jeopardize the outcome of transplantation, such as financial and travel restraints and a pattern of noncompliance.

• Pertinent components include the following:

• Blood chemistries

• Liver function tests

• Complete blood count

• Coagulation profile

• Infectious profile

• Hepatitis B and C serologies

• Epstein-Barr virus serologies (immunoglobulin M [IgM] and immunoglobulin G [IgG])

• Cytomegalovirus (CMV) serologies (IgM and IgG)

• Varicella-zoster serologies (IgM and IgG)

• Rapid plasma reagin (RPR) test for syphilis

• HIV

• Purified protein derivative (PPD) - Tuberculosis skin test with anergy panel, when indicated

• Urinalysis, urine culture, and cytospin (when indicated)

Imaging Studies:

• A complete cardiac workup including angiography is unnecessary in all patients. However, individuals with a significant history, symptoms, type I diabetes, or hypertensive renal disease should undergo a thorough evaluation to rule out significant coronary artery disease.

• ECG (12 lead)

• Chest x-ray (posteroanterior [PA] and lateral)

• Exercise and dipyridamole thallium scintigraphy

• Two-dimensional echocardiography with Doppler (+/- dobutamine)

• Coronary arteriogram (if indicated)

• Special procedures in selected patients dictated by findings on history and physical examination

• Upper GI endoscopy

• Colonoscopy

• Ultrasound of native kidneys

• Peripheral arterial Doppler studies

• Pulmonary function tests

• Carotid duplex studies

• Voiding cystourethrogram

• Urodynamic pressure-flow studies

Other Tests:

• Recipients of kidney transplants undergo an extensive immunological evaluation that primarily serves to avoid transplants that are at risk for antibody-mediated hyperacute rejection. There are 4 components of the immunologic evaluation.

• ABO blood group determination: This test is used to determine if the patient is a potential target of recipient circulating preformed cytotoxic anti-ABO antibody. Transplantation across incompatible blood groups may result in humoral-mediated hyperacute rejection.

• Human leukocyte antigen (HLA) typing: All transplant recipients are tissue typed to determine the HLA class I and class II loci. Six HLA antigens are determined. The kidney donors also are HLA typed, and the degree of incompatibility between the donor and recipient is defined by the number of antigens that are mismatched at each of the HLA loci.

• Serum screening for antibody to HLA phenotypes

• Sensitization to histocompatibility antigens is of great concern in certain populations of transplant candidates. This occurs when the recipient is sensitized because of receiving multiple blood transfusions, a previous kidney transplant, or from pregnancy.

• Transplantation of a kidney into a recipient that is sensitized against donor class I HLA antigens puts the recipient at high risk of developing hyperacute antibody-mediated rejection. All transplant candidates are screened to determine the degree of humoral sensitization to HLA antigens.

• Crossmatching: This is an in vitro assay method that determines whether a potential transplant recipient has preformed anti-HLA class I antibodies against those of the kidney donor. This immunologic test is conducted prior to transplantation. A negative crossmatch must be obtained prior to accepting a kidney for transplantation.

Procedures:

• The medical workup may reveal circumstances requiring surgical intervention to prepare the patient for kidney transplantation.

• Pretransplant native kidney nephrectomy/nephroureterectomy: This no longer is a routine pretransplant procedure. The native kidneys are left in place because they still may produce significant volumes of urine, secrete erythropoietin, and activate vitamin D. Nephrectomy/nephroureterectomy is reserved for specific indications, such as large polycystic kidneys, significant proteinuria, and chronic reflux disease.

• Pretransplant cholecystectomy: Ultrasound evidence of symptomatic or asymptomatic gallstones is an indication. The mortality and morbidity of acute cholecystitis is significant in the transplant recipients that are immunosuppressed.

• Splenectomy: This no longer is a requisite pretransplant surgical procedure. However, splenectomy may be indicated as part of a protocol for ABO-incompatible kidney transplants.

• Multiple random blood transfusions: Once, this was associated with improved, kidney transplant, graft survival in the precyclosporine era. Currently, there is no clinical benefit to transfusion, and the risk of sensitization is significant. In the setting of living kidney transplantation, donor-specific transfusion therapy also has been almost completely eliminated.

TREATMENT

Medical Care: The primary goal of short-term and long-term medical follow-up is enabling surveillance for signs and symptoms of renal allograft dysfunction.

Renal parenchymal dysfunction has many etiologies. The clinical manifestation is typically an increase in serum creatinine. Causes are numerous, and the differential diagnosis must be approached systematically.

The greatest considerations are rejection, nephrotoxicity of calcineurin inhibitors, and recurrence of native kidney disease. The time interval between transplantation and the rise in serum creatinine often is helpful to determine the etiology graft dysfunction.

• Delayed graft function immediately posttransplantation usually is due to acute tubular necrosis (ATN). Frequency is variable among the different transplant centers and approximates roughly 20-30% of cadaver transplants.

• The nephrotoxicity of calcineurin inhibitors, cyclosporine and tacrolimus, is dose related. Occasionally, performing a renal allograft biopsy is necessary if the serum creatinine does not respond to a reduction in dose.

• Hemolytic uremic syndrome (HUS) has an unknown etiology, but it seems to be associated with endothelial injury associated with calcineurin inhibitors and the occurrence of CMV. Laboratory evaluation showing diminished platelet count, anemia, reduced haptoglobin levels, rising lactic dehydrogenase (LDH) levels, and a peripheral blood smear with schistocytes is consistent with the diagnosis. The definitive diagnosis is made with the aid of renal allograft biopsy showing glomerular microthrombi.

• Recurrent renal disease in patients who have had kidney transplants accounts for less than 2% of all graft losses, though it affects as many as 10% of transplant recipients. A few diseases have a high risk of renal allograft loss, such as focal segmental glomerulosclerosis, HUS oxalosis, and membranoproliferative glomerulonephritis. Diabetic nephropathy can recur in renal allografts, but the time to onset is similar to that seen in native kidneys and is an uncommon cause of graft loss.

• Rejection

• Hyperacute rejection of the renal allograft happens within hours of the transplant, and it occurs when circulating, preformed, cytotoxic, antidonor antibodies directed to the ABO blood group antigens or to the donor HLA class I antigens are present. No treatment exists, and nephrectomy is indicated.
• Accelerated acute rejection is a very early, rapidly progressive, aggressive rejection reaction. It can occur within the first week of transplantation. Immediate therapy with anti–T-cell antibodies and pulse corticosteroids may reverse the process. Approximately 50% of cases can be salvaged.
• Acute tubular interstitial cellular rejection is the most common type of rejection reaction with an incidence of approximately 20-25%. Typically, it occurs between 1-3 months posttransplant. It is T-cell mediated, and injury is directed to the renal tubules. The criterion standard for diagnosis is renal allograft biopsy. Mild rejections may be successfully reversed with corticosteroids alone, whereas moderate or severe rejections may require the use of anti–T-cell antibodies, either polyclonal or monoclonal.
• Chronic rejection is a slow and progressive deterioration in renal function characterized by histologic changes involving the renal tubules, capillaries, and interstitium. The precise mechanism of this disease is poorly defined and is an area of intense study. Application of conventional antirejection agents, such as corticosteroids or anti–T-cell antibodies, does not appear to alter the progressive course. Unfortunately, this is a major cause of kidney allograft loss, occurring later than 2 years posttransplant.

Surgical Care:

• Wound complications: In patients who have had transplants, risk factors for and the morbidity of wound complications are significant.

• Bleeding: Kidney transplantation is a vascular surgery procedure; however, it is not an operation associated with much blood loss. Postoperatively, a life-threatening bleeding complication is very rare but could result from rupture of the arterial anastomosis from a mycotic aneurysm.

• Vascular thrombosis: Acute arterial thrombosis occurs in 1% of all kidney transplants. Salvage of the renal allograft is possible if diagnosed within the first one half hour of occurrence (during recovery in the postanesthesia recovery room). Rarely, venous thrombosis occurs. If it occurs, the kidney usually is unsalvageable. The cause often is never satisfactorily identified.

• Urine leak: Leaks occur at the ureterovesical junction or through a ruptured calyx secondary to acute ureteral obstruction. Often, the etiology of early urine leak is due to necrosis of the tip of the ureter. Urine leaks manifest as diminished urine output, an increase in creatinine, and lower abdominal or suprapubic discomfort. Repair employing minimal intervention may be attempted with either a percutaneous nephrostomy and drainage with internal stenting or through a cystoscopic retrograde approach. More aggressive treatment involves operative intervention with reimplantation of the ureter or a ureteroureterostomy, utilizing the ipsilateral native ureter.

• Ureteral stenosis and obstruction: This is a relatively late complication, occurring months or years posttransplant, that could result from ischemia of the ureter or a tight ureteroneocystostomy. Ureteral stenosis is manifested by elevated creatinine and hydronephrosis.

• Lymphocele: This is a circumscribed collection of retroperitoneal lymph that originates from lymphatic vessels about the iliac vasculature and the hilum of the kidney. Significant secondary problems may arise if external compression of the iliac vein (causing leg swelling and discomfort) or compression of the transplant ureter (causing hydronephrosis and renal dysfunction) occurs. The standard principal is that intraperitoneal drainage of the lymphocele should be accomplished with either a laparoscopic or an open surgical approach, with marsupialization of the edges of the lymphocele.

MEDICATION

Medications are used in renal transplantation for immunosuppression.

All kidney transplant recipients require life-long immunosuppression to prevent a T-cell, alloimmune rejection response. Several new immunosuppressive agents have been approved by the Federal Drug Administration (FDA), and several others currently are in clinical trials.

There are 2 broad classifications of immunosuppressive agents, intravenous induction of antirejection agents and maintenance immunotherapy agents. No consensus exists about which is the single best immunosuppressive protocol, and each transplant program utilizes various combinations of agents slightly differently.

The goals are to prevent acute and chronic rejection, to minimize drug toxicity and rates of infection and malignancy, and to achieve the highest possible rates of patient and graft survival.

Drug Category: Antirejection induction agents -- Induction immunotherapy consists of a short course of intensive treatment with intravenous agents. Antilymphocyte antibody induction therapeutics are varied and include polyclonal antisera, mouse monoclonals, and so-called humanized monoclonals. Polyclonal antisera, such as antilymphocyte globulin (ALG), antilymphocyte serum (ALS), and antithymocyte globulin (ATG), are equine, goat, or rabbit antisera directed against human lymphoid cells. The effect is to significantly lower and almost abolish the circulating lymphoid cells that are critical to the rejection response.

The agents are very effective at prophylaxis against early acute rejection, which is especially beneficial in managing the recipient with delayed graft function. The agents provide an effective immunologic cover during a period in which the calcineurin inhibitors are either delayed or given in subtherapeutic doses until graft function improves. Induction agents are used less often if immediate graft function occurs, such as in recipients of living kidney donors, especially HLA-ID grafts.

Drug Name	Antithymocyte globulin, equine (ATGAM) -- Only polyclonal preparation approved by the FDA for prophylaxis of rejection as an induction agent. Primarily IgG from horse hyperimmune serum.
Adult Dose	10-20 mg/kg/d IV for 7-14 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; hypersensitivity to horse proteins
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Infection, leukopenia, and thrombocytopenia may occur; adverse reactions include fever, chills, malaise; to reduce the risk of phlebitis, only administer via IV; medical emergency resources should be immediately available to manage the rash, dyspnea, hypotension, or anaphylaxis if necessary

Drug Name	Muromonab-CD3 (Orthoclone OKT3) -- A mouse, antihuman, monospecific antibody directed against CD3 antigen on T lymphocytes. Binding of OKT3 to CD3 molecule causes T-cell modulation or results in elimination of circulating T cells. Agent is extremely effective at reversing acute rejection episodes.
Adult Dose	5 mg/d IV for 7-14 d
Pediatric Dose	2.5-5 mg/d IV for 7-14 d
Contraindications	Documented hypersensitivity; hypersensitivity to mouse proteins
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Congestive heart failure, pulmonary edema, fever, and infections may occur; adverse reactions include fever, chills, malaise, headache, and cytokine release syndrome

Drug Name	Daclizumab (Zenapax) -- Humanized monoclonal antibody that specifically binds to and blocks IL-2 receptor on surface of activated T cells.
Adult Dose	1 mg/kg/dose for 5 doses, beginning at time of transplant, then q14d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Manage patients receiving the drug in facilities with adequate supportive medical resources

Drug Name	Basiliximab (Simulect) -- Chimeric monoclonal antibody that specifically binds to and blocks IL-2 receptor on the surface of activated T cells.
Adult Dose	20 mg IV at time of transplant and repeated 4 d posttransplant
Pediatric Dose	2-15 years: 12 mg/m^2; not to exceed 20 mg
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Long-term effect on ability of immune system to respond to antigens is unknown

Drug Name	Antithymocyte globulin, rabbit (Thymoglobulin) -- A purified immunoglobulin solution produced by the immunization of rabbits with human thymocytes that is used to treat acute rejection.
Adult Dose	1.25-1.5 mg/kg/d IV for 7-14 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hypersensitivity to rabbit proteins
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.