eMedicine Specialties > Transplantation > Surgery

Renal Transplantation (Medical): Treatment & Medication

Author: Dixon B Kaufman, MD, PhD, Director of Pancreas Transplantation, Professor, Department of Surgery, Division of Transplantation, Feinberg School of Medicine, Northwestern University
Contributor Information and Disclosures

Updated: Jun 12, 2009

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.⁶

Renal parenchymal dysfunction has many etiologies. The clinical manifestation is typically an increase in serum creatinine level. 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 level is often helpful in determining the etiology of graft dysfunction.

• Delayed graft function immediately posttransplantation is usually due to acute tubular necrosis (ATN). Frequency is variable among the different transplant centers and is approximated at roughly 20-30% of deceased donor transplants.
• The nephrotoxicity of calcineurin inhibitors cyclosporine and tacrolimus is dose-related. Occasionally, performing a renal allograft biopsy is necessary if the serum creatinine level does not respond to a reduction in dose.
• Hemolytic uremic syndrome (HUS) and thrombotic microangiopathy (TMA) may be associated with endothelial injury associated with calcineurin inhibitors and the occurrence of CMV.⁷  A systemic process reveals anemia, reduced haptoglobin levels, rising lactic dehydrogenase (LDH) levels, and a peripheral blood smear with schistocytes, all of which are consistent with the diagnosis. At times, HUS and TMA can be confined to the kidney and not show any systemic findings. The definitive diagnosis, whether local or systemic, is made with the aid of renal allograft biopsy that shows 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 dependent on T cells.¹  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 posttransplantation. 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 posttransplantation.

Surgical Care

• Wound complications: In patients who have undergone transplantation, 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 transplantations. 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 is usually unsalvageable. Often, the cause 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 levels, and lower abdominal or suprapubic discomfort. Repair with 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 posttransplantation, 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 principle 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 are in clinical trials.

Two broad classifications of immunosuppressive agents exist: intravenous induction of antirejection agents and maintenance immunotherapy agents. No consensus exists about which is the single best immunosuppressive protocol, and each transplantation program uses 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.

Antirejection induction agents

Induction immunotherapy consists of a short course of intensive treatment with intravenous agents. Antilymphocyte antibody induction therapeutics vary 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 kidneys from living donors, especially HLA-ID grafts.

Daclizumab (Zenapax)

Humanized monoclonal antibody that specifically binds to and blocks IL-2 receptor on surface of activated T cells.

Basiliximab (Simulect)

Chimeric monoclonal antibody that specifically binds to and blocks IL-2 receptor on the surface of activated T cells.

Antithymocyte globulin, rabbit (Thymoglobulin)

A purified immunoglobulin solution produced by the immunization of rabbits with human thymocytes that is used to treat acute rejection.

Methylprednisolone (Solu-Medrol, Adlone, Medrol, Depo-Medrol)

Steroids ameliorate delayed effects of immune reactions.

Alemtuzumab (Campath)

Humanized monoclonal antibody against the CD52 antigen. The anti-CD52 antibody induces lympholysis from complement-mediated lysis or other effector mechanisms.

Maintenance Immunosuppression

Several immunosuppressive agents are currently in use for maintenance immunotherapy in kidney transplant recipients. Optimal maintenance immunosuppressive protocol has not been developed. Maintenance immunosuppressive agents are required for the patient's entire life.

Prednisone (Sterapred)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Azathioprine (Imuran)

Active component of azathioprine is 6-mercaptopurine. Acts as purine analog that interacts with DNA and inhibits lymphocyte cell division.

Mycophenolate mofetil (CellCept)

Inhibitor of enzyme IMPDH. Results in inhibition of lymphocyte proliferation. Used for prophylaxis of organ rejection in patients receiving allogeneic renal allografts

Cyclosporine (Sandimmune, Neoral)

Calcineurin inhibitors that diminish IL-2 production in activated T cells. These agents bind to the intracellular immunophilin cyclophilin, interfering with the action of calcineurin, which inhibits nuclear translocation of the NFAT.

Tacrolimus (Prograf)

Calcineurin inhibitor that diminishes IL-2 production in activated T cells. Binds to intracellular immunophilin and FKBP, interfering with the action of calcineurin, which inhibits nuclear translocation of the NFAT. FDA approved for prophylaxis of organ rejection in patients receiving allogeneic renal allografts.

Sirolimus (Rapamune)

Inhibits lymphocyte proliferation by interfering with signal transduction pathways. Binds to immunophilin FKBP to block action of mTOR. FDA approved for prophylaxis of organ rejection in patients receiving allogeneic renal allografts.
Cyclosporine-sparing regimen has been FDA approved for patients with low-to-moderate rejection risk at 2-4 mo following transplantation. Regimen allows for cyclosporine to be withdrawn after 2-4 mo, which significantly decreases renal toxicity while maintaining similar antirejection effect.
Patients at high immunologic risk must be maintained on combination regimen of sirolimus, cyclosporine, and corticosteroids for first year following transplantation; high-risk patients defined as transplant recipients who are Black, repeat renal transplant recipients who lost a previous kidney transplant for immunologic reasons, and/or patients with high panel-reactive antibody (PRA) values.

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