Complications and Comorbidities> Renal and Urinary>

DEFINITION

• The surgical implantation of a kidney from one donor to a non-identical human recipient (allograft).
• Kidney transplantation that occurs between identical twins referred to as isograft.
• Simultaneous pancreas and kidney (SPK) transplantation has been a successful therapy for patients with end-stage kidney disease secondary to type 1 diabetes mellitus. Other options include pancreas or islet cell transplantation before or after kidney transplantation.
• Most patients with kidney transplantation (and all with pancreas transplantation) are allograft recipients and require lifetime immunosuppression to prevent immune-mediated graft rejection.
• Diabetes, in the context of kidney transplantation, includes both patients who have diagnosed diabetes prior to transplantation and patients who develop post-transplantation diabetes mellitus (PTDM).

EPIDEMIOLOGY

• Diabetes accounts for ~45% of new cases of chronic kidney disease diagnosed each year.
• In 2007, among newly-listed adults for kidney transplantation, ~40% had diabetes.
• For most patients with history of diabetes, this is the cause of end-stage kidney disease necessitating kidney and/or pancreas transplant.
• In addition, about 5 - 25% of non-diabetic kidney transplant recipients will develop post-transplant diabetes mellitus (PTDM) per year.
• Incidence of PTDM is 9%, 16% and 24% at 3, 12 and 36 months after transplantation, respectively.
• PTDM is a strong, independent predictor of allograft failure and poor patient survival.
• Non-modifiable risk factors for PTDM include age, family history, female gender, Hispanic ethnicity and African American race.
• Modifiable risk factors for PTDM include obesity (BMI > 30 kg/m²), hepatitis C, and tacrolimus use.

DIAGNOSIS

• Kidney transplantation remains the renal replacement therapy of choice for patients with end-stage kidney disease, particularly those who lack comorbidities that hinder surgery or complicate immunosuppression therapy.
• Patient's GFR needs to be <20 ml/min/1.7 m² before they can be listed in the United Network for Organ Sharing (UNOS) registry for a cadaveric renal transplant; an exception is when the combination of kidney and other organs is considered.
• Usually, patients with severe obstructive or restrictive lung disease, chronic intestinal malabsorption and diarrhea, illicit drug use, or a compromised social support system are not considered candidates for kidney transplantation.
• Obesity is a relative contraindication for kidney transplantation, associated with worse allograft outcomes and wound healing problems. Most programs exclude patients with BMI of > 40 kg/m² from transplantation.
• Before considering a patient for kidney transplant, need to assess presence of active infections, malignancies and cardiovascular risk.
• Transplant candidates should be screened with hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV), epstein barr virus (EBV), varicella zoster virus (VZV), human immunodeficiency virus (HIV), syphilis (RPR) serologies in addition to PPD test to exclude tuberculosis.
• Potential candidates should also have annual age-appropriate cancer screening tests. This includes colonoscopy, mammography, and pap smear in females and PSA in males.
• For cardiovascular risk stratification, asymptomatic transplant candidates require a cardiac stress test. If symptomatic, often cardiac catheterization needed. In the event of unstable coronary lesions or coronary obstruction, revascularization therapy has to precede transplantation.
• This entire evaluation process is carried by transplant coordinators who are guided by transplant nephrologists.
• The final decision to approve a candidate for transplantation is achieved by a multidisciplinary committee.

SIGNS AND SYMPTOMS

• Signs and symptoms related to presence of chronic kidney disease (See module on Diabetic Nephropathy and Diabetes and Renal Diseases for more details)

CLINICAL TREATMENT

• Transplant recipients are maintained on lifelong immunosuppression.
• Common regimens include low dose corticosteroids; an antiproliferative agent including mycophenolate mofetil (CellCept), mycophenolic acid (Myfortic) or less commonly azathioprine (Immuran); and a calcineurin inhibitor, usually tacrolimus (Prograf) or less commonly cyclosporine (Neoral, Gengraf).
• Sirolimus (Rapamune) is an m-TOR inhibitor that is less frequently used.
• Steroid-sparing immunosuppressive regimens are associated with a higher incidence of subclinical, biopsy-proven rejection, ultimately resulting in increased fibrosis and scarring of the allograft so these regimens are not commonly used.
• Additionally, transplant recipients receive prophylactic antibiotics with Valganciclovir, Trimethoprim-Sulfamethoxazole and Clotrimazole against CMV, pneumocystis carinii pneumonia (PCP) and fungal (candidal) infections respectively.
• Prophylaxis treatment begins one day post transplantation and continues for 3 - 6 months.

• Glucocorticoid use can lead to steroid-induced diabetes.
• Calcineurin inhibitors (commonly used for immunosuppression after transplantation), particularly tacrolimus, may be associated with beta cell injury, and can result in insulin resistance.
• Risk of PTDM is 53% greater in patients treated with tacrolimus compared to patients not treated with tacrolimus, and is dose-dependent
• Risk of PTDM also increased when sirolimus (m-TOR inhibitor) combined with a calcineurin inhibitor. Sirolimus may alter beta cell function and diminish insulin sensitivity.
• Oral hypoglycemics that are cleared by the kidney (i.e. sulfonylureas) should be avoided if possible in patients with allograft dysfunction.
• Insulin dosage may need to be lowered in patients with allograft dysfunction who have decreased insulin clearance.
• After pancreas transplantation, patients usually achieve normal fasting blood glucose and HbA1c levels. Both pancreas after kidney (PAK) and SPK transplantations halt progression of microvascular and macrovascular complications of diabetes.

• Opportunistic infections and malignancies may occur due to immunosuppression after surgery.
• An overt infection can be primary or a reactivation of a previous infection, for example reactivation of mucosal herpes simplex virus.
• Infections are more likely to occur in the first year after transplantation. They include CMV, HSV,PCP.
• EBV infection associated with post-transplant lymphoproliferative disease.
• BK virus infection is associated with allograft nephropathy.
• Non-melanoma skin cancers most common malignancies post-transplantation and are 50-fold more common in kidney transplant recipients compared to the general population.
• Persons with diabetes have a higher risk of developing cardiovascular disease both before and after kidney transplantation compared to persons without diabetes.

FOLLOW UP

• Transplant recipients should be followed by a transplant nephrologist or a general nephrologist with transplantation experience.
• Because of the high risk of acute rejection and opportunistic infections soon after transplantation, patients are followed closely during the first 3 - 6 months after which visits become less frequent.
• Renal panel, complete blood count, urinalysis and calcineurin inhibitor trough levels are the standard laboratory tests monitored routinely after transplantation.
• In addition, patients should have intact-PTH, 25-OH-Vitamin D (vitamin D) checked periodically. Intact-PTH usually falls to normal range shortly post-transplantation if allograft function adequate, however, can take up to one year in some patients.
• Serum BK virus PCR checked monthly, then quarterly and then yearly after the first year.
• Patients who report flu-like symptoms or symptoms suggestive of CMV tissue invasive disease, should be tested by obtaining CMV PCR in the serum.
• Worsening allograft function may result from urinary tract obstruction and hemodynamic mediated (prerenal) azotemia.
• Biopsy of transplanted kidney may diagnose acute allograft rejection, recurrence of primary kidney disease and other etiologies.

EXPERT COMMENTS

• Kidney transplantation remains the best available renal replacement modality in patients with end-stage kidney disease.
• Potential candidates for kidney transplantation should be referred to nephrology.
• Simultaneous pancreas- kidney transplantation is a good option in patients with end-stage kidney disease from type 1 diabetes mellitus. 
• Because of the relative shortage of transplantable organs in the face of a growing end-stage kidney disease population, allografts should be managed closely, emphasizing compliance with medications, laboratory testing and clinic visits.
• Keep a very low threshold to work-up signs or symptoms suspicious of infections or malignancies in transplant patients. Consider consultation with a transplant infectious disease specialist if needed.
• Caring for transplant patients is a complex lifelong process that requires a multidisciplinary team approach.

REFERENCES