Johns Hopkins Diabetes GuideComplications and ComorbiditiesRenal and Urinary

Kidney Transplantation

Nada Alachkar, M.D., Bassam G. Abu Jawdeh, M.D.

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, about 40% had diabetes. This incidence can be as high as 65% in Native Americans.
  • Additionally, about 5 to 25% of non-diabetic kidney transplant recipients will develop post-transplant diabetes mellitus (PTDM) per year.
  • A higher incidence of new onset diabetes after transplant (NODAT ) among recipients receiving tacrolimus compared with cyclosporine has been noted.
  • The incidence of new onset diabetes mellitus after transplant (NODAT) is variable, ranging between 10 and 46% depending on the study design and the definition of NODAT. More specifically, NODAT has been reported to occur in 4–25% of renal transplant recipients, 2.5–25% of liver transplant recipients, 4– 40% of heart transplant recipients, and 30–35% of lung transplant recipients.
  • PTDM is a strong, independent predictor of allograft failure and poor patient survival.

RISK FACTORS:

  • Obesity: NODAT 1.4-fold higher in those with a BMI of 25 to 30 and nearly doubled if the BMI was >30
  • Age is considered the strongest risk factor for development of NODAT. Age ≥60 years was associated with a relative risk (RR) of 2.6 for the development of NODAT versus that observed with younger patients.
  • Race: African Americans and Hispanics have an increased risk of NODAT. Likely, genetic polymorphisms among Black and Hispanic transplant recipients allow for more common disease prevalence compared to their Caucasian counterparts.
  • Family history: A family history of diabetes has been identified as an independent risk factor for the development of NODAT.
  • Medications: Both cyclosporine and tacrolimus increase the risk of NODAT. Compared with cyclosporine, tacrolimus has been observed to be more diabetogenic. Tacrolimus is associated with B-islet cell injury, and in many cases its use can result in insulin resistance. Sirolimus is diabetogenic as well and the risk of NODAT is increased when sirolimus is combined with a calcineurin inhibitor. Animal and human studies showed that sirolimus may alter B-islet cell function and diminish insulin sensitivity as well. Chronic use of glucocorticoids will lead to hyperglycemia in some patients. Glucocorticoids can cause insulin resistance leading to glucose intolerance and diabetes.
  • Infections: Hepatitis C virus (HCV) infection correlates with both pre- and post-transplant diabetes. Cytomegalovirus (CMV) infection has also been reported to increase the risk of NODAT.
  • HLA mismatch: DR and B27 mismatch have been associated with an increased risk of NODAT.
  • Underlying kidney disease: Polycystic kidney disease may confer an increased risk of NODAT.

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/1.73 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 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 for hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV), epstein barr virus (EBV), varicella zoster virus (VZV), human immunodeficiency virus (HIV), and syphilis (RPR) serologies in addition to PPD testing to exclude tuberculosis.
  • Potential candidates should also have annual age-appropriate cancer screening tests. These include 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 out by transplant coordinators who are guided by transplant nephrologists.
  • The final decision to approve a candidate for transplantation is achieved by a multidisciplinary committee.
  • Diabetes mellitus after transplantation may be diagnosed at any time after transplantation by any of the following:
    • Symptoms of diabetes plus random plasma glucose ≥200 mg/dL
    • Fasting plasma glucose ≥126 mg/dL
    • Two-hour plasma glucose ≥200 mg/dL during an oral glucose tolerance test
  • Pre-diabetic hyperglycemia, includes impaired fasting glucose and/or impaired glucose tolerance, and is diagnosed by a fasting plasma glucose between 100 and 125 mg/dL or a two-hour plasma glucose between 140 and 199 mg/dL during an oral glucose tolerance test, respectively, according to ADA guidelines.
  • The HbA1c is not recommended before three months following transplantation because the test may not be valid until new hemoglobin has been synthesized and glycated for the appropriate period in the diabetogenic post-transplant setting.
  • Steroid avoidance or early withdrawal from mainstream immunosuppressive regimens have been studied. Although many transplant programs initially adopted this approach, further evidence showed a high incidence of subclinical biopsy proven rejection associated with steroid minimization protocols. This ultimately resulted in increased fibrosis and scaring of the allograft. Therefore, most transplant centers use low dose steroids for maintenance immunosuppression.

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.)
  • Diabetic transplant patients are at a high risk for developing opportunistic infections and malignancies due to immunosuppression. Close monitoring for various constitutional and specific signs and symptoms is prudent for early detection and management of potentially life threatening infections and cancers.
  • Diabetic patients have a high risk of cardiovascular disease before and after kidney transplantation; very often they develop cardiac or cerebrovascular events and occlusive peripheral vascular disease post transplant compared to non-diabetic transplant recipients.
  • Developing NODAT after kidney transplantation is a strong independent predictor of allograft failure and poor patient survival.
  • NODAT is a strong, independent predictor of global mortality, graft failure, and death-censored graft failure.
  • Other diabetic complications: Ketoacidosis, hyperosmolarity, ophthalmic complications, neurologic complications, and hypoglycemia/shock can occur in patients who develop NODAT.

CLINICAL TREATMENT

Immunosuppression

  • 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 with antibiotics begins one day post transplantation and continues for 3 - 6 months.

Post-Transplant Diabetes Mellitus (PTDM)

  • 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) is combined with a calcineurin inhibitor. Sirolimus may alter beta cell function and diminish insulin sensitivity.
  • Adjustment of immunosuppressions: The glucocorticoid dose should be decreased as soon as possible, but complete steroid withdrawal is not recommended. Switching from tacrolimus to cyclosporine is not recommended, unless there are other tacrolimus-related side effects, since the effect of tacrolimus on glucose tolerance may be reversible even if the agent is not discontinued. Conversion to sirolimus is not recommended. Sirolimus may worsen insulin resistance.
  • Oral hypoglycemics that are cleared by the kidney (i.e. glyburide, metformin) 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 successful 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.
  • In patients who develop overt micro and macroalbuminuria, strict glycemic control in addition to the use of angiotensin inhibitors and statins remains strongly recommended.

Other post-transplant complications

  • 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.
  • All patients, whether or not they have a pre-identified increased risk, should have a fasting blood glucose measured weekly during the first four weeks post-transplant, then every two weeks for two months, then monthly thereafter.
  • HbA1c can be checked after three months post-transplant. HbA1c should be checked every three months with a target of < 7%.
  • Among patients who have HbA1c > 6%, home blood sugar monitoring and assessment of an HbA1c quarterly are recommended.
  • Patients should be instructed to do glucose self-monitoring.

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 due to 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.
  • NODAT is a common and serious condition that affects the overall health and the survival of a transplant recipient. Inability to control NODAT is associated with significant allograft failure as well as overall transplant recipient morbidity.

References

  1. Cimbaluk D et al: Update on human polyomavirus BK nephropathy. Diagn Cytopathol 37:773, 2009  [PMID:19626630]

    Comment: A comprehensive review on BK virus nephropathy.
    Rating: Important

  2. Fishman JA, Rubin RH: Infection in organ-transplant recipients. N Engl J Med 338:1741, 1998  [PMID:9624195]

    Comment: A comprehensive review on infections in organ-transplant recipients
    Rating: Important

  3. Webster AC et al: Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ 331:, 2005  [PMID:16157605]

    Comment: A meta-analysis showing a higher risk for developing post-transplant diabetes mellitus with tacrolimus compared to cyclosporine.

  4. Sharif A, Baboolal K: Risk factors for new-onset diabetes after kidney transplantation. Nat Rev Nephrol 6:415, 2010  [PMID:20498675]

    Comment: A recent review of risk factors associated with post-transplant diabetes mellitus.

  5. Morath C et al: Simultaneous pancreas-kidney transplantation in type 1 diabetes. Clin Transplant 23 Suppl 21:115, 2009  [PMID:19930324]

    Comment: A review of simultaneous pancreas-kidney transplantation in diabetes mellitus type 1.
    Rating: Important

  6. Markell M: New-onset diabetes mellitus in transplant patients: pathogenesis, complications, and management. Am J Kidney Dis 43:953, 2004  [PMID:15168375]

    Comment: A review that discusses the pathogenesis, complications and management of post-transplant diabetes mellitus.

  7. American Diabetes Association: Standards of medical care in diabetes--2011. Diabetes Care 34 Suppl 1:S11, 2011  [PMID:21193625]
  8. Kasiske BL et al: Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 3:178, 2003  [PMID:12603213]

    Comment: Analyzes data from the United Renal Data System and identifies risk factors associated with post-transplant diabetes mellitus.

  9. Moloney FJ et al: A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol 154:498, 2006  [PMID:16445782]

    Comment: Demonstrates a biphasic increase in skin cancer incidence following kidney transplantation; this was determined by the age at transplantation.

  10. Cosio FG et al: New onset hyperglycemia and diabetes are associated with increased cardiovascular risk after kidney transplantation. Kidney Int 67:2415, 2005  [PMID:15882287]

    Comment: Demonstrates a significant relationship between post-transplant hyperglycemia and cardiovascular events.

  11. Desai NM et al: Maintenance steroid therapy for kidney recipients--not ready for relegation. Am J Transplant 9:1263, 2009  [PMID:19459824]

    Comment: Discusses corticosteroid withdrawal from maintenance immunosuppressive therapy; argues that it is still early to adopt this strategy.
    Rating: Important

  12. Ojo AO: Cardiovascular complications after renal transplantation and their prevention. Transplantation 82:603, 2006  [PMID:16969281]

    Comment: Discusses risk factors that confer greater risk of CVD morbidity and mortality in the post transplant period.
    Rating: Important

  13. Donald E. Hricik (editor); Kidney Transplantation second edition; Chapter 5: Evaluation of Kidney Transplant Candidates; 2003.

    Comment: Discusses the approach for evaluation of potential transplant recipients.

  14. Vajdic CM et al: Cancer incidence before and after kidney transplantation. JAMA 296:2823, 2006  [PMID:17179459]

    Comment: Highlights the role of the interaction between the immune system and common viral infections in the etiology of cancer.

  15. Harden PN et al: Annual incidence and predicted risk of nonmelanoma skin cancer in renal transplant recipients. Transplant Proc 33:1302, 2001 Feb-Mar  [PMID:11267301]

    Comment: Identifies risk factors for developing non-melanoma skin cancer post-transplantation.

  16. OPTN/SRTR 2008 Annual Report; http://optn.transplant.hrsa.gov…; last accessed 11/21/11.

    Comment: Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients

  17. Peev V, Reiser J, Alachkar N: Diabetes mellitus in the transplanted kidney. Front Endocrinol (Lausanne) 5:, 2014  [PMID:25221544]
  18. Razonable RR: Strategies for managing cytomegalovirus in transplant recipients. Expert Opin Pharmacother 11:1983, 2010  [PMID:20642369]

    Comment: Reviews strategies for managing cytomegalovirus in transplant recipients.
    Rating: Important

  19. Ciancio G et al: A randomized long-term trial of tacrolimus/sirolimus versus tacrolimums/mycophenolate versus cyclosporine/sirolimus in renal transplantation: three-year analysis. Transplantation 81:845, 2006  [PMID:16570006]

    Comment: Shows better graft function and fewer endocrine side-effects in mycophenolate/tacrolimus regimen when compared to sirolimus/tacrolimus regimen.

  20. Montori VM et al: Posttransplantation diabetes: a systematic review of the literature. Diabetes Care 25:583, 2002  [PMID:11874952]

    Comment: Shows that immunosuppressive regimens including high dose calcineurin inhibitors increase risk for post-transplant diabetes mellitus.

  21. Sung RS et al: Peripheral vascular occlusive disease in renal transplant recipients: risk factors and impact on kidney allograft survival. Transplantation 70:1049, 2000  [PMID:11045641]

    Comment: Shows that peripheral vascular disease after transplantation is associated with reduced survival; it appears that transplantation does not accelerate or retard its progression.

  22. Teutonico A, Schena PF, Di Paolo S: Glucose metabolism in renal transplant recipients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus. J Am Soc Nephrol 16:3128, 2005  [PMID:16107580]

    Comment: Shows that sirolimus is associated with worsening insulin resistance.

  23. Larsen JL et al: Tacrolimus and sirolimus cause insulin resistance in normal sprague dawley rats. Transplantation 82:466, 2006  [PMID:16926589]

    Comment: Shows that tacrolimus and sirolimus have a synergistic effect on islet cell apoptosis in Sprague dawley rats.

  24. Kasiske BL et al: Cancer after kidney transplantation in the United States. Am J Transplant 4:905, 2004  [PMID:15147424]

    Comment: Shows that the rates for most malignancies are higher after transplantation; concludes that cancer prevention should be a main focus in kidney transplant recipients.

  25. Ekberg H et al: Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 357:2562, 2007  [PMID:18094377]

    Comment: Shows that the use of a regimen that includes mycophenolate, corticosteroids and low dose tacrolimus is advantageous for renal function, allograft survival and acute rejection rates.

  26. Numakura K et al: Clinical and genetic risk factors for posttransplant diabetes mellitus in adult renal transplant recipients treated with tacrolimus. Transplantation 80:1419, 2005  [PMID:16340785]

    Comment: Suggests that certain genetic polymorphisms may predict patients' risk for developing post-transplant diabetes mellitus.

  27. Sis B et al: Banff '09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups. Am J Transplant 10:464, 2010  [PMID:20121738]

    Comment: The most recent Banff classification of renal allograft pathology.

  28. USRDS 2008 Annual Data Report; http://www.usrds.org…; 2008; last accessed 11/21/11.

    Comment: The national data registry that collects and analyzes information on the end-stage renal disease population in the U.S.

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Last updated: November 5, 2015