Sudhir Thaduri , M.D., Nada Alachkar, M.D.
- The surgical implantation of a kidney (allograft) from one human (donor) to another human (recipient).
- Simultaneous pancreas and kidney (SPK) transplantation has been a successful therapy for patients with end-stage kidney disease (ESKD) or advanced chronic kidney disease (CKD) secondary to type 1 diabetes mellitus. Other options include pancreas or islet cell transplantation before or after kidney transplantation.
- Patients with kidney transplantation and with pancreas transplantation require immunosuppression to prevent immune-mediated graft rejection.
- Diabetes, in the context of kidney transplantation, includes both patients who have diagnosed with diabetes prior to transplantation and patients who develop post-transplantation diabetes mellitus (PTDM); recently replaced by the term: new-onset diabetes after transplant (NODAT).
- 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 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.
- NODAT is a strong, independent predictor of allograft failure and poor patient survival.
- Obesity: NODAT 1.4-fold higher in those with a BMI of 25 to 30 and nearly doubled if the BMI was >30 kg/m2.
- Age is considered the strongest risk factor for the 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.
- 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 eGFR 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 may not be considered candidates for kidney transplantation.
- Obesity is a relative contraindication for kidney transplantation, associated with worse allograft outcomes and wound healing problems. Most programs require patients to be with a BMI of < 40 kg/m2 before considering for 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 serologies in addition to testing to exclude tuberculosis.
- Potential candidates should also have annual age-appropriate cancer screening tests. These include colonoscopy in both genders, 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 is 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 the transplant team with the assistance of the patients’ local nephrologists.
- The final decision to approve a candidate for transplantation is achieved by a multidisciplinary committee.
- Diabetes 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
- A1C ≥6.5 %, three or more months post-transplant
- Prediabetes, 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 within 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
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.
- The risk of overall mortality and infection related mortality is higher among diabetic kidney transplant recipients compared to non-diabetic recipients.
- 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.
- NODAT is a strong, independent predictor of global mortality, graft failure, and death-censored graft failure.
- Recent data are emerging showing less deleterious impact of NODAT on transplant outcomes. It is possible that the adverse outcomes in NODAT could be attributed to an era of high-dose steroid and cyclosporine usage in the past.
- Other diabetic complications: ketoacidosis, hyperosmolarity, ophthalmic complications, neurologic complications, and hypoglycemia/shock can occur in patients who develop NODAT.
- Most transplant recipients are given induction immunosuppression at the time of receiving a transplant and then maintained on immunosuppression until the allograft fails.
- Standard maintenance regimens followed across the US comprise triple immunosuppression using combination of one agent from each class of :
- 1. Calcineurin inhibitors [tacrolimus(Prograf), cyclosporine (Gengraf, Neoral)]
- 2. Anti Proliferative agent [mycophenolate mofetil (Cellcept), azathioprine ( Imuran)]
- 3. Corticosteroids (prednisone/prednisolone/methylprednisolone)
- The category of mTOR Inhibitors comprising either sirolimus (Rapamune) or everolimus ( Zortress ) is uncommonly used by transplant experts in unique situations.
- 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.
- Nearly all transplant recipients receive prophylaxis for opportunitistic infections:
- CMV: valganciclovir
- PCP : trimethoprin - sulfamethoxazole
- Candida/Fungal infections: azoles/nystatin
- Prophylactic agents for opportunistic infections are started right away after the transplant surgery and continued for up to 3-6 months individualized to patient.
Post-Transplant Diabetes Mellitus (PTDM)
Post-Transplant Diabetes Mellitus (PTDM)
Post-Transplant Diabetes Mellitus (PTDM)
- Recently replaced by new-onset diabetes after transplant (NODAT) term.
- 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 directly affect transcriptional regulation of insulin expression.
- The risk of NODAT is 53% greater in patients treated with tacrolimus compared to patients not treated with tacrolimus, and is dose-dependent.
- The risk of NODAT also increased when sirolimus (mTOR 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 or decrease the 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.
- The evidence for use of SGLT-2 inhibitors in transplant recipients is limited, and its use should be assessed carefully by the transplant nephrologist and the endocrinologist.
Other post-transplant complications
Other post-transplant complications
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 can be 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.
- 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, spot urine protein to creatinine ratio, 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.
- The risk of CMV Viremia with or without symptoms is highest in individuals with negative CMV serostatus getting a kidney from a CMV positive donor. They need high index of suspicion after completion of prophylaxis duration.
- 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 of allograft function could result from usual causes of acute kidney Injury but specifically need to keep in mind additional etiologies which are unique in this group: CNI nephrotoxicity, hemodynamic effect, rejection, BK infection, recurrence of original kidney disease, obstruction from surgical complications, organ-specific lymphoma.
- Biopsy of the transplanted kidney is often needed to help 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.
- Among patients who have HbA1c > 6%, home blood sugar monitoring and assessment of an HbA1c quarterly are recommended.
- Vaccination is an important component of long-term care of transplant recipients.
- 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 a transplant center for evaluation and listing on the waiting list.
- Simultaneous pancreas-kidney transplantation should be strongly considered for type 1 diabetes with kidney failure and in selected individuals with type 2 diabetes. It has the advantage of prolonging the longevity of patient and kidney allograft by allowing freedom from dialysis and insulin. It also shortens waiting time for eligible candidates compared to those needing kidney transplant alone.
- 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 condition that affects the overall health and the survival of a transplant recipient. Inability to control NODAT is associated with increase the risk of allograft failure as well as overall transplant recipient morbidity.
- Halden TAS, Kvitne KE, Midtvedt K, et al. Efficacy and Safety of Empagliflozin in Renal Transplant Recipients With Posttransplant Diabetes Mellitus. Diabetes Care. 2019;42(6):1067-1074. [PMID:30862658]
Comment: Double blind RCT of 49 Kidney Transplant recipients with PTDM comparing use of SGLT2 inhibitor ( Empagliflozin ) showed significant improvement of HbA1C in the treatment arm along with reduction of body weight with no major differences in adverse events.
- Gaynor JJ, Ciancio G, Guerra G, et al. Single-centre study of 628 adult, primary kidney transplant recipients showing no unfavourable effect of new-onset diabetes after transplant. Diabetologia. 2015;58(2):334-45. [PMID:25361829]
Comment: A prospective RCT of 628 KTRs showed increased rates of Death with functioning graft in patients with pretransplant diabetes but NODAT had no unfavorable effect on end points for a study period of 4.5yrs.
- Hayer MK, Farrugia D, Begaj I, et al. Infection-related mortality is higher for kidney allograft recipients with pretransplant diabetes mellitus. Diabetologia. 2014;57(3):554-61. [PMID:24305965]
Comment: In a study including more than 19000 Kidney Transplant Recipients with nearly 3000 Diabetic individuals, the overall risk of mortality (16% Vs 10%) and Infection specfic mortality (3.3 Vs 2 %) was higher in diabetic individuals.
- Peev V, Reiser J, Alachkar N. Diabetes mellitus in the transplanted kidney. Front Endocrinol (Lausanne). 2014;5:141. [PMID:25221544]
- Sis B, Mengel M, Haas M, et al. Banff '09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups. Am J Transplant. 2010;10(3):464-71. [PMID:20121738]
Comment: The most recent Banff classification of renal allograft pathology.
- Sharif A, Baboolal K. Risk factors for new-onset diabetes after kidney transplantation. Nat Rev Nephrol. 2010;6(7):415-23. [PMID:20498675]
Comment: A recent review of risk factors associated with post-transplant diabetes mellitus.
- Razonable RR. Strategies for managing cytomegalovirus in transplant recipients. Expert Opin Pharmacother. 2010;11(12):1983-97. [PMID:20642369]
Comment: Reviews strategies for managing cytomegalovirus in transplant recipients.
- Cimbaluk D, Pitelka L, Kluskens L, et al. Update on human polyomavirus BK nephropathy. Diagn Cytopathol. 2009;37(10):773-9. [PMID:19626630]
Comment: A comprehensive review on BK virus nephropathy.
- Weiss AS, Smits G, Wiseman AC. Twelve-month pancreas graft function significantly influences survival following simultaneous pancreas-kidney transplantation. Clin J Am Soc Nephrol. 2009;4(5):988-95. [PMID:19406961]
Comment: A functioning pancreatic graft at 12 months post SPK showed improved patient and graft survival compared to recipients of a living donor kidney transplant or cadaveric kidney transplant alone. Failure of pancreatic allograft before 1yr resulted in similar patient survival as kidney transplant alone.
- Desai NM, Schnitzler M, Jendrisak MD, et al. Maintenance steroid therapy for kidney recipients--not ready for relegation. Am J Transplant. 2009;9(6):1263-4. [PMID:19459824]
Comment: Discusses corticosteroid withdrawal from maintenance immunosuppressive therapy; argues that it is still early to adopt this strategy.
- Morath C, Schmied B, Mehrabi A, et al. Simultaneous pancreas-kidney transplantation in type 1 diabetes. Clin Transplant. 2009;23 Suppl 21:115-20. [PMID:19930324]
Comment: A review of simultaneous pancreas-kidney transplantation in diabetes mellitus type 1.
- Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357(25):2562-75. [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.
- Ojo AO. Cardiovascular complications after renal transplantation and their prevention. Transplantation. 2006;82(5):603-11. [PMID:16969281]
Comment: Discusses risk factors that confer greater risk of CVD morbidity and mortality in the post transplant period.
- Ciancio G, Burke GW, Gaynor JJ, et al. A randomized long-term trial of tacrolimus/sirolimus versus tacrolimums/mycophenolate versus cyclosporine/sirolimus in renal transplantation: three-year analysis. Transplantation. 2006;81(6):845-52. [PMID:16570006]
Comment: Shows better graft function and fewer endocrine side-effects in mycophenolate/tacrolimus regimen when compared to sirolimus/tacrolimus regimen.
- Moloney FJ, Comber H, O'Lorcain P, et al. A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol. 2006;154(3):498-504. [PMID:16445782]
Comment: Demonstrates a biphasic increase in skin cancer incidence following kidney transplantation; this was determined by the age at transplantation.
- Vajdic CM, McDonald SP, McCredie MR, et al. Cancer incidence before and after kidney transplantation. JAMA. 2006;296(23):2823-31. [PMID:17179459]
Comment: Highlights the role of the interaction between the immune system and common viral infections in the etiology of cancer.
- Larsen JL, Bennett RG, Burkman T, et al. Tacrolimus and sirolimus cause insulin resistance in normal sprague dawley rats. Transplantation. 2006;82(4):466-70. [PMID:16926589]
Comment: Shows that tacrolimus and sirolimus have a synergistic effect on islet cell apoptosis in Sprague dawley rats.
- Webster AC, Woodroffe RC, Taylor RS, et al. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ. 2005;331(7520):810. [PMID:16157605]
Comment: A meta-analysis showing a higher risk for developing post-transplant diabetes mellitus with tacrolimus compared to cyclosporine.
- 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. 2005;16(10):3128-35. [PMID:16107580]
Comment: Shows that sirolimus is associated with worsening insulin resistance.
- Numakura K, Satoh S, Tsuchiya N, et al. Clinical and genetic risk factors for posttransplant diabetes mellitus in adult renal transplant recipients treated with tacrolimus. Transplantation. 2005;80(10):1419-24. [PMID:16340785]
Comment: Suggests that certain genetic polymorphisms may predict patients' risk for developing post-transplant diabetes mellitus.
- Cosio FG, Kudva Y, van der Velde M, et al. New onset hyperglycemia and diabetes are associated with increased cardiovascular risk after kidney transplantation. Kidney Int. 2005;67(6):2415-21. [PMID:15882287]
Comment: Demonstrates a significant relationship between post-transplant hyperglycemia and cardiovascular events.
- Markell M. New-onset diabetes mellitus in transplant patients: pathogenesis, complications, and management. Am J Kidney Dis. 2004;43(6):953-65. [PMID:15168375]
Comment: A review that discusses the pathogenesis, complications and management of post-transplant diabetes mellitus.
- Kasiske BL, Snyder JJ, Gilbertson DT, et al. Cancer after kidney transplantation in the United States. Am J Transplant. 2004;4(6):905-13. [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.
- Kasiske BL, Snyder JJ, Gilbertson D, et al. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant. 2003;3(2):178-85. [PMID:12603213]
Comment: Analyzes data from the United Renal Data System and identifies risk factors associated with post-transplant diabetes mellitus.
- Montori VM, Basu A, Erwin PJ, et al. Posttransplantation diabetes: a systematic review of the literature. Diabetes Care. 2002;25(3):583-92. [PMID:11874952]
Comment: Shows that immunosuppressive regimens including high dose calcineurin inhibitors increase risk for post-transplant diabetes mellitus.
- Sung RS, Althoen M, Howell TA, et al. Peripheral vascular occlusive disease in renal transplant recipients: risk factors and impact on kidney allograft survival. Transplantation. 2000;70(7):1049-54. [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.
- Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med. 1998;338(24):1741-51. [PMID:9624195]
Comment: A comprehensive review on infections in organ-transplant recipients
- Harden PN, Fryer AA, Reece S, et al. Annual incidence and predicted risk of nonmelanoma skin cancer in renal transplant recipients. Transplant Proc. 2001;33(1-2):1302-4. [PMID:11267301]
Comment: Identifies risk factors for developing non-melanoma skin cancer post-transplantation.
- 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.
- USRDS 2008 Annual Data Report; http://www.usrds.org/2008/view/ckd_00_intro.asp; 2008; last accessed 9/2/2021.
Comment: The national data registry that collects and analyzes information on the end-stage renal disease population in the U.S.
- OPTN/SRTR 2008 Annual Report; https://srtr.transplant.hrsa.gov/annual_reports/2018_ADR_Preview.aspx (accessed 9/9/21).
Comment: Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients
- American Diabetes Association, Standards of medical care in diabetes; January 01 2021; volume 44 issue Supplement 1. https://care.diabetesjournals.org/content/44/Supplement_1
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