Guidelines for Post-Kidney Transplant Management in the Community Setting

Purpose: To create a consensus statement that clarifies the responsibilities of the Transplant Center and medical care providers outside the transplant center in the management of the kidney transplant patients

Source: AST Kidney-Pancreas Committee

Target: Transplant Centers, Transplant Care Providers outside the Transplant Center
(referred to in this document as “Primary Providers”)

Background: Kidney transplant recipients require unique medical care that includes attention not only to the function of the transplant itself, but also to common medical problems that are more prevalent, more atypical, and more severe in presentation than in the general population. Due to the successes of kidney transplantation, patients are now living with kidney function for many years. This has led to the recognition that several care providers may be necessary to implement the growing list of guidelines and strategies for long-term management. This fact, coupled with patients’ financial or geographic difficulties in continuing long-term follow-up in the transplant center, and the established relationships of patients with their referring and primary care providers, create a need for care of the kidney transplant recipient outside of the Transplant Center. When care is shared among providers, there is risk of duplication of efforts, or worse, lack of attention to medical problems, due to a lack of delineation of responsibilities. While Transplant Centers have a commitment to assuring excellent graft survival and patient survival, these focused goals may lead to a lack of attention to a number of medical issues that may ultimately contribute to these outcomes. The Primary Provider is a valuable partner for Transplant Centers in the management of medical conditions that impact patient and graft survival, and should be supported by the Transplant Center when conditions are complex or unique to transplantation. In an effort to improve collaborative management, this committee has defined medical conditions or circumstances that communication among providers is warranted. It is hoped that knowledge of these conditions can be reinforced in Transplant Center communications with Primary Providers and will provide a general template for Primary Providers to inform and consult with the patient’s Transplant Center.

General considerations for management of medical conditions in kidney transplant recipients:
Post transplant management for renal transplant patients is a complicated yet life saving mission that needs to be addressed by qualified care providers. Even though there are protocols and generic guidelines on post transplant follow up, the individual patients’ complexity can certainly evade predetermined protocols and situations will frequently arise that are not covered by any guidelines. The expertise of the transplant centers should be used as a critical resource for the long-term follow-up of renal transplant patients. In order to simplify the logistics of following these complex patients, responsibilities in following different medical issues should be clearly defined. At the time of transplant or possibly prior to transplant the patient together with the Transplant Center should elaborate a detailed follow up plan specifying physicians’ and patients’ responsibilities for different areas of care.
A Primary Provider may be a physician within the Transplant Center, the referring physician, or other physician or mid-level care provider that is mutually acceptable to the patient and the Transplant Center. The degree of collaboration should be clarified by the Transplant Center at the time of transfer of care to the Primary Provider.
Importantly, the Transplant Center must be explicit in its expectation of the care responsibilities to be assumed by the Primary Provider, and similarly, the Primary Provider has an obligation to consult with the Transplant Center in cases of changes in medical status. This document describes the most pertinent issues in the care of the Kidney Transplant Recipient and outlines general considerations in the flow of information between Transplant Center and Primary Provider.

Recommendations for management of medical conditions unique to kidney transplant recipients:

I. Renal function

Scope of the Problem
Chronic kidney disease (CKD) is under-recognized and undertreated in kidney transplant recipients. As serum creatinine may not reflect true glomerular filtration rate (GFR), renal function should be estimated with one of the several formulae that are available. The Kidney Disease: Improving Global Outcomes (KDIGO) initiative recommends that all kidney transplant recipients be considered as having CKD, regardless of GFR or presence or absence of markers of kidney damage. CKD related complications are also prevalent in the transplant setting, especially at lower levels of kidney function, and are often overlooked.

Upon transfer of care to providers outside the Transplant Center, expectations for care and recommendations should be given by the Transplant Center for the following assessments:

Surveillance recommendations to be provided to Primary Providers

• Management plan for renal function monitoring
• Management plan for monitoring of urinary protein excretion.
• Management plan for monitoring of blood pressure control, calcium and phosphorus abnormalities, anemia, hypoalbuminemia, acidosis, and lipid abnormalities.

Examples, but not a comprehensive list of conditions that warrant Transplant Center consultation and/or management include:

Recommendations for Collaborative Management/Referral to Transplant Center

• Significant change in renal function
• New onset of significant proteinuria
• Significant increase in baseline proteinuria
• Interpretation and management following a kidney biopsy performed for any reason
• Referral for re-transplantation evaluation in patients with a failing allograft

II. Immunosuppression/therapeutic drug monitoring

Scope of the Problem
Immunosuppression regimens and protocols are in a continued state of evolution. For this reason, decisions regarding immunosuppressive regimens should be made by one designated care provider to prevent confusion in management. Together with the patient, the Transplant Center should decide who will be the decision maker for the patients’ immunosuppression. This will be in many cases the Transplant Center itself but in other cases the Transplant Center might assign a Primary Provider to take over decision-making power for long-term immunosuppression. The decision to assign a different care provider should be consensual with the patient and only after agreement with the Transplant Center, taking into consideration the designated care providers’ qualifications to follow long-term immunosuppression.

If immunosuppression management is to be performed by a Primary Provider outside the Transplant Center, the Transplant Center should provide the following recommendations at the time of transfer of care:

Surveillance recommendations to be provided to Primary Providers

• Therapeutic drug monitoring schedule and goals
• Past and current side effects of immunosuppression experienced by the patient
• Any prior immunosuppression changes and rationale
• Recommendations for periodic updates on the progress of the patient from the Primary Provider to the Transplant Center (at least yearly, ideally the Transplant Center should be copied on all clinic visit notes and laboratory assessments)
• Considerations in immunosuppression management should take into account the lifetime history of both patient and graft and have complete clinical and laboratory data available to aid the complicated decision making process of long term immunosuppression. Care can be transferred to a different Primary Provider or to the Transplant Center at any time, but care provider changes should be minimized to ensure continuity of care. The Transplant Center should be consulted when designating a new care provider for immunosuppression management.

Any condition in which there is a significant change in medical condition or major intercurrent illness that may warrant changes in immunosuppression should be considered an indication for Transplant Center consultation and management. Examples of these conditions include but are not limited to:

Recommendations for Collaborative Management/Referral to Transplant Center

• Major surgery
• Treatment of chronic infections such as Hepatitis B and C or HIV
• Transition of medications from oral to intravenous formulations
• The desire or occurrence of pregnancy
• Severe or opportunistic infection (see “Infectious Disease” below)
• Malignancy (see Malignancy” below)
• If the Transplant Center is not the main care provider for immunosuppression, the designated care provider should update the Transplant Center on the progress of the patient periodically (at least yearly)
• Changes in the medication regimens other than immunosuppression undertaken by other care providers should be discussed with or at least communicated to the Transplant Center, since other medication can significantly interfere with immunosuppressive medications. This particularly applies to medications that affect Cyp3A4 metabolism. A brief list of common drugs and supplements that interact with this metabolic pathway include:

III. Cardiovascular Disease Management

Scope of the Problem
Cardiovascular disease is the leading cause of death in renal transplant recipients and a major cause of graft loss. Patients often enter the post-transplant period with substantial history of cardiovascular disease and risk from longstanding diabetes, hypertension, and hyperlipidemia. These conditions are exacerbated post-transplant by the immunosuppressive regimens currently prescribed. Despite the increase in prevalence and severity of cardiovascular co-morbidities following transplant, patients have lower mortality rates and less cardiovascular events post-transplant than on dialysis, emphasizing the fact that chronic kidney disease/ESRD is a strong independent cardiovascular risk factor. For this reason, the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend inclusion of transplant recipients in the highest risk category for treatment of hypertension and dyslipidemia.

Upon referral back to referring providers, transplant centers should provide guidelines for CV risk management for the following conditions:

Surveillance recommendations to be provided to Primary Providers

• Fasting lipid profile goals
• Blood pressure goals
• Smoking history and goals for cessation
• Assessment of weight gain following transplant
• Diabetes management plan
• Expectations for microalbuminuria, anemia, and other nontraditional CV risk factors, if applicable (individualized by transplant center)

In general, the management of CV risks should be a primary focus for the Primary Provider, given the frequency of visits and close follow-up required. Occasionally, these goals may be difficult to achieve and consultation/referral to the Transplant Center may be indicated to alter or change immunosuppressive agents to improve control of these conditions. Additionally, cardiovascular endpoints that occur should be reported to the transplant center to permit adequate tracking of complications and consideration of appropriate immunosuppression in these circumstances.

Conditions in which Transplant Center consultation of CV disease is appropriate include the following:

Recommendations for Collaborative Management/Referral to Transplant Center

• Hyperlipidemia uncontrolled, with consideration of immunosuppression change
• Hypertension uncontrolled, with consideration of immunosuppression change
• New onset diabetes after transplant
• Uncontrolled diabetes with consideration of immunosuppression change
• Myocardial infarction
• Coronary artery disease requiring revascularization (CABG, angioplasty/stent)
• Cerebrovascular event
• Peripheral arterial disease requiring revascularization (bypass, angioplasty/stent)

IV. Infectious Disease

Scope of the Problem: In general, kidney transplant recipients are susceptible to a greater number of infections that often present with greater severity than the general population, due to their chronically immunosuppressed state. Excellent reviews that summarize the timing and management of conventional, unconventional/opportunistic, and chronic infections post-transplant are available for the Primary Provider’s review. Given that the signs and symptoms of infection are often atypical in the kidney transplant recipient, routine surveillance strategies have been developed by Transplant Centers for a number of commonly encountered infections post-transplant. Since the fields of transplant immunosuppression and infectious disease evolve rapidly, with an individual’s susceptibility to various pathogens and management strategies that differ from region-to-region and center-to-center, it is necessary for Transplant Centers to communicate their expectations for the standard of care for infectious disease issues to Primary Providers.

Screening protocols and infectious disease issues specific to the individual patient should be described by the Transplant Center to the Primary Provider at the time of transfer of care/shared management. These recommendations may include but are not limited to the following:

Infectious disease: surveillance recommendations to referring care providers:

• Assessment of risk of CMV disease, prophylaxis strategy and duration, and monitoring strategy
• Assessment of risk of BK virus nephropathy and monitoring strategy
• Assessment of risk of EBV transmission/disease and monitoring strategy
• Prophylaxis strategies for other commonly encountered opportunistic infections such as pneumocystis carinii, candida albicans, and herpesvirus
• Prophylaxis, monitoring, and treatment strategies for hepatitis B, hepatitis C, and HIV when applicable
• Recommendations for vaccination for influenza

By communicating these essential aspects of infectious disease care of the transplant recipient to the referring Primary Provider, the Transplant Center and Primary Provider will both have significant responsibility in the surveillance, diagnosis, and management of these issues. When in the course of management of the post-transplant recipient an infectious disease process is identified that is related to, or impacts the degree or type of immunosuppression provided to the patient, the Transplant Center should assume primary responsibility in disease management. While it is possible to initially manage these complications in a medical setting outside of the Transplant Center, close consultative support should be provided by the Transplant Center until the patient is stabilized and a decision can be made regarding the timing of follow-up at the Transplant Center.

Examples of circumstances that warrant Transplant Center referral and management include but are not limited to the following:

Recommendations for collaborative management/referral to Transplant Center

• Unexplained fever
• Protracted diarrhea/gastrointestinal symptoms
• Recurrent UTIs
• Fever associated with renal dysfunction
• Fever associated with mental status changes
• CMV viremia or disease
• BK virus viremia, nephropathy, or viruria
• EBV viremia or disease
• Opportunistic infections (e.g. pneumocystis, herpes zoster, nocardiosis, West Nile virus, cryptosporidium)
• Newly diagnosed or progressive Hepatitis B, C, and HIV

V. Malignancy

Scope of Problem:
Post transplant malignancy continues to be a recognized side effect of prolonged immunosuppression. The incidence of malignancy in the transplant recipient (20% incidence of malignancy after 10 years of chronic immunosuppression) is estimated to be 3-4 fold higher than the general population. This risk is associated with the intensity and chronicity of the immunosuppression received by the transplant recipient. Certain malignancies are known to have much higher frequency in the post-transplant patient compared to the general population. Many of these are related to viral infections with oncogenic potential such as human papillomavirus (HPV), Ebstein Barr virus (EBV), human herpes virus 8 (HHV-8), and Hepatitis B or C infection. Malignancy in the post-transplant renal recipient can be diagnosed under several scenarios including de novo disease, recurrence of a prior malignancy, or as a donor-transmitted malignancy.

Malignancies seen with increased frequency in the post-transplant population include:

• Skin cancer –particularly squamous cell carcinoma (SCC) involving sun exposed areas, but also basal cell carcinoma, melanoma, and Merkel cell
• Oral cancers—pharynx, larynx, oral cavity
• Urogenital cancers— vulvar, male and female anogenital areas, uterine cervix, urinary tract (especially in patients having received cumulative cyclophosphamide doses over 20 gms)
• Renal cell carcinoma in multi-cystic kidney disease or multicystic transformation of contracted native kidneys
• Hodgkin’s and non-Hodgkin’s lymphomas, including post-transplant lymphoproliferative disorder (PTLD)
• Kaposi sarcoma
• Hepatocellular carcinomas (HCC) generally, but not exclusively related to recipient infection with Hepatitis B or advanced hepatitis C.

Transplant Centers are increasingly dependent upon Primary Providers for the periodic assessment of malignancy risk. While guidelines for screening are constantly in evolution, the general principles listed below represent a current comprehensive reference for providers to follow:

Surveillance recommendations to be provided to Primary Providers

• Renal transplant recipients should be screened for solid organ malignancy in an age appropriate manner following the guidelines of the American Cancer Society for the general population.
• Due to the significantly increased risk for skin cancer, all patients should have a yearly skin examination and patients with a history of skin cancer should have follow-up more frequently as indicated.
• Patients who have received prior treatment with chemotherapeutic agents such as cyclophosphamide or who have a history of analgesic nephropathy are at increased risk for urogenital malignancies. Urologic evaluation should be performed in these recipients in all cases of new onset microhematuria.
• Female renal transplant recipients have a higher risk for cervical, vaginal, and perineal carcinoma and should have yearly pelvic exams and PAP smears, including patients who have undergone total hysterectomies.
• Lymphomas including PTLD should be considered in all individuals with clinical symptoms suggesting organ involvement.
• Hepatitis B carriers and Hepatitis C with advanced fibrosis—every 6 month abdominal ultrasound and serum alpha fetoprotein levels

Recommendations for Collaborative Management/Referral to Transplant Center

• The occurrence of all cancers in the renal transplant recipient should be reported to the transplant center as soon as they are identified.

Good communication provides for active collaboration between Transplant Center and Primary Provider and facilitates accomplishment of three important goals. First, it involves the Transplant Center early in making appropriate adjustments in the anti-rejection therapy in conjunction with the treating oncologist so that coordination of care is achieved. Successful treatment of advanced cancers will likely require significant minimization or even withdrawal of maintenance immunosuppression. Second, the evaluation of maintenance immunosuppression is an ongoing process, balancing the risks of allograft rejection with the risks of over immunosuppression. A discussion with the Transplant Center about the recipient’s current immunosuppressive therapy is warranted any time the patient develops clinical indications that would suggest high risk for the development or recurrence of malignancy. Examples would include recurrent squamous cell carcinomas of the skin or the development of aggressive peri-genital/anal HPV infection which has a high oncogenic potential. Finally, Transplant Centers are required by OPTN/UNOS policy to complete yearly clinical updates on all transplant recipients including the occurrence of malignancy. Communication between the transplant center and the community improves timely reporting of malignancy to the OPTN/UNOS and SRTR national databases. This will help the transplant community track the true incidence of post-transplant malignancy in renal transplant recipients

Summary Statement:
This document was created with the concept that the sharing of responsibilities of the kidney transplant recipient between Transplant Center and Primary Provider is necessary in enhancing care. This is not meant to be a comprehensive management document, but rather, a description of medical issues that can be managed by either the Transplant Center or the referring practice, with recommendations for collaborative care. An overriding issue is that there must be a management strategy in place for the medical conditions described above, and that primary responsibility is clearly assigned. While each program, region, and referring practice is unique in its healthcare delivery, it is hoped that the general delineations of care outlined within this consensus statement may help define responsibilities and can aid the Transplant Center and Primary Provider work collaboratively.

The American Society of Transplantation is an international organization of transplant professionals dedicated to advancing the field of transplantation through the promotion of research, education, advocacy, and organ donation to improve patient care.

Approved by the AST Board of Directors, May 29, 2009