Clinical Practice Guidelines

KDIGO Clinical Practice Guidelines for the Care of the Kidney Transplant Recipient

Rationale

The success of kidney transplantation has enabled substantial growth in the number of transplantations performed worldwide. Indeed, in countries of the developed world, the major barrier to meeting the needs of end-stage kidney disease with kidney transplantation is the shortage of organ donors. While the number of transplantations has grown dramatically in economically developed nations, the story may be quite different in many developing countries, where the cost and access to care are still major limitations to fully implementing transplantation as a treatment for end-stage kidney disease. To address barriers to successful kidney transplantation worldwide, “Kidney Disease: Improving Global Outcomes” (KDIGO) sponsored an international Controversies Conference on “The Care of the Kidney Transplant Recipient” in Lisbon, Portugal, February 2-5, 2006. Specifically, the goal of this conference was to define key questions and to develop recommendations to improve the outcomes of kidney transplant recipients worldwide, not just in developed countries. Formal, evidence-based guidelines are a natural extension of the Lisbon Conference. Indeed, there is a need for guidelines that establish minimal standards for transplantation that will encourage and enable programs worldwide to perform kidney transplantation in a cost-effective manner.

The success of kidney transplantation in developed countries has also created a challenge of providing long-term care to large numbers of transplant recipients. As the number of transplantations performed has grown, and kidney allograft survival has improved, the number of patients with functioning kidney allografts who need ongoing medical care has also grown. Many transplant centers are finding it increasingly difficult to provide long-term care to growing numbers of kidney transplant recipients. By the same token, kidney transplant recipients who live away from transplant centers are seeking care locally in order to circumvent the added burden of travel for follow-up at their transplant center. Out of necessity, more and more care is being provided by nephrologists and caregivers (physician and non-physician) who are not transplant physicians or transplant surgeons. Thus, there is a need for evidence-based guidelines that set minimal standards of care for primary care nephrologists and other caregivers, and help define the relationship between primary care givers in the community, and specialized expertise in transplant centers.

Goals

The proposed Clinical Practice Guidelines are designed to 1) facilitate transplantation as a treatment for end-stage kidney disease, and 2) improve survival and quality of life for kidney transplantation recipients worldwide.

1. There have never been randomised, controlled trials to prove that transplantation is a better treatment for end-stage kidney disease than chronic maintenance dialysis. However, observational studies suggest that survival and quality of life are better after successful kidney transplantation than with chronic dialysis treatment. Nevertheless, many suitable candidates for kidney transplantation may never receive a kidney allograft, which may be due in large part due to a lack of access to care, which in turn may be due to cost. These guidelines are designed to provide minimal, acceptable standards of care that can allow the maximum number of patients to benefit from transplantation. They are also designed to emphasize the most economical approaches to the care of transplant recipients, which will help enable centers worldwide to offer kidney transplantation to the greatest number of qualified candidates.
2. Short term outcomes, e.g. one-year graft survival, of kidney transplant recipients have improved dramatically. However, the rates of late allograft failure, due to both premature death and graft dysfunction, have changed little. This has necessarily shifted the focus of transplant care to preventing complications such as infection, cardiovascular disease, and malignancies, while maintaining graft function and preventing chronic allograft nephropathy. At the same time, the demands of caring for kidney transplant recipients have grown in proportion to their numbers. Centers performing a large number of transplantations often cannot provide long-term primary care for the increasing number of recipients who are surviving with functioning kidney allografts. Therefore, many of these patients now receive most of their post transplant care in the hands of local, general nephrologists, internists and other primary physicians who may have limited experience in caring for kidney transplant recipients. The second major goal of these guidelines is to provide a framework to the primary caregivers of kidney transplant recipients that will help them co-manage these patients in conjunction with a transplant center. These guidelines will supplement, not supplant, the expertise provided by qualified transplant centers. The goal of these guidelines will thereby improve the quality of life and outcomes of transplant recipients worldwide.

Target Audience

These guidelines will be written for physicians and other caregivers who provide long term care for recipients of kidney transplantation. These include transplant physicians and surgeons, but also general nephrologists, other primary care physicians, as well as nurse practitioners and others who provide medical care to transplant recipients. These guidelines are not written for patients or their families, although patients are the intended beneficiaries. However, after the guidelines are developed, and as an implementation tool, patient education material based on the guidelines will be developed and made available to transplant recipients to improve their understanding and cooperation of the care process.

Target Population

These guidelines will address issues that are most important to the care of patients who have a functioning kidney transplant. Although many aspects of these guidelines may be pertinent to recipients who have been transplanted with an organ other than, or in addition to, a kidney, they will not specifically target these populations. Similarly, they will not cover the evaluation and selection of kidney transplant candidates, or the management of kidney transplant candidates prior to transplantation. They will not cover the evaluation and management of living kidney donors.

Scope

Whereas a kidney transplant recipient may develop any disease that also occurs in the general population, these guidelines are not intended to cover all aspects of medicine. Rather, they will focus on diseases and complications that are more prevalent in patients who have undergone kidney transplantation, as well as diseases and complications whose management may be altered by the fact that the patient is a kidney transplant recipient receiving immunosuppressive medications. The fact that virtually all kidney transplant recipients (excepting rare identical twin transplants) receive immunosuppressive medications greatly affects both the incidence and management of disease in kidney transplant recipients. In addition, kidney function is rarely normal in recipients of kidney transplants. As in the general population, the level of kidney function, or stage of CKD-T also affects the incidence and management of disease after kidney transplantation. Issues to be addresses in these guidelines include:

1. Cardiovascular Disease
   Cardiovascular disease (CVD) is the most common cause of death in kidney transplant recipients, at least in developed countries where most kidney transplants have been performed to date. Evidence from randomized controlled trials and controlled observational studies in the general population has suggested that managing risk factors such as hypertension, diabetes, dyslipidemia, and cigarette smoking reduces the incidence of CVD. There has been only one adequately powered randomized controlled trial examining the effects risk factor intervention on CVD events, i.e. the Assessment of Lescol in Renal Transplantation (ALERT) trial. However, there have been some observational studies suggesting that traditional and non-traditional risk factors are associated with CVD in kidney transplant recipients, and managing traditional CVD risk factors according to guidelines for the general population may be effective in kidney transplant recipients. Some interventions, such as smoking cessation and aspirin prophylaxis are relatively inexpensive.

   The Guideline Development Group will review evidence regarding the incidence and risk factors for CVD in kidney transplant recipients. Does the incidence warrant prophylactic, risk-factor management? Is the incidence and the need for risk factor management the same in different regions around the world, or is CVD prevention only a problem in developed countries where the incidence of CVD is high? Is the evidence that traditional risk factor interventions recommended for the general population in developed countries apply to kidney transplant recipients strong enough to make specific recommendations for this population? What, if any, post transplant screening should be carried out for CVD?

   1.1 Hypertension. What is the incidence of hypertension after kidney transplantation? What evidence suggests that hypertension adversely affects CVD, all-cause mortality, graft dysfunction and the rate of graft failure? How should hypertension be treated? Are there special considerations for kidney transplant patients, or should hypertension be treated according to guidelines developed for the general population? Should angiotensin converting enzyme inhibitors and receptor antagonist be used as they would be used for non-transplant patients with CKD?

   1.2 Diabetes. In the general population, it has been difficult to show that intensive blood glucose control reduces the incidence of CVD. Intensive glucose control may be more difficult to achieve after kidney transplantation than in the general population, given the higher incidence of autonomic neuropathy, etc., in kidney transplant recipients. What is the evidence that guidelines for control of diabetes in the general population are applicable for kidney transplant recipients? What is the role of pancreas and islet transplantation? What is the incidence and risk factors for new onset diabetes after transplantation (NODAT)? How does the incidence of NODAT differ in different populations around the world? What are the consequences of NODAT? What can be done to prevent NODAT?

   1.3 Dyslipidemias. Is there recent evidence that affects the recommendations in the KDOQI Guidelines on Dyslipidemias after Kidney Transplantation? Are these K/DOQI guidelines applicable worldwide?

   1.4 Tobacco. What are the prevalence of cigarette smoking and the use of other tobacco products in kidney transplant recipients, and how is it associated with CVD and other outcomes? What should be done to encourage abstinence from the use of tobacco products?

   1.5 Aspirin Prophylaxis. In which, if any, kidney transplant recipients is aspirin prophylaxis indicated? Is there any evidence that aspirin is safe in kidney transplant recipients, or does reduced kidney function and/or immunosuppressive medications increase the risk of gastrointestinal bleeding or other complications of aspirin?

   1.6 “Non-traditional” Risk Factors. What is the incidence of putative, non-traditional risk factors in kidney transplant recipients, such as elevated inflammatory markers (C reactive protein, fibrinogen, interleukin 6, etc.), insulin resistance, and elevated homocysteine? Are there any reasons to believe that the case for managing these so-called “non-traditional” risk factors is different in kidney transplant recipients than in the general population?

   1.7 Kidney Allograft Function and the Choice of Immunosuppressive Agents. How do immunosuppressive agents affect risk factors for CVD? How is kidney function, which may be reduced by calcineurin inhibitors, associated with CVD and CVD risk factors? Should CVD risk factors influence the choice of immunosuppressive agents in kidney transplant recipients?

2. Infection.
   What is the incidence of major (viral, bacterial, fungal and parasitic) infections after kidney transplantation in different regions around the world? How should recent guidelines developed for recipients of kidney transplant be used in different regions? What measures are most cost-effective?

   2.1 Cytomegalovirus.

   2.2. Varicella zoster virus.

   2.3 EBV.

   2.4 Herpes virus type 8.

   2.5 Tuberculosis.

   2.6 Pneumocystis jiroveci.

   2.7 Hepatitis B.

   2.8 Hepatitis C.

   2.7 Immunizations. Which immunizations are indicated and contraindicated in kidney transplant recipients and does this vary throughout the world?

   The recent guidelines developed by the AST and infectious disease experts provide a good framework, which will be used to explore the evidence for these issues and their applicability in different parts of the world.

3. Cancer.
   Cancer is a common cause of morbidity and mortality after kidney transplantation. What are the incidences of different tumors and how does geographic location affect these incidences (Kaposi’s sarcoma, for example is much more common in certain regions than in others)? Are cancer screening measures that are recommended for the general population, e.g. mammography, colonoscopy, fecal occult blood testing, gynecological examinations, cervical papilloma virus screening, digital rectal examinations, prostate specific antigen screening, etc. also indicated in kidney transplant recipients who may have a shortened life expectancy due to infection and CVD? What is the evidence that the immunosuppressive medication regimen should be altered when patients develop cancer?

   3.1 Posttransplant lymphoproliferative disorders (PTLD). What is the incidence and what are the risk factors for PTLD? What is the evidence that preventative strategies, such as monitoring whole blood EBV quantitative DNA levels, cost effective?

   3.2 Cancer of the kidney and urinary track.

   3.2 Cervical carcinoma.

   3.3 Liver cancer.

   3.4 Non-melanoma skin cancer.

   3.5 Others

4. Anemia.
   What is the incidence and prevalence of anemia (at different times) after kidney transplantation? What morbidity and mortality is associated with anemia after kidney transplantation? Are guidelines for non-transplant chronic kidney disease patients applicable to kidney transplant recipients? How do immunosuppressive agents, viral infections, and graft function affect anemia and its treatment after kidney transplantation? When and how should anemia be treated in kidney transplant recipients?
5. Mineral and Bone Disorder (MBD).
   What is the incidence and prevalence of bone disease (at different times) after kidney transplantation? What morbidity and mortality is associated with bone disease after kidney transplantation? Are guidelines for non-transplant chronic kidney disease patients applicable to kidney transplant recipients? How do immunosuppressive agents and graft function affect bone disease and its treatment after kidney transplantation? What screening and prophylaxis is indicated? The KDIGO CKD-MBD guidelines now under development will address this problem and the recommendations made in the present guideline will be coordinated with that group.
6. Preventing acute rejection and maintaining long term graft function.
   There have been a large number of randomized trials comparing various immunosuppressive agent combinations in different transplant patient populations around the world. There are even some meta-analyses of these trials. However, the quality of the trials has often been low, and there have been few critical appraisals of their internal and external validities. Cost effectiveness has only rarely been assessed. Thus, strategies and combinations of immunosuppressive agents that are very expensive may not necessarily be safer and more cost-effective than others that are cheaper and have the potential of making transplantation available to larger numbers of patients.

   Most randomized trials of immunosuppressive agents have assessed only short-term outcomes. Combinations of agents that may be safe and effective in preventing acute rejection and graft failure in the first few months after kidney transplantation may be less effective and even sub optimal for long term maintenance. There have been a number of randomized controlled trials investigating different strategies for discontinuing potentially toxic (and in some cases expensive) immunosuppressive agents.

   The cost of immunosuppressive medications is often the major long-term cost of kidney transplantation. In areas of the world where using expensive immunosuppressive agents is not an option, using cheaper agents and strategies may be a much better alternative to dialysis, or even death when long term maintenance dialysis is not an option.

7. When to refer the kidney transplant recipient to a transplant center.
8. Gaps in knowledge. The evidence review process and the expertise of the Guideline Development Group will be used to identify gaps in knowledge in the care of kidney transplant recipient and make research recommendations for implementation subsequent to the release of the guidelines.