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Guideline Summary
Guideline Title
KDIGO clinical practice guideline for the care of kidney transplant recipients.
Bibliographic Source(s)
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9(Suppl 3):S1-155. [937 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)

Complications that occur after kidney transplant

  • Acute rejection
  • Chronic allograft injury
  • Recurrent kidney disease
  • Viral and other infections
  • New-onset diabetes mellitus after transplantation (NODAT)
  • Hypertension
  • Dyslipidemias
  • Cardiovascular disease (CVD)
  • Malignancies (cancers of the skin and lip and other malignancies)
  • Transplant bone disease
  • Hematologic complications (anemia, thrombocytopenia, neutropenia)
  • Hyperuricemia and gout
  • Growth failure
  • Sexual dysfunction
  • Male and female infertility
  • Depression and anxiety
Guideline Category
Evaluation
Management
Prevention
Treatment
Clinical Specialty
Cardiology
Critical Care
Infectious Diseases
Internal Medicine
Nephrology
Oncology
Pediatrics
Surgery
Intended Users
Advanced Practice Nurses
Nurses
Pharmacists
Physician Assistants
Physicians
Guideline Objective(s)
  • To assist the practitioner caring for adults and children after kidney transplantation
  • To describe the prevention and treatment of complications that occur after kidney transplantation
  • To improve patient care for kidney transplant recipients
  • To encourage and enable the establishment and development of transplant programs worldwide
  • To help define areas where evidence is lacking and research is needed
Target Population

Kidney transplant recipients

Interventions and Practices Considered

Immunosuppressive Therapy

  1. Induction therapy with a biologic agent (interleukin 2 receptor antagonist (IL2-RA)] or lymphocyte-depleting agent) as part of the initial immunosuppressive regimen
  2. Initial maintenance immunosuppressive medication (calcineurin inhibitors [tacrolimus or cyclosporine A], antiproliferative agent [mycophenolate], corticosteroids, mammalian target of rapamycin inhibitors [mTORi])
  3. Long-term maintenance immunosuppressive medications
  4. Strategies to reduce drug costs
  5. Monitoring immunosuppressive medications
  6. Treatment of acute rejection (corticosteroids, lymphocyte-depleting antibodies or OKT3 [muromonab (anti-T-cell antibody)], plasma exchange, intravenous immunoglobulin, anti-CD20 antibody, mycophenolate)
  7. Treatment of chronic allograft injury

Graft Monitoring and Infections

  1. Monitoring allograft function (urine volume, urine protein excretion, creatinine, glomerular filtration rate, allograft ultrasound)
  2. Kidney allograft biopsy
  3. Screening for and treating recurrent kidney disease
  4. Preventing, detecting, and treating nonadherence
  5. Vaccination with approved, inactivated vaccines and avoiding live vaccines
  6. Screening for and treatment of viral diseases (BK polyoma virus, cytomegalovirus, Epstein-Barr virus, post-transplant lymphoproliferative disease, herpes simplex virus, varicella zoster virus, hepatitis B and C, human immunodeficiency virus)
  7. Urinary tract infection and Pneumocystis jirovecii pneumonia (PCP) prophylaxis with daily trimethoprim-sulfamethoxazole; treatment of bacterial pyelonephritis
  8. Tuberculosis prophylaxis and treatment
  9. Candida prophylaxis with oral clotrimazole lozenges, nystatin, or fluconazole

Management of Cardiovascular Disease (CVD) Risk

  1. Screening for new-onset diabetes after transplantation (NODAT)
  2. Managing NODAT or diabetes present at transplantation
  3. Monitoring of blood pressure and treatment of hypertension
  4. Obtaining complete lipid profile and evaluating for secondary causes of dyslipidemias
  5. Screening, counseling, and treatment of tobacco use
  6. Assessing for obesity and offering a weight-reduction plan to obese patients
  7. Managing CVD as in the general population, with appropriate diagnostic tests and treatments
  8. Aspirin for atherosclerotic CVD

Management of Malignancy Risks

  1. Counseling on risks of cancer of the skin and lip
  2. Annual skin and lip examination
  3. Referral to appropriate specialist
  4. Treatment of patients with a history of skin cancer with oral acitretin
  5. Individualized cancer screening programs for non-skin malignancies
  6. Screening for cervical, breast, prostate, and colon cancer as in the general population
  7. Hepatic ultrasound and alpha feto-protein every 12 months in patients with compensated cirrhosis
  8. Reducing immunosuppressive medications in patients with cancer

Management of Other Post-Transplant Complications

  1. Monitoring for and treatment of transplant bone disease
  2. Monitoring for and treatment of hematological complications (anemia, neutropenia, thrombocytopenia, erythrocytosis)
  3. Treating hyperuricemia and gout (use of colchicine, avoiding allopurinol and non-steroidal anti-inflammatory drugs and cyclo-oxygenase-2 inhibitors)
  4. Measuring growth and development in children
  5. Using recombinant human growth hormone in children with growth failure and avoiding corticosteroids in children
  6. Evaluating adults for sexual dysfunction
  7. Counseling about contraception and safe sex practices
  8. Considerations for male and female fertility and pregnancy
  9. Counseling on healthy lifestyle, with exercise, proper diet, and weight reduction
  10. Questioning about depression and anxiety as part of routine follow-up care
Major Outcomes Considered
  • All-cause mortality
  • Kidney function, delayed or slow graft function, acute rejection, graft failure/survival
  • Chronic allograft nephropathy
  • Viral, bacterial, or fungal infections
  • Cancer incidence
  • New-onset diabetes after transplantation (NODAT)
  • Fractures
  • Bone mineral density
  • Erythrocytosis
  • Neutropenia
  • Quality of life
  • Cardiovascular disease events
  • Reduction in risk factors associated with hypertension, dyslipidemias, tobacco use and obesity
  • Bleeding
  • Growth and growth retardation
  • Gout
  • Pregnancy outcomes and pregnancy complications
  • Erectile dysfunction
  • Levels of immunosuppressives in breast milk
  • Adverse events

Methodology

Methods Used to Collect/Select the Evidence
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

Literature Searches and Article Selection

The MEDLINE, Cochrane Central Registry for trials, and Cochrane database of systematic reviews were searched from 1985 through January 2007 by the Evidence Review Team (ERT) to capture all citations relevant to the topic of kidney transplantation, including original articles, systematic reviews and previous guidelines. The Cochrane Renal Group ran parallel searches in their Renal Registry database and these supplemented the primary ERT searches. The search was updated through February 2008 and supplemented by articles identified by Work Group members through November 2008.

During citation screening, journal articles reporting original data were reviewed. Editorials, letters, stand-alone abstracts, unpublished reports and articles published in non-peer-reviewed journals were excluded. The Work Group also decided to exclude publications from journal supplements and Transplantation Proceedings journal because of potential differences in the process of how they get solicited, selected, reviewed and edited compared to peer reviewed publications.

Potentially relevant existing systematic reviews were examined. If these reviews were deemed to adequately address topics of interest (even if only selected outcomes were reviewed), de novo searches on these topics were limited to the time period since the end of the literature search within the systematic reviews.

The MEDLINE and Cochrane search results were screened by the ERT for relevance using predefined eligibility criteria (see Table 32 in the original guideline document). Restrictions by sample size and duration of follow-up were based on methodological and clinical considerations. Generally, it was deemed that trials with fewer than 100 people would be unlikely to have sufficient power to find significant differences in patient-centered clinical outcomes in kidney transplant recipients (KTRs). However, for specific topics where sparse data were available, lower sample-size thresholds were used to provide some information for descriptive purposes.

For most topics, the minimum mean duration of follow-up of 6 months was chosen based on clinical reasoning. For the treatments of interest, the proposed effects on patient-centered clinical outcomes require long-term exposure and, typically, would not be expected to become evident before several months of follow-up. For all treatment topics, all randomized controlled trials (RCTs) in children with five or more individuals per arm were included.

From the onset of the guideline development process, it was known that for numerous topics of interest (e.g., care of comorbidities and complications after kidney transplantation) very few or no RCTs of KTRs exist. In addition, several topics required data on predictors of outcomes as opposed to treatment efficacy. Therefore, for selected topics, large observational studies were reviewed. In general, associations from only multivariable regression analyses were considered. The observational studies were not graded for quality. For these topics, the ERT completed its search in December 2007 and did not update the search.

Limitations of Approach

While the literature searches were intended to be comprehensive, they were not exhaustive. MEDLINE and various Cochrane databases were the only databases searched. Hand searches of journals were not performed, and review articles and textbook chapters were not systematically searched. However, important studies known to the domain experts that were missed by the electronic literature searches were added to retrieved articles and reviewed by the Work Group. Not all topics and subtopics covered by this guideline could be thoroughly and systematically reviewed. Decisions to restrict the topics were made to focus the systematic reviews on those topics where existing evidence was thought to be likely to provide support for the guideline. Although nonrandomized studies were reviewed, the majority of the ERT and Work Group resources were devoted to review of randomized trials, since these were deemed to be most likely to provide data to support level 1 recommendations with very high- or high-quality (A or B) evidence. Where randomized trials are lacking, it was deemed to be sufficiently unlikely that studies previously unknown to the Work Group would result in a higher-quality level 1 recommendation. A small number of supplemental sets of evidence were collected with a nonsystematic review approach. Any such evidence that is summarized is noted. Decisions to take a nonsystematic review approach for these topics were made due to time constraints and resource limitations.

Number of Source Documents

Table 33 and Figure 2 in the original guideline document summarize the numbers of abstracts screened, articles retrieved and data extracted and included in summary tables. A total of 114 randomized controlled trials in 120 publications were systematically reviewed.

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Grading of Recommendations Assessment, Development and Evaluation (GRADE) System for Grading Quality of Evidence for an Outcome

Step 1: Starting Grade for Quality of Evidence Based on Study Design
Randomized trials High
Observational study Low
Any other evidence Very low
Step 2: Reduce Grade
Study quality -1 level if serious limitations
-2 levels if very serious limitations
Consistency -1 level if important inconsistency
Directness -1 level if some uncertainty
-2 levels if major uncertainty
Other -1 level if sparse or imprecise data
-1 level if high probability of reporting bias
Step 3: Raise Grade
Strength of association +1 level if strong,a no plausible confounders
+2 levels if very strong, b no major threats to validity
Other +1 level if evidence of a dose response gradient
+1 level if all residual plausible confounders would have reduced the observed effect
Final Grade for Quality of Evidence for an Outcome
High
Moderate
Low
Very low

aStrong evidence of association is defined as 'significant relative risk (RR) of >2 (<0.5)' based on consistent evidence from two or more observational studies, with no plausible confounders.
bVery strong evidence of association is defined as 'significant RR of >5 (<0.2)' based on direct evidence with no major threats to validity.

Modified with permission from Uhlig et al. Grading evidence and recommendations for clinical practice guidelines in nephrology. A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006; 70: 2058–2065; and Atkins et al. Grading quality of evidence and strength of recommendations. BMJ 2004; 328:1490.

Final Grade for Overall Quality of Evidence

Grade Quality of Evidence Meaning
A High The Work Group is confident that the true effect lies close to that of the estimate of the effect.
B Moderate The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
C Low The true effect may be substantially different from the estimate of the effect.
D Very Low The estimate of effect is very uncertain, and often will be far from the truth.
Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

Data Extraction

The Evidence Review Team (ERT) designed data-extraction forms to capture information on various aspects of the primary studies. Data fields for all topics included study setting, patient demographics, eligibility criteria, kidney transplantation details, numbers of subjects randomized, study design, study funding source, descriptions of interventions (or predictors), description of outcomes, statistical methods used, results, quality of outcomes, limitations to generalizability and free-text fields for comments and assessment of biases.

Summary Tables

Summary tables were developed to tabulate the data from studies pertinent to each question of intervention. Each summary table contains a brief description of the outcome, baseline characteristics of the population, intervention, results and methodological quality. Baseline characteristics include a description of the study size, country of residence, age, percentage of deceased donors and dates of transplant. Intervention and concomitant therapies and the results were all captured. The final column was assigned for a grade for methodological quality. The studies were listed by outcome within the table based on the hierarchy of important outcomes (see Table 34 in the original guideline document). Categorical and continuous outcomes were summarized in separate sets of tables. Work Group members were asked to proof all data in summary tables on randomized controlled trials (RCTs). Separate sets of summary tables were created for nonrandomized studies of incidence and predictors of outcomes.

Due to the large number of recommendations included here and the large volume of literature reviewed, summary tables are not published with this report. They are available as a supplement (see the 'Availability of Companion Documents' field).

Evaluation of Individual Studies

Grading the Quality of Evidence

A structured approach, based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) and facilitated by the use of Evidence Profiles (see Table 36 in the original guideline document for an example), was employed in order to grade the quality of the overall evidence. For each topic, the discussion on grading of the quality of the evidence was led by the ERT, and the discussion regarding the strength of the recommendations was led by the Work Group Chairs. The 'quality of a body of evidence' refers to the extent to which the Work Group's confidence in an estimate of effect is sufficient to support a particular recommendation.

Grading the Quality of Evidence for Each Outcome

Following GRADE, the quality of a body of evidence pertaining to a particular outcome of interest was initially categorized based on study design. For questions of interventions, the initial quality grade was 'High' when the body of evidence consisted of RCTs. In theory, the initial grade would have been 'Low' if the evidence consisted of observational studies or 'Very Low' if it consisted of studies of other study designs; however, the quality of bodies of evidence was formally determined only for topics where the Work Group performed systematic reviews of RCTs. The grade for the quality of evidence for each intervention/outcome pair was decreased if there were serious limitations to the methodological quality of the aggregate of studies, if there were important inconsistencies in the results across studies, if there was uncertainty about the directness of evidence including limited applicability of the findings to the population of interest, if the data were imprecise or sparse, or if there was thought to be a high likelihood of bias. The final grade for the quality of the evidence for an intervention/outcome pair could be one of the following four grades: 'High,' 'Moderate,' 'Low' or 'Very Low' (see the 'Rating Scheme for the Strength of the Evidence' field).

Grading the Overall Quality of Evidence

Each clinical outcome was ranked by the Work Group as to its level of clinical importance to the patient. The quality of the overall body of evidence was then determined based on the quality grades for all outcomes of interest, taking into account explicit judgments about the relative importance of each outcome. The resulting four final categories for the quality of overall evidence were: 'A,' 'B,' 'C' or 'D' (see the 'Rating Scheme for the Strength of the Evidence' field). This evidence grade is indicated within each recommendation.

See the original guideline document for additional discussion of evaluation of individual studies.

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

Overview of the Process

The Work Group, Kidney Disease: Improving Global Outcomes (KDIGO) Co-Chairs, the Evidence Review Team (ERT), liaisons and KDIGO support staff met for four 2-day meetings for training in the guideline development process, topic discussion and consensus development.

Creation of Groups

The KDIGO Co-Chairs appointed the Co-Chairs of the Work Group, who then assembled the Work Group to be responsible for the development of the guideline. The Work Group consisted of domain experts, including individuals with expertise in adult and pediatric nephrology, transplant surgery and medicine, critical-care medicine, cardiology, infectious diseases, oncology and epidemiology, along with a patient advocate. Tufts Center for Kidney Disease Guideline Development and Implementation at Tufts Medical Center in Boston, MA, USA, was contracted to provide expertise in guideline development methodology and systematic evidence review. The ERT consisted of physician–methodologists with expertise in nephrology and internal medicine, and research associates and assistants. The ERT instructed and advised Work Group members in all steps of literature review, critical literature appraisal and guideline development. The Work Group and the ERT collaborated closely throughout the project. The ERT also included methodological input and assistance with literature searches from methodology experts at the Cochrane Renal Group in Sydney, Australia.

Systematic Review: General Process

The first task of the Work Group was to define the overall topics and goals for the guideline. The Work Group Co-Chairs drafted a preliminary list of topics. The Work Group identified the key clinical questions. The Work Group and ERT further developed and refined each topic, specified screening criteria, literature search strategies and data extraction forms.

The ERT performed literature searches, and organized screening of abstracts and articles. The ERT also coordinated the methodological and analytic processes of the report, and defined and standardized the methodology of performing literature searches, data extraction and summarizing the evidence. Throughout the project, the ERT offered suggestions for guideline development, led discussions on systematic review, literature searches, data extraction, assessment of quality and applicability of articles, evidence synthesis, grading of evidence and recommendations and consensus development. With input from the Work Group, the ERT finalized eligible studies, performed all data extraction and summarized data into summary tables. They also created preliminary evidence profiles, which were completed by the Work Group members. The Work Group members reviewed all included articles, data-extraction forms and summary tables for accuracy and completeness. The Work Group took the primary role of writing the recommendations and rationale statements, and retained final responsibility for the content of the recommendation statements and the accompanying narrative.

Refinement of Topics

The Work Group Co-Chairs prepared the first draft of the scope of work document as a series of mock (preliminary) recommendations to be considered by Work Group members. At their first 2-day meeting, members added further mock guideline topics until the initial working document included all topics of interest to the Work Group. The inclusive, combined set of questions formed the basis for the deliberation and discussion that followed. The Work Group strove to ensure that all topics deemed clinically relevant and worthy of review were identified and addressed. The four major topic areas of interest for the care of KTRs included immunosuppression, infections, cardiovascular disease (CVD), and cancer. In addition, there were several miscellaneous topics.

At the initiation of the guideline development process, it was agreed that this guideline would focus on patients who have had kidney transplantations. Thus, with few exceptions (e.g., the timing of vaccinations), all topics, systematic reviews and study eligibility criteria were restricted to patients with existing kidney transplantations. The guideline does not address management issues regarding choosing patients for kidney transplantation, pretransplant care, intraoperative care (except for the timing of initiating immunosuppression) or management of patients who have lost their grafts. In addition, in regards to care of comorbidities and complications after kidney transplantation (e.g., infections, cancer and CVD), this guideline focuses primarily on monitoring and prevention of the conditions, as opposed to treatment of the conditions (with some exceptions, e.g., for infectious diseases). However, where the recommended treatment of conditions differed from the general population (e.g., due to drug interactions with immunosuppression agents), standard treatment recommendations are offered.

Based on the list of topics, the Work Group and ERT developed a list of specific research questions for which systematic review would be performed (see Table 32 in the original guideline document). For each systematic review topic, the Work Group Co-Chairs and the ERT formulated well-defined systematic review research questions using a well-established system. For each question, explicit criteria were agreed on for the population, intervention or predictor, comparator, outcomes of interest and study design features. A list of outcomes of interest was generated. The Work Group ranked patient-centered clinical outcomes (such as death, graft loss or infections) as more important than intermediate outcomes (such as cholesterol level or hypertension). The outcomes were further categorized as being of critical, high or moderate importance to KTRs. Outcomes of low importance were not considered for the purpose of systematic review and evidence synthesis. In general, eligibility criteria were determined based on clinical value, relevance to the guideline and clinical practice, determination whether a set of studies would affect recommendations or the strength of evidence and practical issues such as available time and resources.

Grading the Strength of the Recommendations

The strength of a recommendation is graded as Level 1 or Level 2. The KDIGO nomenclature for grading the strength of a recommendation and the implications of each level for patients, clinicians and policymakers is shown in the 'Rating Scheme for the Strength of the Recommendations' field. Recommendations can be for or against doing something. Table 41 in the original guideline document shows that the strength of a recommendation is determined not just by the quality of the evidence, but also by other, often complex, judgments regarding the size of the net medical benefit, values and preferences and costs. Formal decision analyses, including cost analysis, were not conducted.

Ungraded Statements

The KDIGO consensus statement on grading had recommended a category for a 'consensus-based statement.' This category was designated for guidance by the Work Group based predominantly on expert opinion in areas of low- or very low-quality evidence. However, it became clear that 'consensus-based' was not a distinguishing feature, since all recommendations are supported by Work Group consensus. Still, it was felt that having a category that allows the Work Group to issue general advice would be useful. Typically, an ungraded statement meets the following criteria: it provides guidance based on common sense; it provides reminders of the obvious; it is not sufficiently specific to allow application of evidence to the issue, and therefore it is not based on systematic evidence review. Common examples include recommendations about frequency of testing, referral to specialists and routine medical care. The Work Group strove to minimize the use of ungraded recommendations. This grading scheme with two levels for the strength of a recommendation together with four levels of grading the quality of the evidence, and the option of an ungraded statement for general guidance, was adopted by the KDIGO Board in December 2008.

Rating Scheme for the Strength of the Recommendations

Nomenclature and Description for Grading Recommendations

Implications
Grade* Patients Clinicians Policy
Level 1
'The Work Group recommends'
Most people in your situation would want the recommended course of action and only a small proportion would not. Most patients should receive the recommended course of action. The recommendation can be adopted as a policy in most situations.
Level 2
'The Work Group suggests'
The majority of people in your situation would want the recommended course of action, but many would not. Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with her or his values and preferences. The recommendation is likely to require debate and involvement of stakeholders before policy can be determined.

*The additional category 'Not Graded' was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counseling and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations.

Cost Analysis

Refer to the 'Major Recommendations' field for specific recommendations and Chapter 4 of the original guideline document for a discussion of strategies to reduce drug costs.

Method of Guideline Validation
External Peer Review
Internal Peer Review
Description of Method of Guideline Validation

Peer review by Kidney Disease: Improving Global Outcomes (KDIGO) Board of Directors in December 2008 and the public (March 2009), with subsequent revisions.

Recommendations

Major Recommendations

Definitions of the strength of recommendation (Level 1, Level 2, or Not Graded), and the quality of the supporting evidence (A-D) are provided at the end of the 'Major Recommendations' field.

Immunosuppression

Induction Therapy

  • The Work Group recommends starting a combination of immunosuppressive medications before, or at the time of, kidney transplantation. (1A)
  • The Work Group recommends including induction therapy with a biologic agent as part of the initial immunosuppressive regimen in kidney transplant recipients (KTRs). (1A)
    • The Work Group recommends that an interleukin 2 receptor antagonist (IL2-RA) be the first line induction therapy. (1B)
    • The Work Group suggests using a lymphocyte-depleting agent, rather than an IL2-RA, for KTRs at high immunologic risk. (2B)

Initial Maintenance Immunosuppressive Medications

  • The Work Group recommends using a combination of immunosuppressive medications as maintenance therapy including a calcineurin inhibitor (CNI) and an antiproliferative agent, with or without corticosteroids. (1B)
  • The Work Group suggests that tacrolimus be the first-line CNI used. (2A)
    • The Work Group suggests that tacrolimus or cyclosporine A (CsA) be started before or at the time of transplantation, rather than delayed until the onset of graft function. (2D tacrolimus; 2B CsA)
  • The Work Group suggests that mycophenolate be the first-line antiproliferative agent. (2B)
  • The Work Group suggests that, in patients who are at low immunological risk and who receive induction therapy, corticosteroids could be discontinued during the first week after transplantation. (2B)
  • The Work Group recommends that if mammalian target of rapamycin inhibitors (mTORi) are used, they should not be started until graft function is established and surgical wounds are healed. (1B)

Long-Term Maintenance Immunosuppressive Medications

  • The Work Group suggests using the lowest planned doses of maintenance immunosuppressive medications by 2–4 months after transplantation, if there has been no acute rejection. (2C)
  • The Work Group suggests that CNIs be continued rather than withdrawn. (2B)
  • If prednisone is being used beyond the first week after transplantation, the Work Group suggests prednisone be continued rather than withdrawn. (2C)

Strategies to Reduce Drug Costs

  • If drug costs block access to transplantation, a strategy to minimize drug costs is appropriate, even if use of inferior drugs is necessary to obtain the improved survival and quality of life benefits of transplantation compared with dialysis. (Not Graded)
    • The Work Group suggests strategies that may reduce drug costs include:
      • Limiting use of a biologic agent for induction to patients who are high-risk for acute rejection (2C)
      • Using ketoconazole to minimize CNI dose (2D)
      • Using a non-dihydropyridine calcium-channel blocker (CCB) to minimize CNI dose (2C)
      • Using azathioprine rather than mycophenolate (2B)
      • Using adequately tested bioequivalent generic drugs (2C)
      • Using prednisone long-term (2C)
  • Do not use generic compounds that have not been certified by an independent regulatory agency to meet each of the following criteria when compared to the reference compound (Not Graded):
    • Contains the same active ingredient
    • Is identical in strength, dosage form, and route of administration
    • Has the same use indications
    • Is bioequivalent in appropriate bioavailability studies
    • Meets the same batch requirements for identity, strength, purity and quality
    • Is manufactured under strict standards
  • It is important that the patient, and the clinician responsible for the patient's care, be made aware of any change in a prescribed immunosuppressive drug, including a change to a generic drug. (Not Graded)
  • After switching to a generic medication that is monitored using blood levels, obtain levels and adjust the dose as often as necessary until a stable therapeutic target is achieved. (Not Graded)

Monitoring Immunosuppressive Medications

  • The Work Group recommends measuring CNI blood levels (1B), and suggest measuring at least:
    • Every other day during the immediate postoperative period until target levels are reached (2C)
    • Whenever there is a change in medication or patient status that may affect blood levels (2C)
    • Whenever there is a decline in kidney function that may indicate nephrotoxicity or rejection (2C)
  • The Work Group suggests monitoring CsA using 12-h trough (C0), 2-h post-dose (C2) or abbreviated area under concentration–time curve (AUC). (2D)
  • The Work Group suggests monitoring tacrolimus using 12-h trough (C0). (2C)
  • The Work Group suggests monitoring mycophenolate mofetil (MMF) levels. (2D)
  • The Work Group suggests monitoring mTORi levels. (2C)

Treatment of Acute Rejection

  • The Work Group recommends biopsy before treating acute rejection, unless the biopsy will substantially delay treatment. (1C)
  • The Work Group suggests treating subclinical and borderline acute rejection. (2D)
  • The Work Group recommends corticosteroids for the initial treatment of acute cellular rejection. (1D)
    • The Work Group suggests adding or restoring maintenance prednisone in patients not on steroids who have a rejection episode. (2D)
    • The Work Group suggests using lymphocyte-depleting antibodies or OKT3 (muromonab anti-T-cell antibody) for acute cellular rejections that do not respond to corticosteroids, and for recurrent acute cellular rejections. (2C)
  • The Work Group suggests treating antibody-mediated acute rejection with one or more of the following alternatives, with or without corticosteroids (2C):
    • Plasma exchange
    • Intravenous immunoglobulin
    • Anti-CD20 antibody
    • Lymphocyte-depleting antibody
  • For patients who have a rejection episode, the Work Group suggests adding mycophenolate if the patient is not receiving mycophenolate or azathioprine, or switching azathioprine to mycophenolate. (2D)

Treatment of Chronic Allograft Injury (CAI)

  • The Work Group recommends kidney allograft biopsy for all patients with declining kidney function of unclear cause, to detect potentially reversible causes. (1C)
  • For patients with CAI and histological evidence of CNI toxicity, the Work Group suggests reducing, withdrawing, or replacing the CNI. (2C)
    • For patients with CAI, estimated glomerular filtration rate (eGFR) >40 ml/min/1.73 m2, and urine total protein excretion <500 mg/g creatinine (or equivalent proteinuria by other measures), the Work Group suggests replacing the CNI with a mTORi. (2D)

Graft Monitoring and Infections

Monitoring Kidney Allograft Function

  • The Work Group suggests measuring urine volume (2C):
    • Every 1–2 h for at least 24 h after transplantation (2D)
    • Daily until graft function is stable (2D)
  • The Work Group suggests measuring urine protein excretion, (2C) at least:
    • Once in the first month to determine a baseline (2D)
    • Every 3 months during the first year (2D)
    • Annually, thereafter (2D)
  • The Work Group recommends measuring serum creatinine, (1B) at least:
    • Daily for 7 days or until hospital discharge, whichever occurs sooner (2C)
    • 2–3 times per week for weeks 2–4 (2C)
    • Weekly for months 2 and 3 (2C)
    • Every 2 weeks for months 4–6 (2C)
    • Monthly for months 7–12 (2C)
    • Every 2–3 months, thereafter (2C)
  • The Work Group suggests estimating GFR whenever serum creatinine is measured, (2D) using:
    • One of several formulas validated for adults (2C); or
    • The Schwartz formula for children and adolescents (2C)
  • The Work Group suggests including a kidney allograft ultrasound examination as part of the assessment of kidney allograft dysfunction. (2C)

Kidney Allograft Biopsy

  • The Work Group recommends kidney allograft biopsy when there is a persistent, unexplained increase in serum creatinine. (1C)
  • The Work Group suggests kidney allograft biopsy when serum creatinine has not returned to baseline after treatment of acute rejection. (2D)
  • The Work Group suggests kidney allograft biopsy every 7–10 days during delayed function. (2C)
  • The Work Group suggests kidney allograft biopsy if expected kidney function is not achieved within the first 1–2 months after transplantation. (2D)
  • The Work Group suggests kidney allograft biopsy when there is:
    • New onset of proteinuria (2C)
    • Unexplained proteinuria ≥3.0 g/g creatinine or ≥3.0 g/24 h (2C)

Recurrent Kidney Disease

  • The Work Group suggests screening KTRs with primary kidney disease caused by focal segmental glomerulosclerosis (FSGS) for proteinuria (2C) at least:
    • Daily for 1 week (2D)
    • Weekly for 4 weeks (2D)
    • Every 3 months, for the first year (2D)
    • Every year, thereafter (2D)
  • The Work Group suggests screening KTRs with potentially treatable recurrence of primary kidney disease from immunoglobulin A (IgA) nephropathy, membranoproliferative glomerulonephritis (MPGN), anti-glomerular basement membrane (GBM) disease, or antineutrophil cytoplasmic autoantibody (ANCA) associated vasculitis for microhematuria, (2C) at least:
    • Once in the first month to determine a baseline (2D)
    • Every 3 months during the first year (2D)
    • Annually, thereafter (2D)
  • During episodes of graft dysfunction in patients with primary hemolytic uremic syndrome (HUS), the Work Group suggests screening for thrombotic microangiopathy (e.g., with platelet count, peripheral smear for blood cell morphology, plasma haptoglobin, and serum lactate dehydrogenase). (2D)
  • When screening suggests possible treatable recurrent disease, the Work Group suggests obtaining an allograft biopsy. (2C)
  • Treatment of recurrent kidney disease:
    • The Work Group suggests plasma exchange if a biopsy shows minimal change disease or FSGS in those with primary FSGS as their primary kidney disease. (2D)
    • The Work Group suggests high-dose corticosteroids and cyclophosphamide in patients with recurrent ANCA-associated vasculitis or anti-GBM disease. (2D)
    • The Work Group suggests using an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin II receptor blocker (ARB) for patients with recurrent glomerulonephritis and proteinuria. (2C)
    • For KTRs with primary hyperoxaluria, the Work Group suggests appropriate measures to prevent oxalate deposition until plasma and urine oxalate levels are normal (2C), including:
      • Pyridoxine (2C)
      • High calcium and low oxalate diet (2C)
      • Increased oral fluid intake to enhance urinary dilution of oxalate (2C)
      • Potassium or sodium citrate to alkalinize the urine (2C)
      • Orthophosphate (2C)
      • Magnesium oxide (2C)
      • Intensive hemodialysis to remove oxalate (2C)

Preventing, Detecting, and Treating Nonadherence

  • Consider providing all KTRs and family members with education, prevention, and treatment measures to minimize nonadherence to immunosuppressive medications. (Not Graded)
  • Consider providing KTRs at increased risk for nonadherence with increased levels of screening for nonadherence. (Not Graded)

Vaccination

  • The Work Group recommends giving all KTRs approved, inactivated vaccines, according to recommended schedules for the general population, except for hepatitis B virus (HBV) vaccination. (1D)
    • The Work Group suggests HBV vaccination (ideally prior to transplantation) and antibody to hepatitis B surface antigen (HBsAb) titers 6–12 weeks after completing the vaccination series. (2D)
      • The Work Group suggests annual HBsAb titers. (2D)
      • The Work Group suggests revaccination if the antibody titer falls below 10 mIU/mL. (2D)
  • The Work Group suggests avoiding live vaccines in KTRs. (2C)
  • The Work Group suggests avoiding vaccinations, except influenza vaccination, in the first 6 months following kidney transplantation. (2C)
    • The Work Group suggests resuming immunizations once patients are receiving minimal maintenance doses of immunosuppressive medications. (2C)
    • The Work Group recommends giving all KTRs, who are at least 1 month post-transplant, influenza vaccination prior to the onset of the annual influenza season, regardless of status of immunosuppression. (1C)
  • The Work Group suggests giving the following vaccines to KTRs who, due to age, direct exposure, residence or travel to endemic areas, or other epidemiological risk factors are at increased risk for the specific diseases:
    • Rabies (2D)
    • Tick-borne meningoencephalitis (2D)
    • Japanese B encephalitis-inactivated (2D)
    • Meningococcus (2D)
    • Pneumococcus (2D)
    • Salmonella typhi-inactivated (2D)
      • Consult an infectious disease specialist, a travel clinic, or public health official for guidance on whether specific cases warrant these vaccinations. (Not Graded)

Viral Diseases

BK Polyoma Virus (BKV)

  • The Work Group suggests screening all KTRs for BKV with quantitative plasma nucleic acid testing (NAT) (2C) at least:
    • Monthly for the first 3–6 months after transplantation (2D)
    • Then every 3 months until the end of the first post-transplant year (2D)
    • Whenever there is an unexplained rise in serum creatinine (2D) and
    • After treatment for acute rejection (2D)
  • The Work Group suggests reducing immunosuppressive medications when BKV plasma NAT is persistently greater than 10,000 copies/mL (107 copies/l). (2D)

Cytomegalovirus (CMV)

  • CMV prophylaxis: The Work Group recommends that KTRs (except when donor and recipient both have negative CMV serologies) receive chemoprophylaxis for CMV infection with oral ganciclovir or valganciclovir for at least 3 months after transplantation, (1B) and for 6 weeks after treatment with a T-cell-depleting antibody. (1C)
  • In patients with CMV disease, the Work Group suggests weekly monitoring of CMV by NAT or pp65 antigenemia. (2D)
  • CMV treatment:
    • The Work Group recommends that all patients with serious (including most patients with tissue invasive) CMV disease be treated with intravenous ganciclovir. (1D)
    • The Work Group recommends that CMV disease in adult KTRs that is not serious (e.g., episodes that are associated with mild clinical symptoms) be treated with either intravenous ganciclovir or oral valganciclovir. (1D)
    • The Work Group recommends that all CMV disease in pediatric KTRs be treated with intravenous ganciclovir. (1D)
    • The Work Group suggests continuing therapy until CMV is no longer detectable by plasma NAT or pp65 antigenemia. (2D)
  • The Work Group suggests reducing immunosuppressive medication in life-threatening CMV disease, and CMV disease that persists in the face of treatment, until CMV disease has resolved. (2D)
    • The Work Group suggests monitoring graft function closely during CMV disease. (2D)

Epstein-Barr Virus (EBV) and Post-Transplant Lymphoproliferative Disease (PTLD)

  • The Work Group suggests monitoring high-risk (donor EBV seropositive/recipient seronegative) KTRs for EBV by NAT (2C):
    • Once in the first week after transplantation (2D)
    • Then at least monthly for the first 3–6 months after transplantation (2D)
    • Then every 3 months until the end of the first post-transplant year (2D) and
    • Additionally after treatment for acute rejection (2D)
  • The Work Group suggests that EBV-seronegative patients with an increasing EBV load have immunosuppressive medication reduced. (2D)
  • The Work Group recommends that patients with EBV disease, including post-transplant lymphoproliferative disease (PTLD), have a reduction or cessation of immunosuppressive medication. (1C)

Herpes Simplex Virus (HSV) 1, 2 and Varicella Zoster Virus (VZV)

  • The Work Group recommends that KTRs who develop a superficial HSV 1, 2 infection be treated (1B) with an appropriate oral antiviral agent (e.g., acyclovir, valacyclovir, or famciclovir) until all lesions have resolved. (1D)
  • The Work Group recommends that KTRs with systemic HSV 1, 2 infection be treated (1B) with intravenous acyclovir and a reduction in immunosuppressive medication. (1D)
    • The Work Group recommends that intravenous acyclovir continue until the patient has a clinical response, (1B) then switch to an appropriate oral antiviral agent (e.g., acyclovir, valacyclovir, or famciclovir) to complete a total treatment duration of 14–21 days. (2D)
  • The Work Group suggests using a prophylactic antiviral agent for KTRs experiencing frequent recurrences of HSV 1, 2 infection. (2D)
  • The Work Group recommends that primary VZV infection (chicken pox) in KTRs be treated (1C) with either intravenous or oral acyclovir or valacyclovir; and a temporary reduction in amount of immunosuppressive medication. (2D)
    • The Work Group recommends that treatment be continued at least until all lesions have scabbed. (1D)
  • The Work Group recommends that uncomplicated herpes zoster (shingles) be treated (1B) with oral acyclovir or valacyclovir (1B), at least until all lesions have scabbed. (1D)
  • The Work Group recommends that disseminated or invasive herpes zoster be treated (1B) with intravenous acyclovir and a temporary reduction in the amount of immunosuppressive medication (1C), at least until all lesions have scabbed. (1D)
  • The Work Group recommends that prevention of primary varicella zoster be instituted in varicella susceptible patients after exposure to individuals with active varicella zoster infection (1D):
    • Varicella zoster immunoglobulin (or intravenous immunoglobulin) within 96 h of exposure (1D)
    • If immunoglobulin is not available or more than 96 h have passed, a 7-day course of oral acyclovir begun 7–10 days after varicella exposure. (2D)

Hepatitis C Virus (HCV)

Note: The Work Group reviewed the KDIGO Hepatitis C Guidelines that were applicable to KTRs, and ultimately agreed with the pertinent guideline statements. Only minor modifications (to guideline statement 4.4.1 in the KDIGO Hepatitis C Guidelines were made.

  • The Work Group suggests that HCV-infected KTRs be treated only when the benefits of treatment clearly outweigh the risk of allograft rejection due to interferon-based therapy (e.g., fibrosing cholestatic hepatitis, life-threatening vasculitis). (2D)
  • The Work Group suggests monotherapy with standard interferon for HCV-infected KTRs in whom the benefits of antiviral treatment clearly outweigh the risks. (2D)
  • The Work Group suggests that all conventional current induction and maintenance immunosuppressive regimens can be used in HCV-infected patients. (2D)
  • Measure alanine aminotransferase (ALT) in HCV-infected patients monthly for the first 6 months and every 3–6 months, thereafter. Perform imaging annually to look for cirrhosis and hepatocellular carcinoma. (Not Graded) (See 'Non-Skin Malignancies,' below.)
  • Test HCV-infected patients at least every 3–6 months for proteinuria. (Not Graded)
    • For patients who develop new-onset proteinuria (either urine protein/creatinine ratio >1 or 24-h urine protein >1 g on two or more occasions), perform an allograft biopsy with immunofluorescence and electron microscopy. (Not Graded)
  • The Work Group suggests that patients with HCV-associated glomerulopathy not receive interferon. (2D)

Hepatitis B Virus (HBV)

  • The Work Group suggests that any currently available induction and maintenance immunosuppressive medication can be used in HBV-infected KTRs. (2D)
  • The Work Group suggests that interferon treatment should generally be avoided in HBV-infected KTRs. (2C)
  • The Work Group suggests that all hepatitis B surface antigen (HBsAg)-positive KTRs receive prophylaxis with tenofovir, entecavir, or lamivudine. (2B)
    • Tenofovir or entecavir are preferable to lamivudine, to minimize development of potential drug resistance, unless medication cost requires that lamivudine be used. (Not Graded)
    • During therapy with antivirals, measure HBV DNA and ALT levels every 3 months to monitor efficacy and to detect drug resistance. (Not Graded)
  • The Work Group suggests treatment with adefovir or tenofovir for KTRs with lamivudine resistance (>5 log10 copies/ml rebound of HBV-DNA). (2D)
  • Screen HBsAg-positive patients with cirrhosis for hepatocellular carcinoma every 12 months with liver ultrasound and alpha feto-protein. (Not Graded) (See 'Non-Skin Malignancies,' below.)
  • The Work Group suggests that patients who are negative for HBsAg and have HBsAb titer <10 mIU/ml receive booster vaccination to raise the titer to ≥100 mIU/mL. (2D)

Human Immunodeficiency Virus (HIV)

  • If not already done, screen for HIV infection. (Not Graded)
  • To determine antiretroviral therapy, refer HIV-infected KTRs to an HIV specialist, who should pay special attention to drug-drug interactions and appropriate dosing of medications. (Not Graded)

Other Infections

Urinary Tract Infection (UTI)

  • The Work Group suggests that all KTRs receive UTI prophylaxis with daily trimethoprim-sulfamethoxazole for at least 6 months after transplantation. (2B)
  • For allograft pyelonephritis, the Work Group suggests initial hospitalization and treatment with intravenous antibiotics. (2C)

Pneumocystis jirovecii Pneumonia (PCP)

  • The Work Group recommends that all KTRs receive PCP prophylaxis with daily trimethoprim-sulfamethoxazole for 3–6 months after transplantation. (1B)
  • The Work Group suggests that all KTRs receive PCP prophylaxis with daily trimethoprim-sulfamethoxazole for at least 6 weeks during and after treatment for acute rejection. (2C)
  • The Work Group recommends that KTRs with PCP diagnosed by bronchial alveolar lavage and/or lung biopsy be treated with high-dose intravenous trimethoprim-sulfamethoxazole, corticosteroids, and a reduction in immunosuppressive medication. (1C)
  • The Work Group recommends treatment with corticosteroids for KTRs with moderate to severe PCP (as defined by partial pressure of oxygen in arterial blood (PaO2) <70 mmHg in room air or an alveolar gradient of >35 mmHg). (1C)

Tuberculosis (TB)

  • The Work Group suggests that TB prophylaxis and treatment regimens be the same in KTRs as would be used in the local, general population who require therapy. (2D)
  • The Work Group recommends monitoring CNI and mTORi blood levels in patients receiving rifampin. (1C)
    • Consider substituting rifabutin for rifampin to minimize interactions with CNIs and mTORi. (Not Graded)

Candida Prophylaxis

  • The Work Group suggests oral and esophageal Candida prophylaxis with oral clotrimazole lozenges, nystatin, or fluconazole for 1–3 months after transplantation, and for 1 month after treatment with an antilymphocyte antibody. (2C)

Cardiovascular Disease

Diabetes Mellitus

Screening for New-Onset Diabetes after Transplantation

  • The Work Group recommends screening all nondiabetic KTRs with fasting plasma glucose, oral glucose tolerance testing, and/or hemoglobin A1c (HbA1c) (1C) at least:
    • Weekly for 4 weeks (2D)
    • Every 3 months for 1 year (2D) and
    • Annually, thereafter (2D)
  • The Work Group suggests screening for new-onset diabetes after transplantation (NODAT) with fasting glucose, oral glucose tolerance testing, and/or HbA1c after starting, or substantially increasing the dose, of CNIs, mTORi, or corticosteroids. (2D)

Managing NODAT or Diabetes Present at Transplantation

  • If NODAT develops, consider modifying the immunosuppressive drug regimen to reverse or ameliorate diabetes, after weighing the risk of rejection and other potential adverse effects. (Not Graded)
  • Consider targeting HbA1c 7.0%–7.5%, and avoid targeting HbA1c ≤6.0%, especially if hypoglycemic reactions are common. (Not Graded)
  • The Work Group suggests that, in patients with diabetes, aspirin (65–100 mg/d) use for the primary prevention of cardiovascular disease (CVD) be based on patient preferences and values, balancing the risk for ischemic events to that of bleeding. (2D)

Hypertension, Dyslipidemias, Tobacco Use, and Obesity

Hypertension

  • The Work Group recommends measuring blood pressure at each clinic visit. (1C)
  • The Work Group suggests maintaining blood pressure at <130 mmHg systolic and <80 mmHg diastolic if ≥18 years of age, and <90th percentile for sex, age, and height if <18 years old. (2C)
  • To treat hypertension (Not Graded):
    • Use any class of antihypertensive agent
    • Monitor closely for adverse effects and drug-drug interactions and
    • When urine protein excretion ≥1 g/d for ≥18 years old and ≥600 mg/m2/24 h for <18 years old, consider an ACE-I or an ARB as first-line therapy.

Dyslipidemias

Note: These recommendations are based on Kidney Disease Outcomes Quality Initiative (KDOQI) Dyslipidemia Guidelines External Web Site Policy and are thus Not Graded.

  • Measure a complete lipid profile in all adult (≥18 years old) and adolescent (puberty to 18 years old) KTRs [Based on KDOQI Dyslipidemia Recommendation 1]:
    • 2–3 months after transplantation
    • 2–3 months after a change in treatment or other conditions known to cause dyslipidemias
    • At least annually, thereafter
  • Evaluate KTRs with dyslipidemias for secondary causes [Based on KDOQI Dyslipidemia Recommendation 3]:
    • For KTRs with fasting triglycerides ≥500 mg/dl (≥5.65 mmol/l) that cannot be corrected by removing an underlying cause, treat with:
      • Adults: therapeutic lifestyle changes and a triglyceride-lowering agent [Based on KDOQI Recommendation 4.1];
      • Adolescents: therapeutic lifestyle changes [Based on KDOQI Recommendation 5.1]
    • For KTRs with elevated low-density lipoprotein cholesterol (LDL-C):
      • Adults: If LDL-C ≥100 mg/dl (≥2.59 mmol/l), treat to reduce LDL-C to <100 mg/dl (<2.59 mmol/l) [Based on KDOQI Guideline 4.2]
      • Adolescents: If LDL-C ≥130 mg/dl (≥3.36 mmol/l), treat to reduce LDL-C to <130 mg/dl (<3.36 mmol/l) [Based on KDOQI Guideline 5.2]
    • For KTRs with normal LDL-C, elevated triglycerides and elevated non-high-density lipoprotein cholesterol (HDL-C):
      • Adults: If LDL-C <100 mg/dl (<2.59 mmol/l), fasting triglycerides ≥200 mg/dl (≥2.26 mmol/l), and non-HDL-C ≥130 mg/dl (≥3.36 mmol/l), treat to reduce non-HDL-C to <130 mg/dl (<3.36 mmol/l) [Based on KDOQI Guideline 4.3]
      • Adolescents: If LDL-C <130 mg/dl (<3.36 mmol/l), fasting triglycerides ≥200 mg/dl (≥2.26 mmol/l), and non-HDL-C ≥160 mg/dl (≥4.14 mmol/l), treat to reduce non-HDL-C to <160 mg/dl (<4.14 mmol/l) [Based on KDOQI Guideline 5.3]

Tobacco Use

  • Screen and counsel all KTRs, including adolescents and children, for tobacco use, and record the results in the medical record. (Not Graded)
    • Screen during initial transplant hospitalization.
    • Screen at least annually, thereafter.
  • Offer treatment to all patients who use tobacco. (Not Graded)

Obesity

  • Assess obesity at each visit. (Not Graded)
    • Measure height and weight at each visit, in adults and children.
    • Calculate body mass index (BMI) at each visit.
    • Measure waist circumference when weight and physical appearance suggest obesity, but BMI is <35 kg/m2.
  • Offer a weight-reduction program to all obese KTRs. (Not Graded)

Cardiovascular Disease (CVD) Management

  • Consider managing CVD at least as intensively in KTRs as in the general population, with appropriate diagnostic tests and treatments. (Not Graded)
  • The Work Group suggests using aspirin (65–100 mg/d) in all patients with atherosclerotic CVD, unless there are contraindications. (2B)

Malignancy

Cancer of the Skin and Lip

  • The Work Group recommends that KTRs, especially those who have fair skin, live in high sun-exposure climates, have occupations requiring sun exposure, have had significant sun exposure as a child, or have a history of skin cancer, be told that their risk of skin and lip cancer is very high. (1C)
  • The Work Group recommends that KTRs minimize life-long sun exposure and use appropriate ultraviolet light-blocking agents. (1D)
  • The Work Group suggests that adult KTRs perform skin and lip self-examinations and report new lesions to a health-care provider. (2D)
  • For adult KTRs, the Work Group suggests that a qualified health professional, with experience in diagnosing skin cancer, perform annual skin and lip examination on KTRs, except possibly for KTRs with dark skin pigmentation. (2D)
  • The Work Group suggests that patients with a history of skin or lip cancer, or premalignant lesions, be referred to and followed by a qualified health professional with experience in diagnosing and treating skin cancer. (2D)
  • The Work Group suggests that patients with a history of skin cancer be offered treatment with oral acitretin, if there are no contraindications. (2B)

Non-Skin Malignancies

  • Develop an individualized screening plan for each KTR that takes into account the patient's past medical and family history, tobacco use, competing risks for death, and the performance of the screening methodology. (Not Graded)
  • Screen for the following cancers as per local guidelines for the general population (Not Graded):
    • Women: cervical, breast, and colon cancer
    • Men: prostate and colon cancer
  • Obtain hepatic ultrasound and alpha feto-protein every 12 months in patients with compensated cirrhosis. (Not Graded) [See recommendations for HCV and HBV above.]

Managing Cancer with Reduction of Immunosuppressive Medication

  • The Work Group suggests consideration be given to reducing immunosuppressive medications for KTRs with cancer. (2C)
  • Important factors for consideration include (Not Graded):
    • The stage of cancer at diagnosis
    • Whether the cancer is likely to be exacerbated by immunosuppression
    • The therapies available for the cancer
    • Whether immunosuppressive medications interfere with ability to administer the standard chemotherapy
  • For patients with Kaposi sarcoma, the Work Group suggests using mTORi along with a reduction in overall immunosuppression. (2C)

Other Complications

Transplant Bone Disease

Note: See the NGC summary of the KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD–MBD).

  • In patients in the immediate post-kidney transplant period, the Work Group recommends measuring serum calcium and phosphorus at least weekly, until stable. (1B)
  • In patients after the immediate post-kidney transplant period, it is reasonable to base the frequency of monitoring serum calcium, phosphorus, and parathyroid hormone (PTH) on the presence and magnitude of abnormalities, and the rate of progression of CKD. (Not Graded)
    • Reasonable monitoring intervals would be (Not Graded):
      • In CKD stages 1–3T, for serum calcium and phosphorus, every 6–12 months; and for PTH, once, with subsequent intervals depending on baseline level and CKD progression
      • In CKD stage 4T, for serum calcium and phosphorus, every 3–6 months; and for PTH, every 6–12 months
      • In CKD stage 5T, for serum calcium and phosphorus, every 1–3 months; and for PTH, every 3–6 months
      • In CKD stages 3–5T, measurement of alkaline phosphatases annually, or more frequently in the presence of elevated PTH
    • In CKD patients receiving treatments for CKD–MBD, or in whom biochemical abnormalities are identified, it is reasonable to increase the frequency of measurements to monitor for efficacy and side-effects. (Not Graded)
    • It is reasonable to manage these abnormalities as for patients with CKD stages 3–5. (Not Graded)
  • In patients with CKD stages 1–5T, the Work Group suggests that 25(OH)D (25-hydroxyvitamin D, calcidiol) levels might be measured, and repeated testing determined by baseline values and interventions. (2C)
  • In patients with CKD stages 1–5T, the Work Group suggests that vitamin D deficiency and insufficiency be corrected using treatment strategies recommended for the general population. (2C)
  • In patients with an eGFR greater than approximately 30 ml/min/1.73 m2, the Work Group suggests measuring bone mineral density (BMD) in the first 3 months after kidney transplant if they receive corticosteroids or have risk factors for osteoporosis as in the general population. (2D)
  • In patients in the first 12 months after kidney transplant with eGFR greater than approximately 30 ml/min/1.73 m2 and low BMD, the Work Group suggests that treatment with vitamin D, calcitriol/alfacalcidol, or bisphosphonates be considered. (2D)
    • The Work Group suggests that treatment choices be influenced by the presence of CKD–MBD, as indicated by abnormal levels of calcium, phosphorus, PTH, alkaline phosphatases, and 25(OH)D. (2C)
    • It is reasonable to consider a bone biopsy to guide treatment, specifically before the use of bisphosphonates due to the high incidence of adynamic bone disease. (Not Graded)
    • There are insufficient data to guide treatment after the first 12 months. (Not Graded)
  • In patients with CKD stages 4–5T, the Work Group suggests that BMD testing not be performed routinely, because BMD does not predict fracture risk as it does in the general population and BMD does not predict the type of kidney transplant bone disease. (2B)
  • In patients with CKD stages 4–5T with a known low BMD, the Work Group suggests management as for patients with CKD stages 4–5 not on dialysis. (2C)

Hematological Complications

  • Perform a complete blood count at least (Not Graded):
    • Daily for 7 days, or until hospital discharge, whichever is earlier
    • 2–3 times per week for weeks 2–4
    • Weekly for months 2–3
    • Monthly for months 4–12
    • Then at least annually, and after any change in medication that may cause neutropenia, anemia or thrombocytopenia
  • Assess and treat anemia by removing underlying causes whenever possible and using standard measures applicable to CKD. (Not Graded)
  • For treatment of neutropenia and thrombocytopenia, include treatment of underlying causes whenever possible. (Not Graded)
  • The Work Group recommends using ACE-Is or ARBs for initial treatment of erythrocytosis. (1C)

Hyperuricemia and Gout

  • The Work Group suggests treating hyperuricemia in KTRs when there are complications, such as gout, tophi, or uric acid stones. (2D)
    • The Work Group suggests colchicine for treating acute gout, with appropriate dose reduction for reduced kidney function and concomitant CNI use. (2D)
    • The Work Group recommends avoiding allopurinol in patients receiving azathioprine. (1B)
    • The Work Group suggests avoiding nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 (COX-2) inhibitors whenever possible. (2D)

Growth and Development

  • The Work Group recommends measuring growth and development in children (1C):
    • At least every 3 months if <3 years old (including head circumference) (Not Graded)
    • Every 6 months in children ≥3 years until final adult height (Not Graded)
  • The Work Group recommends using recombinant human growth hormone (rhGH) 28 IU/m2/wk (or 0.05 mg/kg/d) in children with persistent growth failure after kidney transplantation. (1B)
  • The Work Group suggests minimizing or avoiding corticosteroid use in children who still have growth potential. (2C)

Sexual Function and Fertility

Sexual Function

  • Evaluate adults for sexual dysfunction after kidney transplantation. (Not Graded)
  • Include discussion of sexual activity and counseling about contraception and safe sex practices in follow-up of adult KTRs. (Not Graded)

Female Fertility

  • The Work Group suggests waiting for at least 1 year after transplantation before becoming pregnant, and only attempting pregnancy when kidney function is stable with <1 g/d proteinuria. (2C)
  • The Work Group recommends that mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) be discontinued or replaced with azathioprine before pregnancy is attempted. (1A)
  • The Work Group suggests that mTORi be discontinued or replaced before pregnancy is attempted. (2D)
  • Counsel female KTRs with child-bearing potential and their partners about fertility and pregnancy as soon as possible after transplantation. (Not Graded)
  • Counsel pregnant KTRs and their partners about the risks and benefits of breastfeeding. (Not Graded)
  • Refer pregnant patients to an obstetrician with expertise in managing high-risk pregnancies. (Not Graded)

Male Fertility

  • The Work Group suggests that male KTRs and their partners be advised that:
    • Male fertility may improve after kidney transplantation (2D)
    • Pregnancies fathered by KTRs appear to have no more complications than those in the general population. (2D)
  • The Work Group recommends that adult male KTRs be informed of the possible risks of infertility from mTORi. (1C)
    • The Work Group suggests that adult male KTRs who wish to maintain fertility should consider avoiding mTORi, or banking sperm prior to mTORi use. (2C)

Lifestyle

  • The Work Group recommends that patients are strongly encouraged to follow a healthy lifestyle, with exercise, proper diet, and weight reduction as needed. (1C) (See also 'Obesity,' above.)

Mental Health

  • Include direct questioning about depression and anxiety as part of routine follow-up care after kidney transplantation. (Not Graded)

Definitions:

Nomenclature and Description for Grading Recommendations

Implications
Grade* Patients Clinicians Policy
Level 1
'The Work Group recommends'
Most people in your situation would want the recommended course of action and only a small proportion would not. Most patients should receive the recommended course of action. The recommendation can be adopted as a policy in most situations.
Level 2
'The Work Group suggests'
The majority of people in your situation would want the recommended course of action, but many would not. Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with her or his values and preferences. The recommendation is likely to require debate and involvement of stakeholders before policy can be determined.

*The additional category 'Not Graded' was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counseling and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations.

Final Grade for Overall Quality of Evidence

Grade Quality of Evidence Meaning
A High The Work Group is confident that the true effect lies close to that of the estimate of the effect.
B Moderate The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
C Low The true effect may be substantially different from the estimate of the effect.
D Very Low The estimate of effect is very uncertain, and often will be far from the truth.
Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is identified and graded for each recommendation (see the 'Major Recommendations' field).

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Improved care for kidney transplant recipients

Potential Harms
  • Randomized controlled trials have shown that the withdrawal of corticosteroids from maintenance immunosuppressive medication regimens, when carried out weeks to months after transplantation, is associated with a high risk of acute rejection.
  • Different immunosuppressive medications have different toxicity profiles and patients vary in their susceptibility to adverse effects. Adverse effects include new-onset diabetes mellitus, dyslipidemias, hypertension, osteopenia, anemia and leucopenia, delayed wound healing, diarrhea, nausea/vomiting, proteinuria, and decreased glomerular filtration rate (GFR) (see Table 2 in the original guideline document for toxicity profiles of immunosuppressive medications).
  • Reported adverse events related to recombinant human growth hormone (rhGH) include asthma, acute rejection, deterioration in kidney function, papilledema, raised fasting glucose and glucose intolerance.
  • In randomized controlled trials of acitretin treatment, several individuals had adverse effects attributed to therapy; however, these adverse effects generally resolved upon discontinuation of treatment. Adverse effects that resulted in treatment withdrawal included: headache, dyslipidemia, musculoskeletal complaints, and skin rash.
  • A major issue of concern in the management of human immunodeficiency virus (HIV) patients is the need to be aware of potential drug–drug interactions among antiretroviral therapy and other medications, including immunosuppressants.

Contraindications

Contraindications
  • The following vaccines are contraindicated in kidney transplant recipients:
    • Varicella zoster
    • Bacillus Calmette-Guerin (BCG)
    • Smallpox
    • Intranasal influenza
    • Live oral typhoid Ty21a and other newer vaccines
    • Measles (except during an outbreak)
    • Mumps
    • Rubella
    • Oral polio
    • Live Japanese B encephalitis vaccine
    • Yellow fever
  • Aspirin therapy should not be recommended in people under 30 years of age due to lack of evidence of benefit, and is contraindicated in patients under the age of 21 years because of the associated risk of Reye's syndrome.
  • The combined use of mammalian target of rapamycin inhibitor(s) (mTORi) and calcineurin inhibitors (CNIs) should be avoided, because these agents potentiate nephrotoxicity, particularly when used in the early post-transplant period.
  • Table 21 in the original guideline document lists cautions and contraindications for a number of drugs used in the pharmacological management of diabetes in kidney transplant recipients.

Qualifying Statements

Qualifying Statements
  • This Clinical Practice Guideline document is based upon the best information available as of March 2009. It is designed to provide information and assist decision making. It is not intended to define a standard of care, and should not be construed as one, nor should it be interpreted as prescribing an exclusive course of management. Variations in practice will inevitably and appropriately occur when clinicians take into account the needs of individual patients, available resources, and limitations unique to an institution or type of practice. Every health-care professional making use of these recommendations is responsible for evaluating the appropriateness of applying them in the setting of any particular clinical situation. The recommendations for research contained within this document are general and do not imply a specific protocol.
  • This guideline was written for transplant-care providers throughout the world. As such, it addresses issues that are important to the care of kidney transplant recipients (KTRs) in both developed and developing countries, but nowhere was the quality of care compromised for utilitarian purposes. Nevertheless, the Work Group recognizes that, in many parts of the world, treatment of end-stage kidney disease (chronic kidney disease [CKD] stage 5) with dialysis is not feasible, and transplantation can only be offered as a life-saving therapy if it is practical and cost-effective. Therefore, in providing a comprehensive, evidence-based guideline for the care of the KTRs, they were cognizant of the fact that programs in some areas of the world may need to adopt cost-saving measures in order to make transplantation possible.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Implementation Tools
Foreign Language Translations
Pocket Guide/Reference Cards
Quick Reference Guides/Physician Guides
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
Living with Illness
Staying Healthy
IOM Domain
Effectiveness
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9(Suppl 3):S1-155. [937 references] PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2009 Nov
Guideline Developer(s)
Kidney Disease: Improving Global Outcomes - Nonprofit Organization
Source(s) of Funding

Kidney Disease: Improving Global Outcomes (KDIGO) gratefully acknowledges the following sponsors that make their initiatives possible: Abbott, Amgen, Belo Foundation, Coca-Cola Company, Dole Food Company, Genzyme, Hoffmann-LaRoche, JC Penney, NATCO-The Organization for Transplant Professionals, National Kidney Foundation-Board of Directors, Novartis, Robert and Jane Cizik Foundation, Shire, Transwestern Commercial Services, and Wyeth. KDIGO is supported by a consortium of sponsors and no funding is accepted for the development of specific guidelines.

Guideline Committee

Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group

Composition of Group That Authored the Guideline

Work Group Members: Bertram L. Kasiske, MD (Co-chair), Hennepin County Medical Center, Minneapolis, MN; Martin G. Zeier, MD, FASN (Co-chair), University Hospital of Heidelberg, Heidelberg, Germany; Jonathan C. Craig, MBChB, MM (Clin Epi), DCH, FRACP, PhD, The Children's Hospital at Westmead, Westmead, Australia; Henrik Ekberg, MD, PhD, Lund University, Malmö, Sweden; Catherine A. Garvey, RN, BA, CCTC, University of Minnesota, Minneapolis, MN; Michael D. Green, MD, MPH, Children's Hospital of Pittsburgh, Pittsburgh, PA; Vivekanand Jha, MD, FRCP, Postgraduate Medical Institute, Chandigarh, India; Michelle A. Josephson, MD, University of Chicago, Chicago, IL; Bryce A. Kiberd, MD, Dalhousie University, Halifax, Canada; Henri A. Kreis, MD, Université Paris Descartes & Hôpital Necker, Paris, France; Ruth A. McDonald, MD, University of Washington, Seattle Children's Hospital, Seattle, WA; John M. Newmann, PhD, MPH, Health Policy Research & Analysis, Reston, VA; Gregorio T. Obrador, MD, MPH, Universidad Panamericana School of Medicine, Mexico City, Mexico

Liaison to The Transplantation Society and the Global Alliance of Transplantation: Jeremy R. Chapman, MD, FRACP, FRCP, Westmead Hospital, Westmead, Australia

Liaison to the American Society of Transplantation: Flavio G. Vincenti, MD, University of California at San Francisco, San Francisco, CA

Evidence Review Team: Tufts Center for Kidney Disease Guideline Development and Implementation, Tufts Medical Center, Boston, MA, USA: Ethan M. Balk, MD, MPH, Project Director and Director, Evidence-based Medicine; Martin Wagner, MD, MS, Assistant Project Director; Gowri Raman, MD, Research Fellow; Samuel Abariga, MD, MS, Research Associate; Amy Earley, BS, Project Coordinator

In addition, support and supervision were provided by: Katrin Uhlig, MD, MS, Director, Guideline Development and Joseph Lau, MD, Methods Consultant.

Financial Disclosures/Conflicts of Interest

Kidney Disease: Improving Global Outcomes (KDIGO) makes every effort to avoid any actual or reasonably perceived conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the Work Group. All members of the Work Group are required to complete, sign, and submit a disclosure and attestation form showing all such relationships that might be perceived or actual conflicts of interest. This document is updated annually and information is adjusted accordingly. All reported information is published in its entirety at the end of the original guideline document in the Work Group members' Biographic and Disclosure Information section, and is on file at the National Kidney Foundation (NKF), Managing Agent for KDIGO.

Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies of the guideline: Available in English External Web Site Policy and Russian External Web Site Policy from the Kidney Disease: Improving Global Outcomes (KDIGO) Web site.

Availability of Companion Documents

The following are available:

  • KDIGO clinical practice guideline for the care of kidney transplant recipients. Supporting tables. New York: Kidney Disease: Improving Global Outcomes; 2009 Nov. 138 p. Electronic copies: Available in Portable Document Format (PDF) from the Kidney Disease: Improving Global Outcomes (KDIGO) Web site External Web Site Policy.
  • KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. 2010;77:299-311. Electronic copies: Available in PDF from the KDIGO Web site External Web Site Policy. Also available in various foreign language translations from the KDIGO Web site External Web Site Policy.
  • Managing your adult patients who have a kidney transplant. New York: Kidney Disease: Improving Global Outcomes; 2010. 9 p. Electronic copies: Available in PDF from the KDIGO Web site External Web Site Policy.
  • Managing kidney transplant recipients. New York: Kidney Disease: Improving Global Outcomes; 2010. 9 p. Electronic copies: Available in PDF from the KDIGO Web site External Web Site Policy.
  • Methods for development of KDIGO clinical practice guidelines. Electronic copies: Available from the KDIGO Web site External Web Site Policy.
Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on October 26, 2012. This summary was updated by ECRI Institute on August 2, 2013 following the U.S. Food and Drug Administration advisory on Nizoral (ketoconazole).

Copyright Statement

Copyright © 2012 by KDIGO. All rights reserved.

Single photocopies may be made for personal use as allowed by national copyright laws. Special rates are available for educational institutions that wish to make photocopies for non-profit educational use. No part of this publication may be reproduced, amended, or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without explicit permission in writing from KDIGO. Details on how to seek permission for reproduction or translation, and further information about KDIGO's permissions policies can be obtained by contacting Anita Viliusis, KDIGO Permissions Manager, at anita.viliusis@kidney.org.

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