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KDOQI Commentary                                                                                        ...
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KDOQI Commentary                                                                                        ...
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KDOQI Commentary                                                                                        ...
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KDOQI Commentary                                                                                        ...
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KDOQI Commentary                                                                                        ...
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KDOQI Commentary                                                                                        ...
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KDOQI Commentary                                                                                        ...
KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
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KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...

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KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...

  1. 1. ARTICLE IN PRESS VOL xx, NO x, MONTH 2010 KDOQI COMMENTARY KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients Margaret Bia, MD,1 Deborah B. Adey, MD,2 Roy D. Bloom, MD,3 Laurence Chan, MD,4 Sanjay Kulkarni, MD,5 and Steven Tomlanovich, MD6 In response to recently published KDIGO (Kidney Disease: Improving Global Outcomes) guidelines for the care of kidney transplant recipients (KTRs), the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) organized a working group of transplant nephrologists and surgeons to review these guidelines and comment on their relevance and applicability for US KTRs. The following commentar- ies on the KDIGO guidelines represent the consensus of our work group. The KDIGO transplant guidelines concentrated on aspects of transplant care most important to this population in the posttransplant period, such as immunosuppression, infection, malignancy, and cardiovascular care. Our KDOQI work group concurred with many of the KDIGO recommendations except in some important areas related to immunosup- pression, in which decisions in the United States are largely made by transplant centers and are dependent in part on the specific patient population served. Most, but not all, KDIGO guidelines are relevant to US patients. However, implementation of many may remain a major challenge because of issues of limitation in resources needed to assist in the tasks of educating, counseling, and implementing and maintaining lifestyle changes. Although very few of the guidelines are based on evidence that is strong enough to justify their being used as the basis of policy or performance measures, they offer an excellent road map to navigate the complex care of KTRs. Am J Kidney Dis xx:xxx. © 2010 by the National Kidney Foundation, Inc. INDEX WORDS: Kidney transplant recipients (KTRs); calcineurin inhibitor (CNI); mycophenolate compound (MPA compound); inhibitor of mammalian target of rapamycin (mTOR inhibitor); KDIGO; KDOQI. I n 2007, there were 16,119 kidney transplants performed in the United States (10,082 de- ceased donor and 6,037 living donor)1 and kidney allograft. KDIGO (Kidney Disease: Im- proving Global Outcomes) is an international initiative formed to “improve the care and out- 158,739 US patients living with a functioning comes of kidney disease patients worldwide From the 1Yale School of Medicine, New Haven, CT; Address correspondence to Margaret Bia, MD, Section of 2 University of Vermont/Fletcher Allen Health Care, Burling- Nephrology, Department of Internal Medicine, Yale School ton, VT; 3Hospital of the University of Pennsylvania, Phila- of Medicine, PO Box 208029, New Haven, CT 06520-8029. delphia, PA; 4University of Colorado Denver, Aurora, CO; E-mail: margaret.bia@yale.edu 5 Yale School of Medicine, New Haven, CT; and 6University © 2010 by the National Kidney Foundation, Inc. of California, San Francisco, CA. 0272-6386/10/xx0x-0001$36.00/0 doi:10.1053/j.ajkd.2010.04.010 Reprint requests to Kerry Willis, PhD, National Kidney Foundation, 30 E 33rd St, New York, NY 10016. E-mail: kerryw@kidney.org American Journal of Kidney Diseases, Vol xx, No x (Month), 2010: pp xxx 1
  2. 2. ARTICLE IN PRESS 2 Bia et al through promoting coordination, collaboration, areas, only 25% of recommendations were graded and integration of initiatives to develop and 1. Furthermore, evidence for only 2% of recom- implement clinical practice guidelines.”2 To this mendations were graded A, 13.6% were graded end, a KDIGO work group has recently pub- B, 38.9% were graded C, and 45.5% were graded lished a new comprehensive set of recommenda- D.3 The KDIGO authors make it clear that for tions for the care of kidney transplant recipients guidelines in which the evidence was meager, (KTRs).3 The last clinical practice transplant they chose to give guidance rather than remain guideline for US patients was published in 2000 silent. They also make it clear that the guideline by the American Society of Transplantation (AST) was not developed for regulatory agencies; this and was based primarily on expert opinion. Pre- is important to keep in mind because so few of vious KDIGO practice guidelines have been pub- the recommendations are based on evidence that lished for the care of patients with hepatitis C is strong enough to justify their being used as the and chronic kidney disease (CKD)4 and CKD– basis of policy or performance measures. mineral and bone disorders (CKD-MBD).5 Be- cause global guidelines need to be adapted to the KDOQI PROCESS FOR INTERPRETATION OF regional context in which they are used, the THE KDIGO GUIDELINE IN THE CARE OF US National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) program TRANSPLANT PATIENTS organized a work group of transplant nephrolo- Differences in target population, individual gists and surgeons to review the newest KDIGO patient immunologic risk, prevalence of concomi- guideline and comment on the relevance and tant diseases (such as diabetes mellitus), availabil- applicability for US KTRs. ity of resources, and systems of payment must all be considered in interpreting global recommenda- KDIGO GUIDELINE PROCESS tions to specific regions. The following commen- The KDIGO transplant guideline concentrated taries on the KDIGO guideline represent the mainly on aspects of transplant care most impor- consensus of a work group convened by KDOQI tant to this population in the posttransplant pe- to evaluate the relevance and applicability of the riod, such as immunosuppression, infection, ma- guideline to US patients and practices. It is lignancy, and cardiovascular care. The guidelines beyond the scope of our review to make a com- do not address pretransplant evaluation or issues ment on each of the more than 150 KDIGO related to patients returning to dialysis therapy recommendations. We chose instead to address with a failed allograft. The target audience for guidelines for which we questioned applicability the guideline is physicians, coordinators, pharma- to US KTRs, as well as those that we believed cists, and other medical professionals who di- needed reinforcement or clarification. Emphasis rectly or indirectly care for KTRs. The KDIGO is placed not on critiquing the guidelines, but on guideline was based on published evidence and determining their appropriateness for our US graded according to the strength of the data (Fig patients. The relative importance of a recommen- 1). Because of the paucity of evidence in many dation, relevance to US patients, comparison to Figure 1. Rating guideline recommendations. Within each recommendation, the strength of recommendation is indicated as Level 1, Level 2, or Not Graded, and the quality of the supporting evidence is shown as A, B, C, or D. *The additional category Not Graded typically was used to provide guidance based on common sense or when 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. Ungraded recommendations generally are written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2. Adapted from the KDIGO transplant guideline3 with permission of KDIGO.
  3. 3. ARTICLE IN PRESS KDOQI Commentary 3 existing guidelines, and ease of implementation Box 1. 2006 OPTN/SRTR Annual Report form the basis of these commentaries. Induction Immunosuppressiona Members of the KDOQI commentary work ● 78% used induction therapy, composed of: group reached consensus on most commentaries Œ Thymoglobulin in 39% and have indicated when this was not the case. Œ Interleukin 2 receptor antagonist in 28% We have relisted each KDIGO recommendation Œ Alemtuzumab in 9% by section with the grade for evidence support- Œ Other in 2% ● 22% did not receive induction therapy ing it, followed by our work group’s rationale and commentary on the guideline. If a guideline Initial Immunosuppression (at discharge) recommendation statement was classified by the ● 94% on CNI, composed of KDIGO work group as important enough to Œ 15% CsA become a strong recommendation (category 1), Œ 79% Tac the statement is highlighted by showing the guide- ● 87% on MPA ● 9% on mTOR inhibitor line text in bold. ● 26% steroid free Maintenance Immunosuppression (1 year and beyond) ● 99% on CNI COMMENTARY ON SECTION I OF THE KDIGO ● 87% on MPA TRANSPLANT GUIDELINE: ● 18% on mTOR inhibitors IMMUNOSUPPRESSION ● 20% steroid free Abbreviations: CNI, calcineurin inhibitors; CsA, cyclo- KDIGO Recommendations in Chapter 1: sporine; MPA, mycophenolic acid compounds; mTOR, Induction Therapy mammalian target of rapamycin; OPTN/SRTR, Organ 1.1: We recommend starting a combination of immu- Procurement and Transplantation Network/Scientific Reg- nosuppressive medications before, or at the time istry of Transplant Recipients; Tac, tacrolimus. of, kidney transplantation. (1A) Data source: Andreoni et al.6 1.2: We recommend including induction therapy with a biologic agent as part of the initial immunosup- preted with these differences in mind. The last pressive regimen in KTRs. (1A) published survey of immunosuppression use in 1.2.1: We recommend that an IL2-RA [interleu- US transplant centers was in the 2006 Organ kin-2 receptor antagonist] be the firstline induction therapy. (1B) Procurement and Transplantation Network/Scien- 1.2.2: We suggest using a lymphocyte-depleting tific Registry of Transplant Recipients (OPTN/ agent, rather than an IL2-RA, for KTRs at SRTR) Annual Report6 and reported on the use high immunologic risk. (2B) of calcineurin inhibitors (CNIs), mycophenolate acid compounds (MPA), mammalian target of KDOQI Rationale and Commentary rapamycin (mTOR) inhibitors, and induction It clearly is important to start immunosuppres- therapy (Box 1). sion before or at the time of transplant. Induction Guidelines for induction therapy will be most therapy with a biologic agent, such as interleukin relevant not to community nephrologists, but to 2 (IL-2) receptor antagonists or thymoglobulin, those working in transplant centers in which decreases the frequency of acute rejection and induction is used. Not all patients need induction now is used in up to 80% of US transplant therapy. The cost of induction therapy is substan- centers. However, individual US transplant cen- tial and should be viewed in the context of ters determine immunosuppression protocols risk/benefit for a particular donor/recipient pro- based on their particular patient population, or- file. In the United States, the use of lymphocyte- gan source, experience, ease of use, and cost of depleting antibodies (thymoglobulin and alemtuz- therapy. Ethnic diversity of the population and umab) for induction is increasing.6 Many centers the number of high-risk patients vary in different will use these agents in low-risk patients to regions of the United States, which explains in minimize exposure to other maintenance drugs part variations in protocols used in different (ie, steroids). It is unlikely that the current KDIGO centers. Applicability of the recommended guidelines recommending IL-2 receptor antago- KDIGO guidelines in this section must be inter- nists as first-line induction therapy will alter US
  4. 4. ARTICLE IN PRESS 4 Bia et al transplant practices in which these decisions tend stated, mycophenolate compounds (MMF and to be transplant-center specific and based on mycophenolate sodium) are used as the initial factors described previously. antiproliferative agent of choice in most US transplant centers. KDIGO Recommendations in Chapter 2: Initial and Maintenance Immunosuppressive Steroid Therapy Discontinuation Medications Steroid sparing with discontinuation within 2.1: We recommend using a combination of immuno- the first few weeks after transplant has gained suppressive medications as maintenance therapy widespread acceptance in the United States, with including a CNI and an antiproliferative agent, more than 25% of patients being discharged after with or without corticosteroids. (1B) transplant off steroid therapy.6 Although the 2.2: We suggest that tacrolimus be the first-line CNI KDOQI work group agreed that steroid therapy used. (2A) 2.2.1: We suggest that tacrolimus or CsA be could be discontinued in low-risk patients after started before or at the time of transplanta- induction therapy, we did not think that this tion, rather than delayed until the onset of suggestion should be accepted as a universal graft function. (2D tacrolimus; 2B CsA) guideline for several reasons. Although short- 2.3: We suggest that mycophenolate be the first-line and medium-term results in corticosteroid therapy antiproliferative agent. (2B) discontinuation protocols show equivalent pa- 2.4: We suggest that, in patients who are at low immuno- tient and graft survival, there may be a price to logical risk and who receive induction therapy, pay in the long term. Acute rejection rates are corticosteroids could be discontinued during the first week after transplantation. (2B) higher in well-designed randomized clinical tri- 2.5: We recommend that if mTOR inhibitors are als of steroid withdrawal. In addition, the pres- used, they should not be started until graft ence of chronic interstitial fibrosis and tubular function is established and surgical wounds are atrophy may be greater in corticosteroid-free healed. (1B) patients, portending decreased long-term graft function. The heterogeneity of the US donor and KDOQI Rationale and Commentary recipient population may have a role in this Initial Immunosuppression issue. Newer transplant regimens decrease pred- We agree that optimum initial maintenance nisone dosage to 5 mg/d. Apart from less bone therapy includes a CNI and an antiproliferative disease, the potential metabolic benefits of corti- agent and that tacrolimus is the preferred CNI for costeroid-free protocols versus 5 mg/d seem to most patients. The Symphony Study, a large be less significant. What is clear is that discontinu- multicenter clinical trial, showed that the combi- ation of steroid therapy early after transplant nation of low-dose tacrolimus, mycophenolate seems to be associated with less risk of rejection mofetil (MMF), and steroids with daclizumab than discontinuation of steroids later ( 1 year). induction provided superior efficacy without the It should be noted that there are no studies of negative impact on renal function compared with different times in the first year to determine when either cyclosporine or a CNI-free regimen of corticosteroid therapy can be discontinued safely. low-dose sirolimus.7,8 However, in a small num- In some centers, steroid therapy discontinuation ber of patients, other issues, such as age, ethnic- is accomplished up to 6 months posttransplant. ity, risk of new-onset diabetes mellitus, and pre- Late discontinuation of steroid therapy ( 1 year vious toxicity with tacrolimus, may result in the posttransplant) is no longer recommended and initial use of cyclosporine. Immediate CNI use forms the basis of KDIGO guideline 2.5, with has not been shown to cause a delay in renal which we agree. It also must be emphasized that recovery. Although many centers briefly hold or steroid therapy withdrawal should be performed modify the CNI dose in the setting of delayed only when there is close frequent monitoring of graft function, especially when using antilympho- the patient. cyte-depleting induction agents, treatment with these drugs should be initiated before or at the Early Use of mTOR Inhibitors time of discharge from the hospital and not Sirolimus and everolimus (agents known as withheld because of delayed graft function. As mTOR inhibitors) delay wound healing, prolong
  5. 5. ARTICLE IN PRESS KDOQI Commentary 5 delayed graft function, and are no longer used in more study before it could be accepted as a the early posttransplant period (KDIGO recom- guideline. mendation 2.5). Furthermore, studies show an increased rejection rate with early use of these Steroid Therapy Withdrawal compounds in place of CNIs. The Symphony We agree that late steroid therapy with- Study showed that the highest rejection rate drawal ( 1 year) is inadvisable, but stress that occurred in the arm using low-dose sirolimus the definition of “early” steroid discontinua- with MMF and steroids.7,8 tion has not been well defined and may occur KDIGO Recommendations in Chapter 3: after the first week (see commentary under Long-term Maintenance Immunosuppressive Chapter 2). Medications KDIGO Recommendations in Chapter 4: 3.1: We suggest using the lowest planned doses of Strategies to Reduce Drug Costs maintenance immunosuppressive medications by 2-4 months after transplantation, if there has been 4.1: If drug costs block access to transplantation, a no acute rejection. (2C) strategy to minimize drug costs is appropriate, 3.2: We suggest that CNIs be continued rather than even if use of inferior drugs is necessary to obtain withdrawn. (2B) the improved survival and quality of life benefits 3.2: If prednisone is being used beyond the first week of transplantation compared with dialysis. (Not after transplantation, we suggest prednisone be Graded) continued rather than withdrawn. (2C) 4.1.1: We suggest strategies that may reduce drug costs include: KDOQI Rationale and Commentary • limiting use of a biologic agent for Decreasing Immunosuppressive Dosage induction to patients who are high-risk for acute rejection (2C); Although our work group agreed with sugges- • using ketoconazole to minimize CNI tion 3.1, we stress that dosing of immunosuppres- dose (2D); sion should at all times take into account the • using a nondihydropyridine CCB to mini- individual patient’s risk profile, balancing rejec- mize CNI dose (2C); tion with the adverse effects of medications. In • using azathioprine rather than mycophe- nolate (2B); some patients, this may mean higher drug dosing/ • using adequately tested bioequivalent ge- drug levels to account for a higher risk of rejec- neric drugs (2C); tion. Although most US transplant centers now • using prednisone long-term. (2C) strive for a lower dose of immunosuppressive 4.2: Do not use generic compounds that have not been medication after the early posttransplant period, certified by an independent regulatory agency to the transplant center should define each patient’s meet each of the following criteria when compared target drug dosing based on immunologic risk, to the reference compound (Not Graded): which depends on ethnicity, age, history of previ- • contains the same active ingredient; ous transplant, and level of HLA antibodies. • is identical in strength, dosage form, and route of administration; Continue or Withdraw CNI Therapy • has the same use indications; • is bioequivalent in appropriate bioavailability Although we agreed that mTOR inhibitors studies; should not be used in the early posttransplant • meets the same batch requirements for identity, period,7,8 newer clinical trials have explored strength, purity and quality; switching from CNIs to mTOR inhibitors 3-6 • is manufactured under strict standards. months posttransplant.9,10 Early results suggest 4.3: It is important that the patient, and the clinician relative safety with improvement in renal func- responsible for the patient’s care, be made aware of tion. Whether the trade-off of less nephrotoxic- any change in a prescribed immunosuppressive ity with a different side-effect profile of mTOR drug, including a change to a generic drug. (Not Graded) inhibitors will be beneficial in the long term 4.4: After switching to a generic medication that is remains to be determined. The work group monitored using blood levels, obtain levels and believed that suggestion 3.2 to continue CNI adjust the dose as often as necessary until a stable therapy indefinitely in all patients required therapeutic target is achieved. (Not Graded)
  6. 6. ARTICLE IN PRESS 6 Bia et al KDOQI Rationale and Commentary pharmacies regarding medications. Transplant Drug costs are becoming an increasing issue in centers and practices that see many transplant transplantation that impacts on patient adherence patients bear an inordinate part of this burden. and ultimately affects graft survival. Currently, im- KDIGO Recommendations in Chapter 5: munosuppressive drugs in the United States are Monitoring Immunosuppressive Medications covered by the Centers for Medicare & Medicaid Services (CMS), the primary insurer for many 5.1: We recommend measuring CNI blood levels (1B), and suggest measuring at least: KTRs, for 3 years after transplant, although legisla- • every other day during the immediate postopera- tion is being considered to continue this coverage tive period until target levels are reached (2C); for the life of the kidney. Most KTRs are using • whenever there is a change in medication or many other medications in addition to immunosup- patient status that may affect blood levels (2C); • whenever there is a decline in kidney function that pressive drugs. In general, the transplant commu- may indicate nephrotoxicity or rejection. (2C) nity (patients, health care providers, and policy 5.1.1: We suggest monitoring CsA using 12-h makers) need to embrace the concept of cost con- trough (C0), 2-h post-dose (C2) or abbrevi- tainment and the risk(s) to the patient and graft by ated AUC. (2D) these measures. However, this needs to be balanced 5.1.2: We suggest monitoring tacrolimus using 12-h trough (C0). (2C) by who benefits and how much risk is at stake. Use of drugs that block the cytochrome P-450 5.2: We suggest monitoring MMF levels. (2D) 5.3: We suggest monitoring mTOR inhibitor levels. (2C) 3A system in an attempt to decrease CNI dosing and costs are rarely used in the United KDOQI Rationale and Commentary States. The concern is that inadvertent cessa- Because immunosuppressive drugs are classi- tion of treatment with these drugs, causing a fied as narrow therapeutic agents, drug-level significant decrease in drug levels, could result monitoring is a necessary tool to maximize effi- in an acute rejection episode. Therefore, the ciency and minimize toxicity. The blood drug work group did not think that many of the 4.1.1 level is not synonymous with level of immuno- suggestions should be accepted as a guideline. suppression, but may correlate imperfectly with Switching from a mycophenolate compound to this effect. In most US transplant centers, levels an azathioprine compound in the later posttrans- of CNI and mTOR inhibitors are monitored. plant period may be considered in some pa- MPA monitoring is problematic because of the tients as another cost-saving maneuver, espe- poor correlation between trough levels and area cially in view of recent US registry data under the curve (AUC) exposure. Optimal moni- showing similar long-term survival with these toring of MPA requires a 4- to 6-hour abbrevi- drugs.11 Although we agree with the sugges- ated AUC measurement, which is logistically tions outlined in 4.2, it should be recognized difficult in the outpatient setting. Although stud- that many generic formulations have never ies show that monitoring MPA levels in the early been tested in transplant patients. Patient con- posttransplant period may be helpful in cyclospor- fusion with medications when a different ge- ine-treated patients, recent evidence suggests that neric formulation or even different strengths of such monitoring may be less important in pa- the same drug from different manufacturers is tients on tacrolimus therapy.12 With most US dispensed at each refill can lead to inadvertent KTRs now being started on tacrolimus as the medication errors, possibly affecting out- CNI of choice, MPA monitoring is not routine in comes. Patient education is crucial to avoid many US transplant centers. Although one per- errors in medication administration. We agree son in our work group believed there may still be with recommendation 4.4 that it is crucial to some value in monitoring MPA levels, the other monitor patients after an immunosuppressive members questioned the value and applicability dosage change, brand change, or change to a of this practice (KDIGO suggestion 5.2). Cur- generic drug. However, it needs to be recog- rently, many US centers measure MPA only in nized that implementation of this guideline can the setting of possible drug-related toxicities or become burdensome as practices become inun- side effects. Although we agree with suggestion dated with inquiries from patients, payors, and 5.3 to monitor mTOR inhibitor levels, it should
  7. 7. ARTICLE IN PRESS KDOQI Commentary 7 be appreciated that therapeutic levels of this most frequently as first-line treatment for acute agent have yet to be defined in controlled studies. rejection, followed by lymphocyte-depleting anti- bodies in steroid-resistant rejection, but there may KDIGO Recommendations in Chapter 6: be exceptions to this approach. Decision making Treatment of Acute Rejection regarding appropriate initial treatment for acute 6.1: We recommend biopsy before treating acute rejection should be based on clinical and patho- rejection, unless the biopsy will substantially logic information. Timing of the rejection episode delay treatment. (1C) posttransplant, type of induction agent used before 6.2: We suggest treating subclinical and borderline acute rejection, degree of deterioration in kidney function rejection. (2D) at the time of rejection, and histologic grade of the 6.3: We recommend corticosteroids for the initial treatment of acute cellular rejection. (1D) rejection may influence selection of the appropriate 6.3.1: We suggest adding or restoring maintenance initial antirejection therapy. There is increasing prednisone in patients not on steroids who recognition of the role of antibody-mediated mecha- have a rejection episode. (2D) nisms in acute rejection. This process requires 6.3.2: We suggest using lymphocyte-depleting anti- special blood tests (to detect donor-specific antibod- bodies or OKT3 [muromonab-CD3] for acute cellular rejections that do not respond to ies) and histochemical stains (immunofluorescence corticosteroids, and for recurrent acute cellu- for C4d) for diagnosis.14 Coordination with the lar rejections. (2C) transplant center is critical to ensure that all appro- 6.4: We suggest treating antibody-mediated acute rejec- priate testing is performed and specific treatment is tion with one or more of the following alternatives, initiated. After treatment of an acute episode, opti- with or without corticosteroids (2C): mizing overall immunosuppression is required. • plasma exchange; Considerations should include changing the CNI, • intravenous immunoglobulin; • anti-CD20 antibody; adding a mycophenolate compound or increasing • lymphocyte-depleting antibody. the dose, adding corticosteroids to previously ste- roid-free regimens, or adding/substituting an mTOR 6.5: For patients who have a rejection episode, we suggest adding mycophenolate if the patient is not inhibitor. More than 85% of patients are already receiving mycophenolate or azathioprine, or switch- using MPA agents, so the number available for ing azathioprine to mycophenolate. (2D) switching will be relatively small. KDOQI Rationale and Commentary KDIGO Recommendations in Chapter 7: We concur that biopsies should be performed on Treatment of Chronic Allograft Injury (CAI) all KTRs suspected of having an acute rejection 7.1: We recommend kidney allograft biopsy for all (recommendation 6.1). Expert interpretation of the patients with declining kidney function of unclear biopsy specimen by pathologists accustomed to cause, to detect potentially reversible causes. (1C) reading kidney transplant biopsies is as important 7.2: For patients with CAI and histological evidence of as expertise in performing the biopsy. It is contro- CNI toxicity, we suggest reducing, withdrawing, or replacing the CNI. (2C) versial whether subclinical and borderline rejec- 7.2.1: For patients with CAI, eGFR 40 mL/min/ tions should be treated (recommendation 6.2 sup- 1.73 m2, and urine total protein excretion ported by low evidence [2D]). Subclinical rejections 500 mg/g creatinine (or equivalent protein- are diagnosed in patients who have protocol biop- uria by other measures), we suggest replac- sies performed by design, not for deterioration in ing the CNI with a mTOR inhibitor. (2D) kidney function. Recent data suggest that the risk of subclinical rejection in patients on tacrolimus KDOQI Rationale and Commentary and mycophenolate compound therapy is so low We agree with the need for kidney transplant that protocol biopsies may no longer be indi- biopsy in patients with decreasing kidney function cated.13 Whether this is true in patients with high (7.1) and again stress the importance of expertise in immunologic risk or patients on minimization pro- pathologic interpretation. Important causes of tocols (ie, steroid-free protocols or lower CNI doses) chronic allograft injury (CAI), which include rejec- is uncertain. Whether borderline rejection should tion, BK nephropathy, CNI toxicity, or recurrent be treated or some infiltrates may be protective also disease, require special histochemical stains for is uncertain. In most US centers, steroids are used diagnosis that are not readily available in all labora-
  8. 8. ARTICLE IN PRESS 8 Bia et al tories. Therefore, coordination with the transplant 8.2: We suggest measuring urine protein excretion, (2C) center where these techniques are available is essen- at least: • Once in the first month to determine a baseline tial. For patients with CAI caused by CNI toxicity, (2D); withdrawing the CNI should occur only after at- • Every 3 months during the first year (2D); tempts at decreasing the dosage have failed. One • Annually, thereafter. (2D) also must ensure that all other causes of CAI are 8.3: We recommend measuring serum creatinine, (1B) at excluded to avoid inappropriate drug adjustments least: or missed treatment options. Although our work • Daily for 7 days or until hospital discharge, group thought that KDIGO suggestion 7.2.1 may whichever occurs sooner (2C); be reasonable in some patients, we also want to • 2-3 times per week for weeks 2-4 (2C); • Weekly for months 2 and 3 (2C); emphasize that the role of mTOR inhibitors in the • Every 2 weeks for months 4-6 (2C); treatment of CAI/CNI toxicity is poorly defined. It • Monthly for months 7-12 (2C); is clear that switching from a CNI to an mTOR • Every 2-3 months, thereafter. (2C) inhibitor should be avoided in patients with se- 8.3.1: We suggest estimating GFR whenever se- verely decreased glomerular filtration rate (GFR) rum creatinine is measured, (2D) using: and/or the presence of proteinuria; however, the exact • One of several formulas validated for guidelines for when to switch are still evolving. adults (2C); or • The Schwartz formula for children and adolescents. (2C) SUMMARY OF COMMENTARY ON SECTION I: 8.4: We suggest including a kidney allograft ultrasound IMMUNOSUPPRESSION examination as part of the assessment of kidney allograft dysfunction. (2C) In the United States, immunosuppressive protocols KDOQI Rationale and Commentary used may vary from center to center based on their particular patient population, organ source, experience Routine Screening Tests and Time and Frequency and opinion of the transplant team, ease of use, and cost of Monitoring of therapy. Although data about the efficacy and safety of Regular surveillance and vigilant monitoring of steroid-free regimens are still evolving, it is clear that if steroids are to be eliminated, this should be done in the kidney allograft function are important in improv- early transplant period and not late (after 1 year). ing short- and long-term outcomes. Early detection Community nephrologists need to coordinate any alter- of kidney allograft dysfunction will allow timely ations in immunosuppressive medications with the trans- diagnosis and treatment that may improve patient plant center and be vigilant for potential drug interactions and graft survival. Frequency and types of routine with the addition of any new medications. Drug monitor- ing is an essential monitoring tool throughout the post- screening tests after kidney transplant are shown in transplant course, but not always applicable to every Fig 2. Although there is no standard protocol for the immunosuppressive medication. Transplant biopsies fre- frequency and type of monitoring, recommenda- quently are necessary to determine the cause of renal tions are guided by the likelihood of problems dysfunction, and the interpretation must be performed by pathologists with resources and experience in handling specific to the particular transplant population. In and reading the transplant biopsy specimen. the early posttransplant period, when rejection and complications are the most likely, testing is per- formed more frequently. Thereafter, the follow-up interval will depend in part on the patient’s general COMMENTARY ON SECTION II OF KDIGO condition and the development of additional prob- TRANSPLANT GUIDELINE: GRAFT lems. The AST recommended routine posttrans- MONITORING AND INFECTIONS plant 2-3 visits per week during month 1, every 1-3 weeks during month 2-3, every 4-8 weeks during KDIGO Recommendations in Chapter 8: months 4-12, and every 2-4 months after the Monitoring Kidney Allograft Function first year. These early visits often are provided 8.1: We suggest measuring urine volume (2C): by the transplant physician or surgeon of the • Every 1-2 hours for at least 24 hours after transplant center. After 3-6 months, monitor- transplantation (2D); ing may be performed by the transplant physi- • Daily until graft function is stable. (2D) cian or community nephrologist.15 In a recent
  9. 9. ARTICLE IN PRESS KDOQI Commentary 9 Figure 2. Routine screen- ing after kidney transplant. Complete blood cell count in- cludes white blood cells, hemo- globin, and platelets. Screen for diabetes is by fasting blood glucose level, glucose toler- ance test, or hemoglobin A1c level. Lipid profile includes fast- ing cholesterol, low-density li- poprotein cholesterol, high- density lipoprotein cholesterol, and triglyceride levels. Screens for BK polyoma virus (BKV) and Epstein-Barr virus (EBV) use plasma nucleic acid test- ing (NAT); EBV screen is for patients with no antibody to EBV at transplant. Adapted from the KDIGO transplant guideline3 with permission of KDIGO. survey of posttransplant outpatient visits in kidney transplant recipient. Formulas to esti- Medicare beneficiaries in the United States, mate GFR using serum creatinine values have frequency of visits to transplant centers varied been tested in KTRs, but no formula consis- by center and region; most visits were to tently has been shown to be superior to an- nephrologists.16 other. As with CKD, considerable renal patho- At each clinic visit, education regarding logic states can be present without dramatic medication adherence, diet, and healthy life- changes in serum creatinine levels. style should be given. Screening for tobacco In 2005, the definition of CKD was amended use should be implemented before discharge to include all KTRs regardless of markers of and annually. Although the work group did not kidney damage or GFR.20,21 Although the work agree that screening all adults for Epstein-Barr group agreed that CKD staging in KTRs is virus (EBV) was of value (see commentary useful, it must be noted that there is consider- under Chapter 13 for EBV), screening for all able difference in the rate of progression in other elements listed in Fig 2, including screen- these 2 groups. Progression is much slower in ing for proteinuria, is reasonable. In addition KTRs in whom kidney half-life is longer at to these tests, monitoring for HLA antibodies every level of CKD. Renal ultrasound is the against the donor (donor-specific antibodies), preferred imaging study in KTRs (KDIGO which is not described in the KDIGO guide- suggestion 8.4).22 line, is becoming more common in some US centers. The optimal timing and frequency of KDIGO Recommendations in Chapter 9: Kidney such screening has yet to be determined.17,18 Allograft Biopsy Serum Creatinine and Estimated GFR 9.1: We recommend kidney allograft biopsy when there is a persistent, unexplained increase in Serum creatinine measurement remains the serum creatinine. (1C) most commonly used index of renal allograft 9.2: We suggest kidney allograft biopsy when serum function. It is reliable for detecting acute changes creatinine has not returned to baseline after treat- in kidney function. Furthermore, serum creati- ment of acute rejection. (2D) nine level at year 1 after transplant is a risk 9.3: We suggest kidney allograft biopsy every 7-10 days during delayed function. (2C) factor for subsequent outcomes19 and may 9.4: We suggest kidney allograft biopsy if expected help in the management of the frequency of kidney function is not achieved within the first 1-2 visits. However, it is less reliable for detecting months after transplantation. (2D) long-term changes in kidney function in the 9.5: We suggest kidney allograft biopsy when there is:
  10. 10. ARTICLE IN PRESS 10 Bia et al • New onset of proteinuria (2C); ogy, in consultation with the referring nephrolo- • Unexplained proteinuria 3.0 g per gram creati- gist, using appropriate stains and other studies. nine or 3.0 g per 24 hours. (2C) Molecular Markers KDOQI Rationale and Commentary In addition to conventional histopathologic Biopsy examination, several US transplant centers are using molecular markers, as well as genomic or Renal allograft biopsy is the gold standard for proteomic methods, to enhance our understand- diagnosing the cause of a change in renal allo- ing of the mechanism of immunologic and non- graft function. It is useful in all clinical situations immunologic pathway of injury. As an example, described in KDIGO suggestions 9.1-9.4. Poten- polymerase chain reaction (PCR) has been used tial causes of allograft dysfunction include vol- to detect messenger RNA for IL-2 and other ume depletion; compromised renal blood flow; biomarkers in biopsy samples. Using this ap- urinary outflow obstruction; parenchymal causes, proach, IL-2, upregulated during rejection, could such as acute rejection (cellular and/or humoral); be detected 2 days before rejection was apparent chronic allograft nephropathy; recurrent or de using histologic or clinical criteria. Such PCR novo disease; or BK nephropathy. Patients show- approaches have been used to detect other gene ing a 20%-25% increase in creatinine level above products upregulated during acute rejection, such baseline values warrant consideration for biopsy. as granzyme B, perforin, transforming growth Other indications for pursuing renal allograft factor , IL-10, and IL-15.25-27 These newer biopsy would be a less-than-expected response methods are performed almost exclusively in to treatment of acute rejection. The expected transplant centers and may become a standard response would be dependent on the severity of method of transplant biopsy analysis in the fu- tissue injury noted on the diagnostic biopsy speci- ture. men. Delayed graft function lasting longer than 5-7 days warrants biopsy, with repeated biopsies KDIGO Recommendations in Chapter 10: performed every 7-10 days until graft function Recurrent Disease recovers. New-onset proteinuria, protein 2.0 10.1: We suggest screening KTRs with primary kidney g/g creatinine or 2.0 g/24 h, also merits a disease caused by FSGS for proteinuria (2C) at kidney biopsy. De novo and recurrent glomerular least: diseases are common causes of new-onset pro- • Daily for 1 week (2D); • Weekly for 4 weeks (2D); teinuria. Patients with de novo or recurrent glo- • Every 3 months, for the first year (2D); Every merular diseases should be followed up closely year, thereafter. (2D) by transplant nephrologists or community neph- 10.2: We suggest screening KTRs with potentially treat- rologists with close communication with the able recurrence of primary kidney disease from transplant center because treatment of some recur- IgA nephropathy, MPGN, anti-GBM disease, or rent kidney diseases may prevent or delay the ANCA-associated vasculitis for microhematuria, (2C) at least: onset of graft failure.23,24 • Once in the first month to determine a baseline (2D); Safety and Accuracy • Every 3 months during the first year (2D); The safety of kidney transplant biopsies has Annually, thereafter. (2D) been documented and the overall risk of compli- 10.3: During episodes of graft dysfunction in patients cations is low. Most biopsies are performed in with primary HUS, we suggest screening for thrombotic microangiopathy (e.g., with platelet the transplant center by transplant nephrologists. count, peripheral smear for blood cell morphology, Community nephrologists also may perform bi- plasma haptoglobin, and serum lactate dehydroge- opsies of the kidney in KTRs more than a year nase). (2D) posttransplant. It is prudent to obtain a diagnostic 10.4: When screening suggests possible treatable recur- ultrasound before biopsy to rule out unexpected rent disease, we suggest obtaining an allograft biopsy. (2C) alterations in blood flow or urinary tract obstruc- 10.5: Treatment of recurrent kidney disease: tion. It is imperative that a pathologist familiar 10.5.1: We suggest plasma exchange if a biopsy with the transplant process interprets the pathol- shows minimal change disease or FSGS
  11. 11. ARTICLE IN PRESS KDOQI Commentary 11 in those with primary FSGS as their mendation 10.2 for screening routinely for micro- primary kidney disease. (2D) hematuria. Recurrent disease is confirmed with a 10.5.2: We suggest high-dose corticosteroids and cyclophosphamide in patients with recur- renal allograft biopsy. Histologic recurrence of rent ANCA-associated vasculitis or anti- disease is much more common than is clinical GBM disease. (2D) disease recurrence. There is no proven therapy 10.5.3: We suggest using an ACE-I [ACE inhibi- for treatment of recurrent disease.30 tor] or an ARB for patients with recurrent glomerulonephritis and proteinuria. (2C) Membranoproliferative Glomerulonephritis 10.5.4: For KTRs with primary hyperoxaluria, we suggest appropriate measures to pre- Recurrence of membranoproliferative glomer- vent oxalate deposition until plasma and ulonephritis (MPGN) is common, as high as 80% urine oxalate levels are normal (2C), with MPGN type II (dense-deposit disease). The including: most common cause of MPGN type I is hepatitis • Pyridoxine (2C); • High calcium and low oxalate diet C–associated immune complex formation. We (2C); agree with the proposed regularly scheduled • Increased oral fluid intake to enhance screening for microhematuria and proteinuria in urinary dilution of oxalate (2C); recommendation 10.2. Patients with known hepa- • Potassium or sodium citrate to alkalin- titis C–associated MPGN pretransplant also may ize the urine (2C); • Orthophosphate (2C); be screened for cryoglobulins, which are associ- • Magnesium oxide (2C); ated with MPGN.31 • Intensive hemodialysis to remove ox- alate. (2C) Hemolytic Uremic Syndrome Hemolytic uremic syndrome (HUS) typically KDOQI Rationale and Commentary is divided into diarrheal associated (D ) and Recurrent disease accounts for a substantial non–diarrheal associated (D ). D disease oc- amount of graft loss after renal transplant. It is curs mostly in children and rarely recurs post- difficult to assess the percentage of grafts lost to transplant. However, D HUS is more common recurrent disease because many patients present in adults and can recur. In HUS associated with a with end-stage renal disease without benefit of a complement abnormality, such as factor H defi- diagnostic native renal biopsy. The likelihood of ciency or factor I mutation, recurrence rates can recurrent disease after transplant is dependent on be as high as 80%. Screening for evidence of the disease, with certain diseases at particularly recurrence allows for an earlier diagnosis, which high risk of recurrence.28 will require biopsy in most cases, and provides an opportunity for earlier intervention. There is Recurrent Focal Segmental Glomerulosclerosis no comment in the guideline regarding recur- We agree with recommendation 10.1 regard- rence of thrombotic thrombocytopenic purpura, ing frequent and regular screening for protein- but early detection of recurrence provides an uria in patients with primary focal segmental opportunity for treatment with plasmapheresis glomerulosclerosis (FSGS) as the cause of end- and intravenous immune globulin (IVIG). stage renal disease. If the patient is still produc- ing urine at the time of transplant, a preoperative Biopsy and Treatment urine protein-creatinine ratio can be a very help- As stated, kidney biopsy and interpretation by ful baseline measure of proteinuria. Early detec- a pathologist with expertise in transplant speci- tion of FSGS recurrence, which can present with men readings is critical in the diagnosis of dis- normal light microscopy, but foot-process efface- ease recurrence. Treatment for most recurrent ment on electron microscopy,29 provides the best disease in renal transplantation is based on a opportunity for intervention and amelioration of combination of case reports, case cohorts, and disease. retrospective reviews. Recurrent diseases post- transplant are not common enough that random- IgA Nephropathy ized controlled trials can be implemented; there- Recurrence rates of immunoglobulin A (IgA) fore, most recommendations for treatment are nephropathy are variable. We agree with recom- based on a consensus of opinion. Despite this, we
  12. 12. ARTICLE IN PRESS 12 Bia et al agree in general with the recommendations de- 12.1.1.1: We suggest annual HBsAb tailed in 10.5. [antibody to hepatitis B sur- face antigen] titers. (2D) 12.1.1.2: We suggest revaccination if KDIGO Recommendations in Chapter 11: the antibody titer falls below Preventing, Detecting, and Treating 10 mIU/mL. (2D) Nonadherence 12.2: We suggest avoiding live vaccines in KTRs. (2C) 11.1: Consider providing all KTRs and family members 12.3: We suggest avoiding vaccinations, except influ- with education, prevention, and treatment mea- enza vaccination, in the first 6 months following sures to minimize nonadherence to immunosup- kidney transplantation. (2C) pressive medications. (Not Graded) 12.3.1: We suggest resuming immunizations once 11.2: Consider providing KTRs at increased risk for patients are receiving minimal mainte- nonadherence with increased levels of screening nance doses of immunosuppressive medi- for nonadherence. (Not Graded) cations. (2C) 12.3.2: We recommend giving all KTRs, who are at least 1-month post-transplant, KDOQI Rationale and Commentary influenza vaccination prior to the onset Noncompliance or nonadherence to diet and of the annual influenza season, regard- less of status of immunosuppression. medication is a common problem in KTRs. Nonad- (1C) herence to medication is associated with a high risk of acute rejection and allograft loss. We agree that 12.4: We suggest giving the following vaccines to KTRs who, due to age, direct exposure, residence or early efforts should be made to identify KTRs at travel to endemic areas, or other epidemiological increased risk of nonadherence and that these pa- risk factors are at increased risk for the specific tients should be monitored closely. Prevention, iden- diseases: tification, and treatment of nonadherence are inte- • rabies, (2D) gral to the monitoring of kidney allograft function • tick-borne meningoencephalitis, (2D) • Japanese B encephalitis—inactivated, (2D) and long-term care of KTRs. Certain subgroup of • Meningococcus, (2D) KTRs, younger patients, African Americans, and • Pneumococcus, (2D) those with financial hardships, have an enhanced • Salmonella typhi—inactivated. (2D) risk of nonadherence.32,33 12.4.1: Consult an infectious disease specialist, a In addition to identifying patients at risk, it is travel clinic or public health official for guidance on whether specific cases war- important to have a system for addressing patient rant these vaccinations. (Not Graded) nonadherence. This requires coordinated efforts of social workers, transplant coordinators, financial KDOQI Rationale and Commentary counselors, pharmacists, primary nephrologists, and KTRs are at particular risk of viral infections the patient’s family.34 A combination of educa- because of the preferential suppression of T lympho- tional, behavioral, and social support interventions cytes by both induction and maintenance immuno- provides the best results. Because there is no per- suppression. The risk and consequence of develop- fect measure of adherence, consideration should be ing a viral infection warrant use of selected vaccines. given to multiple approaches for adherence moni- The suggestions regarding which vaccines are safe toring. Similar team approaches also are important and which are contraindicated are based on whether in other areas requiring adherence, such as diet, the vaccine contains live or killed virus. Live virus exercise, tobacco, alcohol, and drug use. vaccines are contraindicated in immunosuppressed KTRs. The KDIGO recommendations for vaccina- KDIGO Recommendations in Chapter 12: tions agree with updated guidelines recently pub- Vaccination lished by the AST.35 Specific comments on the 12.1: We recommend giving all KTRs approved, KDIGO suggestions regarding vaccinations are inactivated vaccines, according to recommended listed in the following sections. schedules for the general population, except for HBV vaccination. (1D) Hepatitis B 12.1.1: We suggest HBV vaccination (ideally prior to transplantation) and HBsAb titers The work group did not concur with KDIGO 6-12 weeks after completing the vaccina- suggestion 12.1.1. Neither revaccination against tion series. (2D) hepatitis after transplant nor following up hepa-
  13. 13. ARTICLE IN PRESS KDOQI Commentary 13 titis B antibody titers annually is a common persistently greater than 10 000 cop- practice in the United States. Hepatitis B is not ies/mL (107 copies/L). (2D) as prevalent in the United States as in other 13.2: CYTOMEGALOVIRUS parts of the world and evidence supporting 13.2.1: CMV prophylaxis: We recommend that screening in all patients posttransplant is lack- KTRs (except when donor and recipi- ent both have negative CMV serolo- ing. However, screening for seroconversion in gies) receive chemoprophylaxis for patients at risk (receiving a hepatitis B core CMV infection with oral ganciclovir or antibody–positive kidney) is appropriate. These valganciclovir for at least 3 months patients may benefit from lamivudine or ente- after transplantation, (1B) and for 6 cavir therapy.36 weeks after treatment with a T-cell– depleting antibody. (1C) 13.2.2: In patients with CMV disease, we suggest Live Vaccine and Timing of Vaccine weekly monitoring of CMV by NAT or There is no particular reason for a 6-month pp65 antigenemia. (2D) lag between transplant and vaccination. The 13.2.3: CMV treatment: 13.2.3.1: We recommend that all pa- theory is that vaccines are less likely to be tients with serious (includ- effective in the period when immunosuppres- ing most patients with tissue sion is high. In the United States, most individu- invasive) CMV disease be als are on their baseline maintenance immuno- treated with intravenous suppression therapy by 3 months posttransplant. ganciclovir. (1D) 13.2.3.2: We recommend that CMV Decisions regarding the timing of vaccines are disease in adult KTRs that is made based on immunosuppression exposure not serious (e.g. episodes that and risk of infection. Recipients also should are associated with mild avoid intimate contact with individuals who clinical symptoms) be treated have received live vaccines.37 This includes with either intravenous gan- avoiding close contact with children who have ciclovir or oral valganciclo- vir. (1D) received oral polio vaccine for 3 weeks and 13.2.3.3: We recommend that all may include close contact with adults receiv- CMV disease in pediatric ing the attenuated varicella vaccine to prevent KTRs be treated with intra- zoster. Immunosuppressed individuals are ad- venous ganciclovir. (1D) vised to avoid contact for 7 days with individu- 13.2.3.4: We suggest continuing therapy until CMV is no longer detect- als who have received live virus nasal sprays able by plasma NAT or pp65 for influenza. We concur with the recommenda- antigenemia. (2D) tion for flu vaccine, but common practice in 13.2.4: We suggest reducing immunosuppressive the United States is to wait 3-6 months after medication in life-threatening CMV dis- transplant before it is administered. ease, and CMV disease that persists in the face of treatment, until CMV disease has resolved. (2D) KDIGO Recommendations in Chapter 13: Viral 13.2.4.1: We suggest monitoring graft Diseases function closely during CMV disease. (2D) 13.1: BK POLYOMA VIRUS 13.1.1: We suggest screening all KTRs for BKV 13.3: EPSTEIN-BARR VIRUS AND POST-TRANS- with quantitative plasma NAT (2C) at PLANT LYMPHOPROLIFERATIVE DISEASE least: 13.3.1: We suggest monitoring high-risk (donor • monthly for the first 3-6 months after EBV seropositive/recipient seronegative) transplantation (2D); KTRs for EBV by NAT (2C): • then every 3 months until the end of • once in the first week after transplanta- the first post-transplant year (2D); tion (2D); • whenever there is an unexplained rise • then at least monthly for the first 3-6 in serum creatinine (2D); months after transplantation (2D); • and after treatment for acute rejection. • then every 3 months until the end of (2D) the first post-transplant year (2D); 13.1.2: We suggest reducing immunosuppressive • and additionally after treatment for medications when BKV plasma NAT is acute rejection. (2D)
  14. 14. ARTICLE IN PRESS 14 Bia et al 13.3.2: We suggest that EBV-seronegative pa- 13.5.4: Measure ALT in HCV-infected patients tients with an increasing EBV load have monthly for the first 6 months and every immunosuppressive medication reduced. 3-6 months, thereafter. Perform imaging (2D) annually to look for cirrhosis and hepato- 13.3.3: We recommend that patients with EBV cellular carcinoma. (Not Graded) [Based disease, including PTLD, have a reduc- on KDIGO Hepatitis C Recommendation tion or cessation of immunosuppres- 4.4.1.] (See Recommendation 19.3.) sive medication. (1C) 13.5.5: Test HCV-infected patients at least every 3-6 months for proteinuria. (Not Graded) 13.4: HERPES SIMPLEX VIRUS 1, 2 AND VARI- [Based on KDIGO Hepatitis C Recom- CELLA ZOSTER VIRUS mendation 4.4.4.] 13.4.1: We recommend that KTRs who de- 13.5.5.1: For patients who develop new velop a superficial HSV 1, 2 infection onset proteinuria (either urine be treated (1B) with an appropriate protein/creatinine ratio 1 or oral antiviral agent (e.g. acyclovir, vala- 24-hour urine protein 1 g on cyclovir, or famciclovir) until all le- two or more occasions), per- sions have resolved. (1D) form an allograft biopsy with 13.4.2: We recommend that KTRs with sys- immunofluorescence and elec- temic HSV 1, 2 infection be treated tron microscopy. (Not Graded) (1B) with intravenous acyclovir and a [Based on KDIGO Hepatitis C reduction in immunosuppressive medi- Recommendation 4.4.4.] cation. (1D) 13.5.6: We suggest that patients with HCV asso- 13.4.2.1: We recommend that intrave- ciated glomerulopathy not receive inter- nous acyclovir continue un- feron. (2D) [Based on KDIGO Hepatitis til the patient has a clinical C Recommendation 4.4.5.] response, (1B) then switch to an appropriate oral antiviral 13.6: HEPATITIS B VIRUS agent (e.g. acyclovir, valacy- 13.6.1: We suggest that any currently available clovir, or famciclovir) to com- induction and maintenance immunosup- plete a total treatment duration pressive medication can be used in HBV- of 14-21 days. (2D) infected KTRs. (2D) 13.4.3: We suggest using a prophylactic antiviral 13.6.2: We suggest that interferon treatment agent for KTRs experiencing frequent should generally be avoided in HBV recurrences of HSV 1,2 infection. (2D) infected KTRs. (2C) 13.4.4: We recommend that primary VZV infec- 13.6.3: We suggest that all HBsAg-positive KTRs tion (chicken pox) in KTRs be treated receive prophylaxis with tenofovir, ente- (1C) with either intravenous or oral acy- cavir, or lamivudine. (2B) clovir or valacyclovir; and a temporary 13.6.3.1: Tenofovir or entecavir are pref- reduction in amount of immunosuppres- erable to lamivudine, to mini- sive medication. (2D) mize development of potential drug resistance, unless medica- 13.5: HEPATITIS C VIRUS tion cost requires that lami- 13.5.1: We suggest that HCV-infected KTRs be vudinebe used. (Not Graded) treated only when the benefits of treat- 13.6.3.2: During therapy with antivi- ment clearly outweigh the risk of allo- rals, measure HBV DNA and graft rejection due to interferon-based ALT levels every 3 months to therapy (e.g. fibrosing cholestatic hepati- monitor efficacy and to detect tis, life-threatening vasculitis). (2D) drug resistance. (Not Graded) [Based on KDIGO Hepatitis C Recom- 13.6.4: We suggest treatment with adefovir or mendation 2.1.5.] tenofovir for KTRs with lamivudine resis- 13.5.2: We suggest monotherapy with standard tance ( 5 log10 copies/mL rebound of interferon for HCV-infected KTRs in HBV-DNA). (2D) whom the benefits of antiviral treatment 13.6.5: Screen HBsAg-positive patients with cir- clearly outweigh the risks. (2D) [Based rhosis for hepatocellular carcinoma every on KDIGO Hepatitis C Recommenda- 12 months with liver ultrasound and tions 2.2.4 and 4.4.2.] alpha feto-protein. (Not Graded) (See 13.5.3: We suggest that all conventional current Recommendation 19.3.) induction and maintenance immunosup- 13.6.6: We suggest that patients who are negative pressive regimens can be used in HCV for HBsAg and have HBsAb titer 10 infected patients. (2D) [Based on KDIGO mIU/mL receive booster vaccination to Hepatitis C Recommendation 4.3.] raise the titer to 100 mIU/mL. (2D)
  15. 15. ARTICLE IN PRESS KDOQI Commentary 15 13.7: HUMAN IMMUNODEFICIENCY VIRUS be detected beyond the first year, it is not clear how 13.7.1: If not already done, screen for HIV long screening should be continued posttransplant, infection. (Not Graded) although most centers screen for the first year only. 13.7.2: To determine antiretroviral therapy, refer HIV-infected KTRs to an HIV specialist, Ongoing clinical trials are exploring effective treat- who should pay special attention to drug– ment for BK nephropathy.38,39 Decisions about drug interactions and appropriate dosing decreases in immunosuppression, currently the of medications. (Not Graded). mainstay of BK viremia management, always should be made in consultation with the transplant KDOQI Rationale and Commentary center. Viral infections are particularly problematic in transplant recipients because of the preferential Cytomegalovirus inhibition of T-lymphocyte function by both induc- KDIGO recommendation 13.2.1 regarding cyto- tion and maintenance immunosuppression. Use of megalovirus (CMV) prophylaxis is reasonable and induction immunosuppression with lymphocyte- applicable to the US population. Universal prophy- depleting agents (thymoglobulin or alemtuzumab) laxis for CMV now is recommended over initiating is associated with a greater risk of viral infection pre-emptive treatment after CMV develops.40 A posttransplant. In general, the greater the cumula- major concern for US patients is the cost of CMV tive exposure to immunosuppression, the greater prophylaxis with oral valgancyclovir. Leukopenia the risk of infectious complications. The presenta- can be observed in patients using mycophenolate tion of viral infections can be asymptomatic, vague, preparations when prophylaxis with valgancyclo- and nonspecific or life-threatening acute illness. vir is used. Screening for CMV is best performed Many viral infections seen in KTRs are rarely seen using NAT methods (13.2.2). CMV antigenemia in immunocompetent patients and therefore do not assays are still in use in many facilities, but are not enter into the differential diagnosis for physicians as sensitive as PCR assays.41 There is no utility in unfamiliar with transplant recipients. Close commu- checking for serologic response to CMV with IgG or IgM titers posttransplant because the immune nication with the transplant center is crucial in response is not predictable. Patients with CMV caring for the transplant population. Early detection disease should be cared for by clinicians familiar and institution of therapy provide the best chance with treating this disease. It is recommended that for viral eradication. treatment be continued until viral load is undetect- able, followed by prophylactic doses of valgancy- BK Virus clovir for an additional 3 months.35 Although the work group agreed with KDIGO suggestions for BK virus screening posttransplant, Epstein-Barr Virus we did not think it was practical to require screen- Current practice regarding EBV screening varies ing exclusively with quantitative plasma nucleic among centers in the United States and many do acid testing (NAT) because many US centers use not routinely screen for EBV posttransplant, even initial urinary screening and then test plasma only in recipient-negative donor-positive cases. In con- if urine screening results are positive. However, trast to KDIGO recommendation 13.1.1, routine there is no disagreement that some type of screen- EBV screening is not recommended in AST infec- ing for BK virus is critical to avoid BK nephropa- tious disease guidelines.35 In many centers, EBV thy, for which there is no specific treatment when it screening is reserved for children, who are much is established. Complicating screening for BK vi- more commonly EBV negative pretransplant than rus is the variability in results between laboratories adults. EBV-induced posttransplant lymphoprolif- and uncertainty about the level of viremia that erative disorder (PTLD) affects many more pediat- should trigger a response to decrease in immunosup- ric than adult KTRs. If screening is someday to be pression. In the presence of viremia and increase in routinely implemented in US centers, details regard- serum creatinine level, a renal allograft biopsy is ing the best method of screening and levels of indicated to confirm the presence of BK nephropa- viremia above which a clinical intervention should thy. Because BK viremia and viruria certainly can be triggered need to be better defined.
  16. 16. ARTICLE IN PRESS 16 Bia et al Herpes and Varicella Human Immunodeficiency Virus Systemic herpesvirus infections can be life Human immunodeficiency virus (HIV)-posi- threatening in transplant recipients and should be tive individuals are now acceptable for transplant treated aggressively with intravenous antiviral if CD4 count is 200 cells/ L and viral load agents, as described in the KDIGO recommenda- (VL) is undetectable.35,43 Transplant should be tions. Less aggressive cutaneous infection can be performed at centers with expertise in managing treated with oral antiviral agents, as outlined in HIV-positive individuals and care should be co- the KDIGO guidelines. ordinated carefully with HIV specialists. Some Varicella exposure is particularly concerning in antiretroviral agents, in particular the protease transplant recipients. The work group disputes the inhibitors, have potentially serious drug interac- recommended dosing of acyclovir for varicella tions with immunosuppressive agents.35 exposure. Acyclovir at a dose of 10 mg/kg or about 800 mg 4 times daily of oral acyclovir would be KDIGO Recommendations in Chapter 14: Other standard dosing. We agree with the use of varicella immune globulin and emphasize the need to avoid Infections the varicella vaccine because it is a live virus. 14.1: URINARY TRACT INFECTION Should a transplant recipient develop a systemic 14.1.1: We suggest that all KTRs receive UTI varicella infection, hospitalization and high-dose prophylaxis with daily trimethoprim– sulfamethoxazole for at least 6 months intravenous acyclovir therapy are warranted. after transplantation. (2B) Hepatitis C 14.1.2: For allograft pyelonephritis, we suggest initial hospitalization and treatment with Hepatitis C management posttransplant is a intravenous antibiotics. (2C) challenge. The KDIGO guidelines cited here 14.2: PNEUMOCYSTIS JIROVECII PNEUMONIA were based on the recently published KDIGO 14.2.1: We recommend that all KTRs receive guideline for hepatitis C in CKD.4 Hepatitis C PCP prophylaxis with daily tri- typically is not treated posttransplant because of methoprim–sulfamethoxazole for 3-6 the risk ( 50%) of rejection precipitated by months after transplantation. (1B) interferon therapy, particularly in US KTRs in 14.2.2: We suggest that all KTRs receive PCP whom hepatitis C commonly is genotype 1, which prophylaxis with daily trimethoprim– sulfamethoxazole for at least 6 weeks is more resistant to treatment with interferon.42 during and after treatment for acute rejec- However, should hepatitis C–related glomerulo- tion. (2C) nephritis develop, the risk-benefit ratio may fa- 14.2.3: We recommend that KTRs with PCP vor treatment in selected patients. Such decisions diagnosed by bronchial alveolar lavage always should be made in consultation with and/or lung biopsy be treated with hepatology and infectious disease experts and high-dose intravenous trimethoprim– the transplant center. Monitoring liver enzyme sulfamethoxazole, corticosteroids, and a reduction in immunosuppressive levels, specifically alanine aminotransferase medication. (1C) (ALT), may reflect a change in hepatitis activity, 14.2.4: We recommend treatment with cortico- but monitoring hepatitis C viral load is not recom- steroids for KTRs with moderate to mended because it does not seem to correlate severe PCP (as defined by PaO2 <70 with outcome. Annual monitoring for hepatocel- mm Hg in room air or an alveolar lular carcinoma using -fetoprotein and imaging gradient of >35 mm Hg). (1C) is encouraged, but not often practiced. 14.3: TUBERCULOSIS 14.3.1: We suggest that TB prophylaxis and Hepatitis B treatment regimens be the same in KTRs KDIGO recommendations for hepatitis B are as would be used in the local, general reasonable and currently are followed in most population who require therapy. (2D) 14.3.2: We recommend monitoring CNI and US centers, except for recommendation 13.6.6 mTORi [mTOR inhibitor] blood levels in (see previous recommendation under vaccina- patients receiving rifampin. (1C) tions). KTRs with hepatitis C or hepatitis B also 14.3.2.1: Consider substituting rifabu- should be followed up by a hepatologist. tin for rifampin to minimize
  17. 17. ARTICLE IN PRESS KDOQI Commentary 17 interactions with CNIs and cause of the unreliable nature of skin testing. Newer mTORi. (Not Graded) techniques involving interferon release assays are 14.4: CANDIDA PROPHYLAXIS emerging as the new gold standard for detection of 14.4.1: We suggest oral and esophageal Candida latent tuberculosis.44,45 prophylaxis with oral clotrimazole loz- enges, nystatin, or fluconazole for 1-3 months after transplantation, and for 1 Candida Prophylaxis month after treatment with an antilympho- cyte antibody. (2C) Oral candidiasis must be screened for using oral mucosa examination on follow-up visits KDOQI Rationale and Commentary in KTRs. This is especially true in the early Urinary Tract Infection posttransplant period, when immunosuppres- Urinary tract infections (UTIs) after kidney sive medication dosage is the highest. We transplant are very common and account for a agree with these recommendations and empha- large percentage of readmissions posttransplant. size that if fluconazole is used, there is a UTIs are common because of multiple factors, potential for serious drug interactions because including the disrupted anatomy of the urinary of cytochrome P-450 3A4 inhibition. tract with a ureteroneocystotomy, incomplete bladder emptying because of diabetes or pros- tatic hypertrophy, and impaired immune re- sponses. Prophylaxis of UTIs usually is under- SUMMARY OF COMMENTARY ON SECTION II: taken with trimethoprim-sulfamethoxazole for 6 GRAFT MONITORING AND INFECTIONS months posttransplant, although infections often occur despite therapy because of the develop- ment of drug resistance. Although native kidney Improvement in short-term outcomes has not trans- pyelonephritis does not always require hospital- lated into significant improvements in long-term out- ization, it is recommended that all KTRs with comes in KTRs. The lack of significant improvement in this diagnosis be hospitalized because the graft long-term survival may be related to post-transplant dysfunction that usually accompanies transplant complications. Frequent posttransplant monitoring may pyelonephritis requires aggressive investigation improve long-term outcomes by decreasing chronic graft failure or death with a functioning graft. Our work group and treatment. Individuals with recurrent UTIs concurred with the recommendation and schedules of warrant evaluation with urologic assessment. Pa- routine screening in monitoring kidney allograft function tients with recurrent UTIs may benefit from after kidney transplant with a low threshold for perform- long-term suppressive therapy. ing kidney biopsy in cases of graft dysfunction or protein- uria. Expert tissue processing and interpretation of trans- Pneumocystic Pneumonia plant biopsy specimens by pathologists with transplant experience are critical. Regular surveillance of the pa- We agree that Pneumocystis jirovecii pneumonia tient’s kidney function at the transplant center or in the (PCP) prophylaxis is important for the first 3-6 nephrologist’s office offers an opportunity to enhance months posttransplant (14.2.1).After the first month, patient adherence to medication, diet, and healthy life- every-other-day dosing of trimethoprim-sulfame- style. Although CKD in KTRs progresses more slowly than CKD in other patients, the work group agreed that thoxazole or atovaquone is believed to be adequate the KDIGO guidelines on CKD should be followed in prophylaxis. In cases in which neither of these KTRs. agents can be used, an individual may be treated Opportunistic infections are common in KTRs, al- prophylactically with inhaled pentamidine. Our though advances in diagnosis and treatment have led to KDOQI work group emphasized that patients who improved survival in KTRs with infection. It is now standard of care to use vaccinations in KTRs as long as develop PCP should be transferred to the transplant the vaccine does not contain live or attenuated virus. It center promptly for management and adjustments also is routine to screen for or use prophylaxis to prevent in immunosuppression. several posttransplant viral infections. With few excep- tions (related to EBV and BK virus screening and Tuberculosis hepatitis B vaccination posttransplant), we concurred Monitoring for latent tuberculosis has posed a with KDIGO guidelines for vaccination, screening, and treatment of infection posttransplant. challenge in the immunosuppressed population be-

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