SPECIAL FEATURE  Kidney transplantation

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SPECIAL FEATURE

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Assessing pharmacologic and nonpharmacologic risks in candidates for kidney transplantation Angela Q. Maldonado, Eric M. Tichy, Christin C. Rogers, Maya Campara, Christopher Ensor, Christina T. Doligalski, Steven Gabardi, Jillian L. Descourouez, Ian C. Doyle, and Jennifer Trofe-Clark

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n 2004 and 2007, the United Network for Organ Sharing1 and the Centers for Medicare and Medicaid Services,2 respectively, issued mandates requiring transplantation programs to document the participation of a pharmacist on multidisciplinary teams in order to meet accreditation standards, making transplantation the only healthcare specialty in the United States to have such a requirement. Since then, there has been a growing body of literature supporting and describing the role of the transplantation pharmacist in all phases of the transplantation process.3-10 With the advent of widespread transplantation pharmacy services, the scope and degree of pharmacist involvement in this area of healthcare have grown incrementally over time. With increasing demands regarding the presence of transplantation pharmacists in all facets of the trans-

Purpose. Pharmacotherapy concerns and other factors with a bearing on patient selection for kidney transplantation are discussed. Summary. The process of selecting appropriate candidates for kidney transplantation involves multidisciplinary assessment to evaluate a patient’s mental, social, physical, financial, and medical readiness for successful surgery and good posttransplantation outcomes. Transplantation pharmacists can play important roles in the recognition and stratification of pharmacologic and nonpharmacologic risks in prospective kidney transplant recipients and the identification of issues that require a mitigation strategy. Key pharmacotherapyrelated issues and considerations during the risk assessment process include (1) anticoagulation concerns, (2) cytochrome P-450 isoenzyme–mediated drug interactions, (3) mental health–related medication

plantation process, it is important to clarify and develop consensus stan-

Angela Q. Maldonado, Pharm.D., BCPS, CPP, is Clinical Pharmacy Specialist, Department of Transplant Surgery, Vidant Medical Center, Greenville, NC. Eric M. Tichy, Pharm.D., FCCP, BCPS, is Clinical Pharmacy Specialist, Department of Pharmacy, Yale–New Haven Hospital, New Haven, CT. Christin C. Rogers, Pharm.D., FCCP, BCPS, is Clinical Pharmacy Coordinator, Department of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA. Maya Campara, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Department of Pharmacy, University of Illinois at Chicago. Christopher Ensor, Pharm.D., BCPS, is Clinical Pharmacy Specialist, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA. Christina T. Doligalski, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Department of Pharmacy, Tampa General Hospital, Tampa, FL. Steven Gabardi, Pharm.D., FCCP, BCPS, is Clinical Pharmacy

use, (4) chronic pain–related medication use, (5) medication allergies, (6) use of hormonal contraception and replacement therapy, (7) prior or current use of immunosuppressants, (8) issues with drug absorption, (9) alcohol use, (10) tobacco use, (11) active use of illicit substances, and (12) use of herbal supplements. Important areas of nonpharmacologic risk include vaccine delivery, infection prophylaxis and treatment, and socially related factors such as nonadherent behavior, communication barriers, and financial, insurance, or transportation challenges that can compromise posttransplantation outcomes. Conclusion. Consensus opinions of practitioners in transplantation pharmacy regarding the pharmacologic and nonpharmacologic factors that should be considered in assessing candidates for kidney transplantation are presented. Am J Health-Syst Pharm. 2015; 72:781-93

dards and harmonize how patients are evaluated for transplantation.11

Specialist, Departments of Transplant Surgery and Pharmacy and Renal Division, Brigham and Women’s Hospital, Boston, MA. Jillian L. Descourouez, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison. Ian C. Doyle, Pharm.D., BCPS, is Assistant Professor, School of Pharmacy, Pacific University, Hillsboro, OR. Jennifer Trofe-Clark, Pharm.D., FCCP, BCPS, is Clinical Pharmacy Specialist, Department of Pharmacy Services, Hospital of the University of Pennsylvania, Philadelphia, and Adjunct Associate Professor, Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania. Address correspondence to Dr. Maldonado (angela.maldonado@ vidanthealth.com).

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SPECIAL FEATURE  Kidney transplantation

An increasing number of patients are added to the kidney transplant waitlist each year, while the number of donors has remained relatively unchanged, heightening the need for stewardship of resources and allocation. The selection process entailed in placing a candidate on the waiting list involves evaluations by individuals from many disciplines to determine if the patient has the mental, social, physical, financial, and medical readiness to have a successful posttransplantation outcome. Recognition and stratification of both pharmacologic and nonpharmacologic risks during the evaluation process can greatly influence expectations after transplantation and identify the issues that require a mitigation strategy. It is important to have a general consensus on what risks are commonly encountered and to discuss risk management strategies to help ensure successful outcomes and long-term graft and patient survival. Although each transplantation center has its own waitlisting criteria, there are commonalities. The dual role of the transplantation pharmacist in the evaluation process is to critically assess the presence of pharmacotherapy issues, which may be current or future (i.e., posttransplantation) concerns, and to collaborate with clinicians from other disciplines to develop and implement management strategies addressing those issues. The goals of this article are to assess the pharmacologic and nonpharmacologic risks to prospective kidney

transplant recipients and to develop a consensus on mitigation strategies to be implemented before the patient is waitlisted. In response to the varying definitions of pharmacologic and nonpharmacologic risks, we review the pertinent literature available, as well as the strengths and limitations of the information, for each risk as it applies to kidney transplantation and the strategies that may be used to mitigate each risk (as applicable). This document provides the consensus opinion of practitioners in the field of transplantation pharmacy and incorporates evidence in the published literature to develop a framework for the management of the most common pharmacotherapy concerns that pharmacy clinicians encounter when evaluating candidates for kidney transplantation. Although this document serves as a guide, it does not advocate the use of the information presented as a replacement for clinical judgment or evaluation of each patient on a case-by-case basis. The pharmacologic and nonpharmacologic risks for each patient represent a myriad of interactions, with a causal nexus, that require frank discussion by all members of the transplantation team. As regulatory entities increasingly look for pharmacist participation and documentation through each phase of transplantation, it will be important for clinicians to continue to develop standards of practice in the areas of clinical practice expansion and become familiar with the advantages and limitations of each new responsibility.

The assistance of Rita Alloway, Pharm.D., David Taber, Pharm.D., Robert Dupuis, Pharm.D., Tiffany Kaiser, Pharm.D., Gregory Malat, Pharm.D., Pnada Kawewat, Pharm.D., Pamela Jacobsen, Pharm.D., Jenelle Stinson, Pharm.D., James Thielke, Pharm.D., Patricia West-Thielke, Pharm.D., Erica Maceira, Pharm.D., and Travis Dick, Pharm.D., is acknowledged. Members of the American College of Clinical Pharmacy (ACCP) Immunology/Transplantation Practice and Research Network, the American Society of Transplantation (AST) Transplant Pharmacy Community of Practice, and the American Society of Health-System Pharmacists (ASHP) Section of Clinical Specialists and Scientists Transplantation/Immunology Network are acknowledged for their comments and support of this article.

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Assessment of pharmacologic risk Anticoagulation. All kidney transplantation surgeries are considered “high risk for bleed” procedures. In evaluating kidney transplantation candidates currently receiving anticoagulants, the challenge lies in the need to balance the risk of thromboembolism (in case of therapy interruption) against the risk of bleeding during surgery (in case of therapy continuation).12 Knowledge of drug pharmacodynamics and pharmacokinetics, as well as familiarity with anticoagulation and antiplatelet treatment guidelines, is essential in finding the right risk balance and optimizing treatment. Low-dose aspirin therapy is not considered a contraindication to transplantation and can be continued perioperatively.13 The use of aspirin preoperatively may reduce the risk of posttransplantation renal vein thrombosis.14 Transplant recipients taking more potent antiplatelet agents, such as the irreversible adenosine diphosphate (ADP)–receptor inhibitors, may have a higher risk of perioperative bleeding.15 Every effort should be made to discontinue irreversible ADP-receptor inhibitors one week prior to the surgical procedure unless discontinuation is absolutely contraindicated by the patient’s clinical condition. However, if interruption is clinically or temporally prohibitive, perioperative use of ADP receptor antagonists is not considered a contraindication to transplantation. The operating team should be notified of antiplatelet drug use, and blood or platelet

This article represents the opinion of the ACCP Immunology/ Transplantation Practice and Research Network, the AST Transplant Pharmacy Community of Practice, and the ASHP Section of Clinical Specialists and Scientists Transplantation/Immunology Network. This article does not necessarily represent an official ACCP, AST, or ASHP commentary, guideline, or statement of policy or position. The authors have declared no potential conflicts of interest. Copyright © 2015, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/15/0515-0781. DOI 10.2146/ajhp140476

SPECIAL FEATURE  Kidney transplantation

products should be available for transfusion if needed.16 There is no general recommendation that can be applied to patients undergoing kidney transplantation surgery who are on long-term anticoagulation. Several factors must be considered when managing anticoagulation perioperatively, including the underlying indication for anticoagulation, the specific agent used, and the urgency of the surgical procedure. The reader is referred to the comprehensive reference for a summary of the risk of thrombotic events in case of inadequate anticoagulation and guidelines on perioperative management of antithrombotic therapy, including the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban and apixaban, although dabigatran and rivaroxaban are contraindicated in the setting of renal failure.17 Consideration also should be given to medications and herbal supplements with thrombocytopenic adverse effects, which may increase the intraoperative bleeding risk. Drug interactions. The most commonly used posttransplantation immunosuppressive regimens contain at least one medication that is a substrate for cytochrome P-450 (CYP) isoenzyme 3A as well as P-glycoprotein (PGP). The calcineurin inhibitors, such as cyclosporine and tacrolimus, and the mammalian target of rapamycin inhibitors sirolimus and everolimus are substrates of CYP3A and PGP. The addition of medications that inhibit or induce CYP3A as well as PGP has the potential to cause clinically significant drug interactions in kidney transplant recipients; while not contraindicated, the use of such medications requires active management in the posttransplantation phase. Many kidney transplantation candidates enter the transplantation workup phase already on medications that may interact with their postoperative immunosuppressive

regimen; examples include phenytoin, which induces CYP3A isozymes, and diltiazem, which inhibits CYP3A isozymes. The reader is referred to two articles for a comprehensive review of the management of drug interactions in the posttransplantation setting.18,19 Patients may also be on antiretroviral agents for human immunodeficiency virus (HIV) infection. Unfortunately, most antiretroviral agents either induce or inhibit CYP3A or PGP. Pharmacodynamic interactions can also result in positive or negative effects on virological response and graft function. Criteria for considering HIV-infected patients for transplantation, as well as posttransplantation management guidelines, were recently updated.20 A comprehensive reference that provides a summary of all pharmacodynamic and pharmacokinetic interactions with antiretroviral agents and immunosuppressive agents is also available.21 Additionally, other medications used for infection prophylaxis and treatment in kidney transplant recipients can inhibit or induce the CYP3A isoenzyme system. The reader is referred to a comprehensive review of antiinfective and immunosuppressive drug–drug interactions.22 Medications related to mental health. Corticosteroids have the potential to affect the mental health of kidney transplant recipients.23,24 Other routinely used medications, including immunosuppressive agents such as tacrolimus and cyclospor­ine, have the potential to induce significant mental status and central nervous system changes after transplantation. 23-26 Patients who do not have psychiatric concerns prior to transplantation may develop significant mental status derangements afterward as a result of the use of deliriogenic sedation therapy during periods of critical illness or the use of maintenance medications that can be associated with central nervous system adverse effects. Examples of such drugs include corti-

costeroids, which can cause delirium and psychosis, and calcineurin inhibitors, which may cause seizures, tremors, cognitive slowing, and posterior reversible encephalopathy syndrome. 27 Patients referred for transplantation with existing significant mental health comorbidities, as well as patients with previously untreated anxiety or depression, may experience worsening of their underlying psychiatric disorders after the transplantation, which can have an impact on medication adherence and posttransplant outcomes. Generally, transplantation programs tend to advocate a “minimization” approach to promoting the use of psychotropic medications, such as benzodiazepines and antipsychotics, in the pretransplantation period in a clinically responsible manner. This approach is intended to ensure that each transplantation candidate is maintained on the most beneficial and appropriate regimen to control the underlying psychiatric disorder in order for the patient to have a successful transplantation outcome. Minimizing psychotropic medications while awaiting transplantation simply for the sake of minimization may be associated with a worsening of outcomes and should largely be avoided. However, there are cases when an existing psychotropic regimen may be problematic after transplantation. Some psychotropic medications, such as carbamazepine and valproate, are modulators of the CYP3A system and thus pose a threat of significant drug–drug interactions (as described above).18,19,24,25 Other psychotropic medications, if used in combination with tacrolimus-based immunosuppressive regimens, may result in prolongation of the Q-Tc interval. While the use of psychotropic medications may not represent direct contraindications to transplantation, it is prudent to collaborate with the patient’s mental health providers to optimize the drug regimen with the goals of reducing the potential for

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SPECIAL FEATURE  Kidney transplantation

drug interactions and decreasing pill burden. Patients with bipolar disorder who are nonresponsive to all moodstabilizing agents or combination therapies except for lithium pose a unique and significant challenge. While effective, lithium therapy is difficult to manage after transplantation. Variable posttransplantation renal function may predispose patients to acute lithium toxicity. Additionally, coadministration of lithium and cyclosporine may result in synergistic lithium-associated nephrotoxicity due to changes in sodium excretion leading to decreased lithium ion transport at the renal tubular level and, thus, increased lithium exposure. 28,29 Some renal graft recipients develop calcineurin inhibitor–associated nephropathy, which is characterized by worsening renal function over time, further complicating the use of lithium after transplantation.25 Medications for chronic pain. Some patients referred for kidney transplantation have chronic pain due to a variety of nociceptive, psychogenic, or neuropathic comorbidities. These patients may be maintained on a myriad of long-term opioid and nonopioid regimens of varying intensities, which may augment or decrease their quality of life. Patients with pain-related disorders pose significant challenges with regard to perioperative pain management, which typically requires an individualized multidisciplinary approach. It is important for the transplantation pharmacist to discern whether immediate postoperative pain and its progression are harbingers of surgical complications or graft rejection or are manifestations of chronic pain that was present prior to transplantation. As with mental health–related medications, transplantation programs generally tend to advocate a minimization approach to the use of opioid-based pain medications 784

and avoidance of illicit substances for pain management for a period of approximately six months prior to patient waitlisting. The critical nature of abstinence from illicit opioid substances, such as heroin, is implied. However, the same might not be said for rationally used prescriptionbased opioids in well-selected candidates. Simply put, “[opioids] are medications, not addictions,” and with the reasonable outcomes seen in patients with chronic pain due to sickle cell disease or systemic sclerosis, chronic opioid use appears to be nonproblematic prior to or after transplantation.30 Elements of the pharmacist’s review of transplantation candidates should include full assessment of all opioid sources and the adequacy of the pain regimen. Patients should receive their opioids from, and under contract with, pain management specialists or providers experienced in managing their particular type of pain. Importantly, these providers managing chronic pain should be distinct from transplantation program providers. Drug-seeking behavior, as well as “poly-pharmacy” and “polyphysician” behaviors (i.e., an inordinate number of prescription opioid sources), should be reviewed with the patient, and recurrent offenses may be considered relative contraindications to transplantation. Patients who chronically and routinely use high doses of short-acting opioids should be considered candidates for the addition of long-acting opioids, and use of acetaminophen-containing combinations should be minimized before transplantation. Acting in concert with pain management providers, the pharmacist should make recommendations regarding the modifications needed to manage the baseline intensity of perioperative and postoperative analgesia within the context of the projected posttransplantation medication regimen.

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Medication allergies. A history of severe allergic reactions or intolerance to routine medications used in the postoperative phase is an important aspect for evaluation by the transplantation pharmacist. Many transplantation candidates likely have never received the core immunosuppressive medications unless they have received a prior organ transplant. However, when information about intolerance is available, the transplantation pharmacist should assess the severity of the reaction, determine the risk of a similar reaction to other medications in the same class, and evaluate the array of alternatives available. The most common maintenance immunosuppression regimen for kidney transplant recipients consists of tacrolimus and mycophenolic acid, which are used with or without corticosteroids. 31 Although published guidelines do not address allergy or intolerance to medications used after transplantation, the presence of known intolerance may lead to the use of less effective regimens and leave caregivers with limited options if intolerance is encountered after transplantation.32 For example, a patient might have a documented allergy (e.g., hives, anaphylaxis) to a macrolide antibiotic, in which case the team would typically plan to use a tacrolimus-based immunosuppressive regimen. There is only one published report in the literature of a patient with macrolide cross-sensitivity to tacrolimus.33 In the event of concern for a significant allergy to tacrolimus, alternative therapies such as belatacept and modified cyclo­sporine could be considered. In cases of known previous intolerance to tacrolimus or tacrolimus-related adverse events, belatacept, sirolimus, or everolimus are reasonable alternatives, but the lack of data on the long-term outcomes of using these agents warrants caution.34,35 The risk to an individual patient should be assessed according

SPECIAL FEATURE  Kidney transplantation

to the number and classes of medications a patient is unable to receive due to allergy or intolerance. This risk should be balanced against the patient’s immunologic risk, as well as the risk of rejection in relation to the type and quality of the kidney transplant. A frank discussion should be held to determine if the allergies or intolerances to routine immunosuppressive therapy would be prohibitive to patient and graft survival. Hormonal contraception and replacement therapy. While endorgan failure can cause gonadal dysfunction, some female patients retain their fertility and continue to use contraception before transplantation.36 Additionally, the return of fertility after successful kidney transplantation is well documented in the literature and can occur in as little as three weeks.37,38 Current recommendations are to avoid pregnancy for at least the first year after kidney transplantation.39 Avoidance of pregnancy is also recommended in patients with unstable graft function and those at high risk for graft rejection or infection.32,39 In discussing posttransplantation contraceptive choices, the risks of unplanned pregnancy must be balanced against the risks and the relative effectiveness of the various contraceptive choices. Additionally, with most transplant programs using mycophenolic acid in immunosuppression regimens, appropriate and effective contraception, counseling, and pregnancy planning are paramount to the avoidance of fetal harm with this known teratogen. Barrier methods are the least effective of all contraceptives but also pose the least risk; because of insufficient effectiveness, they should only be used in combination with other methods.40-42 The use of intrauterine devices (IUDs), considered a highly effective contraceptive, is controversial in kidney transplant recipients due to possible decreased efficacy and a theoretical increase in infection risk.43,44 While transplantation guide-

lines recommend against IUD use,32 contraception guidelines state that continued use of a previously placed IUD is reasonable after transplantation; however, initial placement of an IUD after transplantation surgery is discouraged.42,45 Progestin-only pills pose minimal risk to the kidney transplant recipient with regard to drug interactions and adverse effects, but they require extraordinary compliance for effective birth control41; depot medroxyprogesterone acetate has a similarly clean drug–drug interaction profile while providing increased effectiveness. However, the use of depot medroxyprogesterone acetate is associated with increased bone loss and should be avoided in kidney transplant recipients with established metabolic bone disease and those requiring high-dose or prolonged corticosteroid therapy. While estrogen-based contraceptives are the most popular contraceptive choice in the United States, all carry risks for kidney transplant patients and have only moderate effectiveness; the risks include thromboembolic events, drug–drug interactions, worsened hypertension, and potential harm in patients with graft rejection (acute or chronic). The benefits of estrogenbased contraceptives in a kidney transplant recipient with an uncomplicated course likely outweigh the potential for harm, provided that close monitoring of immunosuppressant levels is performed,40,46 but their use should be avoided in those with complicated courses, a history of thromboembolic events, or significant hypertension.40-45 The Food and Drug Administration has established a mandatory risk evaluation and mitigation strategy (REMS) program specific to women of childbearing age who will be maintained on mycophenolate products after transplantation.47 This program, meant to address the higher risk of miscarriage during the first three months of pregnancy and the higher risk of orofacial birth defects,

includes prescriber education and enrollment, patient education, and pregnancy monitoring along with recommendations to promote the use of highly effective birth control and the establishment of a pregnancy registry to follow outcomes. Unlike other highly teratogenic medications with REMS programs, mycophenolate is not subject to mandatory documentation of adequate birth control or negative pregnancy tests prior to medication dispensing, increasing the need for careful monitoring by the transplantation team. Ultimately, there is no ideal contraceptive method for women wishing to maintain their fertility after kidney transplantation.48 The decision of appropriate contraception after kidney transplantation must be a patient-specific one, with a thorough risk–benefit analysis that prevents pregnancy while minimizing untoward effects of the contraceptive chosen. Among women in general, hormone replacement therapy (HRT) has been shown to increase the risks of breast cancer, stroke, heart attack, and venous thromboembolism but to improve vasomotor symptoms and genitourinary signs while decreasing the risks of fractures and colorectal cancer (estrogen–progestin combinations only). 49-52 There is little evidence to support HRT use in prospective kidney transplant recipients or after kidney transplantation and no evidence to support the use of vaginally applied low-dose estrogen.46 Given the data available, HRT for any indication should be discouraged in the pretransplantation and posttransplantation populations discussed here. Current use of immunosuppressants. There are several reasons why kidney transplant recipients may have a current or remote history of immunosuppressant use at the time of transplantation evaluation; these may include prior organ transplantation (a kidney or other organ) or

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treatment of autoimmune disorders, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis, and Crohn’s disease. Patients with a history of exposure to immunosuppressive therapy must be carefully evaluated in order to discern their risk for potential complications after transplantation. The degree of and net exposure to immunosuppressants are strongly correlated with the occurrence of two of the most insidious posttransplantation adverse events: infection and malignancy.53 In general, the types of immunosuppressants used for autoimmune disorders differ from those used in transplantation. Some of the more frequently used immunosuppressive agents in patients with autoimmune disorders include the tumor necrosis factor (TNF) inhibitors, cytostatic agents, interleukin inhibitors, interferon beta, and several targeted immunosuppressants. There are some case reports of TNF inhibitor use in the context of kidney transplantation, 54-56 but unfortunately there were no controls in any of the reported cases; therefore, it is difficult to know the true impact that these agents have on infectious and malignancy risks with concomitant induction and maintenance immunosuppression. The degree of immunosuppression and the overall exposure to immunosuppressants strongly influence the occurrence of both infection and malignancy. The risks of infection and malignancy should be weighed with the need to control the underlying disease (e.g., RA) along with adequate transplantation immunosuppression.57 The available literature documents an increased risk and severity of infectious complications in kidney transplantation candidates with SLE; therefore, an intensified focus on prevention and early treatment of infection in this population is warranted. The impact of TNF inhibitor therapy on the development of infection and malignancy 786

after kidney transplantation has also been discussed; however, no data on the risk of using these agents prior to transplantation are available, and there are significant concerns regarding TNF inhibitors’ adverse effects, as well as immune-mediated effects on allograft function and longevity. It is unknown if the efficacy of biological agents in kidney transplant recipients with SLE is similar to that reported in other SLE populations. Regardless of the paucity of data, kidney transplant recipients should be monitored closely after transplantation, as they also appear to be at increased risk for overimmunosuppression and its associated adverse sequelae. A discussion among members of the transplantation, nephrology, and rheumatology teams as to the plan of care at the time of transplantation should occur prior to patient waitlisting, with an emphasis on the theoretical risks versus benefits of continuing biological agents after transplant surgery. Issues with drug absorption. The growing obesity prevalence in the United States is leading to an increase in the number of kidney transplant recipients who have undergone bariatric procedures prior to and after transplantation.58,59 Some types of bariatric surgery are solely restrictive, such as vertical-banded gastroplasty, laparoscopic adjustable gastric banding, and sleeve gastrectomy. Other bariatric procedures (such as jejunoileal bypass, which is no longer performed) are malabsorptive or a combination of restrictive and malabsorptive such as Roux-en-Y gastric bypass and biliopancreatic diversion with a duodenal switch.60 Altered pharmacokinetics are generally more common in patients undergoing malabsorptive as opposed to restrictive bariatric procedures, though published data specific to kidney transplant recipients are limited.61,62 In a pharmacokinetic evaluation of six patients who had undergone Roux-en-Y gastric bypass, a lower

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ratio of tacrolimus area under the concentration–time curve (from time 0 to infinity) to tacrolimus dose was seen in the bypass population when compared with healthy volunteers (17.8 versus 53.92); similar changes in pharmacokinetic values were also reported for sirolimus and mycophenolic acid.62 Patients may experience changes in drug bioavailability due to reduced stomach size and intestinal length (which may alter gastric transit times), changes in gastrointestinal surface area (including alterations in drug exposure to areas with high concentrations of efflux transporters or intestinal CYP3A activity), and alterations in gastric and intestinal pH (which can affect drug solubility).60,63,64 Additionally, patients who have undergone nonbariatric gastrointestinal surgeries and those with gastrointestinal abnormalities such as short-gut syndrome are at risk for drug and nutrient malabsorption. The reader is referred to a recent comprehensive review on this topic for further information.60 Patients with diabetes mellitus who are at risk for delayed gastric emptying may also experience altered immunosuppressive drug pharmacokinetics.65 Although published data do not provide specific immunosuppressive dosage guidelines, the data support the idea that patients who undergo gastric bypass procedures (which are both restrictive and malabsorptive) will likely need higher dosages of cyclosporine, tacrolimus, sirolimus, and mycophenolic acid to achieve desired levels. If the patient is willing to undergo such testing, the clinician might consider performing abbreviated or full pharmacokinetic profiles for mycophenolic acid, sirolimus, everolimus, tacrolimus, and cyclosporine before or after transplantation to better determine dosage requirements. However, for pretransplantation patients, it is important to ascertain if the patient is dialysis dependent at the time of drug admin-

SPECIAL FEATURE  Kidney transplantation

istration, as calcineurin inhibitors are associated with nephrotoxicity. Similarly, patients with other types of gastrointestinal malabsorptive syndromes or with diabetes mellitus and delayed gastric emptying may have altered immunosuppressant pharmacokinetics and should be closely monitored. However, patients who undergo restrictive procedures such as sleeve gastrectomy may not require increased doses. Alcohol use. The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Care of Kidney Transplant Recipients does not mention specific alcohol restrictions for kidney transplant recipients.32 Overall, alcohol abuse after kidney transplantation is relatively rare, and alcohol consumption in this population is generally low.66 The general recommendation is to avoid alcohol consumption after kidney transplantation, as large amounts of alcohol may interfere with liver metabolism, which is of particular concern in the posttransplantation phase due to the presence of immunosuppressive medications. A prospective study by Gueye et al.67 examined the effects of alcohol consumption in 452 patients with alcohol dependence before transplantation compared with 60,523 kidney transplant recipients without alcohol dependence. Of note, the researchers did not focus on patients with moderate or low daily intake after transplantation. The study concluded that alcohol dependence before transplantation is a risk factor for renal allograft failure and death and advised against the use of alcohol in this population. In contrast, Zelle and colleagues68 studied 600 kidney transplant recipients who had their allografts more than one year previously and followed them for several years after transplantation. Moderate drinkers (defined as alcohol intake of 10–30 g/day) were 67% less likely to develop diabetes and 44% less likely

to die relative to other types of drinkers and nondrinkers. Notably, no association was found between alcohol consumption and graft failure. Tobacco use. Smoking prior to transplantation should be considered a high-risk factor, and patients should be required to quit prior to kidney transplantation. The adverse effects of cigarette smoking on surgical complications and patient and graft survival are known.69,70 It is suggested that patients should be screened for tobacco use, counseled on tobacco cessation, and offered treatment when needed.71 Active use of illicit substances. Substance abuse has been associated with direct and indirect damage to organs and may be an issue in both the pretransplantation and posttransplantation phases. Literature regarding illicit substance abuse as a contraindication to transplantation has been published; the reader is referred to a comprehensive review for an overview of the studies addressing substance abuse in the context of organ transplantation.72 There is minimal literature focusing on the effects of nonalcohol substance abuse in kidney transplant recipients. Most of the available information concerns adverse effects on kidney function in general that may be generalized to kidney transplant recipients. In a 22-year study of 647 Veterans Affairs patients, the risks of mild kidney function decline (defined as an increase in serum creatinine concentration of ≥0.6 mg/dL) were 3.0 and 3.9 times greater among persons who had used cocaine and psychedelics, respectively.73 Marijuana, amphetamines, heroin, and other drugs were each associated with an elevated but not significantly higher risk of mild kidney function decline. A wide spectrum of renal complications has been described with the use of heroin, cocaine, methylenedioxymethamphetamine (popularly known as ecstasy), amphetamines, or inhaled solvents

(e.g., glue, aerosols), including rhabdomyolysis, hypertensive renal disease, and glomerular, interstitial, and vascular complications.74 Along with the direct effects of illicit substance abuse on kidney function, the collateral issues of viral, bacterial, and fungal contamination reported with intravenous drug use, as well as with the use of drugs delivered through inhalation, must be considered in an immunocompromised patient. Also, the use of illicit substances must be considered in the priorauthorization and reimbursement processes, as some insurance companies do not authorize or pay for transplantation if there is evidence of substance abuse or a positive toxicology screen. Knowledge of each insurance company’s policies regarding substance abuse is vital during the transplantation evaluation process. Marijuana. Although the basis for prohibiting the use of opioid derivatives (e.g., heroin), cocaine, amphetamines, psychedelics, and phencyclidine prior to waitlisting for kidney transplantation is clear, the issue of marijuana use by kidney transplant recipients has elicited much debate. Advocates for restricting the use of marijuana in kidney transplantation candidates cite its effects on executive brain and cognitive function, as well as the relative risks of nonadherence and unmasking of mental diseases such as psychosis, depression, and schizoaffective disorders75; hyperphagia is also a concern, especially in the setting of long-term corticosteroid-induced weight gain and in patients who are obese or diabetic. An association between marijuana smoking and increased cancer risk is unclear, with conflicting data on potential effects on cellular immunity, cancer progression, and metastases. Proponents of allowing moderate, recreational, or medicinal usage of marijuana in kidney transplant recipients compare the risk to that associated with moderate

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consumption of alcohol.75 There is wide diversity in policies regarding marijuana use among transplantation programs, with requirements ranging from absolute abstinence to tacit acceptance of marijuana use as long as there is no evidence that it is interfering with the patient’s ability to adhere to medical therapy.75-77 Synthetic cannabinoids and amphetamine derivatives. With the advent of designer drugs, the transplant pharmacist should be aware of the illicit use of drugs that may not be part of a standard toxicology screen.78 Drugs such as synthetic cannabinoids (e.g., “Spice,” “K2”) and amphetamine derivatives (“bath salts”) may have deleterious effects on kidney function. In 2013, the Centers for Disease Control and Prevention issued an alert describing 16 cases of acute kidney injury resulting from the use of synthetic marijuana.79 The patients had a median age of 18.5 years, and none had preexisting renal dysfunction prior to the acute kidney injury. The peak serum creatinine concentration among the patients ranged from 3.3 to 21.0 mg/dL, and of the patients from whom renal biopsies were obtained, 75% had acute tubular injury and 38% had acute interstitial nephritis. Five of the 16 patients required dialysis, and all the patients eventually recovered. Due to the widespread availability of these agents, patients often think they are legal and safer than marijuana and may not disclose their use during evaluation. It is important to include these new agents when assessing a patient’s illicit substance use prior to transplantation waitlisting. Use of herbal supplements. The use of herbal medications and dietary supplements prior to transplantation should be considered. Patient-specific risk varies based on the herbal or dietary supplement being used, making it imperative that a comprehensive review be completed prior to the patient being cleared for kidney transplantation. The reader is 788

referred to the American College of Clinical Pharmacy’s White Paper on Herbal Products for a comprehensive review of safety issues, regulatory issues, and the pharmacist’s role in reviewing and counseling patients on usage of herbal medications and dietary supplements.80 Data on the use of herbal medications and dietary supplements in kidney transplant recipients are limited. A study found that 58% of kidney or liver transplant recipients reported using herbal products or dietary supplements, with 34.5% of respondents ingesting more than one product.81 A review of specific herbal products and dietary supplements that should be avoided by kidney transplant recipients has been published (it is not an all-inclusive review).82 Herbal medications have been associated with a long list of potential adverse effects, ranging from toxic and life-threatening effects to abnormal test results.83 In kidney transplant recipients, particular attention should be paid to any supplements that could potentially damage or injure the diseased or transplanted kidney. Additionally, agents whose use can lead to an increased risk of bleeding or thrombosis should be avoided and discontinued prior to transplantation. Herbal products or dietary supplements that affect the immune system, either by inhibition or stimulation, are contraindicated in kidney transplant recipients, as they may increase a patient’s risk for infection or rejection.84 Interactions between herbal products or dietary supplements and immunosuppressant agents may occur via a variety of mechanisms.85 If medication discontinuation is not feasible due to either physician or patient refusal, the kidney transplant recipient should be monitored closely for adverse events and drug interactions. Assessment of nonpharmacologic risk Vaccinations. Kidney transplant

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recipients are at increased risk for complications of vaccine-preventable diseases. Every effort should be made to ensure that transplantation candidates, as well as their household members and caregivers, are upto-date on vaccine administrations before transplantation. Recently, the American Society of Transplantation published the third edition of its transplant infectious disease guidelines, with recommendations for vaccination administration to solid organ transplant recipients. 86 As this is the most up-to-date guidance on vaccine use in kidney transplant recipients, the reader is referred to this important chapter for a detailed review of pretransplantation and posttransplantation vaccine administration. Highlights of these guidelines include the following: (1) Ideally, vaccination status should be documented at the pretransplantation clinic visit and the patient referred for the appropriate vaccines at the time of listing; (2) in general, live vaccines are not administered after transplantation and therefore should be administered pretransplantation when possible; (3) while every effort should be made to vaccinate prior to transplantation (including on an accelerated schedule), inactivated vaccines are generally safe after solid organ transplantation; and (4) there is no evidence to link clinical rejection episodes to vaccine administration. There is concern for lack of vaccine response in the immediate posttransplantation period due to higher immunosuppression loads, and most transplantation centers try to wait until three to six months after transplantation to administer vaccines whenever possible.86 Additionally, the kidney transplant recipient should notify the transplantation center of any planned international travel in the pretransplantation or posttransplantation period, so that vaccines may be administered as applicable. It is recommended that

SPECIAL FEATURE  Kidney transplantation

a minimum of four weeks elapse between vaccine administration and evaluation for seroconversion. Since serologic studies may not be as accurate a measure of immunity after transplantation as they are before transplant surgery, the development of assays to measure cellular immunity is a recommended area of future research.86,87 Colonization w ith resistant organisms. The presence of methicillin-resistant Staphylococcus aure us (MRSA), v ancomycinresistant Enterococcus (VRE) species, and multidrug-resistant (MDR) gram-negative bacterial infections can be problematic in kidney transplant recipients. 88-90 Colonization with MDR organisms prior to kidney transplantation raises the specter that kidney transplant recipients may withstand the critical challenges of the transplantation procedure only to endure the consequences of a predictable infectious complication. S. aureus is a primary cause of gram-positive bacteremia after kidney transplantation, with most posttransplantation MRSA infections generally occurring in the early and intermediate posttransplantation periods (months 1–3).88,91 The frequency of infection seen in MRSA carriers after kidney transplantation appears to be low, but published data on this population are not widely available.92,93 The incidence of posttransplantation infections by MRSA appears to be higher in patients who are newly colonized compared with those who are considered chronic carriers.94 After staphylococci, Enterococcus species are the microorganisms most commonly implicated in healthcareassociated infections in the United States,95 with reports among kidney transplant recipients indicating a pretransplant colonization rate in the range of 3–15%.96,97 Common risk factors for the development of VRE after transplantation include antimicrobial use, simultaneous

kidney and pancreas transplantation, posttransplantation dialysis, reexploration surgery, and nephrostomy tube placement. There is also a trend toward increased isolation of resistant gramnegative microorganisms from kidney transplant recipients.98,99 Some of the more frequently isolated MDR organisms include Pseudomonas species, Burkholderia species, and Enterobacteriaceae. Among abdominal organ transplant recipients, Pseudomonas aeruginosa is responsible for a significant amount of bloodstream infections, with the prevalence ranging from 5% to 14%,100 and up to 10% of postoperative urinary tract infections in kidney transplant recipients.101 The prevalence of colonization with extended-spectrum b-lactamase (ESBL)–producing Enterobacteriaceae among organ transplant recipients has been variously reported to be in the range of 8–77%.98,99,102 In kidney transplant recipients, infection with ESBLproducing Enterobacteriaceae is associated with recurrent urinary tract infections.102 Notwithstanding the high frequency of posttransplantation infections, colonization with MRSA, VRE, Pseudomonas species, MDR organisms, or ESBL-producing Enterobacteriaceae is not considered a contraindication to transplantation.89,90 Overall, in patients colonized with MDR organisms before transplantation, appropriate infection monitoring and institution of early empirical therapy are warranted. Socially related nonpharmacologic risks. The transplantation pharmacist works closely in conjunction with transplantation social workers to develop risk stratification for socially related nonpharmacologic risks. The commonly encountered risks in this category include nonadherence; socioeconomic factors such as financial, insurance, and transportation issues; lack of social support; and barriers to communication, in-

cluding language barriers, illiteracy, and visual or hearing impairment. The level of education completed by kidney transplant recipients is associated with varying effects on behaviors and outcomes. A review of 79,223 kidney transplant recipients in the United States Renal Data System (USRDS) database demonstrated that compared with patients who completed a college education, lesser-educated patients were at increased risk for renal graft failure. In this regard, African-American patients were at particularly high risk (hazard ratio [HR], 1.45 for those who did not finish high school and 1.27 for those with only a high school education); a trend of higher graft failure risk with lower educational attainment was noted among white patients.103 In contrast, several studies have noted that the level of education is not associated with nonadherence, which suggests a complex association between socioeconomic factors other than health literacy. 104-106 Tools such as the (Short Form) Test of Functional Health Literacy in Adults (S-TOFHLA), the Newest Vital Sign (NVS), and the Rapid Estimate of Adult Literacy in Medicine-Transplant (REALM-T) are used to assess health literacy in patients before and after transplantation.107-110 Chisholm et al.107 found that approximately 72% of sampled kidney transplant recipients scored low or marginally in the numerical literacy ranges and that decreasing scores were significantly related to increasing age. Barriers to communication are considered a moderate risk but not a contraindication to transplantation. Unfortunately, no studies were found that quantitated solely the impact of impaired vision or hearing on outcomes in kidney transplant recipients. In the United States, the average deaf high school graduate reads at a fourth-grade level, and 80% of deaf people cannot read and

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SPECIAL FEATURE  Kidney transplantation

understand English.111,112 Although visually impaired patients may be able to comprehend health information, they are limited in the ability to use written or printed drug information.113 Transplantation pharmacists play a critical role in the education of transplant recipients and typically provide the majority of medication education to such patients. There are numerous strategies to overcome patient education challenges related to language, literacy, hearing, and vision impairments.111-113 Nonadherence behaviors; socioeconomic factors such as financial, insurance, and transportation issues; and lack of social support are considered to confer high nonpharmacologic risk and are thus considered relative contraindications to transplantation. In the literature, reported rates of nonadherence for kidney transplant recipients range from 2% to 67%.114 A meta-analysis of studies of renal graft recipients published during the period 1980–2001 indicated a 36% rate of graft loss associated with nonadherence—a rate sevenfold higher than that among adherent recipients (combined odds ratio (OR), 7.1; 95% confidence interval (CI), 4–12%).115 Chisholm et al.,116 after a review of over 50,000 kidney transplant recipients in the USRDS database, reported that nonadherent patients were significantly more likely than adherent patients to experience graft failure (OR, 5.2; p < 0.001). Nonadherence to medical advice and medication therapy in patients awaiting kidney transplantation is a predictor of nonadherence after transplantation and often serves as a discussion point during transplantation selection meetings.117 Patients who succeeded in maintaining a transplanted kidney for 25 years or more have reported that effective methods for adherence to immunosuppressive therapies include reminder processes, predictable refilling of medications, maintaining 790

routines, and problem-solving strategies.118 For an overview of interventions for nonadherence, readers are referred to the “toolbox” created by Chisholm-Burns et al.119 There is a paucity of information that specifically points to transportation problems as a transplant risk. Patients residing in nonmetropolitan areas (i.e., areas with a population of 250,000) (adjusted OR, 0.46; 95% CI, 0.25–0.87).120 In a review of kidney transplant recipient questionnaire respondents, 67% of immunosuppressive therapy–adherent patients but only 35% of nonadherent patients attended all medical appointments, with 29% of the latter group citing a lack of transportation.106 A lack of adequate finances or insurance coverage (or both) often has a negative effect on transplantation outcomes, as it is part of an array of socioeconomic factors affecting nonadherence. Issues of finance and insurance may have varying effects at the different steps of the transplant process. Lower median income and noncommercial insurance (e.g., Medicare, Medicaid) have been cited as barriers to transplantation evaluation and waitlisting in potential kidney transplant recipients.121 Social support is an integral part of the transplantation process, from pretransplantation evaluation through the years after transplantation. A cross-sectional survey of kidney transplant recipients demonstrated this correlation of social support and adherence using two standardized measures: the Modified Social Support Survey (MSSS-5) and the Immunosuppressant Therapy Adherence Scale (ITAS).122 Patients with higher MSSS-5 scores (indicating greater perceived availability of social support) were 2.4 times more likely than those with lower scores to have higher ITAS scores, denoting better adherence.

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Transplantation pharmacists can assist social workers and financial coordinators by reinforcing kidney transplant recipients’ need for sound finances, transportation, and social support prior to transplantation and help clarify the limitations of their insurance coverage. This is especially important as the patients approach the end of the 36-month period after transplantation. In a survey of nondisabled Medicare-covered kidney transplant recipients, 51% were unaware that Medicare coverage of immunosuppressants was time limited and 71% did not know the duration of covered benefits.123 This change in immunosuppression coverage or lack of coverage could lead to intentional or unintentional nonadherence. Transplant pharmacists can provide assistance by enrolling patients in medication assistance programs or other access programs designed to decrease the financial burdens. Conclusion Consensus opinions of practition­ ers in transplantation pharmacy regarding the pharmacologic and nonpharmacologic factors that should be considered in assessing candidates for kidney transplantation are presented. References 1. United Network for Organ Sharing. 2007 attachment 1 to appendix B of UNOS bylaws: designated transplant program criteria. http://optn.transplant. hrsa.gov/policiesandBylaws2/bylaws/ OPTNBylaws/pdfs/bylaw_162.pdf (accessed 2014 Feb 26). 2. Centers for Medicare and Medicaid Services (CMS) HHS. Medicare program; hospital conditions of participation: requirements for approval and re-approval of transplant centers to perform organ transplants. Final rule. Fed Regist. 2007; 72:15197-280. 3. Staino C, Lewin JJ III, Nesbit TW et al. Survey of transplant-related pharmacy services at large comprehensive transplant centers in the United States. Prog Transplant. 2013; 23:23-7. 4. Stemer G, Lemmens-Gruber R. Clinical pharmacy services and solid organ transplantation: a literature review. Pharm World Sci. 2010; 32:7-18. 5. Maldonado AQ, Weeks DL, Bitterman AN et al. Changing transplant recipient education and inpatient transplant

SPECIAL FEATURE  Kidney transplantation

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tice. Human immunodeficiency virus in solid organ transplantation. Am J Transplant. 2013; 13(suppl 4):169-78. 21. Van Maarseveen EM, Rogers CC, Trofe-Clark J et al. Drug-drug interactions between antiretroviral and immunosuppressive agents in HIVinfected patients after solid organ transplantation: a review. AIDS Patient Care STDs. 2012; 26:568-81. 22. Trofe-Clark J, Lemonovich TL, for the AST Infectious Disease Community of Practice. Interactions between antiinfective agents and immunosuppressants in solid organ transplantation. Am J Transplant. 2013; 13(suppl 4):318-26. 23. House RM, Thompson TL II. Psychiatric aspects of organ transplantation. JAMA. 1988; 260:535-9. 24. Wise MG, Brannan SK, Shanfield SB, Moeller FG. Psychiatric aspects of organ transplantation. JAMA. 1988; 260:3437. 25. Plosker GL, Foster RH. Tacrolimus: a further update of its pharmacology and therapeutic use in the management of organ transplantation. Drugs. 2000; 59:323-89. 26. Soi V, Karthikeyan V, Parasuraman R. Altered mental status in a kidney transplant recipient receiving tacrolimus. Am J Kidney Dis. 2008; 51:A29-30. 27. Barr J, Fraser GL, Puntillo K et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013; 41:263-306. 28. Tariq M, Morais C, Sobki S et al. Effect of lithium on cyclosporin induced nephrotoxicity in rats. Ren Fail. 2000; 22:545-60. 29. Va r e e s a n g t h i p K , H a n l a ko r n P, Suwannaton L et al. Abnormal kinetics of erythrocyte sodium lithium countertransport in renal transplant recipients. Transplant Proc. 2004; 36:1367-71. 30. Koch M, Banys P. Methadone is a medication, not an addiction. Liver Transpl. 2002; 8:783-6. 31. Meier-Kriesche HU, Li S, Gruessner RW et al. Immunosuppression: evolution in practice and trends, 1994–2004. Am J Transplant. 2006; 6:1111-31. 32. Kidney Disease: Improving Global Outcomes Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009; 9(suppl 3):S1-155. 33. Riley L, Mudd L, Baize T et al. Crosssensitivity reaction between tacrolimus and macrolide antibiotics. Bone Marrow Transplant. 2000; 25:907-8. 34. Martin ST, Tichy EM, Gabardi S. Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation. Pharmacotherapy. 2011; 31:394-407. 35. Webster AC, Lee VW, Chapman JR et al. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-

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84. Wilasrusmee C, Siddiqui J, Bruch D et al. In vitro immunomodulatory effects of herbal products. Am Surg. 2002; 68:860-4. 85. Anaizi N. Drug interactions involving immunosuppressive agents. Graft. 2001; 4:232-47. 86. Danziger-Isakov L, Kumar D, for the AST Infectious Disease Community of Practice. Vaccination in solid organ transplantation. Am J Transplant. 2013; 13(suppl 4):311-7. 87. Eckerle I, Rosenberger KD, Zwahlen M et al. Serologic vaccination response after solid organ transplantation: a systematic review. PloS One. 2013; 8:e56974. 88. Garzoni C, Vergidis P, for the AST Infectious Disease Community of Practice. Methicillin-resistant, vancomycinintermediate and vancomycin-resistant Staphylococcus aureus infections in solid organ transplantation. Am J Transplant. 2013; 13(suppl 4):50-8. 89. Patel G, Snydman DR, for the AST Infectious Disease Community of Practice. Vancomycin-resistant Enterococcus infections in solid organ transplantation. Am J Transplant. 2013; 13(suppl 4):59-67. 90. Van Duin D, van Delden C, for the AST Infectious Disease Community of Practice. Multidrug-resistant gramnegative bacteria infections in solid organ transplantation. Am J Transplant. 2013; 13(suppl 4):31-41. 91. Florescu DF, Qui F, Brostrom-West S et al. Staphylococcus aureus infections in kidney transplantation: a matched case controlled study. Scand J Infect Dis. 2012; 44:427-32. 92. Moore C, Davis NF, Burke JP et al. Colonisation with methicillin-resistant Staphylococcus aureus prior to renal transplantation is associated with longterm renal allograft failure. Transpl Int. 2014; 27:926-30. 93. Oliveira-Cunha M, Bowman V, di Benedetto G et al. Outcomes of methicillin-resistant Staphylococcus aureus infection after kidney and/or pancreas transplantation. Transplant Proc. 2013; 45:2207-10. 94. Davis KA, Stewart JJ, Crouch HK et al. Methicillin-resistant Staphylococcus aureus (MRSA) nares colonization at hospital admission and its effect on subsequent MRSA infection. Clin Infect Dis. 2004; 39:776-82. 95. Hidron AI, Edwards JR, Patel J et al. NHSN annual update: antimicrobialresistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006–2007. Infect Control Hosp Epidemiol. 2008; 29:996-1011. 96. Freitas MC, Pacheco-Silva A, Barbosa D et al. Prevalence of vancomycin-resistant Enterococcus fecal colonization among kidney transplant patients. BMC Infect Dis. 2006; 6:133.

SPECIAL FEATURE  Kidney transplantation

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