Novel approaches to management of hyperkalaemia in kidney transplantation.

PURPOSE OF REVIEW: Medications used frequently after kidney transplantation, including calcineurin inhibitors, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers and antimicrobials, are considered the leading culprit for posttransplant hyperkalaemia in recipients with a well functioning allograft. Other risk factors include comorbidities such as diabetes, hypertension and heart failure; and consumption of a potassium-enriched diet. We review the mechanisms for hyperkalaemia following kidney transplantation that are addressed using nonpharmacological and pharmacological interventions. We also discuss emerging therapeutic approaches for the management of recurrent hyperkalaemia in solid organ transplantation, including newer potassium binding therapies. RECENT FINDINGS: Patiromer and sodium zirconium cyclosilicate are emerging potassium binders approved for the treatment of hyperkalaemia. Patiromer is a polymer that exchanges potassium for calcium ions. In contrast, sodium zirconium cyclosilicate is a nonpolymer compound that exchanges potassium for sodium and hydrogen ions. Both agents are efficacious in the treatment of chronic or recurrent hyperkalaemia and may result in fewer gastrointestinal side effects than older potassium binders such as sodium polystyrene sulfonate and calcium polystyrene sulfonate. Large-scale clinical studies have not been performed in kidney transplant patients. Patiromer may increase serum concentrations of tacrolimus, but not cyclosporine. Sodium zirconium cyclosilicate does not appear to compromise tacrolimus pharmacokinetics, although it may have a higher sodium burden. SUMMARY: Patiromer and sodium zirconium cyclosilicate may be well tolerated options to treat asymptomatic hyperkalaemia and have the potential to ease potassium dietary restrictions in kidney transplant patients by maintaining a plant-dominant, heart-healthy diet. Their efficacy, better tolerability and comparable cost with respect to previously available potassium binders make them an attractive therapeutic option in chronic hyperkalaemia following kidney transplantation.

Mechanisms and management of drug-induced hyperkalemia in kidney transplant patients.

Hyperkalemia is a common and potentially life-threatening complication following kidney transplantation that can be caused by a composite of factors such as medications, delayed graft function, and possibly potassium intake. Managing hyperkalemia after kidney transplantation is associated with increased morbidity and healthcare costs, and can be a cause of multiple hospital admissions and barriers to patient discharge. Medications used routinely after kidney transplantation are considered the most frequent culprit for post-transplant hyperkalemia in recipients with a well-functioning graft. These include calcineurin inhibitors (CNIs), pneumocystis pneumonia (PCP) prophylactic agents, and antihypertensives (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers). CNIs can cause hyperkalemic renal tubular acidosis. When hyperkalemia develops following transplantation, the potential offending medication may be discontinued, switched to another agent, or dose-reduced. Belatacept and mTOR inhibitors offer an alternative to calcineurin inhibitors in the event of hyperkalemia, however should be prescribed in the appropriate patient. While trimethoprim/sulfamethoxazole (TMP/SMX) remains the gold standard for prevention of PCP, alternative agents (e.g. dapsone, atovaquone) have been studied and can be recommend in place of TMP/SMX. Antihypertensives that act on the Renin-Angiotensin-Aldosterone System are generally avoided early after transplant but may be indicated later in the transplant course for patients with comorbidities. In cases of mild to moderate hyperkalemia, medical management can be used to normalize serum potassium levels and allow the transplant team additional time to evaluate the function of the graft. In the immediate post-operative setting following kidney transplantation, a rapidly rising potassium refractory to medical therapy can be an indication for dialysis. Patiromer and sodium zirconium cyclosilicate (ZS-9) may play an important role in the management of chronic hyperkalemia in kidney transplant patients, although additional long-term studies are necessary to confirm these effects.

Implementing a regional standardized BK polyomavirus screening protocol across eleven transplant centres.

BK polyomavirus (BKPyV) reactivation is regularly monitored after kidney transplant to prevent progression to BK associated nephropathy (BKAN). The New England BK Consortium, made up of 12 transplant centres in the northeastern United States, conducted a quality improvement project to examine adherence to an agreed upon protocol for BKPyV screening for kidney transplants performed in calendar years 2016-2017. In a total of 1047 kidney transplant recipients (KTR) from 11 transplant centres, 204 (19%) had BKPyV infection, defined as detection of BKPyV in plasma, with 41 (4%) KTR progressing to BKAN, defined by either evidence on biopsy tissues or as determined by treating nephrologists. BKPyV infection was treated with reduction of immune suppressants (RIS) in >70% of the patients in all but two centres. There was no graft loss because of BKAN during the two-year follow-up. There were nine cases of post-RIS acute rejection detected during this same period. Adherence to the protocol was low with 54% at 12 months and 38% at 24 months, reflecting challenges of managing transplant patients at all centres. The adherence rate was positively correlated to increased detection of BKPyV infection and was unexpectedly positively correlated to an increase in diagnosis of BKAN.

New England BK consortium: Regional survey of BK screening and management protocols in comparison to published consensus guidelines.

INTRODUCTION: BK polyomavirus (BKPyV) continues to impact renal transplant recipients (RTR). The New England BK Consortium aims to jointly optimize screening and management of BKPyV. METHODS: Our first project was to survey centers' BKPyV screening protocols and compare them to consensus guidelines. RESULTS: Thirteen of 15 centers (86.7%) returned the survey. Only two center reported using monitoring parameters that were in line with consensus guidelines for BKPyV screening, while the majority of centers reported less intensive methods and shorter duration. One center reported performing renal biopsies in all patients with plasma viral loads >10 000 copies/mL, while all other centers only perform for-cause biopsies. For presumptive nephropathy, 11 centers recommend a biopsy for confirmation. For management of documented BKPyV-associated nephropathy, 12 centers propose further immunosuppression reduction. Nine centers report CNI dose reduction as their primary treatment. More than half of centers surveyed reported use of leflunomide, cidofovir or intravenous immunoglobulin. CONCLUSIONS: There was a large variance in BKPyV screening and management strategies among centers. Due to these results, all participating centers agreed to implement uniform screening and aim to optimize management protocols.

Post-Renal Transplantation Outcomes in Elderly Patients Compared to Younger Patients in the Setting of Early Steroid Withdrawal.

BACKGROUND: Previous studies reported improved outcomes for renal recipients undergoing early steroid withdrawal (ESW), with significantly lower rates of new-onset diabetes, cytomegalovirus (CMV), and malignancy. As renal transplants in older adults has increased, studies have shown similar outcomes between elderly and younger patients. We aim to evaluate post-renal transplantation outcomes in elderly patients compared to younger patients who have undergone ESW. METHODS: A retrospective analysis of adults who received transplants between January 2004 and December 2014 and received either basiliximab or antithymocyte globulin for induction, underwent ESW, and received tacrolimus and mycophenolate for maintenance. Patients were stratified based on age (≥60 vs <60). The 1-year primary end point was a composite of patient survival, graft survival, biopsy-proven acute rejection, and serum creatinine. The secondary outcomes included renal function, the incidence of opportunistic infections, malignancies, diabetes, and cardiovascular complications. Cox regression was used to evaluate variables that may affect rejection. RESULTS: The sample included 292 patients; 72 were elderly individuals and 220 were younger adults. No significant differences were found in the primary end point or incidence of CMV, BK virus, or malignancy ( P = 1.0, .82, and .06, respectively). The use of blood pressure medications and the need for lipid-lowering agents were significantly higher in elderly patients at last follow-up. Diabetes was more common in elderly patients (15.2% vs 8.41%, P = .11). The induction agent used did not show any significant effect on rejection risk. CONCLUSION: We report similar outcomes in elderly patients compared to younger patients in the setting of ESW.

Multicenter evaluation of efficacy and safety of low-dose versus high-dose valganciclovir for prevention of cytomegalovirus disease in donor and recipient positive (D+/R+) renal transplant recipients.

BACKGROUND: The cytomegalovirus (CMV) donor-positive/recipient-positive (D+/R+) population is the largest proportion of renal transplant recipients (RTR). Guidelines for prevention of CMV in the intermediate-risk D+/R+ population include prophylaxis with valganciclovir (VGCV) 900 mg/day for 3 months. This study is the first head-to-head analysis, to our knowledge, comparing the efficacy and safety CMV prophylaxis of VGCV 450 vs 900 mg/day for 3 months in D+/R+ RTR. METHODS: A multicenter, retrospective analysis evaluated 478 adult RTR between January 2008 and October 2011. Study participants received VGCV 450 mg/day (Group 1; n=398) or 900 mg/day (Group 2; n=89)×3 months for CMV prophylaxis. All VGCV was adjusted for renal function. All groups included in this study received study-approved induction and maintenance immunosuppression regimens. The primary endpoint was incidence of CMV disease at 12 months. RESULTS: The rates of graft loss, patient survival, T-cell and/or antibody-mediated rejection, hematological adverse events, opportunistic infections, and early VGCV discontinuation were evaluated. Patient demographics were comparable, but had significant differences in ethnicity and donor type between the groups. CONCLUSION: The occurrence of CMV disease at 12 months was similar between the groups (3.5% vs 3.4%; P=1.000). Log-rank test found no statistically significant difference in the time to development of CMV between the 2 groups (P=.939).

Nephrotoxicity of Natural Products.

BACKGROUND: The manufacture and sale of natural products constitute a multi-billion dollar industry. Nearly a third of the American population admit to using some form of complementary or alternative medicine, with many using them in addition to prescription medications. Most patients fail to inform their healthcare providers of their natural product use and physicians rarely inquire. Annually, thousands of natural product-induced adverse events are reported to Poison Control Centers nationwide. Natural product manufacturers are not responsible for proving safety and efficacy, as the FDA does not regulate them. However, concerns exist surrounding the safety of natural products. SUMMARY: This review provides details on natural products that have been associated with renal dysfunction. We have focused on products that have been associated with direct renal injury, immune-mediated nephrotoxicity, nephrolithiasis, rhabdomyolysis with acute renal injury, hepatorenal syndrome, and common adulterants or contaminants that are associated with renal dysfunction. KEY MESSAGES: The potential for natural products to cause renal dysfunction is justifiable. It is imperative that natural product use be monitored closely in all patients. Healthcare practitioners must play an active role in identifying patients using natural products and provide appropriate patient education.

Eculizumab for drug-induced de novo posttransplantation thrombotic microangiopathy: A case report.

De novo thrombotic microangiopathy (TMA) following renal transplantation is a severe complication associated with high rates of allograft failure. Several immunosuppressive agents are associated with TMA. Conventional approaches to managing this entity, such as withdrawal of the offending agent and/or plasmapheresis, often offer limited help, with high rates of treatment failure and graft loss. We herein report a case of drug induced de novo TMA successfully treated using the C5a inhibitor eculizumab in a renal transplant patient. This report highlights a potentially important role for eculizumab in settings where drug-induced de novo TMA is refractory to conventional therapies.

Impact of pretransplant anti-HLA antibodies on outcomes in lung transplant candidates.

RATIONALE: The prevalence of anti-HLA antibodies in lung transplant candidates and their impact on waitlist and transplant outcomes is not known. OBJECTIVES: We examined the prevalence of pretransplant anti-HLA antibodies at varying thresholds and evaluated their impact on outcomes before and after lung transplantation. METHODS: We performed a single-center retrospective cohort study including all patients listed for lung transplantation between January 2008 and August 2012. Per protocol, transplant candidates were assessed by solid phase LABscreen mixed Class I and II and LABscreen Single Antigen assays. MEASUREMENTS AND MAIN RESULTS: Among 224 patients, 34% had anti-HLA antibodies at mean fluorescent intensity (MFI) greater than or equal to 3,000 (group III), and 24% had antibodies at MFI 1,000 to 3,000 (group II). Ninety percent of the patients with pretransplant anti-HLA antibodies had class I antibodies, whereas only seven patients developed class II alone. Patients in group III were less likely to receive transplants than patients without any anti-HLA antibodies (group I) (45.5 vs. 67.7%, P = 0.005). Wait time to transplant was longer in group III than group I, although this difference did not meet statistical significance, and waitlist mortality was similar. Among transplant recipients, antibody-mediated rejection (AMR) was more frequent in group III than in group II (20% vs. 0%, P = 0.01) or group I (6.3%, P = 0.05). CONCLUSIONS: The presence of anti-HLA antibodies at the high MFI threshold (>3,000) was associated with lower transplant rate and higher rates of AMR. Screening for anti-HLA antibodies using the 3,000 MFI threshold may be important in managing transplant candidates and recipients.

Understanding alterations in drug handling with aging: a focus on the pharmacokinetics of maintenance immunosuppressants in the elderly.

PURPOSE OF REVIEW: This review presents current knowledge of the impact of age on the pharmacokinetics of maintenance immunosuppressants. RECENT FINDINGS: Over the past decade, there has been a steady increase in older patients on organ transplant waiting lists. As a result, the average age of transplant recipients has significantly increased. The survival and quality-of-life benefits of transplantation in the elderly population have been demonstrated. Advancing age is associated with changes in immune responses, as well as changes in drug handling. Immunosenescence is a physiological part of aging and is linked to reduced rejection rates, but also higher rates of diabetes, infections and malignancies. Physiologic changes associated with age can have a significant impact on the pharmacokinetics of the maintenance immunosuppressive agents. Taken together, these age-related changes impact older transplant candidates and may have significant implications for managing immunosuppression in the elderly. SUMMARY: Despite the lack of formal efficacy, safety and pharmacokinetic studies of individual immunosuppressants in the elderly transplant population, there are enough data available for practitioners to be able to adequately manage their older patients. A proficient understanding of the factors that impact the pharmacokinetics of the immunosuppressants in the elderly is essential to managing these patients successfully.

Risk evaluation and mitigation strategies: a focus on the mycophenolic acid preparations.

OBJECTIVE: To review risks associated with mycophenolic acid (MPA) preparations and evaluate their required risk evaluation and mitigation strategies (REMS) elements. DATA SOURCES AND EXTRACTION: Articles were identified through a non-date-limited MEDLINE and EMBASE search using the terms fetal toxicity, teratogenicity, risk evaluation and mitigation strategies, REMS, MPA, mycophenolate mofetil, entericcoated MPA, and organ transplant. Information from the Food and Drug Administration (FDA) and the manufacturers of the MPA preparations was also evaluated. DATA SYNTHESIS: The MPA preparations are associated with several potential risks, including gastrointestinal disturbances and myelosuppression; however, their impact on the fetus in pregnant patients taking 1 of these agents poses the greatest risk. The FDA approved REMS programs for all MPA products, both innovator and generic preparations, in September 2012. With evidence of increased risk of miscarriage and birth defects associated with MPA use, the FDA instituted a REMS program that contains both a medication guide and elements to assure safe use (ETASU). CONCLUSION: The medication guides for the MPA products, which were previously FDA approved, should continue to be distributed to patients who get either an initial prescription filled or a refill. The ETASU requires prescribers to complete training and obtain patient signatures on the Patient-Prescriber Acknowledgment Form. A single, national, voluntary pregnancy registry specific to this medication has been established, and pregnant patients should be encouraged to participate. Although the impact of the MPA REMS on clinical practice is not clear, it is a step toward increasing the understanding of fetal risks with MPA.

Methods, strengths, weaknesses, and limitations of bioequivalence tests with special regard to immunosuppressive drugs.

Within the field of solid organ transplantation, the patents for a number of immunosuppressive drugs have expired in the last few years. Tacrolimus, cyclosporine, and mycophenolate mofetil are now available as generic drugs. In some countries, the market penetration of these generic formulations is as high as 70%, whereas in some other countries, this figure is below 10%. Several professional societies have published position papers on the risks and benefits of generic substitution of immunosuppressive drugs. It often appears that transplant professionals are not fully aware of the requirements for registration of generic drugs. This article describes the registration requirements with a focus on bioequivalence testing, the strengths and weaknesses in this process, and the differences between Europe and the US.

Risk evaluation and mitigation strategies: a focus on the mammalian target of rapamycin inhibitors.

OBJECTIVE: To review the history of risk evaluation and mitigation strategies (REMS) with the mammalian target of rapamycin (mToR) inhibitors, evaluate their required REMS elements, and delineate the reasons for them being released from their REMS requirements. DATA SOURCES AND EXTRACTION: Articles were identified through a literature search of MEDLINE and EMBASE (January 2007-July 2012) using the search terms: risk evaluation and mitigation strategies, REMS, everolimus, sirolimus and organ transplant (individual organs also were searched). Information from the Federal Register, the Food and Drug Administration, and the manufacturers of the mToR inhibitors was also evaluated. DATA SYNTHESIS: REMS are strategies implemented to manage known or potential risks associated with medications and to ensure ongoing pharmacovigilance throughout the life of a pharmaceutical product. The mToR inhibitors have been associated with several potential risks, including proteinuria, graft thrombosis, and wound-healing complications. The Food and Drug Administration approved REMS programs for both sirolimus and everolimus. The manufacturers of both medications complied with the components of their approved REMS, but after less than 2 years, both medications have been relieved of their REMS obligations. CONCLUSION: The only element of the sirolimus REMS was a medication guide, whereas the everolimus REMS consisted of a medication guide and a communication plan. The sirolimus REMS was implemented more than 10 years after its initial approval by the Food and Drug Administration, but was released from its REMS requirement within 7 months of its implementation. The everolimus REMS was instituted upon initial approval and was removed approximately 2 years later. Both medications' REMS were always intended to educate health care providers and patients about the potential risks associated with this transplant immunosuppressant. Transplant practitioners should be familiar with the mToR inhibitors' associated risks and properly educate patients regarding the inhibitors' risk-benefit profiles.

A guide to understanding and implementing risk evaluation and mitigation strategies in organ transplantation.

OBJECTIVE: To review the components of the Congressional mandate for risk evaluation and mitigation strategies (REMS) managed by the Food and Drug Administration and assess their impact on health care providers practicing within the organ transplant arena. DATA SOURCES AND EXTRACTION: A non-date-limited search of MEDLINE and EMBASE (January 2007-June 2012) was conducted by using the following search terms: risk evaluation and mitigation strategies, REMS, and organ transplant, including a query of the individual organs. Information from the Federal Register and the Food and Drug Administration was also evaluated. DATA SYNTHESIS: REMS are strategies implemented to manage known or potential risks associated with medications and to ensure ongoing pharmacovigilance throughout the life of a pharmaceutical product. Elements of REMS programs may consist of 3 levels: a medication guide, communication plan, and elements to assure safe use. A medication guide is used to help prevent serious adverse events, aid in patients' decision making, and enhance medication adherence. Communication plans help educate health care providers and encourage adherence with REMS. The elements to assure safe use is a restrictive process implemented when it is deemed necessary to ensure safe access for patients to products with known serious risks. In transplant medicine, REMS currently exist for belatacept (medication guide and communication plan) and the mycophenolic acid derivatives (medication guide and elements to assure safe use). CONCLUSION: REMS are another step in the evolution of the development and marketing of pharmaceutical agents. Use of REMS in solid-organ transplant is becoming common. Transplant clinicians must provide required patient education and become involved with other aspects of REMS implementation to reduce the serious risks of pharmaceuticals and to improve patients' outcomes.

Risk evaluation and mitigation strategies: a focus on belatacept.

OBJECTIVE: To review the elements and components of the risk evaluation and mitigation strategies (REMS) for the costimulation blocker belatacept and associated implications for health care providers working with transplant recipients. DATA SOURCES AND EXTRACTION: The MEDLINE and EMBASE databases (January 1990 to March 2012) were searched by using risk evaluation and mitigation strategies, REMS, belatacept, and organ transplant as search terms (individual organs were also searched). Retrieved articles were supplemented with analysis of information obtained from the Federal Register, the Food and Drug Administration, and the manufacturer of belatacept. DATA SYNTHESIS: REMS are risk-management strategies implemented to ensure that a product's benefits outweigh its known safety risks. Although belatacept offers a novel strategy in maintenance immunosuppression and was associated with superior renal function compared with cyclosporine in phase 2 and 3 trials, belatacept is also associated with increased risk of posttransplant lymphoproliferative disorder and central nervous system infections. The Food and Drug Administration required development of a REMS program as part of belatacept's approval process to ensure safe and appropriate use of the medication and optimization of its risk-benefit profile. CONCLUSION: Elements of the belatacept REMS include a medication guide that must be dispensed with each infusion and a communication plan. In the management of a complex population of patients, it is essential that those who care for transplant recipients, and patients, recognize the implications of potential and known risks of belatacept. The REMS program aims to facilitate careful selection and education of patients and vigilant monitoring.

Potential Effects of Remdesivir on Tacrolimus Exposure in Transplant Recipients With COVID-19 Infection.

Introduction: Remdesivir has proven to have benefits against COVID-19 infection. However, data supporting drug-drug interactions are insufficient. Clinicians have noticed that calcineurin inhibitor (CNI) levels tend to change after starting remdesivir. This retrospective study aimed to evaluate the effect of remdesivir on CNI levels. Methods: This study included adult solid organ transplant recipients hospitalized for COVID-19 who received remdesivir while on CNI. Patients were excluded if they started on other medications known to interact with CNI. The primary end point was the percentage of change in CNI levels after starting remdesivir. Secondary end points included the time until CNI levels reached a maximum increase in trough levels, the incidence of acute kidney injury (AKI), and the time until CNI levels normalized. Results: Of the 86 patients screened, 61 were included (56 on tacrolimus and 5 on cyclosporine). Most patients received kidney transplants (44.3%), and baseline demographics were similar among the transplanted organs. The median increase in tacrolimus level after starting remdesivir was 84.8%, and only 3 patients had no significant change in CNI levels. The median increase in tacrolimus level was more pronounced in lung and kidney recipients than in heart recipients (96.5% vs. 93.9% vs. 64.6 %, respectively). The median time to maximum increase in tacrolimus trough levels was 3 days, and it took 10 days after the remdesivir course for levels to return to baseline. Conclusion: This retrospective analysis demonstrates that CNI levels were significantly elevated after starting remdesivir. However, future studies are warranted to evaluate this interaction further.

Atovaquone versus trimethoprim-sulfamethoxazole as Pneumocystis jirovecii pneumonia prophylaxis following renal transplantation.

Pneumocystis pneumonia (PCP) is associated with significant morbidity and mortality in renal transplant recipients (RTR). Trimethoprim-sulfamethoxazole (TMP-SMZ) is considered the prophylactic agent-of-choice. Some patients require an alternative owing to TMP-SMZ intolerance. This is the first evaluation of full-dose atovaquone vs. TMP-SMZ for PCP prevention in RTR. One hundred and eighty-five RTR were evaluated in this single-center, retrospective analysis. Patients received either single-strength TMP-SMZ daily (group I; n = 160) or 1500 mg/d of atovaquone and of a fluoroquinolone for one month (group II; n = 25). The primary endpoint was the incidence of PCP at 12 months post-transplant. There were no cases of PCP in either group. There were comparable rates of infections from bacterial pathogens and cytomegalovirus, but rates of BK viremia were significantly higher in group I (22.5%) vs. group II (4%; p = 0.03). The incidence of leukopenia was similar in both groups. Higher mean potassium levels were seen in group I at three months post-transplant but were comparable at all other time points. The need for dose reduction and/or premature discontinuation of therapy secondary to adverse events was more prevalent in TMP-SMZ-treated patients. In our experience, atovaquone appears to be effective in preventing PCP post-renal transplant and also demonstrates good tolerability.