Immunosuppressant Dose Reduction Research Articles

Prevention of post-transplant lymphoproliferative disorder in pediatric kidney transplant recipients.

Post-transplant lymphoproliferative disorder (PTLD) is a devastating complication of immunosuppressive treatment in both solid organ transplantations (SOT) and hematopoietic stem cell transplantations (HSCT). Epstein-Barr virus (EBV) infection precedes PTLD in 90% of patients. Rituximab, a monoclonal anti-CD20 antibody, depletes B-lymphocytes, which are the ultimate reservoir for EBV. Although rituximab therapy is commonly used as a preventive measure for PTLD in high-risk HSCT, it is not established in SOT. Pediatric kidney transplant recipients (PKTR) underwent routine EBV-PCR surveillance. Patients with increasing viral loads, despite immunosuppressive dose reduction, were managed with preventive rituximab therapy. Between 2012 and 2023, we identified eight episodes of asymptomatic EBV-PCR-positive blood tests in seven out of 65 PKTR (11%) under our care. EBV DNAemia emerged 120-720days post-transplantation. Five of seven patients with EBV DNAemia (71%) were EBV-seronegative prior to transplantation. All five patients did not respond to MMF dose reduction and were therefore treated with preventive rituximab therapy. Following this treatment, EBV PCR clearance was observed in all patients with only minimal complications. PKTR who are EBV-naïve prior to transplantation are expected to have a higher prevalence of EBV DNAemia. We found that PKTR who were EBV seronegative prior to transplantation were less likely to achieve EBV clearance in response to immunosuppression dose reduction. We suggest that rituximab therapy in PKTR may be safe and effective in EBV clearance and PTLD prevention.

Clinical characteristics and outcomes of Epstein-Barr virus viral load after allogeneic hematopoietic stem cell transplantation

Epstein-Barr virus (EBV) reactivation can occur following allogenic hematopoietic stem cell transplantation (allo-HSCT). However, the clinical characteristics and outcomes of EBV-viral load are not well known. Thus, we retrospectively analyzed the clinical features and prognostic impact of the EBV viral load in 121 allo-HSCT recipients from our hospital. EBV DNA quantification was performed in whole blood after transplantation. Patients were grouped based on whether EBV DNA quantification reached > 1000 copies/mL during follow-up (N = 50) or not (N = 71). Patients with EBV > 1000 EBV copies/mL were relatively more common in the groups with graft versus host disease (GVHD) prophylaxis including ATG, haploidentical donor type, peripheral blood as a donor source, and acute GVHD II–IV. The 20-month OS and DFS were not significantly different between patients with < 1000 EBV copies/mL and patients with > 1000 EBV copies/mL (20-month OS, 56.0% vs. 60.6%; p = 0.503, 20-month DFS, 50.0% vs. 57.7%; p = 0.179). Immunosuppressant (ISS) dose reduction was achieved after the maximum increase in EBV in 41/50 (82%) patients. Additionally, 30/50 (60%) patients achieved a 50% dose reduction or no restarting of ISS within 3 months of the maximum EBV increase. Among cases wherein EBV DNA quantification reached > 1000 copies/mL, those that achieved rapid dose reduction of ISS tended to have longer overall survival (“not reached” vs 5.4 months, p < 0.001) and disease-free survival (88.4 months vs 5.3 months, p < 0.001) than those in patients who did not. Our data highlight the importance of rapid ISS reduction in post-transplant EBV reactivation.

COVID-19 in heart transplant recipients.

Introduction: After solid organ transplantation, patients require lifelong immunosuppressive medication, increasing susceptibility to COVID-19. We evaluated the clinical outcomes of heart transplant recipients in patients with COVID-19. Methods: We enrolled twenty-two COVID-19 cases of adult heart transplantation from February 2020 to September 2021. Results: The most common symptoms in patients were fever and myalgia. The death occurred in 3 (13.6 %). Conclusion: Although heart transplantation mortality may increase in the acute rejection phase concomitant with COVID-19, immunosuppressive dose reduction may not be necessary for all heart transplant patients with COVID-19.

Safety and long-term outcomes of early liver transplantation for pediatric methylmalonic acidemia patients.

LT is a treatment option for MMA patients, but renal function impairment is one of the long-term concerns. The aim of this study was to evaluate the outcomes of early LT in these patients. A total of 11MMA mut-type patients (including 10mut0 cases and 1mut-case) who received LT in our institute were reviewed. Their metabolic profiles were compared between the pre/post-transplant periods. Their immunosuppressant and renal function changes after transplantation were assessed. After a mean follow-up of 97.5±38.4months, there were two deaths, and the actual survival rate was 81.8%. Their metabolic profiles had improved (mean blood ammonia level 366.8±105.5 vs. 53.1±17.4μg/dl, p<.001; C3/C2 ratio 2.68±0.87 vs. 0.73±0.22, p=.003; mean urine MMA level 920.5±376.6 vs. 196.2±85.4, p=.067), and hospital stays were decreased (78.8±74.5 vs. 7.4±7.0days/year, p=.009) after transplantation. The mean age at transplant was 1.81±2.02years old, and nine of these patients received LT before the age of 1.5years old (early LT). Under prospective immunosuppressant dose reduction, three of these early LT patients discontinued the drug and were sustained for more than 5years. Most of the patients had a preserved renal function, and no patient is currently on dialysis. In addition to the improvement in the metabolic parameters, early LT in MMA patients may allow for a dose reduction of the immunosuppressant, and the patient's renal function could be preserved in the long term.

Efficacy and safety of tocilizumab in Behçet's syndrome with refractory arterial lesions: a single-centre observational cohort study in China.

ObjectiveThe aim of this observational cohort study was to assess the effectiveness and safety of the IL-6-receptor inhibitor tocilizumab (TCZ) in Behçet’s syndrome (BS) with refractory arterial involvement.MethodsTen patients admitted to the Rheumatology and Immunology Department of Peking University People’s Hospital between January 2014 and December 2019 were enrolled. The enrolled patients met the BS international criteria and exhibited severe arterial impairments. Refractory arterio-BS was diagnosed based on objective vascular symptoms unexplainable by other known illnesses, and resistance to traditional immunosuppressants and glucocorticoids after 12 weeks. Patients received 8 mg/kg TCZ infusions every 4 weeks for ≥24 weeks, with simultaneous continuation of immunosuppressants and glucocorticoids. Clinical and imaging data were assessed before and after TCZ treatment.ResultsThe enrolled patients were men aged 44.3 (10.5) years; the median disease duration was 186.5 (45.7) months, and the average age of arterial impairment onset was 38.7 (12.9) years. The following trends were observed: improvement and maintenance of symptoms after the 26.8 (7.2)-month follow-up, n = 9; complete remission, n = 6; partial response, n = 3; immunosuppressant dose reduction, n = 4; radiologic improvement of arterial lesions, n = 4; and TCZ discontinuation owing to enlarged abdominal aortic aneurysm relapse, n = 1. The average daily glucocorticoid dose reduced from 54.5 (20.6) to 8.3 (3.6) mg/d (P < 0.001), while the median ESR and CRP values reduced from 50 (2–82) mm/h and 32.9 (2.1–62.3) mg/dl to 4 (1–10) mm/h and 2.9 (0.2–12.1) mg/dl, respectively (P < 0.001). No TCZ-associated side effects were noted.ConclusionTCZ proved to be safe and effective for refractory arterial lesions in BS, with a steroid- and immunosuppressant-sparing benefit.

MP37-18 PHARMACOKINETICS OF IMMUNOSUPPRESSANTS AMONG YOUNG, MIDDLE, AND ELDERLY KIDNEY TRANSPLANT RECIPIENTS: ITS IMPACT FOR CLINICAL OUTCOMES

You have accessJournal of UrologyRenal Transplantation & Vascular Surgery I (MP37)1 Sep 2021MP37-18 PHARMACOKINETICS OF IMMUNOSUPPRESSANTS AMONG YOUNG, MIDDLE, AND ELDERLY KIDNEY TRANSPLANT RECIPIENTS: ITS IMPACT FOR CLINICAL OUTCOMES Ryuichiro Sagehashi, Mitsuru Saito, Takuro Saito, Ryohei Yamamoto, Nobuhiro Fujiyama, Souki Kashima, Atsushi Koizumi, Taketoshi Nara, Kazuyuki Numakura, Shintaro Narita, Shigeru Satoh, and Habuchi Tomonori Ryuichiro SagehashiRyuichiro Sagehashi More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Takuro SaitoTakuro Saito More articles by this author , Ryohei YamamotoRyohei Yamamoto More articles by this author , Nobuhiro FujiyamaNobuhiro Fujiyama More articles by this author , Souki KashimaSouki Kashima More articles by this author , Atsushi KoizumiAtsushi Koizumi More articles by this author , Taketoshi NaraTaketoshi Nara More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Shintaro NaritaShintaro Narita More articles by this author , Shigeru SatohShigeru Satoh More articles by this author , and Habuchi TomonoriHabuchi Tomonori More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002046.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We investigated that pharmacokinetics of immunosuppressants among young, middle, and elderly kidney transplant recipients and its impact for clinical outcomes. METHODS: A total of 179 pairs of recipients and donors who underwent living kidney transplantation in our institute between November 2009 and April 2019 were enrolled in this study. Recipients were divided into three groups according to age at transplantation: the young (<55 years, 98 patients), middle-aged (55–64 years, 54 patients), and elderly groups (≥65 years, 27 patients). All recipients received the combination therapy, consisting of tacrolimus (TAC), mycophenolate mofetil (MMF), prednisolone (PSL), and basiliximab. Moreover, from October 2013, everolimus (EVR) was added and TAC and MMF doses were reduced after 14 postoperative days. In immunologically high-risk patients, single dose of rituximab at 200 mg/body was administered and 1–4 sessions of antibody removal were performed before transplantation. Doses of immunosuppressants were not arranged according to age of recipients. RESULTS: The age of donor in the elderly group was significantly higher than the other groups (p<0.01, respectively); however, no significant difference in the donors’ renal function was observed among groups. Immunologically high-risk patients in the middle-aged and elderly groups were significantly higher than that in the young group (p=0.01, respectively). In the pharmacokinetic analysis, no significant differences in trough levels and AUC of TAC, MPA, and EVR, were observed among the groups. No infectious death was observed in this cohort, and incidences of hospitalization for infectious events did not differ among groups. In addition, incidences of rejection and de novo malignancies between the young and elderly groups were similar. No significant difference of the death censored graft survival was observed among groups. CONCLUSIONS: In the modern immunosuppressive protocol, the aging process itself may have little effect on the pharmacokinetics of immunosuppressants. It may be necessary to refrain from easy dose reduction of immunosuppressants in elderly kidney transplant recipients . Source of Funding: We have no financial relationships to disclose. © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e653-e653 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ryuichiro Sagehashi More articles by this author Mitsuru Saito More articles by this author Takuro Saito More articles by this author Ryohei Yamamoto More articles by this author Nobuhiro Fujiyama More articles by this author Souki Kashima More articles by this author Atsushi Koizumi More articles by this author Taketoshi Nara More articles by this author Kazuyuki Numakura More articles by this author Shintaro Narita More articles by this author Shigeru Satoh More articles by this author Habuchi Tomonori More articles by this author Expand All Advertisement Loading ...

Protecting the vulnerable: SARS-CoV-2 vaccination in immunosuppressed patients with interstitial lung disease

Protecting the vulnerable: SARS-CoV-2 vaccination in immunosuppressed patients with interstitial lung disease

Myasthenia gravis patient and physician opinions about immunosuppressant reduction.

To reduce myasthenia gravis (MG) patient risk of immunosuppressant (IS) exposure adverse events (AEs), such as infections and malignancies, and to reduce treatment burden, international guidelines recommend decreasing IS dose in stable MG patients. Online surveys were conducted of self-identified MG patients and MG physician experts about the importance of IS dose reduction for MG patients who achieve prolonged periods of disease stability. Eighty-four percent of MG patients (n = 283) and 100% of physicians (n = 45) were concerned about long-term IS-associated AEs. Although both groups favored attempting IS reduction, they raised concerns including MG relapse, hospitalization, and uncertainty about the future. Presented with an estimated 12% significant relapse rate with IS dose reduction, 76% of patients would be willing to enroll in a randomized IS dose reduction trial. Patients and physicians favor considering IS dose reduction but are also concerned about potential negative sequelae.

Probable progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome with immunosuppressant dose reduction following lung transplantation: a case report and literature review

BackgroundProgressive multifocal leukoencephalopathy (PML) is a rapidly developing demyelinating disease in the cerebral white matter and is often caused by JC polyomavirus (JCV). PML after lung transplantation is rare and has a poor prognosis, with no established therapies. Reducing the patient’s immunosuppressant doses, thereby restoring immunity, could be used to treat PML. However, some patients develop immune reconstitution inflammatory syndrome (IRIS) with this treatment, an immune-induced inflammatory response to JCV that results in serious neuronal damage. We herein report a case of a 60-year-old female who suffered from PML 5 years after lung transplantation, had worsened brain lesions thought to be related to PML-IRIS at the time of immunosuppressant reduction, and missed treatment opportunities.Case presentationA 60-year-old female developed PML 5 years after lung transplantation. Fluid-attenuated inversion recovery and diffusion-weighted brain magnetic resonance imaging (MRI) revealed multiple high-signal lesions, mainly in the cerebral white matter. Polymerase chain reaction found 0.32 million copies/mL of JCV in the cerebrospinal fluid. Thus, she was given a diagnosis of PML. Mycophenolate mofetil and tacrolimus dosages were reduced, and CD4-positive cell counts and the blood concentration of each immunosuppressant were monitored. Mefloquine was also orally administered at a daily dose of 275 mg for 3 days and was then administered at a dose of 275 mg per week. Although the patient’s CD4-positive cell counts increased and her immune system recovered, her symptoms and brain MRI findings worsened. We suspected PML progression or a transition to PML-IRIS. Steroid pulse therapy to suppress the inflammatory lesions was not possible but was retrospectively indicated. The patient rapidly began to exhibit akinetic mutism and died 4 months after the onset of neurologic symptoms.ConclusionsWhen neurologic symptoms and abnormal brain MRI findings are noted during immune recovery, it is often difficult to distinguish between progressed PML and PML-IRIS. However, the pathogenesis of brain lesions usually involves inflammation and immune-reactive mechanisms for JCV. Steroid pulse therapy, which can reduce inflammation, should thus be administered in organ transplantation cases with differential diagnoses including PML-IRIS.

1489 “Bi-Morphic” Post-Transplant Lymphoproliferative Disorder Masquerading as Inflammatory Bowel Disease

INTRODUCTION: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication occurring in up to 30% of post-transplant patients, usually within the first year; however, recurrent PTLD or development of multiple histologic subtypes is rare.1 Relevant to gastroenterologists, GI tract involvement can occur in up to 25% of cases and present as nonspecific clinical symptoms, abdominal pain, bleeding, or perforation.2 CASE DESCRIPTION/METHODS: An 80-year-old African American male with a past medical history of living-donor kidney transplant presented to clinic to undergo surveillance colonoscopy. Nine months post-transplant, the patient was diagnosed with early PTLD on colonoscopy and treated with 4 cycles of rituximab without evidence of disease on repeat colonoscopy or PET scan. Follow up colonoscopy at 5 years did not show any recurrence of disease and the patient was recommended to undergo his next colonoscopy in another 5 years (10 years following PTLD treatment). Repeat colonoscopy at this time found multiple inflammatory polyps at the ileocecal valve and in the transverse and sigmoid colon. Additionally, the rectosigmoid colon showed evidence of moderate inflammation (Figure 1). Pathology reports indicated polyps of the ileocecal valve were consistent with polymorphic PTLD, whereas the biopsies of the rectosigmoid colon showed monomorphic PTLD (Figure 2). The patient was referred to Oncology and is currently undergoing repeat rituximab therapy for monomorphic PTLD and a dose reduction of immunosuppressants for polymorphic PTLD. DISCUSSION: Importantly, even though rates of PTLD are typically lowest for renal transplants (0.8-2.5%), early and recurrent PTLD is still possible in this population.3 Our patient, despite a previous response to rituximab, demonstrated evidence of rare, recurrent PTLD in addition to multiple pathologic subtypes spread diffusely throughout the colon. In particular, the emergence of monomorphic PTLD carries the worst prognosis with survival rates ranging from 25-60%.5,6 Given the frequency of GI tract involvement, it is essential gastroenterologists maintain high suspicion for PTLD in patients with prior transplantation and have a lower threshold for biopsy, as our case demonstrates advanced disease appearing endoscopically as inflammatory changes. Importantly, this recurrence was found 10 years after initial diagnosis, which signifies the importance of surveillance colonoscopy for early detection, monitoring for recurrence, and establishing disease prognosis in PTLD.

Efficacy of telaprevir-based therapy in stable liver transplant patients with chronic genotype 1 hepatitis C

Background and rationale. The REPLACE study (NCT01571583) investigated telaprevir-based triple therapy in patients who have recurrent genotype 1 hepatitis C virus (HCV) infection following liver transplantation and are on a stable immunosuppressant regimen of tacrolimus or cyclosporin A. Patients received telaprevir 750 mg 8-hourly with pegylated interferon 180 μg weekly and ribavirin 600 mg daily, followed by a further 36 weeks of pegylated interferon and ribavirin alone and 24 weeks of follow-up. Efficacy (sustained virological response [SVR] 12 weeks after last planned study dose), safety and tolerability of telaprevir throughout the study were assessed. Pharmacokinetics of telaprevir, tacrolimus and cyclosporin A were also examined.Results. In total, 74 patients were recruited. Overall, 72% (53/74; 95% CI: 59.9 to 81.5) of patients achieved SVR at 12 weeks following completion of treatment. Anticipated increases in plasma concentrations of tacrolimus and cyclosporin A occurred during telaprevir treatment and were successfully managed through immunosuppressant dose reduction and, for tacrolimus, reduced dosing frequency. Safety and tolerability of telaprevir-based triple therapy were generally comparable with previous data in non-transplant patients, although rates of reported anemia (55% [41/74]) were higher. Elevated plasma creatinine (46% [34/74]) was observed during REPLACE - consistent with the post-liver transplant population and the co-administered immunosuppressants.Conclusion. Telaprevir-based triple therapy in patients with recurrent genotype 1 HCV infection following liver transplantation produced high rates of SVR. Therapeutic concentrations of immunosuppressants were maintained successfully through dose modification during telaprevir treatment.

Comparative evaluation of isavuconazonium sulfate, voriconazole, and posaconazole for the management of invasive fungal infections in an academic medical center

BackgroundInvasive fungal infections are a major cause of morbidity and mortality. Newer antifungals may provide similar efficacy with improved safety compared to older more established treatments. This study aimed to compare clinically relevant safety and efficacy outcomes in real world patients treated with isavuconazole, voriconazole, or posaconazole.MethodsThis single center retrospective matched cohort study evaluated adults between January 2015 and December 2017. The primary outcome was a composite safety analysis of antifungal related QTc prolongation, elevated liver function tests (> 5 times ULN), or any documented adverse drug event. Key secondary outcomes included: individual safety events, 30-day readmissions, magnitude of drug interactions with immunosuppressive therapy, and overall cost.ResultsA total of 100 patients were included: 34 patients in the voriconazole group and 33 patients within each of the isavuconazole and posaconazole groups. The composite safety outcome occurred in 40% of the total cohort and was different between isavuconazole (24.2%), voriconazole (55.9%), and posaconazole (39.4%; p = 0.028). Change in QTc (p < 0.01) and magnitude of immunosuppression dose reduction (p = 0.029) were different between the three groups. No differences in mortality, length of stay, readmission, or infection recurrence were observed between groups (p > 0.05 for all). The overall medication cost, when including therapeutic drug monitoring, was not different between treatments (p = 0.36).ConclusionsPatients treated with isavuconazole resulted in fewer composite safety outcomes, driven by decreased incidence of QTc prolongation, compared to patients treated with voriconazole or posaconazole. Overall drug cost was not significantly different between the treatment therapy options.

Acute rejection in vascularized composite allotransplantation

Acute rejection is the most common complication after vascularized composite allotransplantation (VCA). This review provides a state-of-the-art analysis of prevention, diagnosis and treatment of acute rejection episodes and highlights recent findings with the potential to improve patient care and enhance understanding of the underlying biologic processes. Recent reports suggest that maintenance immunosuppression dose reduction and steroid withdrawal are realistic goals in VCA, despite the known high immunogenicity of the skin component. It appears that utilization of sentinel flaps, in-depth histological analyses and application of novel biomarkers have facilitated early diagnosis and characterization of acute rejection episodes, leading to timely institution of appropriate therapy. The successful management of the first highly sensitized face transplant recipient suggests the possibility of carefully considering these high-risk VCA candidates for transplantation. Acute rejection is higher in VCA than in any other organ in the field of transplantation, although most episodes are controlled by high-dose steroids and optimization of maintenance immunosuppression. Because of limitations in patient number and the duration of follow-up, the long-term safety and effectiveness of VCA remain unclear. Moreover, the tests currently used to diagnose acute rejection are of limited value. Better diagnostic tools and a better understanding of the immunologic events during acute rejection are therefore needed to improve diagnosis, treatment and outcomes of this life-changing restorative surgery.

Immunosuppressant dose reduction and long-term rejection risk in renal transplant recipients with severe bacterial pneumonia.

Due to lifelong immunosuppression, renal transplant recipients (RTRs) are at risk of infectious complications such as pneumonia. Severe pneumonia results in respiratory failure and is life‑threatening. We aimed to examine the influence of immunosuppressant dose reduction on RTRs with bacterial pneumonia and respiratory failure. From January 2001 to January 2011, 33 of 1,146 RTRs at a single centre developed bacterial pneumonia with respiratory failure. All patients were treated using mechanical ventilation and aggressive therapies in the intensive care unit. Average time from kidney transplantation to pneumonia with respiratory failure was 6.8 years. In-hospital mortality rate was 45.5% despite intensive care and aggressive therapies. Logistic regression analysis indicated that a high serum creatinine level at the time of admission to the intensive care unit (odds ratio 1.77 per mg/dL, 95% confidence interval 1.01-3.09; p = 0.045) was a mortality determinant. Out of the 33 patients, immunosuppressive agents were reduced in 17 (51.5%). We found that although immunosuppressant dose reduction tended to improve in-hospital mortality, this was not statistically significant. Nevertheless, during a mean follow-up period of two years, none of the survivors (n = 18) developed acute rejection or allograft necrosis. In RTRs with bacterial pneumonia and respiratory failure, higher serum creatinine levels were a mortality determinant. Although temporary immunosuppressant dose reduction might not reduce mortality, it was associated with a minimal risk of acute rejection during the two-year follow-up. Our results suggest that early immunosuppressant reduction in RTRs with severe pneumonia of indeterminate microbiology may be safe even when pathogens are bacterial in nature.

Case Report: Thrombotic Microangiopathy Post-intravenous Immunoglobulin in the Context of BK Nephropathy and Renal Transplantation

Intravenous immunoglobulin (IVIg) is a blood product with immunomodulating properties that have been widely applied in the management of renal transplant recipients. In general, IVIg has been considered a relatively safe therapy, with most adverse events being mild and transient. Although rare, a serious and well-recognized complication of IVIg is large-vessel thrombotic events, which are thought to be related to hyperviscosity. We describe here two cases in which there was a temporal relationships between the administration of IVIg, an acute decline in allograft function, and the histologic finding of de novo thrombotic microangiopathy (TMA). In both cases, IVIg had been administered to facilitate immunosuppressive dose reduction in the context of BK nephropathy. We believe this is the first report of TMA associated with IVIg administration in renal allograft recipients.

The impact of surveillance and rapid reduction in immunosuppression to control BK virus-related graft injury in kidney transplantation

We prospectively screened 609 consecutive kidney (538) and kidney-pancreas (71) transplant recipients for BK viremia over a 4-year interval using polymerase chain reaction viral load detection and protocol kidney biopsies. We found that BK viremia is common at our center: total cases 26.7%, cases during first year 21.3% (mean 4 months), and recipients with ≥ 10 000 copies/ml 12.3%. We found few predictive clinical or demographic risk factors for any BK viremia or viral loads ≥ 10,000 copies/ml, other than prior treatment of biopsy confirmed acute rejection and/or higher immunosuppressive blood levels of tacrolimus (P = 0.001) or mycophenolate mofetil (P = 0.007). Viral loads at diagnosis (<10 000 copies/ml) demonstrated little impact on graft function or survival. However, rising copy numbers demand early reductions in immunosuppressive drug doses of at least 30-50%. Viral loads >185 000 copies/ml at diagnosis were predictive of BK virus-associated nephropathy (BKVAN; OR: 113.25, 95% CI: 17.22-744.6, P < 0.001). Surveillance for BK viremia and rapid reduction of immunosuppression limited the incidence of BKVAN to 1.3%. The addition of leflunomide or ciprofloxacin to immunosuppressive dose reduction did not result in greater rates of viral clearance. These data support the role of early surveillance for BK viremia to limit the impact on transplant outcome, although the most effective schedule for screening awaits further investigation.

Risk Factors for &lt;i&gt;Pneumocystis jiroveci&lt;/i&gt; Pneumonia in Glomerulonephritis Patients Receiving Immunosuppressants

Pneumocystis jiroveci pneumonia (PJP) infection is a rare but lethal complication in immunocompromised hosts. However, risk factors for PJP infection in glomerulonephritis (GN) patients receiving immunosuppressants are unknown. From August 2009 to July 2010, we encountered a cluster occurrence of PJP infection in our renal biopsy patients. Seven of 73 GN patients under immunosuppressant agents developed PJP infection, which were diagnosed by the Giemsa and Gomori's methenamine silver stains of the bronchoalveolar lavage specimen. The average time of PJP onset was 2.4 months after immunosuppressant initiation. We found that the immunosuppressant regimens were equal between patients with and without the development of PJP infection regarding the daily dose per body weight, treatment duration, and accumulative dose per body weight. Logistic regression analysis indicated that high serum creatinine, low hemoglobin, and low absolute lymphocyte count at immunosuppressant initiation, and high chronicity indices of kidney pathology were predictors of PJP infection. In addition, patients with PJP infection had persistently worse renal function, more severe anemia, and more severe lymphocytopenia as compared to those without. Prophylactic therapy for P. jiroveci and immunosuppressant dose reduction should be considered in GN patients with high chronicity of their kidney diseases and/or persistent lymphocytopenia.

Ureteral Stents: A Risk Factor for Polyomavirus BK Viremia in Kidney Transplant Recipients Undergoing Protocol Screening

Background Polyomavirus BK nephropathy (BKN) remains a common cause of early renal transplant dysfunction and graft loss. To date, little has been reported on the role, if any, of transplant ureteral stents in the development of polyomavirus BK viremia (BVK) and BKN. Methods We performed a single-center, retrospective analysis of renal transplant recipients who underwent renal transplantation followed by monthly BKV screening at Albany Medical Center between January 1, 2006, and December 31, 2009. A transplant ureteral stent was placed at the discretion of the surgeon. The immunosuppression protocol employed for deceased donor and unrelated living -donor recipients was antithymocyte antibody induction with methylprednisolone, mycophenolate mofetil, tacrolimus, and sirolimus. Results During the study period, 186 recipients were identified; 124 (67%) underwent intraoperative transplant ureteral stent placement, while 62 patients (33%) did not undergo stent placement. With our monthly screening protocol, we detected BKV in 32 of the 186 recipients (17%) following transplantation; 27 of the 32 (84%) viremic patients were stent recipients. In all patients who developed BKV, an immunosuppression dose reduction protocol was employed. Ureteral stent placement conferred a statistically significant elevated risk of developing BKV (odds ratio = 3.17, 95% confidence interval 1.16–8.70). Patient gender, age, ethnicity, diabetes status, and retransplant status were not statistically significant factors in the development of BKV. Conclusion Our study demonstrated the elevated risk of BKV in recipients who undergo transplant ureteral stenting. Monthly BK polymerase chain reaction screening appears to be a useful tool for the early detection of BKV in this higher-risk group.

Recurrent and Persistent Cytomegalovirus Infection in a Kidney Recipient Caused by the L595S Mutation in Ul97 Phosphotransferase Gene

Ganciclovir (GCV) is the first therapeutic choice for prevention and treatment of active cytomegalovirus (CMV) infection in solid organ transplant recipients in Bahia state, Brazil. Prolonged and repeated GCV therapy may result in drug-resistant virus, associated with progressive and disseminated disease. We present a case report of a young male kidney recipient, who was CMV-seronegative with a CMV-seropositive donor (D(+)/R(-)), and who developed clinical GCV resistance, confirmed by mutation in viral UL97 phosphotransferase responsible for GCV activation. Under prophylactic therapy with intravenous GCV for 6 weeks post-transplantation, he developed severe anaemia and hepatic enzyme increases, probably due to drug side effects. At this moment, the drug was discontinued and he started to be monitored by pp65 antigen test. At week 10 post-transplantation, he presented fever, myalgia, thrombocytopenia and neutropaenia, with a positive CMV antigen test. During treatment with intravenous GCV, antigenaemia assay demonstrated a higher number of positive cells, requiring GCV at higher doses. Pre-emptive therapy lasted for 31 days and he started the maintenance therapy with oral GCV. However, antigenaemia assay demonstrated an extremely high number of positive cells, and he was rehospitalized and prescribed intravenous GCV. Severe leukopaenia led to GCV interruption, but immunosuppressive dose reduction helped to control the active CMV infection. GCV-resistant CMV infection resulted in increased morbidity, rehospitalization episodes and increased costs; therefore, implementation of resistance diagnostic tests in the transplantation routine is of great importance. We documented the first case of GCV-resistant CMV infection due to the L595S mutation in UL97 phosphotransferase gene in a kidney recipient from Bahia state, Brazil.

Intensive Polyoma Virus Nephropathy Treatment as a Preferable Approach for Graft Surveillance

Background Polyoma BK virus nephropathy (BKVN) is one of the important causes of graft failure and loss among renal transplant patients. Reduction of immunosuppression is the most important preferred treatment approach; however, there is no agreed protocol for additional treatments. Objective Our aim was to investigate the effects on graft survival of intensive treatment protocols for BKVN among renaltransplant patients. Methods 214 patients were included in the study. All patients underwent investigation for the presence of BKV in plasma samples every 3 months starting from the third month after transplantation. Biopsies were obtained upon detection of graft dysfunction or viremia. If BKVN was positive, viremia was investigated monthly. Results Plasma plus biopsy-proven BKVN were detected in 19 patients (8.9%), whose mean age was 45.8 ± 12.0 years; 68.4% (n = 13) were male and 94.7% (n = 18) were recipients of a living-donor kidney. There were 5.2% (n = 1) diabetic subjects, and the mean time prior to dialysis was 39.6 ± 44.8 (3–125) months. BKVN was observed at a mean of 6.8 ± 2.9 (4–14) months after the transplantation. It positively correlated with the baseline serum creatinine level ( r = 0.159; P = .02), application and cumulative dose of antithymocyte globulin ( r = 0.177; r = 0.165; respectively; P = .01), mean tacrolimus dose ( r = 0.303; P < .001), and hepatitis B virus positivity ( r = 0.169; P = .01). Immunosuppression was decreased in all patients who developed BKVN. In addition, leflunomide was applied in 68%, intravenous immunoglobulin in 74%, and cidofovir in 32% of patients. Acute rejection rates did not increase significantly after lowering immunosuppression ( P > .05). Conclusion BKVN is one of the important problems in renal transplant patients. Intensive treatment of BKVN with heterogeneous regimens, including combined treatment with leflunamide + IVIG together with immunosuppressive dose reduction, was an effective approach to prolong graft survival.