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Beyer AP, Moise PA, Wong M, Gao W, Xiang C, Shen P, Pavlakis M, Vincenti F, Wang W. Clinical events and healthcare resource utilization associated with neutropenia and leukopenia among adult kidney transplant recipients receiving valganciclovir. World J Transplant 2025; 15:102671. [DOI: 10.5500/wjt.v15.i2.102671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/09/2024] [Accepted: 01/23/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) prophylaxis with valganciclovir and ganciclovir is associated with elevated neutropenia and leukopenia risk in kidney transplant recipients, although the impact of these events on healthcare resource utilization (HCRU) and clinical outcomes is unclear.
AIM To quantify clinical events and HCRU associated with neutropenia and leukopenia among adults receiving valganciclovir and/or ganciclovir post-kidney transplantation.
METHODS Adult kidney transplant recipients receiving valganciclovir and/or ganciclovir prophylaxis were identified in the TriNetX database from 2012 to 2021. Patient characteristics were evaluated in the 1-year period pre-first transplant. HCRU and adjusted event rates per person-year were evaluated in follow-up year 1 and years 2-5 after first kidney transplantation among cohorts with vs without neutropenia and/or leukopenia.
RESULTS Of 15398 identified patients, the average age was 52.39 years and 58.70% were male. Patients with neutropenia and/or leukopenia had greater risk of clinical events for CMV-related events, opportunistic infections, use of granulocyte colony stimulating factor, and hospitalizations (relative risk > 1 in year 1 and years 2-5). Patients with vs without neutropenia and/or leukopenia had higher HCRU in year 1 and years 2-5 post kidney transplantation, including the mean number of inpatient admissions (year 1: 3.47 vs 2.76; years 2-5: 2.70 vs 2.29) and outpatient visits (48.97 vs 34.42; 31.73 vs 15.59, respectively), as well as the mean number of labs (1654.55 vs 1182.27; 622.37 vs 327.89).
CONCLUSION Adults receiving valganciclovir and/or ganciclovir prophylaxis post-kidney transplantation had greater risk of neutropenia and/or leukopenia, which were associated with higher clinical event rates and HCRU up to 5 years post-transplantation. These findings suggest the need for alternative prophylaxis options with lower myelosuppressive effects to improve patient outcomes.
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Affiliation(s)
- Andrew P Beyer
- Department of Value and Implementation Outcomes Research, Merck & Co., Inc., Rahway, NJ 07065, United States
| | - Pamela A Moise
- Medical Affairs, Merck & Co., Inc., Rahway, NJ 07065, United States
| | - Michael Wong
- Scientific Affairs, Merck & Co., Inc., Rahway, NJ 07065, United States
| | - Wei Gao
- Analysis Group, Boston, MA 02199, United States
| | | | | | - Martha Pavlakis
- The Transplant Center, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
| | - Flavio Vincenti
- The Transplant Services, University of California San Francisco, San Francisco, CA 94143, United States
| | - Weijia Wang
- Department of Value and Implementation Outcomes Research, Merck & Co., Inc., Rahway, NJ 07065, United States
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Tashiro Y, Hyodo Y, Kitamura S, Fujimoto T, Endo T, Nishioka S, Yokoyama N, Hara T, Chiba K, Miyake H. Impact of Fc-gamma receptor IIIA polymorphism on late-onset neutropenia and clinical outcomes in kidney transplant recipients following rituximab induction therapy. Clin Exp Nephrol 2025; 29:681-689. [PMID: 39804516 PMCID: PMC12049374 DOI: 10.1007/s10157-024-02610-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 12/01/2024] [Indexed: 05/04/2025]
Abstract
BACKGROUND This study aimed to investigate the association between the Fc-gamma receptor IIIA (FCGR3A) 158 polymorphism and clinical outcomes in kidney transplantation (KTx) patients. Specifically, we focused on late-onset neutropenia (LON) in ABO-incompatible (ABOi) or HLA-incompatible (HLAi) KTx recipients who underwent rituximab (RTx) desensitization therapy. METHODS FCGR3A 158F/V polymorphisms were identified in 85 ABOi or HLAi KTx recipients who underwent RTx desensitization at our institution between April 2008 and October 2021. We analyzed these polymorphism groups in relation to their preoperative background and incidence of LON, infection, and rejection. In addition, we examined the risk factors for LON development. RESULTS The following FCGR3A 158F/V polymorphisms were identified: FF genotype (n = 45); FV genotype (n = 36), and VV genotype (n = 4). LON occurred in 25 out of 85 recipients within 1 year after KTx, significantly more frequently in patients with the FCGR3A FV + VV genotype (17/40) than in those with the FF genotype (8/45) (p = 0.01). A multivariate analysis identified the V-allele as an independent risk factor for LON (OR, 4.03; 95% CI, 1.38-11.73, p = 0.01). However, there were no significant differences in the incidence rates of post-transplant infection and rejection between the FF and FV + VV genotypes. CONCLUSION Recipients with the FCGR3A 158 V-allele were identified as having a higher risk of developing LON following KTx with RTx desensitization therapy. However, the presence of this V-allele did not affect the safety or efficacy of RTx desensitization before KTx.
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Affiliation(s)
- Yuki Tashiro
- Division of Urology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Yoji Hyodo
- Division of Urology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
| | - Satoshi Kitamura
- Division of Urology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Takuya Fujimoto
- Department of Urology, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Hyogo, Japan
| | - Takahito Endo
- Division of Urology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Shun Nishioka
- Division of Urology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Naoki Yokoyama
- Division of Urology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Takuto Hara
- Division of Urology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Koji Chiba
- Division of Urology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Hideaki Miyake
- Division of Urology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
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Haddad S, Dee K, Chiang AD, Feller F, Ding T, Ayers GD, Potts M, LaRue RW. Relationship Between Body Weight and Leukopenia in Non-Kidney Solid Organ Transplant Recipients With Normal Renal Function Who Are Receiving Valganciclovir for CMV Prophylaxis. Transpl Infect Dis 2025; 27:e14418. [PMID: 39692604 PMCID: PMC12017309 DOI: 10.1111/tid.14418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/07/2024] [Accepted: 11/22/2024] [Indexed: 12/19/2024]
Abstract
BACKGROUND Cytomegalovirus (CMV) disease causes significant morbidity among solid organ transplant (SOT) recipients. To prevent CMV disease, eligible recipients are frequently started on valganciclovir (VGC) prophylaxis post-transplant. Leukopenia has been documented as a primary adverse events of the drug (1). This study's primary aim was to determine whether a patient's weight at the start of VGC prophylaxis was associated with the development of leukopenia. METHODS This was a single center, retrospective cohort study that included adults > 18 years of age, who had received an organ transplant (heart, liver, or lung) at an academic transplant center from January 1, 2018 through December 31, 2022. A creatinine clearance of > 60 mL/min was required. RESULTS All 294 included patients received 900 mg/day of VGC for CMV prophylaxis, without dose adjustment. Fifty-two percent of the patients developed leukopenia while receiving VGC prophylaxis. The mean weight at initiation of VGC was higher in patients who did not develop leukopenia (97.9 kg) compared to those who did (90.7 kg; p = 0.0112). It was found that with each 1 kg increase in body weight, the likelihood of developing leukopenia decreased by 1.7% (p = 0.004, odds ratio = 0.983, 95% confidence interval [CI], 0.972-0.994). Patients with a baseline body-mass index (BMI) > 25 had a longer median freedom time from leukopenia after initiation of VGC as compared to the group with baseline BMI < 25 (log-rank p = 0.035). CONCLUSION These data suggest that in SOT recipients with normal renal function, receiving a fixed dose of VGC resulted in a significant, inverse relationship between body weight and the development of leukopenia.
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Affiliation(s)
- Sara Haddad
- Department of Medicine, Division of Infectious DiseasesVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Kevin Dee
- Department of Medicine, Division of Infectious DiseasesVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Augusto Dulanto Chiang
- Department of Medicine, Division of Infectious DiseasesVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Fionna Feller
- Department of Medicine, Division of Infectious DiseasesVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Tan Ding
- Department of BiostatisticsVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Gregory D. Ayers
- Department of BiostatisticsVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Marissa Potts
- Department of Medicine, Division of Infectious DiseasesVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Richard W. LaRue
- Department of Medicine, Division of Infectious DiseasesVanderbilt University Medical CenterNashvilleTennesseeUSA
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Hall AD, Hendricks HA, Bowers KA, Geller JI, Bondoc AJ, Tiao GM, Taylor AE, Otto WR, Paulsen GC, Danziger‐Isakov LA. Impact of Hepatoblastoma on Infectious Complications Following Pediatric Liver Transplantation. Pediatr Transplant 2025; 29:e70035. [PMID: 39868651 PMCID: PMC11771635 DOI: 10.1111/petr.70035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 12/27/2024] [Accepted: 01/13/2025] [Indexed: 01/28/2025]
Abstract
BACKGROUND Liver transplantation is the standard therapy for end-stage liver disease in pediatric patients with biliary atresia (BA), congenital and metabolic conditions, and for an unresectable malignant tumor like hepatoblastoma (HB). BA is the leading indication for pediatric liver transplantation, while HB is the most common childhood liver cancer. Despite improved outcomes through advanced surgical techniques and novel immunosuppression, pediatric liver transplantation (pLT) is complicated by post-transplant infections. METHODS A retrospective review was performed of pLT recipients at Cincinnati Children's Hospital Medical Center (CCHMC) and stratified patients by underlying disease to assess impact on post-transplant infectious events. RESULTS BA patients were youngest at pLT (12.5 months; p < 0.001) compared to other disease cohorts (HB 30.8, other 43.7). All HB patients received organs from deceased donors. In the year following pLT, 93% of the patients experienced at least one infectious event (IE). HB patients had the highest mean number of IE across disease groups (5.5 IE/patient vs. BA 4.5, other 4.0; p = 0.055), with significantly more patients with fever and neutropenia (p < 0.001) and EBV infections (p = 0.012). HB patients were more likely to develop IE earlier after pLT than non-HB groups (p = 0.013), especially Clostridioides difficile (p < 0.01) and fever and neutropenia (p < 0.01). Despite having variable IE experiences, 1-and-5-year survival across disease groups were similar. CONCLUSIONS IE were frequently observed in HB patients after pLT, possibly related to pre-and-postoperative chemotherapy and associated neutropenia. Underlying disease may help inform targeted infection-related patient management following pLT.
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Affiliation(s)
- Ashton D. Hall
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical CenterUniversity of CincinnatiCincinnatiOhioUSA
| | - Hope A. Hendricks
- Department of PediatricsDuke University School of MedicineDurhamNorth CarolinaUSA
| | - Katherine A. Bowers
- Center for Clinical and Translational Science and Training, Cincinnati Children's Hospital Medical CenterUniversity of CincinnatiCincinnatiOhioUSA
| | - James I. Geller
- Division of Oncology, Cincinnati Children's Hospital Medical CenterUniversity of CincinnatiCincinnatiOhioUSA
| | - Alexander J. Bondoc
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical CenterUniversity of CincinnatiCincinnatiOhioUSA
| | - Greg M. Tiao
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical CenterUniversity of CincinnatiCincinnatiOhioUSA
| | - Amy E. Taylor
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical CenterUniversity of CincinnatiCincinnatiOhioUSA
| | - William R. Otto
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical CenterUniversity of CincinnatiCincinnatiOhioUSA
| | - Grant C. Paulsen
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical CenterUniversity of CincinnatiCincinnatiOhioUSA
| | - Lara A. Danziger‐Isakov
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical CenterUniversity of CincinnatiCincinnatiOhioUSA
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Kern M, Hamm SR, Pedersen CR, Møller DL, Loft JA, Hasselbalch RB, Heftdal LD, Pries-Heje MM, Perch M, Sørensen SS, Rasmussen A, Garred P, Iversen KK, Bundgaard H, Sabin CA, Nielsen SD. Leukocyte Count in Solid Organ Transplant Recipients After SARS-CoV-2 mRNA Vaccination and Infection. Vaccines (Basel) 2025; 13:103. [PMID: 40006650 PMCID: PMC11860179 DOI: 10.3390/vaccines13020103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/20/2024] [Accepted: 01/20/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Solid organ transplant (SOT) recipients are at risk of severe COVID-19. Vaccination is an important preventive measure but may have side effects, including decreased leukocyte counts. We aimed to describe the prevalence and relative incidence of decreased leukocyte counts and changes in leukocyte counts before and after SARS-CoV-2 mRNA vaccination and SARS-CoV-2 infection in SOT recipients. METHODS Changes in leukocyte counts from before to after each vaccine dose were investigated using linear mixed models. We determined the prevalence of decreased leukocyte counts before and after each vaccine dose and before and after SARS-CoV-2 infection. Self-controlled case series analysis was used to investigate whether the period after either vaccination or infection was associated with risk of decreased leukocyte count. RESULTS We included 228 adult kidney, lung, and liver transplant recipients. Prior to the first vaccine dose, the mean leukocyte count was 7.3 × 109 cells/L (95% CI 6.9-7.6). Both the leukocyte counts, and the prevalence of decreased leukocyte counts remained unchanged from before to after vaccination regardless of the number of vaccine doses provided. There was no association between vaccination and decreased leukocyte counts (incidence rate ratio (IRR): 0.6; 95% CI: 0.2-2.1; p = 0.461). In contrast, SARS-CoV-2 infection was associated with increased risk of a decreased leukocyte count (IRR: 7.1; 95% CI: 2.8-18.1; p < 0.001). CONCLUSIONS SARS-CoV-2 mRNA vaccination was not associated with risk of decreased leukocyte count and did not affect the prevalence of decreased leukocyte counts in SOT recipients. In contrast, SARS-CoV-2 infection was associated with a higher risk of a decreased leukocyte count.
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Affiliation(s)
- Marita Kern
- Viro-Immunology Research Unit, Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark (S.R.H.)
| | - Sebastian Rask Hamm
- Viro-Immunology Research Unit, Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark (S.R.H.)
| | - Christian Ross Pedersen
- Department of Surgical Gastroenterology and Transplantation, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark
| | - Dina Leth Møller
- Viro-Immunology Research Unit, Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark (S.R.H.)
| | - Josefine Amalie Loft
- Viro-Immunology Research Unit, Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark (S.R.H.)
| | - Rasmus Bo Hasselbalch
- Department of Cardiology, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark
- Department of Emergency Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark
| | - Line Dam Heftdal
- Viro-Immunology Research Unit, Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark (S.R.H.)
| | - Mia Marie Pries-Heje
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark
| | - Michael Perch
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Søren Schwartz Sørensen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
- Department of Nephrology, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark
| | - Allan Rasmussen
- Department of Surgical Gastroenterology and Transplantation, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark
| | - Peter Garred
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
- Laboratory of Molecular medicine, Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark
| | - Kasper Karmark Iversen
- Department of Cardiology, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark
- Department of Emergency Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Henning Bundgaard
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Caroline A. Sabin
- Centre for Clinical Research, Epidemiology, Modelling and Evaluation, Institute for Global Health, UCL, Royal Free Campus, Rowland Hill St., London NW3 2PF, UK
| | - Susanne Dam Nielsen
- Viro-Immunology Research Unit, Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark (S.R.H.)
- Department of Surgical Gastroenterology and Transplantation, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
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Grieves K, Keller BC, Waldman G, Clark JE. Impact of reduced mycophenolate exposure on chronic lung allograft dysfunction incidence after lung transplant. JHLT OPEN 2024; 6:100156. [PMID: 40145047 PMCID: PMC11935493 DOI: 10.1016/j.jhlto.2024.100156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
Abstract
Background Mycophenolate mofetil (MMF) is a key immunosuppression agent for lung transplant recipients (LTR); however, the side effects often lead to dose modifications. Kidney transplant literature has shown reductions in MMF dosing led to an increased incidence of rejection, but data are limited in LTR. The objective was to evaluate the impact of reduced MMF exposure on chronic lung allograft dysfunction (CLAD) in LTR within 36 months of transplant (TXP). Methods This single-center, retrospective cohort analyzed LTRs who had an MMF dose reduction or hold ≥7 days between April 1, 2016 and October 31, 2019. LTR who died ≤1 month from TXP were excluded. The primary outcome was incidence of CLAD 36 months from TXP compared to the International Society for Heart and Lung Transplantation (ISHLT) registry data. Secondary outcomes were incidence of treated acute cellular rejection and characterization of MMF dose modifications. Results Of 109 patients evaluated, 102 (93.6%) patients had 194 MMF dose modifications within 36 months of TXP, largely due to hematologic toxicities (74.7%). Before modification, 142 (73.2%) were receiving MMF 1,000 mg/day and 52 (26.8%) were receiving 500 mg/day. Incidence of CLAD was 36.4% at 36 months compared to 32.6% reported by ISHLT (p = 0.5216). Incidence of patients with decline in forced expiratory volume in 1 sec ≥10% was 45.1% at 36 months. Conclusions In our cohort, most LTRs had an MMF dose modification within 36 months, yet CLAD incidence was consistent with rates reported in the ISHLT Thoracic Organ Transplant Registry. In contrast, more patients demonstrated reduced allograft function compared to post-TXP peak, consistent with "potential" CLAD.
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Affiliation(s)
- Kaitlyn Grieves
- Department of Pharmacy, Massachusetts General Hospital (MGH), Boston, Massachusetts
| | - Brian C. Keller
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital (MGH), Boston, Massachusetts
| | - Georgina Waldman
- Department of Pharmacy, Massachusetts General Hospital (MGH), Boston, Massachusetts
| | - Jacqueline E. Clark
- Department of Pharmacy, Massachusetts General Hospital (MGH), Boston, Massachusetts
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Mooslechner AA, Schuller M, Pfeifer V, Klötzer KA, Prietl B, Kirsch AH, Stiegler P, Sucher R, Sourij H, Rosenkranz AR, Eller K. Pre-Transplant Frequencies of FoxP3 +CD25 + in CD3 +CD8 + T Cells as Potential Predictors for CMV in CMV-Intermediate Risk Kidney Transplant Recipients. Transpl Int 2024; 37:12963. [PMID: 38868358 PMCID: PMC11167633 DOI: 10.3389/ti.2024.12963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 05/15/2024] [Indexed: 06/14/2024]
Abstract
Cytomegalovirus (CMV) infection detrimentally influences graft survival in kidney transplant recipients, with the risk primarily determined by recipient and donor serostatus. However, recipient CD8+ T cells play a crucial role in CMV control. The optimal preventive strategy (prophylaxis vs. pre-emptive treatment), particularly for seropositive (intermediate risk) recipients, remains uncertain. We investigated CD8+ T cell subpopulation dynamics and CMV occurrence (DNAemia ≥ 100 IU/mL) in 65 kidney transplant recipients, collecting peripheral blood mononuclear cells before (T1) and 1 year after transplantation (T2). Comparing the two timepoints, we found an increase in granulocyte, monocyte and CD3+CD8+ T cells numbers, while FoxP3+CD25+, LAG-3+ and PD-1+ frequencies were reduced at T2. CMV DNAemia occurred in 33 recipients (55.8%) during the first year. Intermediate risk patients were disproportionally affected by posttransplant CMV (N = 29/45, 64.4%). Intermediate risk recipients developing CMV after transplantation exhibited lower leukocyte, monocyte, and granulocyte counts and higher FoxP3+CD25+ frequencies in CD3+CD8+ T cells pre-transplantation compared to patients staying CMV negative. Pre-transplant FoxP3+CD25+ in CD3+CD8+ T cells had the best discriminatory potential for CMV infection prediction within the first year after transplantation (AUC: 0.746). The FoxP3+CD25+ CD3+CD8+ T cell subset may aid in selecting intermediate risk kidney transplant recipients for CMV prophylaxis.
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Affiliation(s)
- Agnes A. Mooslechner
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - Max Schuller
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Verena Pfeifer
- Center for Biomarker Research in Medicine, CBmed GmbH, Graz, Austria
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Konstantin A. Klötzer
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Barbara Prietl
- Center for Biomarker Research in Medicine, CBmed GmbH, Graz, Austria
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Alexander H. Kirsch
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Philipp Stiegler
- Division of General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Robert Sucher
- Division of General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Harald Sourij
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Alexander R. Rosenkranz
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Kathrin Eller
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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Huelsboemer L, Boroumand S, Kochen A, Dony A, Moscarelli J, Hauc SC, Stögner VA, Formica RN, Pomahac B, Kauke-Navarro M. Immunosuppressive strategies in face and hand transplantation: a comprehensive systematic review of current therapy regimens and outcomes. FRONTIERS IN TRANSPLANTATION 2024; 3:1366243. [PMID: 38993787 PMCID: PMC11235358 DOI: 10.3389/frtra.2024.1366243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 02/21/2024] [Indexed: 07/13/2024]
Abstract
Background Recipients of Vascularized Composite Allotransplants require effective immunosuppressive therapy to prevent graft rejection. This systematic review summarizes the current body of literature on immunosuppressive regimens used in face and hand transplants while summarizing their outcome in terms of rejection, renal failure, and infections. Methods A systematic search of electronic databases was conducted to identify relevant studies from 1998 until July 1st, 2023. We included all studies that discussed immunosuppressive strategies in face and hand transplant recipients according to PRISMA. Results The standard triple maintenance therapy was mostly adjusted due to nephrotoxicity or high incidence of rejection. The most common alternative treatments utilized were sirolimus (25/91; 27.5%) or everolimus (9/91; 9.9%) following hand- and photophoresis (7/45; 15.6%), sirolimus (5/45; 11.1%) or belatacept (1/45; 2.2%) following face transplantation. Episodes of rejection were reported in 60 (65.9%) of hand- and 33 (73%) of face transplant patients respectively. Graft loss of 12 (13.2%) hand and 4 (8.9%) face transplants was reported. Clinical CMV infection was observed in 6 (6.6%) hand and 7 (15.5%) face transplant recipients. Conclusions Based on the herein presented data, facial grafts exhibited a heightened incidence of rejection episodes and CMV infections. Facial mucosa adds complexity to the immunological graft composition highlighting the need of individualized immunosuppressive regimens and further research.
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Affiliation(s)
- Lioba Huelsboemer
- Division of Reconstructive and Plastic Surgery, Yale School of Medicine, New Haven, CT, United States
| | - Sam Boroumand
- Division of Reconstructive and Plastic Surgery, Yale School of Medicine, New Haven, CT, United States
| | - Alejandro Kochen
- Division of Reconstructive and Plastic Surgery, Yale School of Medicine, New Haven, CT, United States
- Regenerative Wound Healing Center, Yale School of Medicine, New Haven, CT, United States
| | - Alna Dony
- Division of Reconstructive and Plastic Surgery, Yale School of Medicine, New Haven, CT, United States
- School of Medicine, University of Leeds, Leeds, United Kingdom
| | - Jake Moscarelli
- Division of Reconstructive and Plastic Surgery, Yale School of Medicine, New Haven, CT, United States
| | - Sacha C. Hauc
- Division of Reconstructive and Plastic Surgery, Yale School of Medicine, New Haven, CT, United States
| | - Viola A. Stögner
- Division of Reconstructive and Plastic Surgery, Yale School of Medicine, New Haven, CT, United States
| | - Richard N. Formica
- Department of Medicine, Section of Nephrology and Transplantation, Yale School of Medicine, New Haven, CT, United States
| | - Bohdan Pomahac
- Division of Reconstructive and Plastic Surgery, Yale School of Medicine, New Haven, CT, United States
| | - Martin Kauke-Navarro
- Division of Reconstructive and Plastic Surgery, Yale School of Medicine, New Haven, CT, United States
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9
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Almaghlouth NK, Arvanitis P, Vieira K, London A, Farmakiotis D. Using a commercially available assay that measures cytomegalovirus (CMV)-specific T-cell immunity to predict protection against CMV: A prospective, blinded clinical study. Diagn Microbiol Infect Dis 2024; 108:116139. [PMID: 37984109 DOI: 10.1016/j.diagmicrobio.2023.116139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/13/2023] [Accepted: 11/14/2023] [Indexed: 11/22/2023]
Abstract
The Viracor CMV-T-cell immunity Panel (TCIP) measures %CMV-specific CD4+ and CD8+ T-cells. In this blinded clinical study, we evaluated the performance of the TCIP in predicting CMV events. Prospectively enrolled donor or recipient CMV-seropositive kidney transplant recipients (KTR) were evaluated with monthly TCIP testing until either discontinuation of valganciclovir prophylaxis or CMV DNAemia prompting treatment initiation. Also, prospectively enrolled KTR with low-level untreated DNAemia or after completion of treatment were evaluated for progression or relapse of CMV infection. Among 46 KTR, those with CMV events had significantly lower %CMV-specific CD8+ T-cells (p = 0.024), and the CMV protection ROC AUC was significant (AUC 0.78, p = 0.026). The positive predictive values of CD4+ and CD8+ T-cell positivity >0.2 % for CMV protection were: 96.3 % for CMV DNAemia prompting treatment initiation, 92.6 % for any DNAemia, 100 % for DNAemia >1000 IU/mL. The TCIP could be a useful adjunct tool in individualized management of CMV infection.
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Affiliation(s)
- Nouf K Almaghlouth
- Division of Infectious Diseases, 593 Eddy Street, Gerry House 111, Providence, RI 02903, United States
| | - Panagiotis Arvanitis
- Division of Infectious Diseases, 593 Eddy Street, Gerry House 111, Providence, RI 02903, United States
| | - Kendra Vieira
- Division of Infectious Diseases, 593 Eddy Street, Gerry House 111, Providence, RI 02903, United States
| | - Abby London
- Internal Medicine Residency Program, The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Dimitrios Farmakiotis
- Division of Infectious Diseases, 593 Eddy Street, Gerry House 111, Providence, RI 02903, United States.
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10
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Farkas K, Varga M, Dinnyes I, Rem L, Telkes G, Wagner L, Remport A, Piros L, Szijarto A, Huszty G. Low-Dose vs Standard-Dose Valganciclovir for Cytomegalovirus Prophylaxis After Kidney Transplantation: A Single-Center Retrospective Analysis. Transplant Proc 2024; 56:105-110. [PMID: 38199858 DOI: 10.1016/j.transproceed.2023.11.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 11/30/2023] [Indexed: 01/12/2024]
Abstract
BACKGROUND Prophylactic administration of valganciclovir (VG) is an accepted method for the prevention of cytomegalovirus (CMV) infection after kidney transplantation (KTx). The standard dosage of oral VG is 900 mg/day, adjusted to renal function. There is growing evidence that low-dose 450 mg/day VG might be safe and effective. We compared low-dose vs standard-dose prophylaxis after KTx in a single-center follow-up study. METHODS Data from 603 renal transplantations at a single center were retrospectively analyzed (2011-2014, 12-month follow-up). Recipients with donor IgG positive-recipient IgG positive (D+/R+), (D+/R-), and (D-/R+) CMV serostatus were routinely treated with 450 mg/day VG for 3 months. Based on the same prophylactic dose, patients could be categorized into two groups according to their postoperative renal function: those receiving standard-dose VG due to a lower estimated glomerular filtration rate (eGFR) (average eGFR<60 mL/min/1.73 m2) and those receiving low-dose VG due to higher eGFR (average eGFR>60 mL/min/1.73 m2). RESULTS Estimated glomerular filtration rate-based VG serum alterations significantly affected the risk of CMV infection with a higher incidence in higher VG levels (standard-dose: 357 patients, CMV: 33 cases (9.2 %); low-dose: 246 patients, CMV: 10 cases (4.1%). The occurrence of known risk factors: serologic risk distribution and rate of induction therapy were not statistically different between the 2 groups. Treatment of an acute rejection episode influenced the infection rate significantly in the standard-dose group. As a side effect of prophylaxis, leucopenia (<3G/L) was 2.46 times higher in standard-dose vs low-dose group. CONCLUSION Low-dose VG administration is safe and non-inferior to the standard dose in the prophylaxis of CMV infection after KTx.
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Affiliation(s)
- Katalin Farkas
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Marina Varga
- Department of Laboratory Medicine, Semmelweis University, Faculty of Medicine, Budapest, Hungary
| | - Izabella Dinnyes
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Lili Rem
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Gabor Telkes
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Laszlo Wagner
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Adam Remport
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Laszlo Piros
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Attila Szijarto
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Gergely Huszty
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary.
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11
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Jorgenson MR, Descourouez JL, Saddler CM, Smith JA, Odorico JS, Rice JP, Mandelbrot DA. Real world experience with conversion from valganciclovir to letermovir for cytomegalovirus prophylaxis: Letermovir reverses leukopenia and avoids mycophenolate dose reduction. Clin Transplant 2023; 37:e15142. [PMID: 37755141 DOI: 10.1111/ctr.15142] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/06/2023] [Accepted: 09/18/2023] [Indexed: 09/28/2023]
Abstract
PURPOSE Valganciclovir (VGC) is the gold-standard for cytomegalovirus (CMV) prophylaxis (PPX) after solid organ transplant (SOT). Letermovir (LTV) was recently approved in high-risk kidney transplant and has reduced myelosuppressive toxicity. Conversion from VGC to LTV may be pursued in the setting of leukopenia. It is unknown if this strategy is effective. METHODS Adult patients receiving abdominal SOT were included if converted from VGC to LTV between January 1, 2018 and January 31, 2023. Primary objective was to describe the impact of LTV conversion as measured by WBC recovery, mycophenolate modification, and use of GCSF, and prophylaxis efficacy assessed by course completion and breakthrough DNAemia. Secondary objective was to evaluate rates of post-prophylaxis CMV. RESULTS Seventy five SOT recipients met inclusion criteria. Mean change in WBC in response to LTV conversion by day 14 was +2.02 ± 2.52 k/uL. 75%(56/75) of the population did not require mycophenolate adjustment or had their dose increased after conversion. GCSF was required in 38.7%(29/75) prior to conversion; only 21.3%(16/75) of patients required GCSF after conversion. Early termination was uncommon, 14.7%(11/75) stopped due to lack of ongoing insurance approval, only one patient stopped due to adverse effects (1.3%). One patient had clinically significant breakthrough (1.3%) that was successfully managed with VGC. Incidence of post prophylaxis CMV was 40%. CONCLUSION Withholding of VGC with LTV conversion may improve leukopenia without need for additional supportive measures. Most importantly, this strategy avoided additional mycophenolate modifications. In our study, LTV was associated with low rates of breakthrough. Post-prophylaxis CMV was similar to VGC prophylaxis.
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Affiliation(s)
- Margaret R Jorgenson
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - Jillian L Descourouez
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - Christopher M Saddler
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - Jeannina A Smith
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - Jon S Odorico
- Depart of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - John P Rice
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - Didier A Mandelbrot
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
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12
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Regev-Sadeh S, Borovitz Y, Steinberg-Shemer O, Gilad O, Shoham S, Yacobovich J. Cytopenias in pediatric kidney transplant recipients: preceding factors and clinical consequences. Pediatr Nephrol 2023; 38:3445-3454. [PMID: 37079102 DOI: 10.1007/s00467-023-05905-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 01/30/2023] [Accepted: 02/01/2023] [Indexed: 04/21/2023]
Abstract
BACKGROUND Kidney trans plantation is associated with secondary complications, including the risk of developing posttransplant cytopenias. This study aimed to evaluate the characteristics, identify predictors, and assess the management and consequences of cytopenias in the pediatric kidney transplant population. METHODS This is a single-center retrospective analysis of 89 pediatric kidney transplant recipients. Possible factors preceding cytopenias were compared with the goal of recognizing predictors for posttransplant cytopenias. Posttransplant neutropenias were analyzed for the total study period and separately for the period beyond 6 months posttransplant (late neutropenias), to rule out confounding influences of induction and initial intensive therapy. RESULTS Sixty patients (67%) developed at least one episode of posttransplant cytopenia. All episodes of posttransplant thrombocytopenias were mild or moderate. Posttransplant infections and graft rejection were found to be significant predictors for thrombocytopenia (HR 6.06, 95% CI 1.6-22.9, and HR 5.82, 95% CI 1.27-26.6, respectively). A total of 30% of posttransplant neutropenias were severe (ANC ≤ 500). Pretransplant dialysis and posttransplant infections were significant predictors for late neutropenias (HR 11.2, 95% CI 1.45-86.4, and HR 3.32, 95% CI 1.46-7.57, respectively). Graft rejection occurred in 10% of patients with cytopenia, all following neutropenia, within 3 months from cytopenia appearance. In all such cases, mycophenolate mofetil dosing had been held or reduced prior to rejection. CONCLUSIONS Posttransplant infections are substantial contributors to developing posttransplant cytopenias. Preemptive transplantation appears to reduce risk of late neutropenia, the accompanying reduction in immunosuppressive therapy, and the ensuing risk of graft rejection. An alternative response to neutropenia, possibly using granulocyte colony stimulating factor, may diminish graft rejection. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
| | - Yael Borovitz
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
- Nephrology Institute, Schneider Children's Medical Center, Petach Tikva, Israel.
| | - Orna Steinberg-Shemer
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center, Petach Tikva, Israel
| | - Oded Gilad
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center, Petach Tikva, Israel
| | - Shoval Shoham
- Research Authority, Schneider Children's Medical Center, Petach Tikva, Israel
| | - Joanne Yacobovich
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center, Petach Tikva, Israel
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13
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Mimura K, Shimomura A, Watanabe K, Koda H, Nakayama K, Kitagawa D, Shimizu C. Severe cytopenia during adjuvant chemotherapy for early breast cancer in a patient with idiopathic CD4+ lymphocytopenia. Oncol Lett 2023; 26:357. [PMID: 37545613 PMCID: PMC10398621 DOI: 10.3892/ol.2023.13943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 06/22/2023] [Indexed: 08/08/2023] Open
Abstract
Idiopathic CD4+ lymphocytopenia (ICL) is a rare immunodeficiency disorder characterized by decreased CD4+ T-cell counts in the absence of human immunodeficiency virus (HIV) infection. Similar to HIV infection, ICL is commonly associated with acquired immunodeficiency syndrome-defining cancers, such as Kaposi sarcoma, non-Hodgkin lymphoma and cervical cancer; however, the presentation of breast cancer in a patient with ICL is rare. The current study presented the clinical course of a patient with early breast cancer and ICL. Following surgery, the patient underwent adjuvant chemotherapy comprising doxorubicin plus cyclophosphamide, followed by paclitaxel. The patient's immunodeficiency status required the prophylactic administration of clarithromycin, trimethoprim-sulfamethoxazole and valganciclovir. Throughout the course of chemotherapy, the patient experienced severe complications of febrile neutropenia, anemia, neutropenia and thrombocytopenia, and was eventually forced to discontinue anticancer chemotherapy, as the relative dose intensity (RDI) could not be maintained. Similar hematological complications and reduced RDI, leading to worse outcomes, are also common in patients with HIV infection receiving chemotherapy, suggesting that CD4+ T cell-deficient patients are prone to developing cytopenia during chemotherapy. The present study demonstrates the importance of further data accumulation in patients with ICL with cancer and the development of a methodology for maintaining the RDI.
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Affiliation(s)
- Kaito Mimura
- Department of Breast and Medical Oncology, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Akihiko Shimomura
- Department of Breast and Medical Oncology, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
- National Center for Global Health and Medicine Research Course in Advanced Medical Specialties, Juntendo University Cooperative Graduate School, Tokyo 113-8421, Japan
| | - Koji Watanabe
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Hanako Koda
- Department of Surgery, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Kanako Nakayama
- Department of Breast Surgical Oncology, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Dai Kitagawa
- Department of Breast Surgical Oncology, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Chikako Shimizu
- Department of Breast and Medical Oncology, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
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14
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Lim IV, Yurttaş NÖ, Ayer M, Poturoğlu Ş, Kınacı E, Özden İ. Entecavir-induced neutropenia in an adult living donor liver transplant recipient: Successful conversion to tenofovir alafenamide. Clin Case Rep 2023; 11:e7741. [PMID: 37575459 PMCID: PMC10421973 DOI: 10.1002/ccr3.7741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 08/15/2023] Open
Abstract
At 22 weeks post-transplantation for HBV-related cirrhosis, an adult woman developed neutropenia which was aggravated by COVID-19 (ANC 0.4 × 109/L). Covid resolution and all "conventional" modifications were ineffective. Success within 2 weeks was achieved by switching entecavir to tenofovir alafenamide. A step-by-step judicious approach to post-transplant neutropenia is vital.
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Affiliation(s)
- I. Vern Lim
- Department of General Surgery, Liver Transplantation & Hepatopancreatobiliary Surgery UnitBaşakşehir Çam & Sakura City HospitalIstanbulTurkey
| | - Nurgül Özgür Yurttaş
- Department of Internal Medicine, Division of HematologyBaşakşehir Çam & Sakura City HospitalIstanbulTurkey
| | - Mesut Ayer
- Department of Internal Medicine, Division of HematologyBaşakşehir Çam & Sakura City HospitalIstanbulTurkey
| | - Şule Poturoğlu
- Department of Internal Medicine, Division of GastroenterologyBaşakşehir Çam & Sakura City HospitalIstanbulTurkey
| | - Erdem Kınacı
- Department of General Surgery, Liver Transplantation & Hepatopancreatobiliary Surgery UnitBaşakşehir Çam & Sakura City HospitalIstanbulTurkey
| | - İlgin Özden
- Department of General Surgery, Liver Transplantation & Hepatopancreatobiliary Surgery UnitBaşakşehir Çam & Sakura City HospitalIstanbulTurkey
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15
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Harshman LA, Williams R, Engen RM. Neutropenia in pediatric solid organ transplant. Pediatr Transplant 2022; 26:e14378. [PMID: 35986635 DOI: 10.1111/petr.14378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/12/2022] [Accepted: 08/01/2022] [Indexed: 01/19/2023]
Abstract
Neutropenia is generally defined as an absolute neutrophil count in the circulation of less than 1500/mm3 and occurs in up to 25%-30% of pediatric solid organ transplant recipients (SOT) within the first year after transplantation. In the SOT population, neutropenia is most often a result of drug-induced bone marrow suppression but can also be secondary to viral infection, nutritional deficiencies, lymphoproliferative infiltrate, and inherited causes. Outcomes for patients with neutropenia vary by degree of neutropenia and type of solid organ transplant. Management of neutropenia should begin by addressing the underlying cause, including reducing or removing medications when appropriate, treating infections, and addressing nutrient deficiencies; however, consultation with an experienced pediatric hematologist and use of granulocyte colony-stimulating factor (G-CSF) may be helpful in some cases. Overall, data on clinical outcomes for G-CSF use remain limited, but observational studies may support its use in patients with infections or severe neutropenia.
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Affiliation(s)
- Lyndsay A Harshman
- Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
| | - Robin Williams
- Division of Pediatric Hematology/Oncology, University of Minnesota Masonic Children's Hospital, Minneapolis, Minnesota, USA
| | - Rachel M Engen
- Division of Nephrology, Department of Pediatrics, University of Wisconsin Madison, Madison, Wisconsin, USA
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16
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Baradaran H, Hashem Zadeh A, Dashti-Khavidaki S, Laki B. Management of drug-induced neutropenia, thrombocytopenia, and anaemia after solid organ transplantation: A comprehensive review. J Clin Pharm Ther 2022; 47:1895-1912. [PMID: 36250775 DOI: 10.1111/jcpt.13775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/12/2022] [Accepted: 08/18/2022] [Indexed: 12/24/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Advances in the development of more effective immunosuppressive drugs have increased graft survival and drug induced adverse effects. Haematological complications including neutropenia, thrombocytopenia, and anaemia are common side effects that affect the grafts' and patients' outcomes. Several studies have stated the important role of various medications in haematological complications after transplantation. They have reported the incidence and different mechanisms of drug induced cytopenia, as well as an overview of possible treatment modalities. However, there is no comprehensive protocol for the management of these complications following transplantation. This narrative review was performed to develop a comprehensive practical approach for management of drug induced haematological complications following solid organ transplantation. METHOD PubMed, Embase, Cochrane library, Web of Science, and Google scholar databases were searched without time limitations until March, 2021. In addition, some valid drug information data bases (Uptodate and Micromedex) were searched for detailed information until October, 2021. RESULTS AND DISCUSSION Several immunosuppressive and antimicrobial medications may induce neutropenia, thrombocytopenia or anaemia following transplantation. Most of these agents cause dose-related cytopenia, which resolves with dose reduction or drug withdrawal. However, any change in medications may result in negative consequences such as severe infections, bleeding, cardiovascular complications, acute allograft rejection, and graft or patient loss. Thus, cautious evaluation of the patient's condition and the pharmacological properties of the culprit medication are required. WHAT IS NEW AND CONCLUSION Three algorithms are presented to guide healthcare providers in the stepwise management of drug-induced neutropenia, thrombocytopenia, and anaemia after solid organ transplantation.
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Affiliation(s)
- Hananeh Baradaran
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Simin Dashti-Khavidaki
- Liver Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahareh Laki
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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17
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Azhar A, Tsujita M, Talwar M, Balaraman V, Bhalla A, Eason JD, Nouer SS, Sumida K, Remport A, Hall IE, Griffin R, Rofaiel G, Molnar MZ. CMV specific T cell immune response in hepatitis C negative kidney transplant recipients receiving transplant from hepatitis C viremic donors and hepatitis C aviremic donors. Ren Fail 2022; 44:831-841. [PMID: 35546431 PMCID: PMC9103398 DOI: 10.1080/0886022x.2022.2072744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 04/12/2022] [Accepted: 04/22/2022] [Indexed: 12/03/2022] Open
Abstract
Kidney transplants (KT) from hepatitis C (HCV) viremic donors to HCV negative recipients has shown promising renal outcomes, however, high incidence of cytomegalovirus (CMV) viremia were reported. We performed a prospective cohort study of 52 HCV negative KT recipients from Methodist University Hospital including 41 receiving transplants from HCV aviremic donors and 11 from HCV viremic donors. CMV specific CD4+ and CD8 + T cell immunity was measured by intracellular flow cytometry assay. Primary outcome was the development of positive CMV specific CD4+ and CD8 + T cell immune response in the entire cohort and each subgroup. The association between donor HCV status and CMV specific CD4+ and CD8 + T cell immune response was analyzed by Cox proportional hazard models. Mean recipient age was 48 ± 13 years, with 73% male and 82% African American. Positive CMV specific CD4+ and CD8 + T cell immune response was found in 53% and 47% of the cohort at 1 month, 65% and 70% at 2 months, 80% and 75% at 4 months, 89% and 87% at 6 months, and 94% and 94% at 9 months post-transplant, respectively. There was no significant difference in the incidence of positive CMV specific T cell immune response between recipients of transplants from HCV aviremic donors compared to HCV viremic donors in unadjusted (for CD8+: HR = 1.169, 95%CI: 0.521-2.623; for CD4+: HR = 1.208, 95%CI: 0.543-2.689) and adjusted (for CD8+: HR = 1.072, 95%CI: 0.458-2.507; for CD4+: HR = 1.210, 95%CI: 0.526-2.784) Cox regression analyses. HCV viremia in donors was not associated with impaired development of CMV specific T cell immunity in this cohort.
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Affiliation(s)
- Ambreen Azhar
- Department of Medicine, Division of Nephrology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Makoto Tsujita
- James D. Eason Transplant Institute, Methodist University Hospital, Memphis, TN, USA
- Department of Surgery, Division of Transplant Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Manish Talwar
- James D. Eason Transplant Institute, Methodist University Hospital, Memphis, TN, USA
- Department of Surgery, Division of Transplant Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Vasanthi Balaraman
- James D. Eason Transplant Institute, Methodist University Hospital, Memphis, TN, USA
- Department of Surgery, Division of Transplant Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Anshul Bhalla
- James D. Eason Transplant Institute, Methodist University Hospital, Memphis, TN, USA
- Department of Surgery, Division of Transplant Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - James D. Eason
- James D. Eason Transplant Institute, Methodist University Hospital, Memphis, TN, USA
- Department of Surgery, Division of Transplant Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Simonne S. Nouer
- Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Keiichi Sumida
- Department of Medicine, Division of Nephrology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Adam Remport
- Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary
| | - Isaac E. Hall
- Department of Medicine, Division of Nephrology & Hypertension, University of Utah, Salt Lake City, UT, USA
| | - Randi Griffin
- Office of Clinical Research, University of Tennessee Health Science Center, Memphis, TN, USA
| | - George Rofaiel
- Department of Surgery, Division of Transplantation and Advanced Hepatobiliary Surgery, University of Utah, Salt Lake City, UT, USA
| | - Miklos Z. Molnar
- Department of Medicine, Division of Nephrology & Hypertension, University of Utah, Salt Lake City, UT, USA
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18
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Shadekejiang H, Zhu J, Wu X. Transplant of Kidneys From Hepatitis C Virus-Positive Donors To Hepatitis C Virus-Negative Recipients: A Retrospective Study and Systematic Review. EXP CLIN TRANSPLANT 2022; 20:1076-1084. [PMID: 36718006 DOI: 10.6002/ect.2022.0315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
OBJECTIVES Kidneys from hepatitis C virus-positive donors were often discarded due to the lack of an effective treatment for hepatitis C virus. However, the advent of direct-acting antivirals has facilitated great progress for treatment of hepatitis C virus, providing additional opportunities for patients waiting for kidney transplant. We explored the feasibility and safety of kidney transplant from hepatitis C virus- positive donors to hepatitis C virus-negative recipients in combination with direct-acting antiviral therapy. MATERIALS AND METHODS This was a single-center retrospective study of 7 recipients of hepatitis C virus- positive kidneys from June 2018 to June 2021. All recipients were treated with sofosbuvir/velpatasvir for 12 weeks after kidney transplant. The primary recipients' outcome was achievement of sustained viral eradication at 12 weeks after treatment, and follow-up secondary outcomes were kidney function recovery, liver function, and adverse drug reactions. We reviewed previous studies, from 2017 to 2022, to analyze achievement of sustained viral eradication at 12 weeks after treatment, recipient and graft survival, and adverse event of kidney transplant from a hepatitis C virus-positive donor to a hepatitis C virus-negative recipient. RESULTS Median follow-up time was 71 weeks (range, 56-183 weeks). All recipients achieved sustained viral eradication at 12 weeks after treatment, and their kidney function recovered without severe liver damage or adverse drug reactions. Previous studies suggested that transplant of hepatitis C virus-positive donor kidneys is safe and feasible when combined with direct-acting antiviral therapy. However, details regarding optimal duration of treatment and directacting antiviral regimen remain undetermined, so prospective randomized studies are warranted. CONCLUSIONS Our study further confirms that kidney transplant from hepatitis C virus-positive donors to hepatitis C virus-negative recipients is safe and feasible with direct-acting antiviral treatment. Grafts from hepatitis C virus-infected donors may be effective to resolve the problem of kidney shortage.
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Affiliation(s)
- Halinuer Shadekejiang
- From the Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
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19
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Sandal S, Yao H, Alam A, Arienzo DD, Baran D, Cantarovich M. Granulocyte colony-stimulating factor with or without immunosuppression reduction in neutropenic kidney transplant recipients. Clin Transplant 2022; 36:e14766. [PMID: 35822347 DOI: 10.1111/ctr.14766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 06/21/2022] [Accepted: 06/28/2022] [Indexed: 11/26/2022]
Abstract
Neutropenia post-kidney transplantation is associated with adverse graft and patient outcomes. We aimed to analyze the effect of granulocyte colony-stimulating factor (G-CSF) use with and without immunosuppression reduction on graft outcomes in neutropenic recipients. In this retrospective cohort study, we identified 120 recipients with neutropenia, within the first-year post-transplant. Of these, 45.0% underwent no intervention, 17.5% had immunosuppression reduced, 18.3% were only given G-CSF, and 19.2% had both interventions. Overall, 61 patients experienced the composite outcome of de-novo DSA, biopsy-proven acute rejection, and all-cause graft failure and the cumulative incidence of this outcome did not vary by any of the four interventions (p = 0.93). When stratifying the cohort by G-CSF use alone, those who received G-CSF were more likely to have had severe neutropenia (<500/mm3 :51.1%vs.12.0%, p<0.001), and immunosuppression reduction (51.1%vs.28.0%, p = 0.003). However, the composite outcome was not different in the G-CSF and no G-CSF cohort (53.3%vs.49.3%, p = 0.67), and in a multivariate model, G-CSF use was not associated with this outcome (aHR = 1.18, 95%CI:0.61-2.30). However, a trend towards higher DSA production was noted in the G-CSF cohort (87.5%vs.62.2%) and this observation warrants prospective evaluation. Overall, we conclude that G-CSF use with or without immunosuppression reduction was not associated with graft outcomes. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Shaifali Sandal
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.,Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Han Yao
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
| | - Ahsan Alam
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.,Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - David D Arienzo
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
| | - Dana Baran
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.,Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Marcelo Cantarovich
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.,Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
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20
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Johnson AC, Karadkhele G, Magua W, Vasanth P, Larsen CP. Longitudinal Evaluation of Cytopenias in the Renal Transplant Population. Transplant Direct 2022; 8:e1339. [PMID: 35651583 PMCID: PMC9148693 DOI: 10.1097/txd.0000000000001339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/30/2022] [Accepted: 04/21/2022] [Indexed: 11/26/2022] Open
Abstract
Cytopenias, a common complication for immunosuppressed patients, are known to be associated with adverse transplant outcomes. However, there is little information on cytopenias in recipients treated with the costimulation blockade agent, belatacept. Methods We compared cytopenia incidence and manifestations in patients undergoing kidney transplant at Emory University Hospital on tacrolimus and belatacept. To reduce selection bias, the tacrolimus group was narrowed to include only patients eligible for belatacept. Results Of 1651 patients transplanted between 2009 and 2019, 187 (11%) experienced severe anemia, 309 (19%) experienced leukopenia, and 62 (4%) thrombocytopenia. On multivariable regressions, deceased-donor transplant, cytomegalovirus viremia, and thymoglobulin treatment were associated with risk of developing leukopenia, anemia, and thrombocytopenia. High-risk cytomegalovirus status was also associated with development of leukopenia and anemia. Additionally, azathioprine was associated with development of anemia, and both tacrolimus therapy and Caucasian race were associated with thrombocytopenia. Longitudinal quantifications of hematologic cell lines over the first-year posttransplant were extracted from generalized linear models fit using splines. Only hemoglobin range was significantly different between groups (greater in belatacept patients). Plots of mean cell count for each group suggest an earlier recovery from posttransplant anemia in belatacept patients. Conclusions Belatacept patients are not at increased risk of cytopenia but may have improved recovery from posttransplant anemia.
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Affiliation(s)
| | | | - Wairimu Magua
- Department of Surgery, Emory University, Atlanta, GA
| | - Payas Vasanth
- Division of Nephrology, Department of Medicine, Emory University, Atlanta, GA
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21
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Jarasvaraparn C, Choudhury S, Rusch C, Nadler M, Liss KH, Stoll J, Hmiel S, Khan A, Doyle M, Kulkarni S. Characteristics, risk factors, and outcomes of neutropenia after liver or kidney transplantation in children. Pediatr Transplant 2022; 26:e14131. [PMID: 34494348 PMCID: PMC10591294 DOI: 10.1111/petr.14131] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 08/17/2021] [Accepted: 08/20/2021] [Indexed: 01/19/2023]
Abstract
BACKGROUND While prior adult studies have shown that approximately 20%-38% of subjects undergoing solid-organ transplant develop neutropenia, similar analyses in pediatric subjects are scarce. METHODS We conducted a retrospective chart review of liver transplant (LT) and kidney transplant (KT) recipients at our center during the period 2008-2018. All of the KT and none of the LT subjects during this time period had induction with either anti-thymocyte globulin (ATG) or basiliximab at time of transplant. Neutropenia was defined as absolute neutrophil count (ANC) value ≤1000/mm3 . RESULTS One hundred subjects with LT and 82 subjects with KT were included. The incidence of neutropenia within the first year of transplant in KT was higher compared to LT (54.8% vs 39%, p = .01). The median number of hospitalizations (p = .001) and infectious complications (p = .04) was significantly higher only in the KT subjects who developed neutropenia (compared to those who did not). Multivariate analysis identified factors associated with severity of liver disease at transplant, namely h/o upper gastrointestinal bleeding (p = .02), weight deficit (p = .01), and pre-LT ANC (p = .01), along with high or moderate risk cytomegalovirus status (p = .05) as predictors of neutropenia in LT subjects. Female gender (p = .03) predicted neutropenia, while BK virus infection was protective for neutropenia (p = .04) in KT subjects. CONCLUSIONS The incidence of and morbidity associated with neutropenia within 1 year post-transplant is higher in KT subjects compared to LT subjects. The likely reason for this is the use of induction therapy (ATG, basiliximab) at the time of transplant in KT subjects.
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Affiliation(s)
- Chaowapong Jarasvaraparn
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Shelley Choudhury
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Courtney Rusch
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Michelle Nadler
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Kim H.H. Liss
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Janis Stoll
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Stanley Hmiel
- Department of Pediatrics, Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Adeel Khan
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Maria Doyle
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Sakil Kulkarni
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA
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22
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Brar S, Berry R, Raval AD, Tang Y, Vincenti F, Skartsis N. Outcomes among CMV-mismatched and highly sensitized kidney transplants recipients who develop neutropenia. Clin Transplant 2022; 36:e14583. [PMID: 34984735 DOI: 10.1111/ctr.14583] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 11/23/2021] [Accepted: 12/30/2021] [Indexed: 12/21/2022]
Abstract
Limited data exist on the incidence and clinical outcomes of neutropenia among kidney transplant recipients. Our study included 572 adults who received a kidney transplant at the University of California, San Francisco Medical Center between 2012 and 2018, and were CMV-mismatched or had a PRA ≥ 80%. Recipients with HIV, Hepatitis B and C, and primary non-function were excluded. Participants were followed for at least one year after transplantation. Neutropenia was defined as absolute neutrophil count < 1000 cells/μL. Cox proportional hazards regression models using neutropenia as a time-varying predictor were used to determine the risk of mycophenolic acid and valganciclovir changes, rejection, hospitalizations and use of granulocyte colony stimulating factor. Models were adjusted for demographics and transplant characteristics. Mean follow-up was 3.7 (SD, 1.8) years. The mean age of the cohort was 50.4 (13.1) years, and 57.5% were female. A total of 208 (36.3%) participants had neutropenia. Neutropenia was associated with an increased risk of valganciclovir or MPA dose reductions or discontinuations [adjusted hazard ratio, aHR: 7.78, 95% CI: 4.73- 12.81], rejection [aHR 2.00, 95% CI: 1.10-3.64] and hospitalizations [aHR 3.32, 95% CI: 2.12-5.19]. Neutropenia occurs frequently after kidney transplantation and leads to more medication changes and adverse clinical outcomes. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Sandeep Brar
- Department of Epidemiology and Biostatistics, University of California, San Francisco.,Division of Nephrology, Department of Medicine, University of Alberta, Edmonton
| | - Reyoot Berry
- Division of Nephrology, University of California, San Francisco School of Medicine, San Francisco
| | | | | | - Flavio Vincenti
- Division of Nephrology, University of California, San Francisco School of Medicine, San Francisco
| | - Nikolaos Skartsis
- Division of Nephrology, University of California, San Francisco School of Medicine, San Francisco
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23
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Ecabert D, Pham C, Pierce BJ, Musick WL, Nguyen DT, Graviss EA. Safety of Valganciclovir 450 mg 3 Times Weekly for Cytomegalovirus Prophylaxis in Solid Organ Transplant Recipients Requiring Hemodialysis. Open Forum Infect Dis 2021; 8:ofab436. [PMID: 34646907 PMCID: PMC8501296 DOI: 10.1093/ofid/ofab436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 08/20/2021] [Indexed: 11/14/2022] Open
Abstract
Background Valganciclovir is the most commonly used antiviral for cytomegalovirus (CMV) prophylaxis in solid organ transplant recipients. However, there are limited clinical outcomes-supported data available to guide valganciclovir dosing in patients on hemodialysis (HD). This study aimed to assess the safety of our institution's current dosing strategy of valganciclovir 450 mg 3 times weekly post-HD. Methods This was a single-center retrospective review of all adult nonkidney transplant recipients between May 2016 and June 2018. Patients with end-stage renal disease requiring HD for >28 days posttransplant receiving valganciclovir 450 mg 3 times weekly post-HD were matched with non-HD patients receiving valganciclovir prophylaxis dosed per renal function. The primary endpoints were incidence of leukopenia, neutropenia, and thrombocytopenia while on valganciclovir prophylaxis. Results A total of 465 nonkidney transplants were performed during the study period, with 37 patients included in the HD group who were matched to 111 control patients in the non-HD group. Liver transplant recipients comprised 84% and 72% of each group, with none being CMV D+/R-. The rates of leukopenia (51.4% vs 51.4%, P = 1.00), severe neutropenia (absolute neutrophil count <500 cells/µL, 15.8% vs 14.0%, P = .85), and thrombocytopenia (24.3% vs 20.7%, P = .64) were similar in both HD and non-HD groups. There were no cases of CMV infection while on valganciclovir prophylaxis in either group. Conclusions Valganciclovir 450 mg 3 times weekly was found to have similar rates of leukopenia, neutropenia, thrombocytopenia, and CMV infection in comparison to valganciclovir dosed per renal function in non-HD transplant recipients.
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Affiliation(s)
- Danielle Ecabert
- Houston Methodist Hospital, Department of Pharmacy, Houston, Texas,USA
| | - Christine Pham
- Houston Methodist Hospital, Department of Pharmacy, Houston, Texas,USA
| | - Brett J Pierce
- Houston Methodist Hospital, Department of Pharmacy, Houston, Texas,USA
| | - William L Musick
- Houston Methodist Hospital, Department of Pharmacy, Houston, Texas,USA
| | - Duc T Nguyen
- Houston Methodist Hospital, Department of Pathology and Genomic Medicine, Houston, Texas,USA
| | - Edward A Graviss
- Houston Methodist Hospital, Department of Pathology and Genomic Medicine, Houston, Texas,USA.,Houston Methodist Hospital, Department of Surgery, Houston, Texas,USA
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24
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Mohapatra A, Valson AT, Annapandian VM, David VG, Alexander S, Jacob S, Kakde S, Kumar S, Devasia A, Vijayakumar TS, Tamilarasi V, Jacob CK, Basu G, John GT, Varughese S. Post-transplant complications, patient, and graft survival in pediatric and adolescent kidney transplant recipients at a tropical tertiary care center across two immunosuppression eras. Pediatr Transplant 2021; 25:e13973. [PMID: 33463876 PMCID: PMC7615901 DOI: 10.1111/petr.13973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 12/21/2020] [Accepted: 12/24/2020] [Indexed: 11/27/2022]
Abstract
BACKGROUND We report pediatric PAKT patient and graft outcomes at a large tropical tertiary center spanning two transplant eras. METHODS In this retrospective cohort study, all children ≤18 years who underwent kidney transplantation at our center between 1991 and 2016 were included. Data pertaining to their baseline characteristics, post-transplant events, and outcome were retrieved from transplant records and compared between transplant eras (1991-2005 and 2006-2016). RESULTS A total of 139 children (mean age 15.2 ± 2.9 years) underwent PAKT during this period. The incidence of UTIs, CMV disease, BKVN, invasive fungal infections, new-onset diabetes after transplant, leucopenia, and recurrent NKD was higher in the 2006-2016 era (P < .001 for all), while 1-year cumulative BPAR was comparable (P = .100). Five-year graft and patient survival in the two eras were 89.9% and 94.2% (P = .365) and 92.1% and 95.3% (P = .739), respectively. Incidence of CMV disease, BKVN, graft loss, and death was lower in the calcineurin withdrawal group. Non-adherence accounted for 36% of graft loss; infections caused 43.7% of deaths. On multivariate Cox proportional hazards analysis, independent predictors for graft loss were UTIs and blood transfusion naïve status and for death were serious infections and glomerular NKD. CONCLUSIONS PAKT in India has excellent long-term graft outcomes, though patient outcomes remain suboptimal owing to a high burden of infections. Current immunosuppression protocols need to be re-examined to balance infection risk, graft, and patient survival.
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Affiliation(s)
- Anjali Mohapatra
- Department of Nephrology, Christian Medical College, Vellore, India
| | - Anna T. Valson
- Department of Nephrology, Christian Medical College, Vellore, India
| | | | | | | | - Shibu Jacob
- Department of Nephrology, Christian Medical College, Vellore, India
| | - Shailesh Kakde
- Department of Nephrology, Christian Medical College, Vellore, India
| | - Santosh Kumar
- Department of Urology, Christian Medical College, Vellore, India
| | - Antony Devasia
- Department of Urology, Christian Medical College, Vellore, India
| | | | | | | | - Gopal Basu
- Department of Nephrology, Christian Medical College, Vellore, India
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25
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Efficacy and Safety According to the Dose of Valganciclovir for Cytomegalovirus Prophylaxis in Transplantation: Network Meta-analysis Using Recent Data. Transplant Proc 2021; 53:1945-1950. [PMID: 34253379 DOI: 10.1016/j.transproceed.2021.05.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/26/2021] [Accepted: 05/04/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Valganciclovir is used to prevent posttransplant cytomegalovirus (CMV) infection among patients undergoing kidney transplant. However, the optimal dose remains controversial because continuous use decreases kidney function and can induce leukopenia. The purpose of this study was to identify the appropriate dose of valganciclovir for preventing CMV using network meta-analysis. METHODS We searched the Cochrane Central Register, Ovid MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health, and Web of Science databases for studies published through April 15, 2017, evaluating 900-mg and 450-mg valganciclovir. We performed direct and indirect network meta-analysis using Bayesian models and generated rankings of different doses of valganciclovir by generating a mixed-treatment comparison. RESULTS Twenty-three studies involving 3478 participants were included. Compared with the control group, there was no difference in the incidence of CMV infection between the low-dose (450 mg) (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.50-1.40) and high-dose (900 mg) (OR, 1.0; 95% CI, 0.61-1.60) groups. Low-dose valganciclovir had the best probability (71.1%) for decreasing CMV infection. Leukopenia was significantly more common in the high-dose group than in the control group (OR, 4.3; 95% CI, 2.69-7.10) and in the low-dose group (OR, 2.9; 95% CI, 1.88-4.67), but there was no significant difference in the incidence of leukopenia between the low-dose and control groups (OR, 1.5; 95% CI, 0.99-2.20). CONCLUSIONS The incidence of CMV was not different based on the dose of valganciclovir, although the tendency for CMV infection was decreased at 450 mg. However, the low dose of valganciclovir significantly reduced the incidence of leukopenia.
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26
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Vinson A, Teixeira A, Kiberd B, Tennankore K. Predictors and Complications of Post Kidney Transplant Leukopenia. Prog Transplant 2021; 31:249-256. [PMID: 34159855 DOI: 10.1177/15269248211024614] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Leukopenia occurs frequently following kidney transplantation and is associated with adverse clinical outcomes including increased infectious risk. In this study we sought to characterize the causes and complications of leukopenia following kidney transplantation. METHODS In a cohort of adult patients (≥18 years) who underwent kidney transplant from Jan 2006-Dec 2017, we used univariable Cox proportional Hazards models to identify predictors of post-transplant leukopenia (WBC < 3500 mm3). Factors associated with post-transplant leukopenia were then included in a multivariable backwards stepwise selection process to create a prediction model for the outcome of interest. Cox regression analyses were subsequently used to determine if post-transplant leukopenia was associated with complications. RESULTS Of 388 recipients, 152 (39%) developed posttransplant leukopenia. Factors associated with leukopenia included antithymocyte globulin as induction therapy (HR 3.32, 95% CI 2.25-4.91), valganciclovir (HR 1.84, 95% CI 1.25-2.70), tacrolimus (HR 3.05, 95% CI 1.08-8.55), prior blood transfusion (HR 1.17 per unit, 95% CI 1.09- 1.25), and donor age (HR 1.02 per year, 95% CI 1.00-1.03). Cytomegalovirus infection occurred in 26 patients with leukopenia (17.1%). Other than cytomegalovirus, leukopenia was not associated with posttransplant complications. CONCLUSION Leukopenia commonly occurred posttransplant and was associated with modifiable and non-modifiable pretransplant factors.
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Affiliation(s)
- Amanda Vinson
- 432234Nova Scotia Health Authority Division of Nephrology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Alyne Teixeira
- School of Biomedical Engineering, 3688Dalhousie University, Halifax, Nova Scotia, Canada
| | - Bryce Kiberd
- 432234Nova Scotia Health Authority Division of Nephrology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Karthik Tennankore
- 432234Nova Scotia Health Authority Division of Nephrology, Dalhousie University, Halifax, Nova Scotia, Canada
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27
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Henningsen M, Jaenigen B, Zschiedrich S, Pisarski P, Walz G, Schneider J. Risk Factors and Management of Leukopenia After Kidney Transplantation: A Single-Center Experience. Transplant Proc 2021; 53:1589-1598. [PMID: 34020796 DOI: 10.1016/j.transproceed.2021.04.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 03/23/2021] [Accepted: 04/05/2021] [Indexed: 11/17/2022]
Abstract
BACKGROUND Leukopenia is a common complication after kidney transplantation. The etiology is multifactorial, with medication adverse effects and cytomegalovirus infection as main causes. Optimal strategies to prevent or treat posttransplant leukopenia remain unknown. We aimed to identify risk factors for leukopenia and to investigate the benefit of switching the immunosuppressive therapy to hydrocortisone as a continuous infusion. METHODS We retrospectively evaluated all patients with leukopenia after kidney transplantation between 2007 and 2017 at our center relative to age- and sex-matched controls. RESULTS Leukopenia was associated with the degree of rejection therapy before leukopenia, the immunosuppressive therapy before transplantation, and an induction therapy with rabbit antithymocyte globulin. Patients with leukopenia exhibited increased mortality, an increased incidence of bacterial and viral infections, and more acute rejections. Switching to hydrocortisone as a continuous infusion in patients with severe leukopenia decreased the duration of leukopenia and the incidence of subsequent viral infections, especially with cytomegalovirus. CONCLUSION Leukopenia is a risk factor for infectious complications and mortality, and it is associated with acute rejection. Switching immunosuppressive therapy to hydrocortisone as a continuous infusion is a safe approach to reduce the duration of leukopenia and the incidence of viral infections.
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Affiliation(s)
- Max Henningsen
- Department of Medicine IV, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Bernd Jaenigen
- Department of General and Digestive Surgery, Section of Transplant Surgery, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Stefan Zschiedrich
- Department of Medicine IV, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Przemyslaw Pisarski
- Department of General and Digestive Surgery, Section of Transplant Surgery, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Gerd Walz
- Department of Medicine IV, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Johanna Schneider
- Department of Medicine IV, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
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28
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Persistent Neutropenia after ABOi Kidney Transplantation: A Case Report. TRANSPLANTOLOGY 2021. [DOI: 10.3390/transplantology2020017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Post-transplant neutropenia (PTN) is frequently reported in the first-year after transplantation. Although prevalence and clinical consequences are widely described, there are no guidelines to manage diagnosis and treatment. We report here a case of persistent PTN occurred in a patient undergoing a kidney transplant from an AB0-incompatible living donor. The desensitization protocol consisted of Rituximab administration and immunoadsorption while the pre-transplant protocol, which was initiated 14 days before the transplant, included Tacrolimus, Mofetil Mycophenolate (MMF), antimicrobial and antiviral prophylaxis. Induction therapy consisted of anti-thymocyte globulins and steroids, while maintenance after transplantation consisted of steroid, tacrolimus and MMF. When the first occurrence of leukopenia was observed six weeks after the transplant, firstly antimicrobial/antiviral prophylaxis was stopped and later also MMF treatment was interrupted but severe neutropenia relapsed after MMF resuming treatment. Immunological and virological causes were excluded. The patient was treated with Filgrastim. Bone marrow biopsy, which was performed to exclude a hematological cause of severe persistent neutropenia, revealed a bone marrow hypoplasia with neutrophils maturation interrupted at the early stages. This case highlights the need to establish diagnostic and therapeutic guidelines for PTN which take in consideration all the therapeutic steps including the pre-transplant phase in particular in the context of AB0i where immunosuppression is more consistent.
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29
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Chow JKL, Ruthazer R, Boucher HW, Vest AR, DeNofrio DM, Snydman DR. Factors associated with neutropenia post heart transplantation. Transpl Infect Dis 2021; 23:e13634. [PMID: 33982834 DOI: 10.1111/tid.13634] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/30/2021] [Accepted: 05/06/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Neutropenia is a serious complication following heart transplantation (OHT); however, risk factors for its development and its association with outcomes is not well described. We sought to study the prevalence of neutropenia, risk factors associated with its development, and its impact on infection, rejection, and survival. METHODS A retrospective single-center analysis of adult OHT recipients from July 2004 to December 2017 was performed. Demographic, laboratory, medication, infection, rejection, and survival data were collected for 1 year post-OHT. Baseline laboratory measurements were collected within the 24 hours before OHT. Neutropenia was defined as absolute neutrophil count ≤1000 cells/mm3. Cox proportional hazards models explored associations with time to first neutropenia. Associations between neutropenia, analyzed as a time-dependent covariate, with secondary outcomes of time to infection, rejection, or death were also examined. RESULTS Of 278 OHT recipients, 84 (30%) developed neutropenia at a median of 142 days (range 81-228) after transplant. Factors independently associated with increased risk of neutropenia included lower baseline WBC (HR 1.12; 95% CI 1.11-1.24), pre-OHT ventricular assist device (1.63; 1.00-2.66), high-risk CMV serostatus [donor positive, recipient negative] (1.86; 1.19-2.88), and having a previous CMV infection (4.07; 3.92-13.7). CONCLUSIONS Neutropenia is a fairly common occurrence after adult OHT. CMV infection was associated with subsequent neutropenia, however, no statistically significant differences in outcomes were found between neutropenic and non-neutropenic patients in this small study. It remains to be determined in future studies if medication changes in response to neutropenia would impact patient outcomes.
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Affiliation(s)
- Jennifer K L Chow
- Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, USA
| | - Robin Ruthazer
- Tufts Clinical and Translational Science Institute, Biostatistics, Epidemiology, and Research Design Center, Tufts Medical Center, Boston, MA, USA
| | - Helen W Boucher
- Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, USA
| | - Amanda R Vest
- Division of Cardiology, Tufts University School of Medicine, Tufts Medical Center, Boston, MA, USA
| | - David M DeNofrio
- Division of Cardiology, Tufts University School of Medicine, Tufts Medical Center, Boston, MA, USA
| | - David R Snydman
- Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, USA
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30
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Letermovir for Cytomegalovirus Prophylaxis in Lung Transplant Patients with Valganciclovir-Induced Leukopenia. TRANSPLANTOLOGY 2021. [DOI: 10.3390/transplantology2020013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Cytomegalovirus (CMV) prophylaxis with valganciclovir is the standard of practice in most transplant centers, but treatment-related leukopenia can limit valganciclovir’s use. Therefore, we evaluated letermovir, a novel antiviral agent recently approved for use in hematopoietic cell transplant patients as CMV prophylaxis, in lung transplant recipients unable to tolerate valganciclovir due to severe leukopenia. We performed a retrospective analysis of all lung transplant patients at our center who received letermovir for CMV prophylaxis between 1 December 2018 and 1 January 2020. A repeated measures mixed model was used to analyze white blood cell (WBC) trends, and descriptive statistics were used to analyze secondary endpoints, including CMV DNAemia, renal function, immunosuppression dosing, and allograft function. Seventeen patients were administered letermovir during the study period due to valganciclovir-induced leukopenia (median WBC nadir 1.1 K/uL, range <0.30–2.19 K/uL). Median WBC improvement was noted in 15 (88.2%) patients after starting letermovir. Breakthrough CMV DNAemia necessitating treatment occurred in two patients, with one of the two cases being due to patient noncompliance. CMV resistance to letermovir was detected in two patients, necessitating a change to an alternative agent in one of these patients. No major side effects were reported in any patient. Letermovir is a generally safe and effective alternative for CMV prophylaxis in lung transplant recipients unable to tolerate valganciclovir due to leukopenia.
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31
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Boulay H, Oger E, Cantarovich D, Gatault P, Thierry A, Le Meur Y, Duveau A, Vigneau C, Lorcy N. Among CMV-positive renal transplant patients receiving non-T-cell depleting induction, the absence of CMV disease prevention is a safe strategy: A retrospective cohort of 372 patients. Transpl Infect Dis 2021; 23:e13541. [PMID: 33270341 DOI: 10.1111/tid.13541] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 09/23/2020] [Accepted: 10/22/2020] [Indexed: 11/28/2022]
Abstract
Cytomegalovirus (CMV) is the most common opportunistic pathogen affecting renal transplant recipients, especially in the first months. CMV-seropositive renal transplant recipients (CMV R+) are at intermediate risk for CMV disease, but this risk is enhanced among CMV R+ receiving T-cell depleting induction, compared to CMV R+ receiving non-depleting induction. In this second group, data in favor of prophylactic antiviral treatment with valganciclovir to reduce CMV disease is sparse. In this retrospective and multicentric trial, we included 372 CMV R+ transplanted between January 2012 and April 2015 and receiving non-depleting induction. During the first year following transplantation, CMV disease occurred in 5/222 patients (2.25%) in the prophylaxis group and 9/150 (6%) in the no-prophylaxis group (difference +3.7; 95% CI: 0.5-8; P = .002 for non-inferiority). The incidence of allograft rejection and other infectious diseases was similar between the two groups. Graft and patient survival were similar at the end of follow-up. In conclusion, the absence of prophylaxis did not appear to have a deleterious effect for CMV diseases among CMV R+ receiving non-depleting induction.
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Affiliation(s)
- Hugoline Boulay
- Service de Néphrologie, CHU Pontchaillou, Rennes, France.,Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) UMR_S 1085, Univ Rennes, Rennes, France
| | - Emmanuel Oger
- Service de Pharmacologie clinique et biologique, CHU Pontchaillou, Rennes, France
| | - Diego Cantarovich
- Institut de Transplantation Urologie-Néphrologie, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Philippe Gatault
- Service de Néphrologie et Immunologie Clinique, Centre Hospitalier Universitaire de Tours, Tours, France
| | - Antoine Thierry
- Service de Néphrologie, Hémodialyse et Transplantation Rénale, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Yannick Le Meur
- Service de Néphrologie, Centre Hospitaliser de Brest, Université de Bretagne Occidentale, Brest, France
| | - Agnès Duveau
- Service de Nephrologie-Dialyse-Transplantation, Centre Hospitalier Universitaire d'Angers, Angers, France
| | - Cécile Vigneau
- Service de Néphrologie, CHU Pontchaillou, Rennes, France.,Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) UMR_S 1085, Univ Rennes, Rennes, France
| | - Nolwenn Lorcy
- Service de Néphrologie, CHU Pontchaillou, Rennes, France
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32
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Hellemans R, Wijtvliet V, Bergs K, Philipse E, Vleut R, Massart A, Couttenye MM, Matheeussen V, Abramowicz D. A split strategy to prevent cytomegalovirus after kidney transplantation using prophylaxis in serological high-risk patients and a pre-emptive strategy in intermediate-risk patients: Combining the best of two options? Transpl Infect Dis 2020; 23:e13467. [PMID: 32935909 DOI: 10.1111/tid.13467] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 08/27/2020] [Accepted: 09/06/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) remains an important challenge after kidney transplantation. Current Transplantation Society International Consensus Guidelines recommend antiviral prophylaxis or pre-emptive therapy for high-risk CMV-seronegative recipients with a CMV-seropositive donor (D+/R-) and moderate-risk CMV-seropositive recipients (R+). However, a split strategy according to CMV serostatus is not specifically mentioned. METHODS We evaluated a split strategy to prevent CMV infection after kidney transplantation in which D+/R- patients received valganciclovir (VGC) prophylaxis for 200 days, and R + patients were treated pre-emptively according to CMV DNAemia. Patients were followed until 1-year post-transplant. RESULTS Between April 2014 and March 2018, 40 D+/R- and 92 R + patients underwent kidney transplantation. Forty-six percent received antithymocyte globulin (ATG) induction, and 98% was treated with calcineurin inhibitors, mycophenolic acid (MPA), and steroids. No D+/R- patient developed CMV disease during prophylaxis (median 200 days), but 15% developed post-prophylaxis or late-onset disease. Fifty-three percent developed neutropenia during prophylaxis, including 16/40 (40%) grade 3 or 4 neutropenia requiring reduction/discontinuation of MPA (30%) and/or VGC (35%), and an occasional need for granulocyte colony-stimulating factor (5%). In the R + group, 40% received antiviral therapy for a median duration of 21 days; 5% developed early-onset CMV disease. Only 5% developed neutropenia. D+/R + status (hazard ratio (HR) 2.09,P = .004) and ATG use (HR 2.81, P < .0001) were risk factors for CMV reactivation. CONCLUSIONS Prophylaxis leads to acceptable CMV control in high-risk patients but comes with a high risk of neutropenia. Pre-emptive therapy is effective and limits drug exposure in those at lower risk of CMV.
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Affiliation(s)
- Rachel Hellemans
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerpen, Belgium
| | - Veerle Wijtvliet
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerpen, Belgium
| | - Kristof Bergs
- Department of Microbiology, Antwerp University Hospital, Edegem, Belgium
| | - Ester Philipse
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerpen, Belgium
| | - Rowena Vleut
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerpen, Belgium
| | - Annick Massart
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerpen, Belgium
| | - Marie-Madeleine Couttenye
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerpen, Belgium
| | - Veerle Matheeussen
- Department of Microbiology, Antwerp University Hospital, Edegem, Belgium
| | - Daniel Abramowicz
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerpen, Belgium
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ISİKTAS SAYİLAR E, ERSOY A, ÇELİKÇİ S, AYAR Y, ALİ R, OZKOCAMAN V, ÖZKALEMKAŞ F. Granulocyte colony-stimulating factor usage in drug-induced neutropenia after kidney transplantation: a single-center experience. TURKISH JOURNAL OF INTERNAL MEDICINE 2020. [DOI: 10.46310/tjim.655091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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34
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Tague LK, Scozzi D, Wallendorf M, Gage BF, Krupnick AS, Kreisel D, Byers D, Hachem R, Gelman AE. Lung transplant outcomes are influenced by severity of neutropenia and granulocyte colony-stimulating factor treatment. Am J Transplant 2020; 20:250-261. [PMID: 31452317 PMCID: PMC6940547 DOI: 10.1111/ajt.15581] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 08/01/2019] [Accepted: 08/10/2019] [Indexed: 01/25/2023]
Abstract
Although neutropenia is a common complication after lung transplant, its relationship with recipient outcomes remains understudied. We evaluated a retrospective cohort of 228 adult lung transplant recipients between 2008 and 2013 to assess the association of neutropenia and granulocyte colony-stimulating factor (GCSF) treatment with outcomes. Neutropenia was categorized as mild (absolute neutrophil count 1000-1499), moderate (500-999), or severe (<500) and as a time-varying continuous variable. Associations with survival, acute rejection, and chronic lung allograft dysfunction (CLAD) were assessed with the use of Cox proportional hazards regression. GCSF therapy impact on survival, CLAD, and acute rejection development was analyzed by propensity score matching. Of 228 patients, 101 (42.1%) developed neutropenia. Recipients with severe neutropenia had higher mortality rates than those of recipients with no (adjusted hazard ratio [aHR] 2.97, 95% confidence interval [CI] 1.05-8.41, P = .040), mild (aHR 14.508, 95% CI 1.58-13.34, P = .018), or moderate (aHR 3.27, 95% CI 0.89-12.01, P = .074) neutropenia. Surprisingly, GCSF treatment was associated with a higher risk for CLAD in mildly neutropenic patients (aHR 3.49, 95% CI 0.93-13.04, P = .063), although it did decrease death risk in severely neutropenic patients (aHR 0.24, 95% CI 0.07-0.88, P = .031). Taken together, our data point to an important relationship between neutropenia severity and GCSF treatment in lung transplant outcomes.
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Affiliation(s)
- Laneshia K. Tague
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, Missouri
| | - Davide Scozzi
- Division of Cardiothoracic Surgery, Department of Surgery, Washington University, St. Louis, Missouri
| | | | - Brian F. Gage
- Division of General Medical Sciences, Washington University, St. Louis, Missouri
| | - Alexander S. Krupnick
- Department of Surgery and Carter Center for Immunology, University of Virginia, Charlottesville, Virginia
| | - Daniel Kreisel
- Division of Cardiothoracic Surgery, Department of Surgery, Washington University, St. Louis, Missouri
| | - Derek Byers
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, Missouri
| | - Ramsey Hachem
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, Missouri
| | - Andrew E. Gelman
- Division of Cardiothoracic Surgery, Department of Surgery, Washington University, St. Louis, Missouri
- Department of Pathology & Immunology Washington University, St. Louis, Missouri
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35
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Hemmersbach-Miller M, Alexander BD, Pieper CF, Schmader KE. Age matters: older age as a risk factor for CMV reactivation in the CMV serostatus-positive kidney transplant recipient. Eur J Clin Microbiol Infect Dis 2019; 39:455-463. [PMID: 31758441 DOI: 10.1007/s10096-019-03744-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 10/17/2019] [Indexed: 12/29/2022]
Abstract
Evaluate risk factors for cytomegalovirus (CMV) reactivation during the first year after kidney transplantation in the CMV-seropositive older recipient. Retrospective single-center study. Between 2011 and 2015, 91 patients ≥ 65 years received a kidney transplant; these were matched with 91 controls, aged 40-60. Risk of CMV reactivation in the CMV-seropositive recipients was analyzed. Sixty-three older and 54 younger recipients were included; 50% had received CMV-directed prophylaxis. CMV reactivation was significantly more frequent in the older group (71.4% vs 44.4%, p = 0.003) and occurred earlier (p = 0.003). A multivariate model showed that only age was associated with CMV reactivation (OR 2.48, p = 0.03). After excluding patients that received thymoglobulin, older age group remained the only risk factor of CMV reactivation (OR 3.81, p = 0.014). Recurrent event analysis showed that the older cohort had an HR of 1.94 (p = 0.01) of CMV viremia; there was significant episode-cohort interaction (p < 0.01). While the older group had a higher risk of infection (HR = 2.43), after the initial episode the relative hazards were approximately equal (HR = 1.08, at period 2). This suggests that it is key to specifically avoid the first episode of reactivation. Universal prophylaxis or a hybrid prophylaxis model should be considered in the CMV-seropositive kidney transplant recipient aged ≥ 65 years.
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Affiliation(s)
- Marion Hemmersbach-Miller
- Division of Infectious Diseases, Duke University Medical Center, Durham, NC, USA. .,Duke Clinical Research Institute, Durham, NC, USA.
| | - Barbara D Alexander
- Division of Infectious Diseases, Duke University Medical Center, Durham, NC, USA
| | - Carl F Pieper
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA
| | - Kenneth E Schmader
- Division of Geriatrics, Duke University Medical Center, Durham, NC, USA.,GRECC, Durham VA, Durham, NC, USA
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36
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Lee JH, Kim HY, Lee DY, Kim YJ, Lee HR, Oh JS, Sin YH, Kim JK, Hwang SD. Efficacy and Safety of Ultra-Low-Dose Valganciclovir Chemoprophylaxis for Cytomegalovirus Infection in High-Risk Kidney Transplantation Patients. Transplant Proc 2019; 51:2689-2692. [DOI: 10.1016/j.transproceed.2019.04.078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 03/30/2019] [Accepted: 04/11/2019] [Indexed: 10/26/2022]
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37
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Duggal T, Dempster M, Prashar R. Calcineurin Inhibitors and Neutropenia: Is Cyclosporine Superior to Tacrolimus? AMERICAN JOURNAL OF CASE REPORTS 2019; 20:1407-1410. [PMID: 31548541 PMCID: PMC6777388 DOI: 10.12659/ajcr.917282] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Patient: Female, 51 Final Diagnosis: Tacrolimus induced severe neutropenia Symptoms: Abnormal lab values Medication: — Clinical Procedure: — Specialty: Transplantology
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Affiliation(s)
- Tanu Duggal
- Department of Medicine, Lawrence General Hospital, Lawrence, MA, USA
| | - Meghan Dempster
- Department of Pharmacy, Froedtert Hospital, Milwaukee, WI, USA
| | - Rohini Prashar
- Department of Nephrology, Henry Ford Hospital, Detroit, MI, USA
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38
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Hamel S, Kuo V, Sawinski D, Johnson D, Bloom RD, Bleicher M, Goral S, Lim MA, Trofe‐Clark J. Single‐center, real‐world experience with granulocyte colony‐stimulating factor for management of leukopenia following kidney transplantation. Clin Transplant 2019; 33:e13541. [DOI: 10.1111/ctr.13541] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 02/22/2019] [Accepted: 03/13/2019] [Indexed: 12/20/2022]
Affiliation(s)
- Stephanie Hamel
- Department of Pharmacy Services Hospital of the University of Pennsylvania Philadelphia Pennsylvania
| | - Vicky Kuo
- Department of Pharmacy Services Hospital of the University of Pennsylvania Philadelphia Pennsylvania
| | - Deirdre Sawinski
- Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania
| | - David Johnson
- Department of Pharmacy Services Hospital of the University of Pennsylvania Philadelphia Pennsylvania
| | - Roy D. Bloom
- Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania
| | - Melissa Bleicher
- Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania
| | - Simin Goral
- Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania
| | - Mary Ann Lim
- Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania
| | - Jennifer Trofe‐Clark
- Department of Pharmacy Services Hospital of the University of Pennsylvania Philadelphia Pennsylvania
- Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania
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39
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Khalil MAM, Khalil MAU, Khan TFT, Tan J. Drug-Induced Hematological Cytopenia in Kidney Transplantation and the Challenges It Poses for Kidney Transplant Physicians. J Transplant 2018; 2018:9429265. [PMID: 30155279 PMCID: PMC6093016 DOI: 10.1155/2018/9429265] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 06/04/2018] [Accepted: 06/25/2018] [Indexed: 12/14/2022] Open
Abstract
Drug-induced hematological cytopenia is common in kidney transplantation. Various cytopenia including leucopenia (neutropenia), thrombocytopenia, and anemia can occur in kidney transplant recipients. Persistent severe leucopenia or neutropenia can lead to opportunistic infections of various etiologies. On the contrary, reducing or stopping immunosuppressive medications in these events can provoke a rejection. Transplant clinicians are often faced with the delicate dilemma of balancing cytopenia and rejection from adjustments of immunosuppressive regimen. Differentials of drug-induced cytopenia are wide. Identification of culprit medication and subsequent modification is also challenging. In this review, we will discuss individual drug implicated in causing cytopenia and correlate it with corresponding literature evidence.
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Affiliation(s)
| | | | - Taqi F. Taufeeq Khan
- King Salman Armed Forces Hospital, Tabuk King Abdul Aziz Rd., Tabuk 47512, Saudi Arabia
| | - Jackson Tan
- RIPAS Hospital, Bandar Seri Begawan BA1710, Brunei Darussalam
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40
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Rissling O, Naik M, Brakemeier S, Schmidt D, Staeck O, Hohberger A, Neumayer HH, Budde K. High frequency of valganciclovir underdosing for cytomegalovirus prophylaxis after renal transplantation. Clin Kidney J 2018; 11:564-573. [PMID: 30094022 PMCID: PMC6070081 DOI: 10.1093/ckj/sfx145] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 10/31/2017] [Indexed: 12/13/2022] Open
Abstract
Background The correct valganciclovir dose for cytomegalovirus (CMV) prophylaxis depends on renal function estimated by the Cockcroft–Gault (CG) estimated creatinine clearance (CG-CrCl) formula. Patients with delayed or rapidly changing graft function after transplantation (tx) will need dose adjustments. Methods We performed a retrospective investigation of valganciclovir dosing in renal transplant patients receiving CMV prophylaxis between August 2003 and August 2011, and analysed valganciclovir dosing, CG-CrCl, CMV viraemia (CMV-PCR <750 copies/mL), leucopenia (<3500/µL) and neutropenia (<1500/µL) in the first year post-transplant. On Days 30 and 60 post-transplant, dosing pattern in relation to estimated creatinine clearance was analysed regarding CMV viraemia, leucopenia and neutropenia. Results Six hundred and thirty-five patients received valganciclovir prophylaxis that lasted 129 ± 68 days with a mean dose of 248 ± 152 mg/day of whom 112/635 (17.7%) developed CMV viraemia, 166/635 (26.1%) leucopenia and 48/635 (7.6%) neutropenia. CMV resistance within 1 year post-transplant was detected in three patients. Only 137/609 (22.6%) patients received the recommended dose, while n = 426 (70.3%) were underdosed and n = 43 (7.1%) were overdosed at Day 30 post-tx. Risk factors for CMV viraemia were donor positive D (+)/receptor negative R (−) status and short prophylaxis duration, but not low valganciclovir dose. Risk factors for developing leucopenia were D+/R− status and low renal function. No significant differences in dosing frequency were observed in patients developing neutropenia or not (P = 0.584). Conclusion Most patients do not receive the recommended valganciclovir dose. Despite obvious underdosing in a large proportion of patients, effective prophylaxis was maintained and it was not associated as a risk factor for CMV viraemia or leucopenia.
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Affiliation(s)
- Olesja Rissling
- Department of Nephrology, Charité Universitätskrankenhaus, Berlin, Germany
| | - Marcel Naik
- Department of Nephrology, Charité Universitätskrankenhaus, Berlin, Germany
| | - Susanne Brakemeier
- Department of Nephrology, Charité Universitätskrankenhaus, Berlin, Germany
| | - Danilo Schmidt
- Department of Nephrology, Charité Universitätskrankenhaus, Berlin, Germany
| | - Oliver Staeck
- Department of Nephrology, Charité Universitätskrankenhaus, Berlin, Germany
| | - Arnim Hohberger
- Department of Nephrology, Charité Universitätskrankenhaus, Berlin, Germany
| | | | - Klemens Budde
- Department of Nephrology, Charité Universitätskrankenhaus, Berlin, Germany
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41
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Varnell CD, Fukuda T, Kirby CL, Martin LJ, Warshaw BL, Patel HP, Chand DH, Barletta GM, Van Why SK, VanDeVoorde RG, Weaver DJ, Wilson A, Verghese PS, Vinks AA, Greenbaum LA, Goebel J, Hooper DK. Mycophenolate mofetil-related leukopenia in children and young adults following kidney transplantation: Influence of genes and drugs. Pediatr Transplant 2017; 21:10.1111/petr.13033. [PMID: 28869324 PMCID: PMC5905326 DOI: 10.1111/petr.13033] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/27/2017] [Indexed: 12/31/2022]
Abstract
MMF is commonly prescribed following kidney transplantation, yet its use is complicated by leukopenia. Understanding the genetics mediating this risk will help clinicians administer MMF safely. We evaluated 284 patients under 21 years of age for incidence and time course of MMF-related leukopenia and performed a candidate gene association study comparing the frequency of 26 SNPs between cases with MMF-related leukopenia and controls. We matched cases by induction, steroid duration, race, center, and age. We also evaluated the impact of induction and SNPs on time to leukopenia in all cases. Sixty-eight (24%) patients had MMF-related leukopenia, of which 59 consented for genotyping and 38 were matched with controls. Among matched pairs, no SNPs were associated with leukopenia. With non-depleting induction, UGT2B7-900A>G (rs7438135) was associated with increased risk of MMF-related leukopenia (P = .038). Time to leukopenia did not differ between patients by induction agent, but 2 SNPs (rs2228075, rs2278294) in IMPDH1 were associated with increased time to leukopenia. MMF-related leukopenia is common after transplantation. UGT2B7 may influence leukopenia risk especially in patients without lymphocyte-depleting induction. IMPDH1 may influence time course of leukopenia after transplant.
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Affiliation(s)
- Charles D. Varnell
- Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Tsuyoshi Fukuda
- Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Cassie L. Kirby
- Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Lisa J. Martin
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Barry L. Warshaw
- Division of Nephrology, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Hiren P. Patel
- Division of Nephrology, Nationwide Children’s Hospital, Columbus, OH, USA
| | - Deepa H. Chand
- Division of Nephrology, University of Illinois College of Medicine, Peoria, IL, USA,Abbvie, North Chicago, IL, USA
| | | | - Scott K. Van Why
- Division of Pediatric Nephrology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Rene G. VanDeVoorde
- Division of Nephrology, Monroe Carell Jr. Children’s Hospital, Nashville, TN, USA
| | - Donald J. Weaver
- Division of Nephrology, Levine Children’s Hospital, Charlotte, NC, USA
| | - Amy Wilson
- Division of Nephrology, Riley Hospital for Children, Indianapolis, IN, USA
| | - Priya S. Verghese
- Division of Pediatric Nephrology, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN, USA
| | - Alexander A. Vinks
- Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Larry A. Greenbaum
- Division of Nephrology, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Jens Goebel
- Division of Nephrology, Children’s Hospital Colorado, Aurora, CO, USA
| | - David K. Hooper
- Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA,James M. Anderson Center for Health Systems Excellence, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
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42
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Mavrakanas TA, Fournier MA, Clairoux S, Amiel JA, Tremblay ME, Vinh DC, Coursol C, Thirion DJG, Cantarovich M. Neutropenia in kidney and liver transplant recipients: Risk factors and outcomes. Clin Transplant 2017; 31. [PMID: 28736953 DOI: 10.1111/ctr.13058] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/18/2017] [Indexed: 12/17/2022]
Abstract
No studies have directly compared the key characteristics and outcomes of kidney (KTx) and liver transplantation (LTx) recipients with neutropenia. In this single-center, retrospective, cohort study, we enrolled all adult patients who received a KTx or LTx between 2000 and 2011. Neutropenia was defined as 2 consecutive absolute neutrophil count (ANC) values <1500/mm3 in patients without preexisting neutropenia. The first neutropenia episode occurring during the first year post-transplantation was analyzed. A total of 663 patients with KTx and 354 patients with LTx met the inclusion criteria. Incidence of neutropenia was 20% in KTx and 38% in LTx, respectively. High-risk CMV status and valganciclovir (VGCV) use were significant predictors of neutropenia for KTx recipients, but only VGCV use vs nonuse in LTx recipients. Neutropenia was associated with worse survival in KTx recipients (adjusted HR 1.95, 95% CI 1.18-3.22, P<.01), but not in LTx recipients (adjusted HR 0.75, 95% CI 0.52-1.10, P=.15). Sixteen acute rejection episodes were associated with preceding neutropenia in KTx recipients (HR 1.77, 95% CI 1.16-2.68, P=.007) and 24 acute rejection episodes in LTx recipients (HR 1.41, 95% CI 0.97-2.04, P=.07). Incidence of infection was similar in patients with and without neutropenia among KTx and LTx recipients.
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Affiliation(s)
- Thomas A Mavrakanas
- Division of Nephrology, Department of Medicine, Multi-Organ Transplant Program, McGill University Health Center, Montreal, QC, Canada
| | - Marie-Andrée Fournier
- Department of Pharmacy, University of Montreal Hospital Centre, Montreal, QC, Canada.,Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada
| | - Sarah Clairoux
- Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada.,Department of Pharmacy, McGill University Health Center, Montreal, QC, Canada.,Department of Pharmacy, Sacré-Coeur Hospital, Montreal, QC, Canada
| | - Jacques-Alexandre Amiel
- Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada.,Department of Pharmacy, McGill University Health Center, Montreal, QC, Canada
| | | | - Donald C Vinh
- Division of Infectious Diseases, McGill University Health Center, Montreal, QC, Canada
| | - Christian Coursol
- Department of Pharmacy, McGill University Health Center, Montreal, QC, Canada
| | - Daniel J G Thirion
- Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada.,Department of Pharmacy, McGill University Health Center, Montreal, QC, Canada
| | - Marcelo Cantarovich
- Division of Nephrology, Department of Medicine, Multi-Organ Transplant Program, McGill University Health Center, Montreal, QC, Canada
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Jafari A, Najivash P, Khatami MR, Dashti-Khavidaki S. Cytopenia Occurrence in Kidney Transplant Recipients Within Early Post-transplant Period. J Res Pharm Pract 2017; 6:31-39. [PMID: 28331864 PMCID: PMC5348855 DOI: 10.4103/2279-042x.200983] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Objective: This study assessed incidence, severity, and time to occurrence of drug-induced leukopenia/thrombocytopenia within 1st month after kidney transplantation. Methods: This cross-sectional study was conducted on newly kidney transplant recipients from two hospitals, Iran. Patients with thrombocytopenia due to acute antibody-mediated rejection were excluded from the study. Demographic, clinical, and laboratory data of patients within the 1st month after transplantation were collected. Findings: Of 213 patients, 14.1% and 66.2% experienced leukopenia and thrombocytopenia, respectively. Cytopenia happened more commonly among patients with thymoglobulin-containing regimen (for leukopenia: 24.6% vs. 0%, P < 0.001; for thrombocytopenia 84.4% vs. 41.8%, P < 0.001). Most leukopenia patients experienced Grades 1 and 2 of leukopenia (46.6% and 40% of patients). Most thrombocytopenic patients showed Grade 1 of thrombocytopenia (78.7%). Cumulative dose of thymoglobulin did not differ between patients with and without leukopenia (5.57 ± 1.13 vs. 5.9 ± 1.96 mg/kg; P = 0.613) or with and without thrombocytopenia (5.87 ± 1.86 vs. 5.56 ± 1.38 mg/kg; P = 0.29). Cytopenia were more common among recipients from deceased compared with from living donors (91.3% vs. 8.7% for leukopenia patients, P = 0.001; 69.9% vs. 33.1% for thrombocytopenia, P = 0.02). More patients with kidney from deceased donors received thymoglobulin in their immunosuppressive regimen (82% vs. 37%; P < 0.001). The median time to leukopenia and thrombocytopenia were 3 days and 1 day, respectively. Conclusion: Among immunosuppressive and prophylactic antimicrobial agents, thymoglobulin is more related to cytopenia; therefore, thymoglobulin dose reduction is recommended as the first intervention to manage cytopenia without need for reduction of its cumulative dose. The higher prevalence of cytopenia among recipients from deceased donors may be related to the higher use of thymoglobulin in these patients.
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Affiliation(s)
- Atefeh Jafari
- Department of Clinical Pharmacy, Guilan University of Medical Sciences, Rasht, Iran
| | - Parisa Najivash
- Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad-Reza Khatami
- Nephrology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Center of Excellence in Nephrology, Tehran University of Medical Sciences, Tehran, Iran
| | - Simin Dashti-Khavidaki
- Nephrology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Center of Excellence in Nephrology, Tehran University of Medical Sciences, Tehran, Iran
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Alraddadi B, Nierenberg NE, Price LL, Chow JKL, Poutsiaka DD, Rohrer RJ, Cooper JT, Freeman RB, Snydman DR. Characteristics and outcomes of neutropenia after orthotopic liver transplantation. Liver Transpl 2016; 22:217-25. [PMID: 26336061 PMCID: PMC4731308 DOI: 10.1002/lt.24332] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 08/31/2015] [Accepted: 08/31/2015] [Indexed: 12/13/2022]
Abstract
Neutropenia after orthotopic liver transplantation (LT) is relatively common, but the factors associated with its development remain elusive. We assessed possible predictors of neutropenia (absolute neutrophil count [ANC] ≤ 1000/mm(3) ) within the first year of LT in a cohort of 304 patients at a tertiary medical center between 1999 and 2009 using time-dependent survival analysis to identify risk factors for neutropenia. In addition, we analyzed neutropenia as a predictor of the clinical outcomes of death, bloodstream infection (BSI), invasive fungal infection, cytomegalovirus (CMV) disease, and graft rejection within the first year of LT. Of the 304 LT recipients, 73 (24%) developed neutropenia, 5 (7%) of whom had grade 4 neutropenia (ANC < 500/mm(3) ). The following were independent predictors for neutropenia: Child-Turcotte-Pugh score (hazard ratio [HR] 1.15; 95% confidence interval [CI], 1.03-1.30; P = 0.02), BSI (HR, 2.89; 95% CI, 1.63-5.11; P < 0.001), CMV disease (HR, 4.28; 95% CI, 1.55-11.81; P = 0.005), baseline tacrolimus trough level (HR, 1.02; 95% CI, 1.01-1.03; P = 0.007), and later era LT (2004-2009 versus 1999-2003; HR, 2.28; 95% CI, 1.43-3.65; P < 0.001). Moreover, neutropenia was found to be an independent predictor for mortality within the first year of LT (HR, 3.76; 95% CI, 1.84-7.68; P < 0.001). In conclusion, our data suggest that neutropenia within a year after LT is not unusual and is an important predictor of mortality.
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Affiliation(s)
- Basem Alraddadi
- King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
| | | | - Lori Lyn Price
- The Institute for Clinical Research and Health Policy Studies, Tufts University, Boston, MA
- Tufts Medical Center, School of Medicine, Tufts University, Boston, MA
- Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA
| | - Jennifer K L Chow
- Tufts Medical Center, School of Medicine, Tufts University, Boston, MA
| | - Debra D Poutsiaka
- Tufts Medical Center, School of Medicine, Tufts University, Boston, MA
| | - Richard J Rohrer
- Tufts Medical Center, School of Medicine, Tufts University, Boston, MA
| | - Jeffrey T Cooper
- Tufts Medical Center, School of Medicine, Tufts University, Boston, MA
| | - Richard B Freeman
- Dartmouth-Hitchcock Medical Center, Dartmouth College, New Lebanon, NH
| | - David R Snydman
- Tufts Medical Center, School of Medicine, Tufts University, Boston, MA
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Severe neutropenia in children after renal transplantation: incidence, course, and treatment with granulocyte colony-stimulating factor. Pediatr Nephrol 2015; 30:2029-36. [PMID: 25994524 DOI: 10.1007/s00467-015-3113-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 04/02/2015] [Accepted: 04/06/2015] [Indexed: 10/23/2022]
Abstract
BACKGROUND Infections are an important cause of morbidity and mortality in solid organ transplant recipients. Neutrophils play a crucial role in the initial host defense against bacterial pathogens. Neutropenia is not uncommon after renal transplantation in adults; however, there are scarce published data in children. We conducted a historical cohort study to evaluate the incidence, clinical course, and management of severe neutropenia after renal transplantation in children. METHODS In a single-center study, we collected clinical and laboratory data on all children (<20 years) who underwent renal transplantation from January 2005 to March 2014. All post-transplantation blood counts were reviewed; the lowest absolute neutrophil count was recorded and correlated with clinical information and other laboratory findings. RESULTS Of the 72 patients studied, 46 (64%) had at least one episode of neutropenia [absolute neutrophil count (ANC) <1500/μl] during the study period, 16 of whom (22%) had severe neutropenia (ANC < 500/μl), 2-11 months (median, 3.5) after renal transplantation. Work-up for viral infection or malignancy was performed. Initial management included dose decrease and subsequent discontinuation of antimetabolite, stopping co-trimoxazole and valganciclovir. Bone marrow aspiration in four children revealed normal marrow cellularity in all cases, with myelocyte maturational arrest in two. Eight children (11%) were treated with granulocyte colony-stimulating factor (G-CSF) (5 mcg/kg/day) 1-4 doses (median, 2), with excellent response in all and no adverse effects. Eight children presented with fever during severe neutropenia, and were treated with empiric antibiotics. Mycophenolate/azathioprine were resumed in all patients unless contraindicated (pre-existing BK viremia -1, PTLD -1). Recurrence of neutropenia was seen in five patients, only one of whom required further treatment with G-CSF. Graft function was preserved during and after resolution of neutropenia. Post-transplant neutropenia in children is common, and mostly occurs in the first few months. Its etiology is probably primarily a result of the combination of immunosuppressive agents and prophylactic treatment of infections in the early post-transplant period. CONCLUSIONS Decreasing immunosuppressive or antimicrobial medications carries the risk of acute rejection or infection. Off-label treatment with G-CSF may present a safe and effective alternative.
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47
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Pazdernik M, Malek I, Koudelkova E, Sochman J, Kautzner J. Bone marrow suppression and associated consequences in patients after heart transplantation: A 6-year retrospective review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2015; 159:372-7. [PMID: 26000773 DOI: 10.5507/bp.2015.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 04/22/2015] [Indexed: 11/23/2022] Open
Abstract
AIMS To evaluate the incidence of bone marrow suppression and consequences of MMF dose adjustment in patients within the first year after heart transplantation. METHODS Group I (n=47) was treated with a regimen currently used in patients after heart transplantation (mycophenolatemofetil - MMF, valganciclovir - VGC and trimethoprim/sulfamethoxazole - TMP-SMX). Group II (n=47) received only MMF of potentially myelotoxic medications. The myelotoxic effect and need for dose modification were assessed. The incidence of rejections and infectious episodes associated with MMF adjustment were analyzed during the first 12 months in Group I. RESULTS There was a significantly greater proportion of patients with leukopenia (leukocyte count < 4 x 10^9/L) at 3 months after orthotopic heart transplantation in Group I compared with Group II (19.1% vs 2.1%; P = 0.02). The difference in lymphopenia (lymphocyte count < 0.8 x 10^9/L) at 3 months follow-up was highly significant (38.3 % vs 6.4 %; P = 0.0002). MMF was modified due to bone marrow suppression or severe infection in 63.8% patients in Group I and in only 8.5% of patients in Group II (P < 0.001). Reducing or stopping MMF was not associated with increased rejections. In Group I, at least 1 episode of higher degree cellular or humoral rejection occurred in 35% of patients with the standard MMF dosage compared with only 26% in patients with modified MMF (P = 0.0534). CONCLUSIONS Addition of VGC+TMP-SMX to current immunosuppressive medication regimen in patients after heart transplantation is associated with significant lymphocytopenia and leukopenia. Importantly, modification of immunosuppressive prophylaxis (reducing or stopping MMF) leads to normalization of blood count without increased incidence of rejections.
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Affiliation(s)
- Michal Pazdernik
- Department of Cardiology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic
| | - Ivan Malek
- Department of Cardiology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic
| | - Eva Koudelkova
- Department of Cardiology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic
| | - Jan Sochman
- Department of Cardiology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic
| | - Josef Kautzner
- Department of Cardiology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic
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Yang Y, Yu B, Chen Y. Blood disorders typically associated with renal transplantation. Front Cell Dev Biol 2015; 3:18. [PMID: 25853131 PMCID: PMC4365751 DOI: 10.3389/fcell.2015.00018] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 03/03/2015] [Indexed: 12/11/2022] Open
Abstract
Renal transplantation has become one of the most common surgical procedures performed to replace a diseased kidney with a healthy kidney from a donor. It can help patients with kidney failure live decades longer. However, renal transplantation also faces a risk of developing various blood disorders. The blood disorders typically associated with renal transplantation can be divided into two main categories: (1) Common disorders including post-transplant anemia (PTA), post-transplant lymphoproliferative disorder (PTLD), post-transplant erythrocytosis (PTE), and post-transplant cytopenias (PTC, leukopenia/neutropenia, thrombocytopenia, and pancytopenia); and (2) Uncommon but serious disorders including hemophagocytic syndrome (HPS), thrombotic microangiopathy (TMA), therapy-related myelodysplasia (t-MDS), and therapy-related acute myeloid leukemia (t-AML). Although many etiological factors involve the development of post-transplant blood disorders, immunosuppressive agents, and viral infections could be the two major contributors to most blood disorders and cause hematological abnormalities and immunodeficiency by suppressing hematopoietic function of bone marrow. Hematological abnormalities and immunodeficiency will result in severe clinical outcomes in renal transplant recipients. Understanding how blood disorders develop will help cure these life-threatening complications. A potential therapeutic strategy against post-transplant blood disorders should focus on tapering immunosuppression or replacing myelotoxic immunosuppressive drugs with lower toxic alternatives, recognizing and treating promptly the etiological virus, bacteria, or protozoan, restoring both hematopoietic function of bone marrow and normal blood counts, and improving kidney graft survival.
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Affiliation(s)
- Yu Yang
- Department of Urology, First Affiliated Hospital of PLA General Hospital Beijing, China
| | - Bo Yu
- Department of Urology, First Affiliated Hospital of PLA General Hospital Beijing, China
| | - Yun Chen
- BrightstarTech, Inc. Clarksburg, MD, USA
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Savvidaki E, Kazakopoulos P, Papachristou E, Karavias D, Zavvos V, Voliotis G, Kalliakmani P, Marangos M, Goumenos DS. Replacement of mycophenolate acid with everolimus in patients who became neutropenic after renal transplant. EXP CLIN TRANSPLANT 2015; 12:31-6. [PMID: 24471721 DOI: 10.6002/ect.2013.0109] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Neutropenia after kidney transplant is an adverse event usually treated with a dosage reduction of mycophenolic acid. We evaluated the efficacy and safety of substituting mycophenolic acid with everolimus in patients with persistent neutropenia after kidney transplant. MATERIALS AND METHODS This study was a retrospective analysis. A total of 17 patients who were initially treated with mycophenolic acid (1912 ± 196 mg/d), calcineurin inhibitors, and methylprednisolone for kidney transplant were included. RESULTS In 15 patients, neutropenia occurred within the first 3 months (during valganciclovir administration), and in 2 patients between the fourth and sixth month after transplant. One hundred eighteen episodes of neutropenia were recorded, originally treated by reducing the dosage of mycophenolic acid (765 ± 390 mg/d) and administering granulocyte colony-stimulating factor. Three patients experienced acute rejection 5 to 10 days after reducing the dosage of mycophenolic acid, and they were successfully treated with pulse steroids. Five patients developed cytomegalovirus infection 108 ± 65 days after the onset of neutropenia. After replacing mycophenolic acid with everolimus, episodes of neutropenia were observed in 6 patients. In 1 patient, discontinuing everolimus was necessary after 1.5 months of treatment. In 5 patients with cytomegalovirus infection, neutropenia subsided after termination of valganciclovir treatment. In the remaining 11 patients, no episodes of neutropenia were observed. No episodes of acute rejection occurred, and renal function remained stable during a followup of 47 ± 30 months (estimated glomerular filtration rate [eGFRMDRD6]: 45 ± 14 mL/min/1.73 m2→47 ± 22 mL/min/1.73 m2]. CONCLUSIONS Replacing mycophenolic acid with everolimus appears to be a safe and effective alternative treatment in neutropenic renal transplant recipients.
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Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update. Arch Toxicol 2014; 88:1351-89. [PMID: 24792322 DOI: 10.1007/s00204-014-1247-1] [Citation(s) in RCA: 145] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 04/15/2014] [Indexed: 12/22/2022]
Abstract
This review aims to provide an update of the literature on the pharmacology and toxicology of mycophenolate in solid organ transplant recipients. Mycophenolate is now the antimetabolite of choice in immunosuppressant regimens in transplant recipients. The active drug moiety mycophenolic acid (MPA) is available as an ester pro-drug and an enteric-coated sodium salt. MPA is a competitive, selective and reversible inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), an important rate-limiting enzyme in purine synthesis. MPA suppresses T and B lymphocyte proliferation; it also decreases expression of glycoproteins and adhesion molecules responsible for recruiting monocytes and lymphocytes to sites of inflammation and graft rejection; and may destroy activated lymphocytes by induction of a necrotic signal. Improved long-term allograft survival has been demonstrated for MPA and may be due to inhibition of monocyte chemoattractant protein 1 or fibroblast proliferation. Recent research also suggested a differential effect of mycophenolate on the regulatory T cell/helper T cell balance which could potentially encourage immune tolerance. Lower exposure to calcineurin inhibitors (renal sparing) appears to be possible with concomitant use of MPA in renal transplant recipients without undue risk of rejection. MPA displays large between- and within-subject pharmacokinetic variability. At least three studies have now reported that MPA exhibits nonlinear pharmacokinetics, with bioavailability decreasing significantly with increasing doses, perhaps due to saturable absorption processes or saturable enterohepatic recirculation. The role of therapeutic drug monitoring (TDM) is still controversial and the ability of routine MPA TDM to improve long-term graft survival and patient outcomes is largely unknown. MPA monitoring may be more important in high-immunological recipients, those on calcineurin-inhibitor-sparing regimens and in whom unexpected rejection or infections have occurred. The majority of pharmacodynamic data on MPA has been obtained in patients receiving MMF therapy in the first year after kidney transplantation. Low MPA area under the concentration time from 0 to 12 h post-dose (AUC0-12) is associated with increased incidence of biopsy-proven acute rejection although AUC0-12 optimal cut-off values vary across study populations. IMPDH monitoring to identify individuals at increased risk of rejection shows some promise but is still in the experimental stage. A relationship between MPA exposure and adverse events was identified in some but not all studies. Genetic variants within genes involved in MPA metabolism (UGT1A9, UGT1A8, UGT2B7), cellular transportation (SLCOB1, SLCO1B3, ABCC2) and targets (IMPDH) have been reported to effect MPA pharmacokinetics and/or response in some studies; however, larger studies across different ethnic groups that take into account genetic linkage and drug interactions that can alter a patient's phenotype are needed before any clinical recommendations based on patient genotype can be formulated. There is little data on the pharmacology and toxicology of MPA in older and paediatric transplant recipients.
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