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Yu X, Zhang Y, An Z, Feng X, Yang H. Thrombotic Microangiopathy Associated with Calcineurin Inhibitors: A Real-World Analysis of Postmarketing Surveillance Data. Clin Ther 2025; 47:117-122. [PMID: 39690020 DOI: 10.1016/j.clinthera.2024.11.017] [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: 08/29/2024] [Revised: 11/13/2024] [Accepted: 11/14/2024] [Indexed: 12/19/2024]
Abstract
PURPOSE Calcineurin inhibitors (CNIs) are currently the first-line drugs for preventing and treating post-transplant rejection in organ transplant recipients. However, these drugs, especially tacrolimus, have the potential to induce thrombotic microangiopathy (TMA), a rare but potentially fatal complication that can develop following transplantation. This condition has garnered considerable attention within the medical community. Consequently, the study conducted an observational retrospective pharmacovigilance study to investigate the risk signal of thrombotic microangiopathy associated with CNIs. METHODS A retrospective pharmacovigilance study was conducted to investigate the relationship between CNIs and TMA using data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. A disproportionality analysis was performed to evaluate risk signals. FINDINGS A total of 1019 cases of CNIs-associated TMA were identified, with 785 cases attributed to tacrolimus and 234 cases to cyclosporine A. Overall, the incidence of CNIs related TMA was higher compared to the entire database (ROR = 29.76 [27.84-31.82], IC = 4.64 [4.55-4.74]). A stronger signal was observed for tacrolimus-associated TMA compared to cyclosporine A (ROR = 3.72 [3.20-4.23], IC = 0.63 [0.50-0.77]). Additionally, residing in the Americas may be a protective factor against mortality in tacrolimus-related TMA, while for cyclosporine A-related TMA, patients from Asia and female patients have a significantly higher risk of death. IMPLICATIONS Clinician awareness of CNIs-associated TMA needs to be heightened, particularly with tacrolimus. Special attention should be given to patients' geographic regions and gender differences.
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Affiliation(s)
- Xin Yu
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Department of Pharmacy, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Yi Zhang
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Zhuoling An
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Xin Feng
- Department of Pharmacy, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Hui Yang
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
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Acharya R, Clapp W, Upadhyay K. Safety and Efficacy of Very Early Conversion to Belatacept in Pediatric Kidney Transplantation with Transplant-Associated Thrombotic Microangiopathy: Case Study and Review of Literature. Clin Pract 2024; 14:882-891. [PMID: 38804401 PMCID: PMC11130864 DOI: 10.3390/clinpract14030069] [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: 04/09/2024] [Revised: 05/11/2024] [Accepted: 05/15/2024] [Indexed: 05/29/2024] Open
Abstract
The inhibition of co-stimulation during T-cell activation has been shown to provide effective immunosuppression in kidney transplantation (KT). Hence, the conversion from calcineurin inhibitor (CNI) to belatacept is emerging as a potential alternate maintenance immunosuppressive therapy in those with transplant-associated thrombotic microangiopathy (TA-TMA) or in the prevention of TA-TMA. We present a 17-year-old male who presented with biopsy-proven CNI-associated TA-TMA immediately post-KT. The administration of eculizumab led to the reversal of TMA. Tacrolimus was converted to belatacept with excellent efficacy and safety during a short-term follow-up of one year. Further larger controlled studies are required to demonstrate the efficacy of this approach in children who present with early-onset TMA post-KT.
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Affiliation(s)
- Ratna Acharya
- Department of Pediatrics, Nemours Children’s Hospital, Orlando, FL 32827, USA
| | - William Clapp
- Division of Anatomic Pathology, Department of Pathology, University of Florida, Gainesville, FL 32610, USA
| | - Kiran Upadhyay
- Division of Pediatric Nephrology, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA
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Sakai K, Takahashi M, Ito Y, Yamada S, Ito T, Higuchi Y, Kameda S. Thrombotic microangiopathy in a patient with anti-signal recognition particle antibody-positive immune-mediated necrotizing myopathy. Int J Rheum Dis 2024; 27:e14942. [PMID: 37828793 DOI: 10.1111/1756-185x.14942] [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: 07/10/2023] [Revised: 08/20/2023] [Accepted: 10/04/2023] [Indexed: 10/14/2023]
Abstract
We describe the case of a 61-year-old woman with anti-signal recognition particle (SRP) antibody-positive immune-mediated necrotizing myopathy (IMNM) who exhibited biopsy-confirmed thrombotic microangiopathy (TMA). The patient developed proximal-dominant muscle weakness and was diagnosed with anti-SRP antibody-positive IMNM based on muscle biopsy results and serological examination. A high-dose corticosteroid prescription was initiated, followed by intravenous methylprednisolone and intravenous immunoglobulin therapy (IVIg). The patient showed IVIg-induced hemolytic anemia with preserved ADAMTS13 activity. Transient oral tacrolimus administration was initiated. Approximately 8 weeks after admission, the serum creatinine levels gradually increased. Renal histological examination revealed TMA, including ischemic changes in the renal tubules, stenosis, and occlusion of the interlobular arteries with fibrinoid necrosis of the afferent arteriolar walls. The arteriolar walls demonstrated an accumulation of C1q and C3c. Myofiber damage in patients with IMNM accounts for the activation of the classical pathway of the complement cascade in the sarcolemma due to antibody deposition. Additionally, a membrane attack complex is observed on capillaries in the muscle tissues of patients with anti-SRP antibody-positive IMNM. Although drug-induced pathomechanisms, such as IVIg and tacrolimus, can trigger the development of TMA, we suggest that the presence of serum anti-SRP antibodies would be implicated in complement-associated kidney vascular damage.
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Affiliation(s)
- Kenji Sakai
- Department of Neurology, Joetsu General Hospital, Joetsu, Japan
| | - Megumi Takahashi
- Department of Nephrology, Joetsu General Hospital, Joetsu, Japan
| | - Yumi Ito
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Shota Yamada
- Department of Neurology, Joetsu General Hospital, Joetsu, Japan
| | - Toru Ito
- Department of Nephrology, Joetsu General Hospital, Joetsu, Japan
| | - Yo Higuchi
- Department of Neurology, Joetsu General Hospital, Joetsu, Japan
| | - Shigemi Kameda
- Department of Nephrology, Joetsu General Hospital, Joetsu, Japan
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Von Tokarski F, Fillon A, Maisons V, Thoreau B, Bayer G, Gatault P, Longuet H, Sautenet B, Buchler M, Vigneau C, Fakhouri F, Halimi JM. Thrombotic microangiopathies after kidney transplantation in modern era: nosology based on chronology. BMC Nephrol 2023; 24:278. [PMID: 37730583 PMCID: PMC10512637 DOI: 10.1186/s12882-023-03326-8] [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: 03/15/2023] [Accepted: 09/07/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND Thrombotic microangiopathies (TMAs) are rare but can be severe in kidney transplant. recipients (KTR). METHODS We analysed the epidemiology of adjudicated TMA in consecutive KTR during the. 2009-2021 period. RESULTS TMA was found in 77/1644 (4.7%) KTR. Early TMA (n = 24/77 (31.2%); 1.5% of all KTR) occurred during the first two weeks ((median, IQR) 3 [1-8] days). Triggers included acute antibody-mediated rejection (ABMR, n = 4) and bacterial infections (n = 6). Graft survival (GS) was 100% and recurrence rate (RR) was 8%. Unexpected TMA (n = 31/77 (40.2%); 1.5/1000 patient-years) occurred anytime during follow-up (3.0 (0.5-6.2) years). Triggers included infections (EBV/CMV: n = 10; bacterial: n = 6) and chronic active ABMR (n = 5). GS was 81% and RR was 16%. Graft-failure associated TMA (n = 22/77 (28.6%); 2.2% of graft losses) occurred after 8.8 (4.9-15.5) years). Triggers included acute (n = 4) or chronic active (n = 14) ABMR, infections (viral: n = 6; bacterial: n = 5) and cancer (n = 6). 15 patients underwent transplantectomy. RR was 27%. Atypical (n = 6) and typical (n = 2) haemolytic and uremic syndrome, and isolated CNI toxicity (n = 4) were rare. Two-third of biopsies presented TMA features. CONCLUSIONS TMA are mostly due to ABMR and infections; causes of TMA are frequently combined. Management often is heterogenous. Our nosology based on TMA timing identifies situations with distinct incidence, causes and prognosis.
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Affiliation(s)
- Florent Von Tokarski
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
| | - Alexandre Fillon
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
| | - Valentin Maisons
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
| | - Benjamin Thoreau
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
| | - Guillaume Bayer
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
| | - Philippe Gatault
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
- EA4245, François-Rabelais University, Tours, France
| | - Hélène Longuet
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
| | - Bénédicte Sautenet
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
- Inserm U1246, Hôpital Bretonneau, CHU Tours, Tours, France
| | - Matthias Buchler
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
- EA4245, François-Rabelais University, Tours, France
| | - Cécile Vigneau
- Service de Néphrologie, CHU Pontchaillou, 35033, Rennes, France
- Université Rennes 1, Inserm IRSET, UMR 1085, 35033, Rennes, France
| | - Fadi Fakhouri
- Department of medicine, Service of Nephrology, CHUV and Université de Lausanne, Lausanne, Switzerland
| | - Jean-Michel Halimi
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France.
- EA4245, François-Rabelais University, Tours, France.
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Drug-induced de novo thrombotic microangiopathy diagnosed 2 years after renal transplantation: a case report and literature review. RENAL REPLACEMENT THERAPY 2023. [DOI: 10.1186/s41100-022-00453-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Abstract
Background
Post-transplant de novo thrombotic microangiopathy (TMA) is a rare yet serious complication that generally can develop in renal transplant recipients immediately after reperfusion or several months after transplantation. Here, we report a case of systemic tacrolimus-associated TMA in a patient diagnosed 2 years after renal transplantation.
Case presentation
A 49-year-old woman presented with severe anemia 18 months after undergoing renal transplantation. Anemia was refractory to recombinant human erythropoietin and was suspected to be due to excessive menstruation. Anemia persisted even after hysterectomy, and thereafter, pancytopenia developed. A bone marrow biopsy was performed and showed no evidence of myeloproliferative neoplasms. Furthermore, an increase in serum lactate dehydrogenase level and the appearance of schistocytes on peripheral blood smear was noted 24 months post-transplant. Other possible causes of de novo TMA were excluded, and an allograft biopsy was performed. Pathological findings of the allograft biopsy showed that some afferent arterioles had formed thrombi. Suspecting tacrolimus to be the cause of TMA, 25 months after the transplant, we switched treatment to cyclosporine. Pancytopenia and renal function improved after switching to this calcineurin inhibitor. Subsequently, her allograft renal function stabilized for three years after renal transplantation.
Conclusion
We encountered a case of secondary drug-induced TMA in the late stages of renal transplantation. Therefore, TMA should be suspected when anemia with hemolysis is observed in recipients of kidney transplant.
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Markan A, Ayyadurai N, Singh R. Tacrolimus Induced Thrombotic Microangiopathy (TMA) Presenting as Acute Macular Neuroretinopathy. Ocul Immunol Inflamm 2023; 31:231-232. [PMID: 34855579 DOI: 10.1080/09273948.2021.1998549] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
This report highlights the association of tacrolimus use with acute macular neuroretinopathy (AMN). A 27-year-old woman, a known case of diffuse proliferative membranous glomerulonephritis, developed abnormal body movements, loss of consciousness, and blurring of vision in the left eye, after 3 months of starting tacrolimus. Blood investigations revealed anemia, thrombocytopenia, raised urea and creatinine levels, and raised LDH levels. A diagnosis of tacrolimus induced hemolytic uremic syndrome (HUS) with posterior reversible encephalopathy syndrome (PRES) was made. Ocular examination revealed a reddish-brown petaloid retinal lesion, which was better appreciated on red-free imaging as dark grey area pointing towards the fovea. OCT-A and SD-OCT revealed flow voids in deep retinal plexus, and disruption of ellipsoid and interdigitation zone, respectively, findings consistent with AMN. To the best of our knowledge, it is the first report of association of tacrolimus with AMN.
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Affiliation(s)
- Ashish Markan
- Advanced Eye Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Nikitha Ayyadurai
- Advanced Eye Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ramandeep Singh
- Advanced Eye Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Nishikubo M, Shimomura Y, Hiramoto N, Sawamura N, Yamaguchi T, Hara S, Ishikawa T. Reversible renal-limited thrombotic microangiopathy due to gemcitabine-dexamethasone-cisplatin therapy: a case report. BMC Nephrol 2021; 22:175. [PMID: 33980166 PMCID: PMC8114690 DOI: 10.1186/s12882-021-02386-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 05/04/2021] [Indexed: 01/07/2023] Open
Abstract
Background Gemcitabine and cisplatin are chemotherapeutic agents used for treating multiple cancers, and these agents are sometimes used in combination. Drug-induced thrombotic microangiopathy (TMA) is a rare but potentially fatal complication. It typically presents as a systemic disease with the classical triad of hemolytic anemia, thrombocytopenia, and organ damage. In contrast to systemic TMA, cases of renal-limited TMA, defined as biopsy-proven renal TMA without the classical triad, have been reported with relatively good prognosis. Most cases of renal-limited TMA are associated with calcineurin inhibitors, and cases of drug-induced renal-limited TMA due to gemcitabine-dexamethasone-cisplatin therapy have been rarely reported. Case presentation A 43-year-old woman with lymphoma developed acute kidney injury with marked proteinuria, microhematuria, and abnormal urinary casts after receiving one cycle of gemcitabine-dexamethasone-cisplatin therapy. Although she did not show hemolytic anemia and thrombocytopenia, renal biopsy showed diffuse injury to the glomerular endothelial cells, supporting the diagnosis of renal-limited TMA. Her condition improved only with the cessation of gemcitabine and cisplatin treatment. She received another chemotherapy without gemcitabine and platinum agents, and no recurrence of renal-limited TMA was observed. Conclusions Drug-induced TMA occurs early after gemcitabine and cisplatin use in renal-limited form and is reversible when detected and managed in a timely manner. Urinalysis, which is simple and inexpensive and can be easily performed, is a beneficial screening tool for early-onset drug-induced TMA among patients who receive gemcitabine-dexamethasone-cisplatin therapy.
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Affiliation(s)
- Masashi Nishikubo
- Department of Hematology, Kobe City Medical Center General Hospital, 2-1-1 Minami-machi, Minatojima, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
| | - Yoshimitsu Shimomura
- Department of Hematology, Kobe City Medical Center General Hospital, 2-1-1 Minami-machi, Minatojima, Chuo-ku, Kobe, Hyogo, 650-0047, Japan
| | - Nobuhiro Hiramoto
- Department of Hematology, Kobe City Medical Center General Hospital, 2-1-1 Minami-machi, Minatojima, Chuo-ku, Kobe, Hyogo, 650-0047, Japan
| | - Naohiko Sawamura
- Department of Nephrology, Kobe City Medical Center General Hospital, Kobe, Hyogo, 650-0047, Japan
| | - Takako Yamaguchi
- Department of Pathology, Kobe City Medical Center General Hospital, Kobe, Hyogo, 650-0047, Japan
| | - Shigeo Hara
- Department of Pathology, Kobe City Medical Center General Hospital, Kobe, Hyogo, 650-0047, Japan
| | - Takayuki Ishikawa
- Department of Hematology, Kobe City Medical Center General Hospital, 2-1-1 Minami-machi, Minatojima, Chuo-ku, Kobe, Hyogo, 650-0047, Japan
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Godara A, Migliozzi DR, Pilichowska M, Goyal N, Varga C, Gordon CE. Use of Eculizumab in Transplant-Associated Thrombotic Microangiopathy in a Patient With Polycystic Kidney Disease Immediately Post-Kidney Transplant: A Case Report. Kidney Med 2020; 2:652-656. [PMID: 33089142 PMCID: PMC7568057 DOI: 10.1016/j.xkme.2020.06.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Transplant-associated thrombotic microangiopathy (TMA) in the post-organ transplantation setting occurs from a number of potential inciting factors, such as the use of calcineurin inhibitors, ischemic injury, infections, or antibody-mediated rejection leading to unchecked complement activation and end-organ damage. Delayed recognition of this condition can result in allograft loss. In this case description, we describe the first case of de novo TMA in a patient with polycystic kidney disease that occurred immediately after kidney transplantation. The diagnosis was made promptly on the basis of clinical and laboratory characteristics by a multidisciplinary team and confirmed through kidney biopsy, which showed acute TMA. The patient was successfully managed by replacing tacrolimus with belatacept, which targets cytotoxic T lymphocyte antigen 4, and use of eculizumab, a C5 inhibitor. Eculizumab treatment was discontinued after 3 months of complement inhibition on the patient's request, and relapse of TMA has not been encountered after more than 1 year of follow-up.
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Affiliation(s)
- Amandeep Godara
- Department of Hematology-Oncology, Tufts Medical Center, Boston, MA
| | - Daniel R Migliozzi
- Kidney Transplant Team, Division of Nephrology, Tufts Medical Center, Boston, MA
| | | | - Nitender Goyal
- Kidney Transplant Team, Division of Nephrology, Tufts Medical Center, Boston, MA
| | - Cindy Varga
- Department of Hematology-Oncology, Tufts Medical Center, Boston, MA
| | - Craig E Gordon
- Division of Nephrology, Tufts Medical Center, Boston, MA
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Chowdhary P, Kale S, Saha T, Banerjee S. Guillain–Barre syndrome-like presentation and thrombotic microangiopathy with calcineurin inhibitor - A case report. INDIAN JOURNAL OF TRANSPLANTATION 2020. [DOI: 10.4103/ijot.ijot_70_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Honma F, Fujigaki Y, Nemoto Y, Kikuchi H, Nagura M, Arai S, Ishizawa K, Yamazaki O, Tamura Y, Kondo F, Ohashi R, Uchida S, Shibata S. A Case of Rheumatoid Arthritis Presenting with Renal Thrombotic Microangiopathy Probably due to a Combination of Chronic Tacrolimus Arteriolopathy and Severe Hypertension. Case Rep Nephrol 2019; 2019:3923190. [PMID: 30963011 PMCID: PMC6431373 DOI: 10.1155/2019/3923190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Accepted: 02/18/2019] [Indexed: 11/24/2022] Open
Abstract
A 51-year-old woman with rheumatoid arthritis presented with mild hypertension 20 months after tacrolimus treatment and developing proteinuria 24 months after the treatment. Tacrolimus was discontinued 27 months after the treatment, followed by heavy proteinuria, accelerated hypertension, and deteriorating renal function without ocular fundus lesions as a clinical sign of malignant hypertension. Renal biopsy revealed malignant nephrosclerosis characterized by subacute and chronic thrombotic microangiopathy (TMA), involving small arteries, arterioles, and glomeruli. Focal segmental glomerulosclerosis, probably secondary to chronic TMA, was identified as a cause of heavy proteinuria. The zonal tubulointerstitial injury caused by subacute TMA may have mainly contributed to deteriorating renal function. The presence of nodular hyalinosis in arteriolar walls was indicative of tacrolimus-associated nephrotoxicity. Together with other antihypertensive drugs, administration of aliskiren stabilized renal function with reducing proteinuria. Owing to the preexisting proteinuria prior to severe hypertension and the complex renal histopathology, we postulated that chronic TMA, which was initially triggered by tacrolimus, was aggravated by severe hypertension, resulting in overt renal TMA.
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Affiliation(s)
- Fumika Honma
- Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Yoshihide Fujigaki
- Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Yoshikazu Nemoto
- Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Hirotoshi Kikuchi
- Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Michito Nagura
- Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Shigeyuki Arai
- Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Kenichi Ishizawa
- Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Osamu Yamazaki
- Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Yoshifuru Tamura
- Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Fukuo Kondo
- Department of Pathology, Teikyo University Hospital, Itabashi-ku, Tokyo, Japan
| | - Ryuji Ohashi
- Department of Diagnostic Pathology, Nippon Medical School Musashikosugi Hospital, Kawasaki, Kanagawa, Japan
| | - Shunya Uchida
- Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Shigeru Shibata
- Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
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Mikhail A, Brown C, Williams JA, Mathrani V, Shrivastava R, Evans J, Isaac H, Bhandari S. Renal association clinical practice guideline on Anaemia of Chronic Kidney Disease. BMC Nephrol 2017; 18:345. [PMID: 29191165 PMCID: PMC5709852 DOI: 10.1186/s12882-017-0688-1] [Citation(s) in RCA: 147] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 08/09/2017] [Indexed: 12/16/2022] Open
Abstract
Anaemia is a commonly diagnosed complication among patients suffering with chronic kidney disease. If left untreated, it may affect patient quality of life. There are several causes for anaemia in this patient population. As the kidney function deteriorates, together with medications and dietary restrictions, patients may develop iron deficiency, resulting in reduction of iron supply to the bone marrow (which is the body organ responsible for the production of different blood elements). Chronic kidney disease patients may not be able to utilise their own body's iron stores effectively and hence, many patients, particularly those receiving haemodialysis, may require additional iron treatment, usually provided by infusion.With further weakening of kidney function, patients with chronic kidney disease may need additional treatment with a substance called erythropoietin which drives the bone marrow to produce its own blood. This substance, which is naturally produced by the kidneys, becomes relatively deficient in patients with chronic kidney disease. Any patients will eventually require treatment with erythropoietin or similar products that are given by injection.Over the last few years, several iron and erythropoietin products have been licensed for treating anaemia in chronic kidney disease patients. In addition, several publications discussed the benefits of each treatment and possible risks associated with long term treatment. The current guidelines provide advice to health care professionals on how to screen chronic kidney disease patients for anaemia, which patients to investigate for other causes of anaemia, when and how to treat patients with different medications, how to ensure safe prescribing of treatment and how to diagnose and manage complications associated with anaemia and the drugs used for its treatment.
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Affiliation(s)
- Ashraf Mikhail
- Abertawe Bro Morgannwg University Health Board, Swansea, Wales, United Kingdom.
| | - Christopher Brown
- Abertawe Bro Morgannwg University Health Board, Swansea, Wales, United Kingdom
| | | | - Vinod Mathrani
- Aneurin Bevan University Health Board, Newport, Wales, United Kingdom
| | - Rajesh Shrivastava
- Abertawe Bro Morgannwg University Health Board, Swansea, Wales, United Kingdom
| | - Jonathan Evans
- Nottingham University Hospitals NHS Trust, Nottingham, England
| | - Hayleigh Isaac
- Patient Representative, c/o The Renal Association, Bristol, United Kingdom
| | - Sunil Bhandari
- Hull & East Yorkshire Hospitals NHS Trust, Hull, England
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Merola J, Yoo PS, Schaub J, Smith JD, Rodriguez-Davalos MI, Tichy E, Mulligan DC, Asch W, Formica R, Kashgarian M, Kulkarni S. Belatacept and Eculizumab for Treatment of Calcineurin Inhibitor-induced Thrombotic Microangiopathy After Kidney Transplantation: Case Report. Transplant Proc 2017; 48:3106-3108. [PMID: 27932157 DOI: 10.1016/j.transproceed.2016.04.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 04/27/2016] [Indexed: 11/25/2022]
Abstract
Thrombotic microangiopathy (TMA) after kidney transplantation is an uncommon and challenging cause of graft dysfunction and is associated with early graft loss. An idiosyncratic endothelial reaction to calcineurin inhibitors (CNIs) has been implicated as a frequent cause of TMA. This reaction is marked by uncontrolled activation of complement and subsequent cellular destruction. Usual therapy consists of withdrawal of the inciting drug and plasmapheresis to minimize levels of circulating complement. Recently, eculizumab, a monoclonal antibody to complement component C5, has been used for the treatment of atypical hemolytic uremic syndrome. Belatacept, an inhibitor of T cell costimulatory protein CTLA-4 has been used in immunosuppression strategies aimed at minimization of CNI. Here we report the first case of treatment of CNI-associated TMA/hemolytic uremic syndrome with withdrawal of tacrolimus and initiation of both belatacept and eculizumab. The case describes a favorable clinical course for both graft and patient, and is accompanied by a review of the literature.
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Affiliation(s)
- J Merola
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut
| | - P S Yoo
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
| | - J Schaub
- Department of Medicine, Yale School of Medicine, New Haven, Connecticut
| | - J D Smith
- Department of Medicine, Yale School of Medicine, New Haven, Connecticut
| | | | - E Tichy
- Department of Pharmacy, Yale-New Haven Hospital, New Haven, Connecticut
| | - D C Mulligan
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut
| | - W Asch
- Department of Medicine, Yale School of Medicine, New Haven, Connecticut
| | - R Formica
- Department of Medicine, Yale School of Medicine, New Haven, Connecticut
| | - M Kashgarian
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut
| | - S Kulkarni
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut
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Bilateral Cavernous Sinus Thrombosis in a Patient with Tacrolimus-Associated Posttransplant Thrombotic Microangiopathy. Eur J Ophthalmol 2016; 27:22-24. [DOI: 10.5301/ejo.5000889] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Purpose To report a case of bilateral cavernous sinus thrombosis (CST) in a patient with tacrolimus-associated posttransplant thrombotic microangiopathy. Methods Case report. Results An 8-year-old boy with a medical history of orthotopic heart transplant, posttransplant lymphoproliferative disease, and recurrent infections was hospitalized for nausea, vomiting, and diarrhea. His ocular history included accommodative esotropia, hyperopia with astigmatism, Molluscum contagiosum lid lesions, and idiopathic intracranial hypertension. Shortly after presentation, he developed increased intraocular pressure, an afferent pupillary defect, a layered hyphema, and tense proptosis of the left globe requiring an emergent canthotomy and cantholysis. Over the next month, the patient's hospital course included subdural and subarachnoid hemorrhage, temporal lobe stroke, serotonin syndrome, bilateral CST, and systemic microangiopathy. After an extensive workup, a diagnosis of tacrolimus-associated thrombotic microangiopathy was made. At this point, vision was 20/20 in the right eye and light perception in the left eye. Eight months after the canthotomy and cantholysis, the patient's vision in the left eye deteriorated to no light perception and remained so after 13 months of follow-up. Conclusions An idiosyncratic drug reaction should be considered in the differential diagnosis of CST, especially in a patient on calcineurin inhibitors after solid organ transplant without sinus disease or orbital cellulitis.
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16
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Choi JS, Kim SY, Lee JG, Kim SJ, Song MJ, Yoon BR, Kim MH, Park MS, Paik HC. Tacrolimus-induced, Transplant-associated Thrombotic Microangiopathies after Lung Transplantation. KOREAN JOURNAL OF TRANSPLANTATION 2016. [DOI: 10.4285/jkstn.2016.30.2.94] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Ji Soo Choi
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Song Yee Kim
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jin Gu Lee
- Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Soo Jeong Kim
- Division of Hematology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Myung Jin Song
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Bo Ra Yoon
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Moo Hyun Kim
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Moo Suk Park
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyo Chae Paik
- Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea
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17
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Gao W, Song JL, Yang J, Yang JY, Yan LN. Successful Treatment of Severe Immune Thrombocytopenia After Orthotopic Liver Transplant. EXP CLIN TRANSPLANT 2016; 16:103-106. [PMID: 27001430 DOI: 10.6002/ect.2015.0219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Here, we report a case of severe immune thrombocytopenia that occurred after orthotopic liver transplant. On day 16 after transplant, the patient was readmitted to our hospital with a platelet count of 0 cells/mL, with the count remaining at a low level of 1000 to 10 000 cells/mL for 46 days. A diagnosis was made, after exclusion of other causes, of thrombocytopenia. Platelet blood transfusion and high-dose prednisone (1mg/kg/d) combined with intravenous immunoglobulin (0.5g/kg/d) were administered with no improvement. After additional treatments, which included altered use of immunosuppressive agents, changing adefovir to lamivudine and continuous steroid therapy, the patient was discharged with a platelet count of 55 000 cells/mL. Both liver and renal functions generally stayed well during hospitalization. The patient was discharged uneventfully and achieved remission during 10-month follow-up after discharge.
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Affiliation(s)
- Wei Gao
- From the Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
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18
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Obut F, Kasinath V, Abdi R. Post-bone marrow transplant thrombotic microangiopathy. Bone Marrow Transplant 2016; 51:891-7. [DOI: 10.1038/bmt.2016.61] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 02/01/2016] [Indexed: 12/15/2022]
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Ko S, Chisuwa H, Matsumoto M, Fujimura Y, Okano E, Nakajima Y. Relevance of ADAMTS13 to liver transplantation and surgery. World J Hepatol 2015; 7:1772-1781. [PMID: 26167250 PMCID: PMC4491906 DOI: 10.4254/wjh.v7.i13.1772] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2014] [Revised: 09/30/2014] [Accepted: 04/14/2015] [Indexed: 02/06/2023] Open
Abstract
A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) specifically cleaves unusually-large von Willebrand factor (VWF) multimers under high shear stress, and down-regulates VWF function to form platelet thrombi. Deficiency of plasma ADAMTS13 activity induces a life-threatening systemic disease, termed thrombotic microangiopathy (TMA) including thrombotic thrombocytopenic purpura (TTP). Children with advanced biliary cirrhosis due to congenital biliary atresia sometimes showed pathological features of TMA, with a concomitant decrease of plasma ADAMTS13 activity. Disappearance of their clinical findings of TTP after successful liver transplantation suggested that the liver is a major organ producing plasma ADAMTS13. In situ hybridization analysis showed that ADAMTS13 was produced by hepatic stellate cells. Subsequently, it was found that ADADTS13 was not merely responsible to development of TMA and TTP, but also related to some kinds of liver dysfunction after liver transplantation. Ischemia-reperfusion injury and acute rejection in liver transplant recipients were often associated with marked decrease of ADAMTS13 and concomitant formation of unusually large VWF multimers without findings of TMA/TTP. The similar phenomenon was observed also in patients who underwent hepatectomy for liver tumors. Imbalance between ADAMTS13 and VWF in the hepatic sinusoid might cause liver damage due to microcirculatory disturbance. It can be called as “local TTP like mechanism” which plays a crucial role in liver dysfunction after liver transplantation and surgery.
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Haas M. Emerging Concepts and Controversies in Renal Pathology: C4d-Negative and Arterial Lesions as Manifestations of Antibody-Mediated Transplant Rejection. Surg Pathol Clin 2014; 7:457-467. [PMID: 26837450 DOI: 10.1016/j.path.2014.04.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
The consensus classification of antibody-mediated rejection (AMR) of renal allografts developed at the Sixth Banff Conference on Allograft Pathology, in 2001, identified three findings necessary for the diagnosis of active AMR: histologic evidence, antibodies against the graft, and capillary C4d deposition. Morphologic and molecular studies have noted evidence of microvascular injury, which, in the presence of donor-specific antibodies (DSAs) but the absence of C4d deposition, is associated with development of transplant glomerulopathy and graft loss. Recent studies suggest that intimal arteritis may in some cases be a manifestation of DSA-induced graft injury. These newly recognized lesions of AMR have now been incorporated into a revised Banff diagnostic schema.
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Affiliation(s)
- Mark Haas
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
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21
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22
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Prasad D, Agarwal D, Malhotra V, Mathur M, Garsa R, Gandhi K, Beniwal P. Successful outcome of tacrolimus-associated thrombotic microangiopathy in renal transplant recipient with plasmapharesis. INDIAN JOURNAL OF TRANSPLANTATION 2014. [DOI: 10.1016/j.ijt.2014.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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23
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An updated Banff schema for diagnosis of antibody-mediated rejection in renal allografts. Curr Opin Organ Transplant 2014; 19:315-22. [PMID: 24811440 DOI: 10.1097/mot.0000000000000072] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW To introduce the updated Banff schema for antibody-mediated renal allograft rejection and related revisions to definitions within this schema agreed upon during and immediately subsequent to the 2013 Banff Conference on Allograft Pathology. RECENT FINDINGS The original Banff schema for diagnosis of acute and chronic, active antibody-mediated rejection (ABMR) in renal allografts, formulated at the 2001 and 2007 Banff Conferences, has been of great assistance to pathologists and clinicians faced with an increasing awareness of the role of donor-specific alloantibodies (DSAs) in producing graft injury. This schema requires histologic (primarily microvascular inflammation and transplant glomerulopathy), immunohistologic (C4d in peritubular capillaries), and serologic (circulating DSA) evidence for a definitive diagnosis of ABMR. Still, like other Banff classifications, the 2001/2007 schema for renal ABMR is a working classification subject to revision based on new data. Increasing evidence for C4d-negative ABMR and antibody-mediated arterial lesions led to the development of a consensus at the 2013 Banff Conference for updating the schema to include these lesions. Definitions and thresholds for glomerulitis and chronic glomerulopathy were also revised to improve interobserver agreement and correlation with clinical, molecular, and serologic data. SUMMARY From a consensus reached at the 2013 Banff Conference, an updated schema for diagnosis of acute/active and chronic, active ABMR has been developed that accounts for recent data supporting the existence of C4d-negative ABMR and antibody-mediated intimal arteritis.
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Matsuda D, Toshima T, Ikegami T, Harimoto N, Yamashita YI, Yoshizumi T, Soejima Y, Ikeda T, Shirabe K, Maehara Y. Thrombotic microangiopathy caused by severe graft dysfunction after living donor liver transplantation: report of a case. Clin J Gastroenterol 2014; 7:159-63. [DOI: 10.1007/s12328-013-0446-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Accepted: 12/10/2013] [Indexed: 11/30/2022]
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Nwaba A, MacQuillan G, Adams LA, Garas G, Delriviere L, Augustson B, DeBoer B, Moody H, Jeffrey GP. Tacrolimus-induced thrombotic microangiopathy in orthotopic liver transplant patients: case series of four patients. Intern Med J 2013; 43:328-33. [PMID: 23441660 DOI: 10.1111/imj.12048] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Accepted: 08/26/2012] [Indexed: 12/23/2022]
Abstract
Thrombotic microangiopathy (TMA) is a potentially fatal complication in solid organ and bone marrow transplant patients, with reported incidence of 0.5-3% and mortality of about 75%. To emphasise the importance of early diagnosis and prompt commencement of therapy results in improved clinical outcomes. A retrospective study of all patients who underwent orthotopic liver transplantation (OLTX) at the Western Australian Liver Transplantation Service from May 1994 to December 2010 was conducted to identify patients who developed tacrolimus-induced TMA. We identified four patients with tacrolimus-induced TMA post-OLTX, derived from a cohort of 104 patients treated with tacrolimus in our institution. The mean age at diagnosis was 40 years, and the mean time of onset was 63 ± 7.5 weeks after OLTX. The indications for OLTX in the four patients were fulminant hepatic failure in three (Wilson disease, paracetamol overdose and post-partum thrombotic thrombocytopenic purpura) and hepatitis C virus-related cirrhosis. All patients had tacrolimus post-OLTX. At diagnosis, tacrolimus was discontinued in all patients, and three of the four patients underwent plasma exchange and all patients improved clinically. Mean duration of follow up was 15 ± 7.5 months. There was no mortality 6 months post-TMA. Early diagnosis with immediate discontinuation or conversion of calcineurin inhibitors and plasma exchange should be offered to OLTX patients with TMA as it results in good outcomes.
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Affiliation(s)
- A Nwaba
- West Australian Liver Transplant Service, University of Western Australia, Perth, Australia.
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26
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Živković SA. Neurologic complications after liver transplantation. World J Hepatol 2013; 5:409-416. [PMID: 24023979 PMCID: PMC3767839 DOI: 10.4254/wjh.v5.i8.409] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Revised: 06/21/2013] [Accepted: 07/13/2013] [Indexed: 02/06/2023] Open
Abstract
Neurologic complications are relatively common after solid organ transplantation and affect 15%-30% of liver transplant recipients. Etiology is often related to immunosuppressant neurotoxicity and opportunistic infections. Most common complications include seizures and encephalopathy, and occurrence of central pontine myelinolysis is relatively specific for liver transplant recipients. Delayed allograft function may precipitate hepatic encephalopathy and neurotoxicity of calcineurin inhibitors typically manifests with tremor, headaches and encephalopathy. Reduction of neurotoxic immunosuppressants or conversion to an alternative medication usually result in clinical improvement. Standard preventive and diagnostic protocols have helped to reduce the prevalence of opportunistic central nervous system (CNS) infections, but viral and fungal CNS infections still affect 1% of liver transplant recipients, and the morbidity and mortality in the affected patients remain fairly high. Critical illness myopathy may also affect up to 7% of liver transplant recipients. Liver insufficiency is also associated with various neurologic disorders which may improve or resolve after successful liver transplantation. Accurate diagnosis and timely intervention are essential to improve outcomes, while advances in clinical management and extended post-transplant survival are increasingly shifting the focus to chronic post-transplant complications which are often encountered in a community hospital and an outpatient setting.
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27
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Pathology of C4d-negative antibody-mediated rejection in renal allografts. Curr Opin Organ Transplant 2013; 18:319-26. [DOI: 10.1097/mot.0b013e32835d4daf] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Boyer NL, Niven A, Edelman J. Tacrolimus-associated thrombotic microangiopathy in a lung transplant recipient. BMJ Case Rep 2013; 2013:bcr2012007351. [PMID: 23396921 PMCID: PMC3604378 DOI: 10.1136/bcr-2012-007351] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
A 25-year-old woman with a history of bilateral lung transplant secondary to cystic fibrosis presented with non-specific abdominal complaints and was found to have acute kidney injury, thrombocytopaenia and laboratory findings consistent with a microangiopathic haemolytic anaemia. Her thrombotic microangiopathy (TMA) was attributed to tacrolimus, which was discontinued and replaced with cyclosporine with resolution of her TMA and no subsequent complications. This is the fifth reported case of TMA associated with tacrolimus use in a lung transplant patient, and the third to be successfully managed with cyclosporine substitution. Clinicians must be aware of this uncommon, but likely under-reported complication of tacrolimus therapy in lung transplant recipients. Cyclosporine replacement may be used as a successful therapy to treat tacrolimus-associated TMA without increasing the risk of acute rejection that may be associated with other treatment strategies.
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Affiliation(s)
- Nathan Lewis Boyer
- Department of Internal Medicine, Madigan Army Medical Center, Tacoma, Washington, USA.
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Takahashi N, Wada H, Usui M, Kobayashi T, Habe-Ito N, Matsumoto T, Uemoto S, Nobori T, Isaji S. Behavior of ADAMTS13 and Von Willebrand factor levels in patients after living donor liver transplantation. Thromb Res 2012; 131:225-9. [PMID: 23266519 DOI: 10.1016/j.thromres.2012.12.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Revised: 11/20/2012] [Accepted: 12/05/2012] [Indexed: 01/18/2023]
Abstract
INTRODUCTION Thrombotic microangiopathy (TMA) is one of the important complications occurring after liver transplantation (LT), and it is suggested that a Von Willebrand factor (VWF) and ADAMTS13 may play an important role in the onset of TMA and poor outcome after LT. MATERIALS AND METHODS In 81 patients after living donor LT (LDLT), 17 patients who had both severe thrombocytopenia and hemolytic anemia with fragmented red cell were diagnosed as TMA- like syndrome (TMALS) and 10 patients died. RESULTS ADAMTS13 activities were slightly low, and plasma levels of VWF and VWF propeptide (VWFpp) antigens and the ratio of VWFpp/VWF were significantly high before LDLT. ADAMTS13 activities were significantly reduced from day 1 to day 28 after surgery, and plasma levels of VWF antigen slightly decreased on day 1 and plasma levels of VWFpp continued to be high. The ratio of VWFpp/VWF was significantly high on day 1 after surgery. The mortality was high in the patients with TMALS and the frequency of TMALS was high in non-survivors. VWF levels were significantly low and the ratio of VWFpp/VWF was significantly high in those with TMALS on day 1 after surgery. The ADAMTS13 activity was significantly low, and the VWFpp and the VWFpp/ADAMTS13 ratio were significantly high in non-survivor on day 28 after surgery. CONCLUSION These findings suggest that VWF and ADAMTS13 might therefore play an important role in the onset of TMA and poor outcome after LT. The VWFpp may therefore be a more useful marker for the diagnosis of TMALS than VWF.
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Affiliation(s)
- Naoki Takahashi
- Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Mie, Japan
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Devadoss CW, Vijaya V M, E M, Venkataramana S R, M S G. Tacrolimus associated localized thrombotic microangiopathy developing in early stage after renal transplantation. J Clin Diagn Res 2012; 6:1786-8. [PMID: 23373055 DOI: 10.7860/jcdr/2012/4535.2614] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Accepted: 10/22/2012] [Indexed: 11/24/2022]
Abstract
Calcineurin inhibitor induced thrombotic microangiopathy is a rare but well recognized complication of a renal transplantation that occurs in 1% of the patients who are on tacrolimus immunosuppression. Among the other aetiological factors of the "de-novo" Thrombotic Microangiopathy (TMA), the condition especially has to be differentiated from an antibody mediated rejection, as both have different pathogenesis, therapeutic connotations and outcomes.We report a case of a middle aged female renal transplant recipient treated with tacrolimus, who developed localised thrombotic microangiopathy in the early post transplantation period. Despite the normal trough levels of tacrolimus, a diagnosis of "Tacrolimus induced TMA" was rendered after excluding other causes of the "de-novo" TMA, which included an antibody mediated rejection, a meticulous clinico-pathological correlation and serological studies. The treatment included the substitution of tacrolimus by rapamycin, with the subsequent normalization of the renal function.
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Pathologic features of antibody-mediated rejection in renal allografts: an expanding spectrum. Curr Opin Nephrol Hypertens 2012; 21:264-71. [PMID: 22388553 DOI: 10.1097/mnh.0b013e3283520efa] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
PURPOSE OF REVIEW This review discusses recent findings that are changing and expanding the spectrum of pathologic changes associated with antibodies directed against renal allografts. RECENT FINDINGS This review focuses on four lesions: subclinical antibody-mediated rejection (AMR), C4d-negative AMR, intimal arteritis, and arterial intimal fibrosis. A number of studies have identified morphologic lesions of AMR in protocol biopsies of normally functioning renal allografts, particularly in sensitized recipients, that correlate with subsequent development of chronic changes in the graft, including transplant glomerulopathy. These same studies as well as molecular studies of indication biopsies of conventional renal allografts have noted evidence of microvascular injury, which, in the presence of donor-specific antibodies (DSAs) but the absence of C4d deposition in peritubular capillaries, is associated with development of transplant glomerulopathy and graft loss. Finally, recent studies suggest that intimal arteritis, previously felt to represent a lesion of cell-mediated rejection, and bland arterial intimal fibrosis, resembling arteriosclerosis, may in some cases be manifestations of DSA-induced graft injury. SUMMARY Incorporation of these newly recognized lesions of AMR into a working diagnostic schema with sufficient sensitivity and specificity to minimize undertreatment and overtreatment of patients is an important challenge currently faced by renal pathologists and transplant clinicians.
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Hopfner R, Tran TT, Island ER, McLaughlin GE. Nonsurgical care of intestinal and multivisceral transplant recipients: a review for the intensivist. J Intensive Care Med 2012; 28:215-29. [PMID: 22733723 DOI: 10.1177/0885066611432425] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Intestinal and multivisceral transplantation has evolved from an experimental procedure to the treatment of choice for patients with irreversible intestinal failure and serious complications related to long-term parenteral nutrition. Increased numbers of transplant recipients and improved survival rates have led to an increased prevalence of this patient population in intensive care units. Management of intestinal and multivisceral transplant recipients is uniquely challenging because of complications arising from the high incidence of transplant rejection and its treatment. Long-term comorbidities, such as diabetes, hypertension, chronic kidney failure, and neurological sequelae, also develop in this patient population as survival improves. This article is intended for intensivists who provide care to critically ill recipients of intestinal and multivisceral transplants. As perioperative care of intestinal/multivisceral transplant recipients has been described elsewhere, this review focuses on common nonsurgical complications with which one should be familiar in order to provide optimal care. The article is both a review of the current literature on multivisceral and isolated intestinal transplantation as well as a reflection of our own experience at the University of Miami.
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Affiliation(s)
- Reinhard Hopfner
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Miami, Miller School of Medicine, FL, USA
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Shindoh J, Sugawara Y, Akamatsu N, Kaneko J, Tamura S, Yamashiki N, Aoki T, Sakamoto Y, Hasegawa K, Kokudo N. Thrombotic microangiopathy after living-donor liver transplantation. Am J Transplant 2012; 12:728-36. [PMID: 22070669 DOI: 10.1111/j.1600-6143.2011.03841.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Thrombotic microangiopathy (TMA) is an infrequent but severe life-threatening disorder in solid organ transplant recipients. Few studies of TMA in living donor liver transplant (LDLT) recipients, however, have been reported. We investigated the clinical characteristics and prognostic factors of TMA after LDLT. Among 393 adult LDLT recipients, 30 patients (7.6%) were identified to have TMA. The 1-, 3- and 5-year survival rates of these patients were lower (60.6%, 52.5% and 47.7%, respectively) than those of patients without TMA (93.0%, 89.0% and 87.3%, respectively). Multivariate analysis confirmed that reduced administration of fresh frozen plasma and sensitization against HLA are closely related with TMA (odds ratio [OR]: 2.6 and 16.1, respectively). However, a review of the cases revealed that individual responses to treatment varied considerably and the main etiologies were difficult to determine. A comparison of the clinical factors suggested that late onset (>30 days), poor response to treatment and delayed diagnosis and/or treatment are associated with a poor outcome. Because the prevention of TMA in LDLT patients is difficult, early diagnosis and initiation of intensive therapies may be crucial to improve the prognosis.
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Affiliation(s)
- J Shindoh
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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Liem RI, Anand R, Yin W, Alonso EM. Risk factors for chronic anemia in pediatric orthotopic liver transplantation: analysis of data from the SPLIT registry. Pediatr Transplant 2012; 16:137-43. [PMID: 22188527 PMCID: PMC3288717 DOI: 10.1111/j.1399-3046.2011.01631.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Risk factors for chronic anemia in the post-transplant period have not been clearly delineated in pediatric liver transplant recipients. We analyzed data from children transplanted from 2000 to 2008 with at least two consecutive hemoglobin values from follow-up between six months and five yr post-transplant. A multivariate model was derived to determine independent risk factors associated with chronic anemia. Of 1026 children in this analysis, 242 (23.6%) were found to have chronic anemia. On multivariate analysis, GI bleeding (OR 11.83 [2.08-67.49], p = 0.0054), presence of leukopenia (OR 9.55 [95% CI 3.71-24.62], p < 0.0001), use of cyclosporine (OR 3.69, [95% CI 1.56-8.76], p = 0.0039) and corticosteroids (OR 2.90 [95% CI 1.94-4.33], p < 0.0001), and cGFR <90 mL/min/1.73 m(2) (OR 4.62 [95% CI 2.47-8.67], p < 0.0001) represented the most significant risk factors for chronic anemia. Use of antihypertensive medications (OR 1.89 [95% CI 1.23-2.91], p = 0.0039) was also significantly associated with a higher risk. In summary, chronic anemia is common in children following liver transplant. Our findings underscore the need to define the mechanisms by which these risk factors, some of which are modifiable, result in chronic anemia in pediatric liver transplant recipients.
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Affiliation(s)
- RI Liem
- Divisions of Hematology, Oncology & Stem Cell Transplant; Children’s Memorial Hospital; Department of Pediatrics, Northwestern University Feinberg School of Medicine; Chicago, Illinois
| | - R Anand
- The EMMES Corporation; Rockville, Maryland
| | - W Yin
- The EMMES Corporation; Rockville, Maryland
| | - EM Alonso
- Divisions of Gastroenterology, Hepatology & Nutrition; Children’s Memorial Hospital; Department of Pediatrics, Northwestern University Feinberg School of Medicine; Chicago, Illinois
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Boyer O, Niaudet P. Hemolytic uremic syndrome: new developments in pathogenesis and treatment. Int J Nephrol 2011; 2011:908407. [PMID: 21876803 PMCID: PMC3159990 DOI: 10.4061/2011/908407] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2011] [Accepted: 06/14/2011] [Indexed: 12/27/2022] Open
Abstract
Hemolytic uremic syndrome is defined by the characteristic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. In children, most cases of HUS are caused by Shiga-toxin-producing bacteria, especially Escherichia coli O157:H7. Common vehicles of transmission include ground beef, unpasteurized milk, and municipal or swimming water. Shiga-toxin-associated HUS is a main cause of acute renal failure in young children. Management remains supportive as there is at present no specific therapy to ameliorate the prognosis. Immediate outcome is most often favourable but long-term renal sequelae are frequent due to nephron loss. Atypical HUS represents 5% of cases. In the past 15 years, mutations in complement regulators of the alternative pathway have been identified in almost 60% of cases, leading to excessive complement activation. The disease has a relapsing course and more than half of the patients either die or progress to end-stage renal failure. Recurrence after renal transplantation is frequent.
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Affiliation(s)
- Olivia Boyer
- Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France
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Hori T, Kaido T, Oike F, Ogura Y, Ogawa K, Yonekawa Y, Hata K, Kawaguchi Y, Ueda M, Mori A, Segawa H, Yurugi K, Takada Y, Egawa H, Yoshizawa A, Kato T, Saito K, Wang L, Torii M, Chen F, Baine AMT, Gardner LB, Uemoto S. Thrombotic microangiopathy-like disorder after living-donor liver transplantation: A single-center experience in Japan. World J Gastroenterol 2011; 17:1848-57. [PMID: 21528059 PMCID: PMC3080720 DOI: 10.3748/wjg.v17.i14.1848] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2010] [Revised: 06/09/2010] [Accepted: 06/16/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate thrombotic microangiopathy (TMA) in liver transplantion, because TMA is an infrequent but life-threatening complication in the transplantation field.
METHODS: A total of 206 patients who underwent living-donor liver transplantation (LDLT) were evaluated, and the TMA-like disorder (TMALD) occurred in seven recipients.
RESULTS: These TMALD recipients showed poor outcomes in comparison with other 199 recipients. Although two TMALD recipients successfully recovered, the other five recipients finally died despite intensive treatments including repeated plasma exchange (PE) and re-transplantation. Histopathological analysis of liver biopsies after LDLT revealed obvious differences according to the outcomes. Qualitative analysis of antibodies against a disintegrin-like domain and metalloproteinase with thrombospondin type 1 motifs (ADAMTS-13) were negative in all patients. The fragmentation of red cells, the microhemorrhagic macules and the platelet counts were early markers for the suspicion of TMALD after LDLT. Although the absolute values of von Willebrand factor (vWF) and ADAMTS-13 did not necessarily reflect TMALD, the vWF/ADAMTS-13 ratio had a clear diagnostic value in all cases. The establishment of adequate treatments for TMALD, such as PE for ADAMTS-13 replenishment or treatments against inhibitory antibodies, must be decided according to each case.
CONCLUSION: The optimal induction of adequate therapies based on early recognition of TMALD by the reliable markers may confer a large advantage for TMALD after LDLT.
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Lovric S, Kielstein JT, Kayser D, Bröcker V, Becker JU, Hiss M, Schiffer M, Sommerwerck U, Haller H, Strüber M, Welte T, Gottlieb J. Combination of everolimus with calcineurin inhibitor medication resulted in post-transplant haemolytic uraemic syndrome in lung transplant recipients--a case series. Nephrol Dial Transplant 2011; 26:3032-8. [PMID: 21310739 DOI: 10.1093/ndt/gfq842] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Post-transplant haemolytic uraemic syndrome (HUS) is a rare but serious disease with a high mortality rate, when left untreated. Immunosuppressive drugs like calcineurin inhibitors as well as mammalian target of rapamycin inhibitors have been reported as causative agents for post-transplant HUS. METHODS A retrospective observational study was performed in lung transplant recipients, who took part in an interventional study, in two centres. Haemoglobin, platelets, creatinine and lactate dehydrogenase levels were monitored during routine follow-up and patients with deteriorating kidney function were screened for post-transplant HUS. All cases of post-transplant HUS were identified by clinical and laboratory findings. Outcome was recorded until 6 months after diagnosis. RESULTS A total of 2188 visits in 512 lung transplant recipients (outpatients) were analysed. Out of those, 126 patients took part in an interventional study. In this study, 67 were switched to everolimus in combination with calcineurin inhibitors 4 weeks after transplantation, 59 patients remained on standard immunosuppression (calcineurin inhibitors, mycophenolate mofetil and prednisolone). Five cases of post-transplant HUS were identified in the everolimus group. None of the patients had evidence of gastrointestinal infection or preexisting renal disease. Post-transplant HUS was treated with therapeutic plasma exchange and methylprednisolone pulse therapy. Everolimus was discontinued in all five patients. This treatment regimen led to normalization of haemoglobin, platelets and improved renal function. Two patients developed end-stage renal failure and were maintained on haemodialysis. One patient died due to multiorgan failure. Improvement of renal function was seen in two patients. No further cases were recorded in patients without everolimus during the study period. CONCLUSIONS Our data should raise the awareness of post-transplant HUS in lung transplant recipients. Post-transplant HUS is a rare disease, but it is a serious cause of acute renal failure in lung transplant recipients treated with a combination of everolimus and calcineurin inhibitors.
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Affiliation(s)
- Svjetlana Lovric
- Department of Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
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Mikhail A, Shrivastava R, Richardson D. Renal Association Clinical Practice Guideline on Anaemia of Chronic Kidney Disease. ACTA ACUST UNITED AC 2011; 118 Suppl 1:c101-24. [DOI: 10.1159/000328063] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2010] [Accepted: 11/15/2010] [Indexed: 12/15/2022]
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Troxell ML, Norman D, Mittalhenkle A. Glomerular fibrin thrombi in ABO and crossmatch compatible renal allograft biopsies. Pathol Res Pract 2011; 207:15-23. [DOI: 10.1016/j.prp.2010.10.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2009] [Revised: 09/12/2010] [Accepted: 10/04/2010] [Indexed: 11/29/2022]
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Thrombotic microangiopathy in haematopoietic cell transplantation: an update. Mediterr J Hematol Infect Dis 2010; 2:e2010033. [PMID: 21776339 PMCID: PMC3134219 DOI: 10.4084/mjhid.2010.033] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2010] [Accepted: 10/29/2010] [Indexed: 12/17/2022] Open
Abstract
Allogeneic hematopoietic cell transplantation (HCT) represents a vital procedure for patients with various hematologic conditions. Despite advances in the field, HCT carries significant morbidity and mortality. A rare but potentially devastating complication is transplantation-associated thrombotic microangiopathy (TA-TMA). In contrast to idiopathic TTP, whose etiology is attributed to deficient activity of ADAMTS13, (a member of the A Disintegrin And Metalloprotease with Thrombospondin 1 repeats family of metalloproteases), patients with TA-TMA have > 5% ADAMTS13 activity. Pathophysiologic mechanisms associated with TA-TMA, include loss of endothelial cell integrity induced by intensive conditioning regimens, immunosuppressive therapy, irradiation, infections and graft-versus-host (GVHD) disease. The reported incidence of TA-TMA ranges from 0.5% to 75%, reflecting the difficulty of accurate diagnosis in these patients. Two different groups have proposed consensus definitions for TA-TMA, yet they fail to distinguish the primary syndrome from secondary causes such as infections or medication exposure. Despite treatment, mortality rate in TA-TMA ranges between 60% to 90%. The treatment strategies for TA-TMA remain challenging. Calcineurin inhibitors should be discontinued and replaced with alternative immunosuppressive agents. Daclizumab, a humanized monoclonal anti-CD25 antibody, has shown promising results in the treatment of TA-TMA. Rituximab or the addition of defibrotide, have been reported to induce remission in this patient population. In general, plasma exchange is not recommended.
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Szczepiorkowski ZM, Winters JL, Bandarenko N, Kim HC, Linenberger ML, Marques MB, Sarode R, Schwartz J, Weinstein R, Shaz BH. Guidelines on the use of therapeutic apheresis in clinical practice--evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher 2010; 25:83-177. [PMID: 20568098 DOI: 10.1002/jca.20240] [Citation(s) in RCA: 354] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The American Society for Apheresis (ASFA) Apheresis Applications Committee is charged with a review and categorization of indications for therapeutic apheresis. Beginning with the 2007 ASFA Special Issue (fourth edition), the subcommittee has incorporated systematic review and evidence-based approach in the grading and categorization of indications. This Fifth ASFA Special Issue has further improved the process of using evidence-based medicine in the recommendations by refining the category definitions and by adding a grade of recommendation based on widely accepted GRADE system. The concept of a fact sheet was introduced in the Fourth edition and is only slightly modified in this current edition. The fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis. The article consists of 59 fact sheets devoted to each disease entity currently categorized by the ASFA as category I through III. Category IV indications are also listed.
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Affiliation(s)
- Zbigniew M Szczepiorkowski
- Transfusion Medicine Service, Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, USA.
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Parissis H, Gould K, Dark J. Dangerous drug interactions leading to hemolytic uremic syndrome following lung transplantation. J Cardiothorac Surg 2010; 5:70. [PMID: 20813025 PMCID: PMC2936888 DOI: 10.1186/1749-8090-5-70] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2010] [Accepted: 09/02/2010] [Indexed: 01/01/2023] Open
Abstract
Background To report our experience of a rather uncommon drug interaction, resulting in hemolytic uremic syndrome (HUS). Methods Two consecutive cases of hemolytic uremic syndrome were diagnosed in our service. In both patients the use of macrolides in patients taking Tacrolimus, resulted in high levels of Tacrolimus. Results The first patient was a 48 years old female with Bilateral emphysema. She underwent Single Sequential Lung Transplantation. She developed reperfusion injury requiring prolonged stay. Tacrolimus introduced (Day 51). The patient remained well up till 5 months later; Erythromycin commenced for chest infection. High Tacrolimus levels and a clinical diagnosis of HUS were made. She was treated with plasmapheresis successfully. The second case was a 57 years old female with Emphysema & A1 Antithrypsin deficiency. She underwent Right Single Lung Transplantation. A2 rejection with mild Obliterative Bronchiolitis diagnosed 1 year later and she switched to Tacrolimus. She was admitted to her local Hospital two and a half years later with right middle lobe consolidation. The patient commenced on amoxicillin and clarithromycin. Worsening renal indices, high Tacrolimus levels, hemolytic anemia & low Platelets were detected. HUS diagnosed & treated with plasmapheresis. Conclusions There are 21 cases of HUS following lung transplantation in the literature that may have been induced by high tacrolimus levels. Macrolides in patients taking Cyclosporin or Tacrolimus lead to high levels. Mechanism of action could be glomeruloconstrictor effect with reduced GFR increased production of Endothelin-1 and increased Platelet aggregation.
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Affiliation(s)
- Haralabos Parissis
- Cardiothoracic Department, Royal Victoria Hospital, Grosvernor Rd, Belfast, BT12 6BA, Nothern Ireland.
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Botija G, Ybarra M, Ramos E, Molina M, Sarría J, Martínez-Ojinaga E, Andrés AM, López-Santamaría M, Prieto G. Autoimmune cytopaenia after paediatric intestinal transplantation: a case series. Transpl Int 2010; 23:1033-7. [PMID: 20444240 DOI: 10.1111/j.1432-2277.2010.01091.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Autoimmune cytopaenia is a rare, but severe complication after solid organ transplantation. We retrospectively analysed 57 paediatric intestinal transplants performed in 49 patients between 1999 and 2009. Autoimmune cytopaenia was observed in six patients; it appeared after an average of 10 months post-transplant. Warm autoimmune haemolytic anaemia was developed in three patients, cold autoimmune haemolytic anaemia in one and two presented a mixed type. Incidence and causes for haematological cytopaenia such as the following were investigated: immunosuppression, major blood mismatch, viral infection, malignancy, passenger lymphocyte syndrome and lymphoproliferative disorders. Initial treatment included high-dose steroids, intravenous immunoglobulin, plasmapheresis and maintenance of body temperature above 37°C in those with cold autoantibodies. Inclusion of the spleen in multivisceral transplants seems to be an important risk factor. All patients, except one, relapsed after classic therapy, requiring additional treatments. Sirolimus conversion was performed in four patients. One died after infection. The immunosuppressive therapies associated with other concomitant factors, such as viral infections, lymphoproliferative disorders, graft-versus-host disease, passenger lymphocyte syndrome and the inclusion of the spleen as part of multivisceral graft seem to play an important part in the development of autoimmune processes after intestinal transplantation. Therapy is not well established, especially in those resistant to first-line treatment.
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Affiliation(s)
- Gonzalo Botija
- Department of Pediatric Gastroenterology and Nutrition, Pediatric Intestinal Rehabilitation Unit, Hospital Infantil La Paz, Madrid, Spain
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Said T, Al-Otaibi T, Al-Wahaib S, Francis I, Nair MP, Halim MA, El-Sayed A, Nampoory MRN. Posttransplantation calcineurin inhibitor-induced hemolytic uremic syndrome: single-center experience. Transplant Proc 2010; 42:814-6. [PMID: 20430179 DOI: 10.1016/j.transproceed.2010.02.029] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
INTRODUCTION Calcineurin inhibitor (CNI) induced HUS, although rare, can be a serious complication of renal transplantation. Classical syndrome of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal injury may not be fully manifested. METHODS We retrospectively analyzed our data in 950 kidney recipients under follow-up in our center (1994-2008). We reviewed the kidney biopsies performed for these patients to exclude conflicting diagnoses like antibody mediated rejection. RESULTS HUS was diagnosed in 12 patients (1.26%). None of them had HUS as the original kidney disease. Cyclosporine was the primary immunosuppression in 9 and tacrolimus in 3 patients. The median day of onset was 7 days. Manifestations were anemia (100%), thrombocytopenia (75%), elevated reticulocyte count (62.5%), fragmented red blood cells (8.3%), elevated lactate dehydrogenase (LDH) enzyme (83.3%), increased fibrin degradation product (FDP) (83.3%), reduced haptoglobin level (42.9%) and hyperbilirubinemia (25%). CNI elimination was the first step in the management. Transfusion of fresh frozen plasma (FFP) was used in 10 patients and plasma exchange with FFP in the other two. All grafts recovered function. Cyclosporine or tacrolimus were reintroduction in two patients after complete clinical and laboratory recovery. Both patients developed recurrence of HUS. While the former did not the latter did recover on further treatment of HUS. CONCLUSION Anemia, thrombocytopenia, elevated LDH and FDP are the most frequent manifestations of HUS. Early CNI elimination and fresh plasma transfusion can revert CNI induced HUS and save the graft. Reintroduction of CNI may be deleterious to the graft and should be avoided.
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Affiliation(s)
- T Said
- Hamed Al-Essa Organ Transplant Center, Pathology Department, Faculty of Medicine, Kuwait University, Shuwaikh, Kuwait.
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Patel P, Dhaliwal G, Rajamanickam A, Gebresalassie S, Harte B. Unscripted. J Hosp Med 2010; 5:366-70. [PMID: 20803678 DOI: 10.1002/jhm.806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Preethi Patel
- Department of Hospital Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
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Kadikoy H, Paolini M, Achkar K, Suki W, Gaber AO, Anwar N, Jeroudi A, Barrios R, Abdellatif A. Pulmonary alveolar proteinosis in a kidney transplant: a rare complication of sirolimus. Nephrol Dial Transplant 2010; 25:2795-8. [PMID: 20484303 DOI: 10.1093/ndt/gfq265] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Pulmonary alveolar proteinosis (PAP) has been associated with the immunosuppressant sirolimus in transplant patients. PAP is a progressive lung disease characterized by the accumulation of surfactant-like material in the lungs leading to decreased pulmonary function with shortness of breath and cough as common symptoms. We report a rare case of sirolimus-associated PAP in a kidney transplant recipient with a history of end-stage renal disease secondary to haemolytic uraemic syndrome (HUS) and review of the literature. Discontinuation of sirolimus and initiation of tacrolimus led to resolution of PAP without recurrence of HUS.
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Affiliation(s)
- Huseyin Kadikoy
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
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Thrombotic microangiopathy after living-donor liver re-transplantation. J Anesth 2010; 24:614-7. [DOI: 10.1007/s00540-010-0953-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2010] [Accepted: 04/08/2010] [Indexed: 10/19/2022]
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Abstract
Hemolytic uremic syndrome (HUS) is related to a renal thrombotic microangiopathy, inducing hypertension and acute renal failure (ARF). Its pathogenesis involves an activation/lesion of microvascular endothelial cells, mainly in the renal vasculature, secondary to bacterial toxins, drugs, or autoantibodies. An overactivation of the complement alternate pathway secondary to a heterozygote deficiency of regulatory proteins (factor H, factor I or MCP) or to an activating mutation of factor B or C3 can also result in HUS. Less frequently, renal microthrombi are due to an acquired or a constitutional deficiency in ADAMTS-13, the protease cleaving von Wilebrand factor. Hemolytic anemia with schistocytes, thrombocytopenia without evidence of disseminated intravascular coagulation, and renal failure are consistently found. In typical HUS, a prodromal diarrhea, with blood in the stools, is observed, related to pathogenic enterobacteria, most frequently E. Coli O157:H7. HUS may also occur in the post partum period, and is then related to a factor H or factor I deficiency. HUS may also occur after various treatments such as mitomycin C, gemcitabine, ciclosporin A, or tacrolimus, and as reported more recently bevacizumab, an anti VEGF antibody. Atypical HUS are not associated with diarrhea, may be sporadic or familial, and can be related to an overactivation of the complement alternate pathway. More recently, some of them have been related to a mutation of thrombomodulin, which also regulates the alternate pathway of complement. In adults, several HUS are encountered in the course of chronic nephropathies: nephroangiosclerosis, chronic glomerulonephritis, post irradiation nephropathy, scleroderma, disseminated lupus erythematosus, antiphospholipid syndrome. Overall the prognosis of HUS has improved, with a patient survival greater than 85% at 1 year. Chronic renal failure is observed as a sequella in 20 to 65% of the cases. Plasma infusions and plasma exchanges are effective in most of the cases to treat hemolysis and thrombocytopenia. Steroid therapy is debated, as well as immunosuppressive drugs, including rituximab, in autoimmune forms. A new monoclonal anti-C5 antibody is tested, and seems to be effective in atypical HUS with abnormal complement alternate pathway activation. If terminal renal failure occurs, renal transplantation can be performed but the risk of recurrence, which very low in post infectious forms of HUS, is about 70 to 80% in genetic forms of complement regulatory protein deficiency.
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Affiliation(s)
- Alexandre Hertig
- Service des urgences néphrologiques et transplantation rénale, hôpital Tenon, 4, rue de la Chine, 75020 Paris, France
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Pivotal role of ADAMTS13 function in liver diseases. Int J Hematol 2010; 91:20-9. [PMID: 20054668 DOI: 10.1007/s12185-009-0481-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2009] [Revised: 12/17/2009] [Accepted: 12/21/2009] [Indexed: 02/07/2023]
Abstract
The liver is a major source of clotting and fibrinolytic proteins, and plays a central role in thrombo-regulation. Patients with advanced liver diseases tend to bleed because of reduced plasma levels of several clotting factors and thrombocytopenia, but they do also exhibit thrombotic complications. ADAMTS13 is a metalloproteinase, produced exclusively in hepatic stellate cells, and specifically cleaves highly multimeric von Willebrand factor (VWF). VWF plays a pivotal role in hemostasis and thrombosis, and its function is dependent on its multimeric state. Deficiency of ADAMTS13 results in accumulation of unusually large VWF multimers (UL-VWFM) in plasma, in turn induces platelet clumping or thrombi under high shear stress, followed by microcirculatory disturbances. Considering that UL-VWFM, the substrate of ADAMTS13, is produced in transformed vascular endothelial cells at sites of liver injury, decreased ADAMTS13 activity may be involved in not only sinusoidal microcirculatory disturbances, but also subsequent progression of liver injuries, eventually leading to multiorgan failure. This concept can be applied to the development or aggravation of liver diseases, including liver cirrhosis, alcoholic hepatitis, veno-occlusive disease, and adverse events after liver transplantation. These results promise to bring further understanding of the pathophysiology of liver diseases, and offer new insight for development of therapeutic strategies.
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Abstract
Neurologic complications affect posttransplant recovery of more than 20% of transplant recipients. Etiology is usually related to surgical procedure of transplantation, primary disorders causing failure of transplanted organ, opportunistic infections, and neurotoxicity of immunosuppressive medications. Risk of opportunistic infections and immunosuppressant neurotoxicity is greatest within the first six months, but it persists along with long-term maintenance immunosuppression required to prevent graft rejection. Neurotoxicity may require alteration of immunosuppressive regimen, and prompt therapy of opportunistic infections improves outcomes.
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Affiliation(s)
- Sasa A Zivković
- Neurology Service, VA Pittsburgh Healthcare System, University Drive C, Pittsburgh, PA 15240, USA.
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