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Tachikawa T, Tanaka K, Iwai A, Kim K, Usami I. Pediatric Case of Calcineurin Inhibitor-Induced Pain Syndrome Diagnosed During Cyclosporine Therapy for Aplastic Anemia. Cureus 2025; 17:e80602. [PMID: 40230761 PMCID: PMC11995364 DOI: 10.7759/cureus.80602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2025] [Indexed: 04/16/2025] Open
Abstract
A 15-year-old male with severe aplastic anemia was started on immunosuppressive therapy (IST) comprising antithymocyte globulin and cyclosporine (CsA), along with methylprednisolone and eltrombopag. Eight weeks after starting treatment, the CsA trough level increased to 269 ng/mL, coinciding with bilateral leg pain unresponsive to all analgesics, including fentanyl. MRI revealed diffuse high signal intensity areas on short tau inversion recovery (STIR) sequences in both thigh muscles. After discontinuing CsA and starting nifedipine, the pain improved, and an MRI taken 10 days post-discontinuation showed that the STIR high signal areas disappeared. Re-administration of CsA resulted in a recurrence of pain. Based on the clinical presentation and progression, the patient was diagnosed with calcineurin inhibitor-induced pain syndrome (CIPS). After switching from CsA to tacrolimus, the patient had no recurrence of pain. Although reports of CIPS in pediatric patients are extremely rare, it is important to consider CIPS as a differential diagnosis when a patient taking calcineurin inhibitors presents with severe pain in the lower limbs.
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Affiliation(s)
- Tomohiro Tachikawa
- Pediatrics, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, JPN
| | - Kuniaki Tanaka
- Pediatric Hematology and Oncology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, JPN
| | - Atsushi Iwai
- Pediatric Hematology and Oncology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, JPN
| | - Kiyohiro Kim
- Pediatric Neurology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, JPN
| | - Ikuya Usami
- Pediatric Hematology and Oncology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, JPN
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Odler B, Huemer M, Schwaiger E, Borenich A, Kurnikowski A, Krall M, Hafner-Giessauf H, Eleftheriadis G, Bachmann F, Faura A, José Pérez-Sáez M, Pascual J, Budde K, Rosenkranz AR, Hecking M, Eller K. Influence of Early Postoperative Basal Insulin Treatment and Post-Transplant Diabetes Mellitus Risk on Health-Related Quality of Life in Kidney Transplant Recipients-An Analysis of Data From a Randomized Controlled Trial. Transpl Int 2023; 36:11370. [PMID: 37600749 PMCID: PMC10432682 DOI: 10.3389/ti.2023.11370] [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: 03/18/2023] [Accepted: 07/17/2023] [Indexed: 08/22/2023]
Abstract
Health-related quality of life (HRQOL) improves after kidney transplantation (KT) but declines over time. Studies on the effect of early postoperative basal insulin therapy on HRQOL after KT, especially KTRs at high risk of developing post-transplant diabetes mellitus (PTDM) are missing. Data from a randomized controlled trial on 148 non-diabetic KTRs were analyzed. HRQOL using the KDQOL-SF™ was compared in KTRs who either received early postoperative basal insulin therapy or standard-of-care and in KTRs at risk of developing PTDM. Determinants of HRQOL outcomes were investigated using multivariable linear regression analysis. In total, 148 patients completed the KDQOL-SF at baseline. Standard-of-care or early basal insulin therapy after KT did not influence HRQOL. Overall, KT improved the mental (MCS) and physical component summary (PCS) scores at 6-month after KT, which remained stable during further follow-up visits. However, patients at high-risk for PTDM had significantly greater impairment in the PCS score (baseline, 24 months) without differences in MCS scores. In the multivariable regression analysis, allograft function and hemoglobin levels were associated with decreased MCS and PCS scores, respectively. A limitation of the study is the fact that only around 50% of the ITP-NODAT study patients participated in the HRQOL evaluation. Still, our data clearly show that early basal insulin therapy does not affect HRQOL after KT but is negatively influenced by classical clinical factors and PTDM-risk at 24 months after KT. The latter might be influenced by older age.
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Affiliation(s)
- Balazs Odler
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Matthias Huemer
- Palliative Care Unit Associated With the Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Elisabeth Schwaiger
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine II, Kepler University Hospital, Med Campus III, Linz, Austria
| | - Andrea Borenich
- Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
| | - Amelie Kurnikowski
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Marcell Krall
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | | | - Georgios Eleftheriadis
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Friderike Bachmann
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Anna Faura
- Department of Nephrology, Hospital del Mar, Institute Mar for Medical Research, Barcelona, Spain
| | - María José Pérez-Sáez
- Department of Nephrology, Hospital del Mar, Institute Mar for Medical Research, Barcelona, Spain
| | - Julio Pascual
- Department of Nephrology, Hospital del Mar, Institute Mar for Medical Research, Barcelona, Spain
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Alexander R. Rosenkranz
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Manfred Hecking
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Kathrin Eller
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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Masiak A, Kościńska I, Rutkowska B, Zdrojewski Z. Long-lasting severe knee pain in a SLE patient after renal transplantation: what is the reason? A case report and literature review. Rheumatol Int 2022; 42:349-358. [PMID: 34665297 PMCID: PMC8800873 DOI: 10.1007/s00296-021-05018-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/29/2021] [Indexed: 11/29/2022]
Abstract
Musculo-skeletal complaints in a patient suffering from systemic lupus, with co-existing chronic renal failure, undergoing immunosuppressive treatment after kidney transplantation, can have a varied etiology. The aim of this work was to present a case based review of differential diagnosis of knee pain in such a patient. A literature search was carried out using MEDLINE/PubMed, Google Scholar and EBSCO, with no time limit. We undertook a systematic review of the literature published in English, limited to full-text publications of original articles, letters to the editor, and case reports in peer-reviewed journals, for a discussion and analysis of studies reporting arthralgia in patients with lupus after kidney transplantation. We present a case report of a 45-year-old woman with lupus nephritis, after kidney transplantation, who started to complain of increasing pain in the knees, most pronounced at night and after physical activity approximately 2 years after transplantation. Extensive causal diagnostics were carried out, which revealed bilateral extensive regions of bone infarction in the femur and tibia, chondropathy, degenerative changes of medial meniscuses in the body and posterior horn as well as chondromalacia of the patella. Establishing the right diagnosis is crucial for implementing appropriate treatment.
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Affiliation(s)
- Anna Masiak
- Department of Internal Medicine, Connective Tissue Diseases and Geriatrics, Medical University of Gdansk, ul. Dębinki 7, 80-952, Gdańsk, Poland.
| | - Iga Kościńska
- Department of Internal Medicine, Connective Tissue Diseases and Geriatrics, Medical University of Gdansk, ul. Dębinki 7, 80-952, Gdańsk, Poland
| | - Beata Rutkowska
- Department of Radiology, Medical University of Gdansk, Gdansk, Poland
| | - Zbigniew Zdrojewski
- Department of Internal Medicine, Connective Tissue Diseases and Geriatrics, Medical University of Gdansk, ul. Dębinki 7, 80-952, Gdańsk, Poland
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Prevalence of Musculoskeletal Manifestations in Adult Kidney Transplant's Recipients: A Systematic Review. ACTA ACUST UNITED AC 2021; 57:medicina57060525. [PMID: 34071098 PMCID: PMC8224589 DOI: 10.3390/medicina57060525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 05/19/2021] [Accepted: 05/21/2021] [Indexed: 11/17/2022]
Abstract
Background and Objectives: The musculoskeletal (MSK) manifestations in the kidney transplant recipient (KTxR) could lead to decreased quality of life and increased morbidity and mortality. However, the prevalence of these MSK manifestations is still not well-recognized. This review aimed to investigate the prevalence and outcomes of MSK manifestations in KTxR in the last two decades. Materials and Methods: Research was performed in EBSCO, EMBASE, CINAHL, PubMed/MEDLINE, Cochrane, Google Scholar, PsycINFO, Scopus, Science Direct, and Web of Science electronic databases were searched during the years 2000–2020. Results: The PRISMA flow diagram revealed the search procedure and that 502 articles were retrieved from the initial search and a total of 26 articles were included for the final report in this review. Twelve studies reported bone loss, seven studies reported a bone pain syndrome (BPS) or cyclosporine-induced pain syndrome (CIPS), and seven studies reported hyperuricemia (HU) and gout. The prevalence of MSK manifestations in this review reported as follow: BPS/CIPS ranged from 0.82% to 20.7%, while bone loss ranged from 14% to 88%, and the prevalence of gout reported in three studies as 7.6%, 8.0%, and 22.37%, while HU ranged from 38% to 44.2%. Conclusions: The post-transplantation period is associated with profound MSK abnormalities of mineral metabolism and bone loss mainly caused by corticosteroid therapy, which confer an increased fracture risk. Cyclosporine (CyA) and tacrolimus were responsible for CIPS, while HU or gout was attributable to CyA. Late diagnosis or treatment of post-transplant bone disease is associated with lower quality of life among recipients
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Cadiou S, Le Gruyer A, Giguet B, Robin F, Milin M, Guennoc X, Guggenbuhl P, De Saint-Riquier M. Calcium pyrophosphate deposition (CPPD) in a liver transplant patient: are hypomagnesemia, tacrolimus or both guilty? A case-based literature review. Rheumatol Int 2021; 42:1105-1112. [PMID: 33709178 DOI: 10.1007/s00296-021-04828-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/01/2021] [Indexed: 12/21/2022]
Abstract
Calcium pyrophosphate deposition (CPPD) can be induced by a persistent hypomagnesemia. Tacrolimus is an immunosuppressive treatment especially used in organ transplant, potentially inducer of hypomagnesemia by renal loss. A 53-year-old man, liver transplant 10 months earlier, developed an acute peripheral oligoarthritis of wrist, hip and elbow with fever, associated with acute low back pain. Synovial fluid was sterile, and revealed calcium pyrophosphate crystals. Spinal imaging showed inflammatory changes. Magnesium blood level was low at 0.51 mmol/l, with high fractional excretion in favor of renal loss. Tacrolimus was changed for everolimus, proton pump inhibitor was stopped, and magnesium oral supplementation was started. After 8 months follow-up and slow prednisone tapering, he did not relapse pain. Persistent hypomagnesemia is a rare secondary cause of CPPD. In this entity, drug liability should be investigated such as tacrolimus in organ transplant patient.
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Affiliation(s)
- Simon Cadiou
- Department of Rheumatology, Rennes University Hospital, Rennes 1 University, 35000, Rennes, France.
| | - Antonia Le Gruyer
- Department of Hepato-Gastroenterology, Saint-Brieuc Hospital, 22000, Saint-Brieuc, France
| | - Baptiste Giguet
- Department of Hepato-Gastroenterology, Rennes Univsersity Hospital, Rennes 1 University, 35000, Rennes, France
| | - François Robin
- Department of Rheumatology, Rennes University Hospital, Rennes 1 University, 35000, Rennes, France
| | - Morgane Milin
- Department of Rheumatology, Saint-Brieuc Hospital, 22000, Saint-Brieuc, France
| | - Xavier Guennoc
- Department of Rheumatology, Saint-Brieuc Hospital, 22000, Saint-Brieuc, France
| | - Pascal Guggenbuhl
- Department of Rheumatology, Rennes University Hospital, Rennes 1 University, 35000, Rennes, France
- CHU Rennes, University of Rennes 1, INSERM, Institut NUMECAN (Nutrition Metabolisms and Cancer), UMR INSERM U 1241, 35000, Rennes, France
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Fan Z, Li Z, Shen F, Zhang X, Lei L, Su S, Lu Y, Di L, Wang M, Xu M, Da Y. Favorable Effects of Tacrolimus Monotherapy on Myasthenia Gravis Patients. Front Neurol 2020; 11:594152. [PMID: 33193063 PMCID: PMC7652845 DOI: 10.3389/fneur.2020.594152] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 09/24/2020] [Indexed: 12/11/2022] Open
Abstract
Background and Purpose: Tacrolimus (TAC) has been proven to be a rapid-acting, steroid-sparing agent for myasthenia gravis (MG) therapy. However, evidence related to the effectiveness of TAC alone is rare. Therefore, this study was performed to investigate the effect of TAC monotherapy in MG patients. Methods: Forty-four MG patients who received TAC monotherapy were retrospectively analyzed. A mixed effect model was used to analyze improvements in MG-specific activities of daily living scale (MG-ADL), quantitative MG score (QMG) and MG-ADL subscores. Kaplan-Meier analysis was used to estimate the cumulative probability of minimal manifestations (MM) or better. Adverse events (AEs) were recorded for safety analyses. Results: Of the patients receiving TAC monotherapy, MG-ADL scores were remarkably improved at 3, 6 and 12 months compared with scores at baseline (mean difference and 95% CIs: −3.29 [−4.94, −1.64], −3.97 [−5.67, −2.27], and −4.67 [−6.48, −2.85], respectively). QMG scores significantly decreased at 6 and 12 months, with mean differences and 95% CIs of −4.67(−6.88, −2.45) and −5.77 (−7.55, −4.00), respectively. Estimated median period to achieve “MM or better” was 5.0 (95% CIs, 2.8, 7.2) months. Ocular MG (OMG) and generalized MG (GMG) showed similar therapeutic effects in cumulative probabilities of “MM or better” (P-value = 0.764). A better response was observed in MG-ADL subscores for ptosis and bulbar symptoms. AEs occurred in 37.5% of patients and were generally mild and reversible. Conclusions: TAC monotherapy is a promising option to rapidly alleviate all symptoms of MG, especially for ptosis and bulbar symptoms.
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Affiliation(s)
- Zhirong Fan
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Zunbo Li
- Department of Neurology, Xi'an Gaoxin Hospital, Xi'an, China
| | - Faxiu Shen
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Xueping Zhang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Lin Lei
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Shengyao Su
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yan Lu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Li Di
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Min Wang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Min Xu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yuwei Da
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
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Meena P, Bhargava V, Rana D, Bhalla A, Gupta A. An Approach to Neurological Disorders in a Kidney Transplant Recipient. KIDNEY360 2020; 1:837-844. [PMID: 35372958 DOI: 10.34067/kid.0002052020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 06/11/2020] [Indexed: 11/27/2022]
Abstract
Kidney transplantation is the preferred treatment modality in patients with ESKD. However, there are associated complications that arise from immunosuppressive medications, infections, and associated comorbidities. Neurologic disorders frequently develop in patients who have received a kidney transplant, which in turn increases the associated morbidity and mortality. This review discusses the common neurologic disorders after kidney transplantation, including infections, cognitive decline, drug-related conditions, malignancy, seizure, and other neurologic complications.
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Dalvindt M, Kisch A, Nozohoor S, Lennerling A, Forsberg A. Chronic pain 1-5 years after heart transplantation-A nationwide cross-sectional cohort study. Nurs Open 2020; 7:1146-1156. [PMID: 32587734 PMCID: PMC7308699 DOI: 10.1002/nop2.489] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 03/09/2020] [Indexed: 12/28/2022] Open
Abstract
Aim To provide a multidimensional assessment of self-reported chronic pain 1-5 years after heart transplantation and its relationship with self-reported well-being, fatigue, recovery, self-efficacy and socio-economic factors and to explore differences between heart recipients and a cohort of lung recipients. Design This multicentre, cross-sectional, cohort study is a part of the Swedish national Self-management after thoracic transplantation study. Methods Six questionnaires were distributed at the heart recipients yearly follow-up (1-5 years) at three Swedish university hospitals 2014-2017. Results The study group comprised of 79 heart recipients, 25 women and 54 men with a mean age of 52.68 years. Chronic pain among heart recipients was common and those not in paid employment as well as those with low psychological well-being and high general fatigue reported significantly more pain. Female heart recipients were more affected by pain. General health and vitality, general fatigue, physical fatigue and reduced activity were related to the pain intensity score. Relevance to clinical practice As it is the duty of the healthcare system to provide adequate pain treatment, screening for pain should be a mandatory part of long-term follow-up.
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Affiliation(s)
- Marita Dalvindt
- Institute of Health SciencesLund UniversityLundSweden
- Department of Cardiothoracic SurgerySkåne University Hospital, Lund UniversityLundSweden
| | - Annika Kisch
- Institute of Health SciencesLund UniversityLundSweden
- Department of HaematologySkåne University HospitalLundSweden
| | - Shahab Nozohoor
- Department of Cardiothoracic SurgerySkåne University Hospital, Lund UniversityLundSweden
| | - Annette Lennerling
- The Transplant CentreSahlgrenska University HospitalGothenburgSweden
- Institute of Health and Care SciencesThe Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Anna Forsberg
- Institute of Health SciencesLund UniversityLundSweden
- Department of Cardiothoracic SurgerySkåne University Hospital, Lund UniversityLundSweden
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Calcineurin Inhibition Causes α2δ-1-Mediated Tonic Activation of Synaptic NMDA Receptors and Pain Hypersensitivity. J Neurosci 2020; 40:3707-3719. [PMID: 32269108 DOI: 10.1523/jneurosci.0282-20.2020] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 03/16/2020] [Accepted: 03/22/2020] [Indexed: 12/12/2022] Open
Abstract
Calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, are widely used as standard immunosuppressants in organ transplantation recipients. However, these drugs can cause severe pain in patients, commonly referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin inhibition increases NMDAR activity in the spinal cord, the underlying mechanism remains enigmatic. Using an animal model of CIPS, we found that systemic administration of FK506 in male and female mice significantly increased the amount of α2δ-1-GluN1 complexes in the spinal cord and the level of α2δ-1-bound GluN1 proteins in spinal synaptosomes. Treatment with FK506 significantly increased the frequency of mEPSCs and the amplitudes of monosynaptic EPSCs evoked from the dorsal root and puff NMDAR currents in spinal dorsal horn neurons. Inhibiting α2δ-1 with gabapentin or disrupting the α2δ-1-NMDAR interaction with α2δ-1Tat peptide completely reversed the effects of FK506. In α2δ-1 gene KO mice, treatment with FK506 failed to increase the frequency of NMDAR-mediated mEPSCs and the amplitudes of evoked EPSCs and puff NMDAR currents in spinal dorsal horn neurons. Furthermore, systemic administration of gabapentin or intrathecal injection of α2δ-1Tat peptide reversed thermal and mechanical hypersensitivity in FK506-treated mice. In addition, genetically deleting GluN1 in dorsal root ganglion neurons or α2δ-1 genetic KO similarly attenuated FK506-induced thermal and mechanical hypersensitivity. Together, our findings indicate that α2δ-1-bound NMDARs mediate calcineurin inhibitor-induced tonic activation of presynaptic and postsynaptic NMDARs at the spinal cord level and that presynaptic NMDARs play a prominent role in the development of CIPS.SIGNIFICANCE STATEMENT Calcineurin inhibitors are immunosuppressants used to prevent rejection of transplanted organs and tissues. However, these drugs can cause severe, unexplained pain. We showed that calcineurin inhibition enhances physical interaction between α2δ-1 and NMDARs and their synaptic trafficking in the spinal cord. α2δ-1 is essential for calcineurin inhibitor-induced aberrant activation of presynaptic and postsynaptic NMDARs in the spinal cord. Furthermore, inhibiting α2δ-1 or disrupting α2δ-1-NMDAR interaction reduces calcineurin inhibitor-induced pain hypersensitivity. Eliminating NMDARs in primary sensory neurons or α2δ-1 KO also attenuates calcineurin inhibitor-induced pain hypersensitivity. This new information extends our mechanistic understanding of the role of endogenous calcineurin in regulating synaptic plasticity and nociceptive transmission and suggests new strategies for treating this painful condition.
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Abstract
Renal transplant is the most common organ transplant in the United States, and the frequency of kidney transplants continues to rise as transplant offers improved survival and quality of life compared to dialysis. However, complications are not uncommon and patients frequently encounter issues requiring hospitalization, especially in the first year postoperatively. Complications that arise are typically related to surgical complications, immunosuppressive medications, or infection due to immunosuppression. Neurological complications are fairly common post-operatively, and are associated with increased morbidity and mortality in this population. This review discusses the most common etiologies of neurological complications after kidney transplant, including infection, malignancy, medication related, acute neuropathy, and other neurological pathology.
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11
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Udomkarnjananun S, Townamchai N, Virojanawat M, Avihingsanon Y, Praditpornsilpa K. An Unusual Manifestation of Calcineurin Inhibitor-Induced Pain Syndrome in Kidney Transplantation: A Case Report and Literature Review. AMERICAN JOURNAL OF CASE REPORTS 2018; 19:442-446. [PMID: 29654227 PMCID: PMC5912008 DOI: 10.12659/ajcr.908886] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Patient: Female, 23 Final Diagnosis: Calcineurin inhibitor-induced pain syndrome Symptoms: Back pain Medication: — Clinical Procedure: Supportive treatment Specialty: Transplantology
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Affiliation(s)
- Suwasin Udomkarnjananun
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Natavudh Townamchai
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Mathurot Virojanawat
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Yingyos Avihingsanon
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Kearkiat Praditpornsilpa
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
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12
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Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced K + Channel Dysfunction in DRG Neurons. J Neurosci 2017; 37:8256-8272. [PMID: 28751455 DOI: 10.1523/jneurosci.0434-17.2017] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 07/14/2017] [Accepted: 07/19/2017] [Indexed: 12/26/2022] Open
Abstract
Dysfunction of the fast-inactivating Kv3.4 potassium current in dorsal root ganglion (DRG) neurons contributes to the hyperexcitability associated with persistent pain induced by spinal cord injury (SCI). However, the underlying mechanism is not known. In light of our previous work demonstrating modulation of the Kv3.4 channel by phosphorylation, we investigated the role of the phosphatase calcineurin (CaN) using electrophysiological, molecular, and imaging approaches in adult female Sprague Dawley rats. Pharmacological inhibition of CaN in small-diameter DRG neurons slowed repolarization of the somatic action potential (AP) and attenuated the Kv3.4 current. Attenuated Kv3.4 currents also exhibited slowed inactivation. We observed similar effects on the recombinant Kv3.4 channel heterologously expressed in Chinese hamster ovary cells, supporting our findings in DRG neurons. Elucidating the molecular basis of these effects, mutation of four previously characterized serines within the Kv3.4 N-terminal inactivation domain eliminated the effects of CaN inhibition on the Kv3.4 current. SCI similarly induced concurrent Kv3.4 current attenuation and slowing of inactivation. Although there was little change in CaN expression and localization after injury, SCI induced upregulation of the native regulator of CaN 1 (RCAN1) in the DRG at the transcript and protein levels. Consistent with CaN inhibition resulting from RCAN1 upregulation, overexpression of RCAN1 in naive DRG neurons recapitulated the effects of pharmacological CaN inhibition on the Kv3.4 current and the AP. Overall, these results demonstrate a novel regulatory pathway that links CaN, RCAN1, and Kv3.4 in DRG neurons. Dysregulation of this pathway might underlie a peripheral mechanism of pain sensitization induced by SCI.SIGNIFICANCE STATEMENT Pain sensitization associated with spinal cord injury (SCI) involves poorly understood maladaptive modulation of neuronal excitability. Although central mechanisms have received significant attention, recent studies have identified peripheral nerve hyperexcitability as a driver of persistent pain signaling after SCI. However, the ion channels and signaling molecules responsible for this change in primary sensory neuron excitability are still not well defined. To address this problem, this study used complementary electrophysiological and molecular methods to determine how Kv3.4, a voltage-gated K+ channel robustly expressed in dorsal root ganglion neurons, becomes dysfunctional upon calcineurin (CaN) inhibition. The results strongly suggest that CaN inhibition underlies SCI-induced dysfunction of Kv3.4 and the associated excitability changes through upregulation of the native regulator of CaN 1 (RCAN1).
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Baker RJ, Mark PB, Patel RK, Stevens KK, Palmer N. Renal association clinical practice guideline in post-operative care in the kidney transplant recipient. BMC Nephrol 2017; 18:174. [PMID: 28571571 PMCID: PMC5455080 DOI: 10.1186/s12882-017-0553-2] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 04/16/2017] [Indexed: 02/08/2023] Open
Abstract
These guidelines cover the care of patients from the period following kidney transplantation until the transplant is no longer working or the patient dies. During the early phase prevention of acute rejection and infection are the priority. After around 3-6 months, the priorities change to preservation of transplant function and avoiding the long-term complications of immunosuppressive medication (the medication used to suppress the immune system to prevent rejection). The topics discussed include organization of outpatient follow up, immunosuppressive medication, treatment of acute and chronic rejection, and prevention of complications. The potential complications discussed include heart disease, infection, cancer, bone disease and blood disorders. There is also a section on contraception and reproductive issues.Immediately after the introduction there is a statement of all the recommendations. These recommendations are written in a language that we think should be understandable by many patients, relatives, carers and other interested people. Consequently we have not reworded or restated them in this lay summary. They are graded 1 or 2 depending on the strength of the recommendation by the authors, and AD depending on the quality of the evidence that the recommendation is based on.
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Affiliation(s)
- Richard J Baker
- Renal Unit, St. James's University Hospital, Leeds, England.
| | - Patrick B Mark
- Glasgow Renal and Transplant Unit, Queen Elizabeth University Hospital, Glasgow, Scotland
| | - Rajan K Patel
- Glasgow Renal and Transplant Unit, Queen Elizabeth University Hospital, Glasgow, Scotland
| | - Kate K Stevens
- Glasgow Renal and Transplant Unit, Queen Elizabeth University Hospital, Glasgow, Scotland
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Abstract
Transplantation is the rescue treatment for end-stage organ failure with more than 110,000 solid organs transplantations performed worldwide annually. Recent advances in transplantation procedures and posttransplantation management have improved long-term survival and quality of life of transplant recipients, shifting the focus from acute perioperative critical care needs toward long-term chronic medical problems. Neurologic complications affect up to 30-60 % of solid organ transplant recipients. Common etiologies include opportunistic infections and toxicities of antirejection medications, and wide spectrum of toxic and metabolic disturbances. Most complications are common to all allograft types, but some are relatively specific for individual allograft types (e.g., central pontine myelinolysis in liver transplant recipients). Close collaboration between neurologists and other transplant team members is essential for effective management. Early recognition of complications and accurate diagnosis leading to timely treatment is essential to reduce the morbidity and improve the overall transplant outcome.
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15
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Marchenkova A, Vilotti S, Fabbretti E, Nistri A. Brain natriuretic peptide constitutively downregulates P2X3 receptors by controlling their phosphorylation state and membrane localization. Mol Pain 2015; 11:71. [PMID: 26576636 PMCID: PMC4650943 DOI: 10.1186/s12990-015-0074-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 11/03/2015] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND ATP-gated P2X3 receptors are important transducers of nociceptive stimuli and are almost exclusively expressed by sensory ganglion neurons. In mouse trigeminal ganglion (TG), P2X3 receptor function is unexpectedly enhanced by pharmacological block of natriuretic peptide receptor-A (NPR-A), outlining a potential inhibitory role of endogenous natriuretic peptides in nociception mediated by P2X3 receptors. Lack of change in P2X3 protein expression indicates a complex modulation whose mechanisms for downregulating P2X3 receptor function remain unclear. RESULTS To clarify this process in mouse TG cultures, we suppressed NPR-A signaling with either siRNA of the endogenous agonist BNP, or the NPR-A blocker anantin. Thus, we investigated changes in P2X3 receptor distribution in the lipid raft membrane compartment, their phosphorylation state, as well as their function with patch clamping. Delayed onset of P2X3 desensitization was one mechanism for the anantin-induced enhancement of P2X3 activity. Anantin application caused preferential P2X3 receptor redistribution to the lipid raft compartment and decreased P2X3 serine phosphorylation, two phenomena that were not interdependent. An inhibitor of cGMP-dependent protein kinase and siRNA-mediated knockdown of BNP mimicked the effect of anantin. CONCLUSIONS We demonstrated that in mouse trigeminal neurons endogenous BNP acts on NPR-A receptors to determine constitutive depression of P2X3 receptor function. Tonic inhibition of P2X3 receptor activity by BNP/NPR-A/PKG pathways occurs via two distinct mechanisms: P2X3 serine phosphorylation and receptor redistribution to non-raft membrane compartments. This novel mechanism of receptor control might be a target for future studies aiming at decreasing dysregulated P2X3 receptor activity in chronic pain.
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Affiliation(s)
- Anna Marchenkova
- Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136, Trieste, Italy.
| | - Sandra Vilotti
- Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136, Trieste, Italy.
| | - Elsa Fabbretti
- Center for Biomedical Sciences and Engineering, University of Nova Gorica, 5000, Nova Gorica, Slovenia.
| | - Andrea Nistri
- Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136, Trieste, Italy.
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16
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Chen SR, Zhou HY, Byun HS, Chen H, Pan HL. Casein kinase II regulates N-methyl-D-aspartate receptor activity in spinal cords and pain hypersensitivity induced by nerve injury. J Pharmacol Exp Ther 2014; 350:301-12. [PMID: 24898266 PMCID: PMC4109487 DOI: 10.1124/jpet.114.215855] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 06/02/2014] [Indexed: 12/18/2022] Open
Abstract
Increased N-methyl-d-aspartate receptor (NMDAR) activity and phosphorylation in the spinal cord are critically involved in the synaptic plasticity and central sensitization associated with neuropathic pain. However, the mechanisms underlying increased NMDAR activity in neuropathic pain conditions remain poorly understood. Here we show that peripheral nerve injury induces a large GluN2A-mediated increase in NMDAR activity in spinal lamina II, but not lamina I, neurons. However, NMDAR currents in spinal dorsal horn neurons are not significantly altered in rat models of diabetic neuropathic pain and resiniferatoxin-induced painful neuropathy (postherpedic neuralgia). Inhibition of protein tyrosine kinases or protein kinase C has little effect on NMDAR currents potentiated by nerve injury. Strikingly, casein kinase II (CK2) inhibitors normalize increased NMDAR currents of dorsal horn neurons in nerve-injured rats. In addition, inhibition of calcineurin, but not protein phosphatase 1/2A, augments NMDAR currents only in control rats. CK2 inhibition blocks the increase in spinal NMDAR activity by the calcineurin inhibitor in control rats. Furthermore, nerve injury significantly increases CK2α and CK2β protein levels in the spinal cord. In addition, inhibition of CK2 or CK2β knockdown at the spinal level substantially reverses pain hypersensitivity induced by nerve injury. Our study indicates that neuropathic pain conditions with different etiologies do not share the same mechanisms, and increased spinal NMDAR activity is distinctly associated with traumatic nerve injury. CK2 plays a prominent role in the potentiation of NMDAR activity in the spinal dorsal horn and may represent a new target for treatments of chronic pain caused by nerve injury.
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Affiliation(s)
- Shao-Rui Chen
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hong-Yi Zhou
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hee Sun Byun
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hong Chen
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hui-Lin Pan
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas
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17
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Hu YM, Chen SR, Chen H, Pan HL. Casein kinase II inhibition reverses pain hypersensitivity and potentiated spinal N-methyl-D-aspartate receptor activity caused by calcineurin inhibitor. J Pharmacol Exp Ther 2014; 349:239-47. [PMID: 24610957 PMCID: PMC3989802 DOI: 10.1124/jpet.113.212563] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Accepted: 03/05/2014] [Indexed: 12/25/2022] Open
Abstract
Clinically used calcineurin inhibitors, including tacrolimus (FK506) and cyclosporine A, can induce calcineurin inhibitor-induced pain syndrome (CIPS), which is characterized as severe pain and pain hypersensitivity. Increased synaptic N-methyl-D-aspartate receptor (NMDAR) activity in the spinal dorsal horn plays a critical role in the development of CIPS. Casein kinase II (CK2), a serine/threonine protein kinase, can regulate synaptic NMDAR activity in the brain. In this study, we determined whether spinal CK2 is involved in increased NMDAR activity and pain hypersensitivity caused by systemic administration of FK506 in rats. FK506 treatment caused a large increase in the amplitude of NMDAR-mediated excitatory postsynaptic currents (EPSCs) evoked by primary afferent stimulation and in the frequency of miniature EPSCs of spinal dorsal horn neurons. CK2 inhibition with either 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB) or 4,5,6,7-tetrabromobenzotriazole (TBB) completely normalized the amplitude of evoked NMDAR-EPSCs of dorsal horn neurons in FK506-treated rats. In addition, DRB or TBB significantly attenuated the amplitude of NMDAR currents elicited by puff application of N-methyl-D-aspartate to dorsal horn neurons in FK506-treated rats. Furthermore, treatment with DRB or TBB significantly reduced the frequency of miniature EPSCs of spinal dorsal horn neurons increased by FK506 treatment. In addition, intrathecal injection of DRB or TBB dose-dependently reversed tactile allodynia and mechanical hyperalgesia in FK506-treated rats. Collectively, our findings indicate that CK2 inhibition abrogates pain hypersensitivity and increased pre- and postsynaptic NMDAR activity in the spinal cord caused by calcineurin inhibitors. CK2 inhibitors may represent a new therapeutic option for the treatment of CIPS.
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Affiliation(s)
- Yi-Min Hu
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine (Y.-M.H., S.-R.C., H.C., H.-L.P.), The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Anesthesiology (Y.-M.H.), Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, Peoples Republic of China
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18
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Trimmer JS. Ion channels and pain: important steps towards validating a new therapeutic target for neuropathic pain. Exp Neurol 2014; 254:190-4. [PMID: 24508559 DOI: 10.1016/j.expneurol.2014.01.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 01/24/2014] [Accepted: 01/29/2014] [Indexed: 10/25/2022]
Affiliation(s)
- James S Trimmer
- Department of Neurobiology, Physiology and Behavior, University of California, Davis, CA 95616, USA; Department of Physiology and Membrane Biology, University of California, Davis, CA 95616, USA.
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19
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Bone and mineral disorders after kidney transplantation: therapeutic strategies. Transplant Rev (Orlando) 2013; 28:56-62. [PMID: 24462303 DOI: 10.1016/j.trre.2013.12.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Revised: 08/16/2013] [Accepted: 12/02/2013] [Indexed: 12/14/2022]
Abstract
Mineral and bone diseases (MBD) are common in patients with chronic kidney disease who undergo kidney transplantation. The incidence, types and severity of MBD vary according to the duration of chronic kidney disease, presence of comorbid conditions and intake of certain medications. Moreover, multiple types of pathology may be responsible for MBD. After successful reversal of uremia by kidney transplantation, many bone and mineral disorders improve, while immunosuppression, other medications, and new and existing comorbidities may result in new or worsening MBD. Chronic kidney disease is also common after kidney transplantation and may impact bone and mineral disease. In this article, we reviewed the prevalence, pathophysiology, and impact of MBD on post-transplant outcomes. We also discussed the diagnostic approach; immunosuppression management and potential treatment of MBD in kidney transplant recipients.
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20
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Reilly-Spong M, Park T, Gross CR. Poor sleep in organ transplant recipients: self-reports and actigraphy. Clin Transplant 2013; 27:901-13. [PMID: 24118416 PMCID: PMC3855625 DOI: 10.1111/ctr.12255] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2013] [Indexed: 12/26/2022]
Abstract
Solid organ transplant recipients are at increased risk of poor sleep due to pharmacotherapy and co-morbidities, but sleep problems are often unrecognized and untreated. Study aims were to measure rates of occurrence, characteristics, and correlates of poor sleep in recipients. The Pittsburgh Sleep Quality Index (PSQI) and sleep parameters measured by wrist actigraphy were obtained at baseline from 143 kidney, liver, heart, lung, or pancreas transplant recipients enrolled in a psychosocial intervention trial to improve symptoms and quality of life. Rates of poor sleep were determined using accepted clinical cutoffs; 41% (58 of 143) were poor sleepers (PSQI > 8) and 36% used sleep medications in the past month. Fifteen percent reported having obstructive sleep apnea (OSA) and 4% reported restless legs syndrome (RLS). Based on actigraphy (n = 73), 69% lacked sleep efficiency (SE), 32% took >30 min to fall asleep, 88% awakened during the night for more than 30 min, and 25% slept less than six h per night. Obesity and use of psychotropics or sleep medications, and pain were independent risk factors for poor objectively measured sleep. Poor sleep is an undertreated problem in transplantation. Screening for sleep problems and behavioral therapies with sleep hygiene instruction may benefit recipients.
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Affiliation(s)
- M Reilly-Spong
- College of Pharmacy, University of Minnesota, Minneapolis, MN, USA
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21
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Chen SR, Hu YM, Chen H, Pan HL. Calcineurin inhibitor induces pain hypersensitivity by potentiating pre- and postsynaptic NMDA receptor activity in spinal cords. J Physiol 2013; 592:215-27. [PMID: 24081160 DOI: 10.1113/jphysiol.2013.263814] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Calcineurin inhibitors, such as cyclosporin A and tacrolimus (FK506), have played a pivotal role in the preservation of allograft function. However, these drugs can cause unexplained severe pain in patients, often referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin can regulate NMDA receptor (NMDAR) activity, the causal relationship between spinal synaptic plasticity and CIPS remains unknown. In this study, we showed that systemic administration of FK506 (1.5 mg kg(-1) day(-1)) for 7 days in rats led to long-lasting nociceptive and mechanical hypersensitivity. Whole-cell patch-clamp recordings in spinal cord slices revealed that FK506 treatment caused a large increase in the amplitude of NMDAR-mediated excitatory postsynaptic currents (EPSCs) of dorsal horn neurons evoked by dorsal root stimulation. The amplitude of NMDAR currents elicited by puff NMDA application to dorsal horn neurons was also significantly greater in FK506-treated than in vehicle-treated rats. The frequency of spontaneous and miniature EPSCs in most dorsal horn neurons was profoundly increased in FK506-treated rats and was reduced by blocking NMDARs. Furthermore, blocking GluN2A or GluN2B subunits similarly reduced the amplitude of evoked EPSCs and the frequency of miniature EPSCs in dorsal horn neurons of FK506-treated rats. In addition, intrathecal injection of an NMDAR antagonist or systemic administration of memantine effectively reversed nociceptive and mechanical hypersensitivity in FK506-treated rats. Our findings indicate that calcineurin inhibition increases glutamate-mediated nociceptive input by potentiating presynaptic and postsynaptic NMDAR activity in spinal cords. NMDAR antagonists may represent a new therapeutic option for the treatment of CIPS.
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Affiliation(s)
- Shao-Rui Chen
- H.-L. Pan: Department of Anesthesiology and Perioperative Medicine, Unit 110, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009, USA.
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22
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Zhang R, Chouhan KK. Metabolic bone diseases in kidney transplant recipients. World J Nephrol 2012; 1:127-33. [PMID: 24175250 PMCID: PMC3782213 DOI: 10.5527/wjn.v1.i5.127] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2011] [Revised: 06/01/2012] [Accepted: 09/25/2012] [Indexed: 02/06/2023] Open
Abstract
Metabolic bone disease after kidney transplantation has a complex pathophysiology and heterogeneous histology. Pre-existing renal osteodystrophy may not resolve completely, but continue or evolve into a different osteodystrophy. Rapid bone loss immediately after transplant can persist, at a lower rate, for years to come. These greatly increase the risk of bone fracture and vertebral collapse. Each patient may have multiple risk factors of bone loss, such as steroids usage, hypogonadism, persistent hyperparathyroidism (HPT), poor allograft function, metabolic acidosis, hypophosphatemia, vitamin D deficiency, aging, immobility and chronic disease. Clinical management requires a comprehensive approach to address the underlying and ongoing disease processes. Successful prevention of bone loss has been shown with vitamin D, bisphosphonates, calcitonin as well as treatment of hypogonadism and HPT. Novel approach to restore the normal bone remodeling and improve the bone quality may be needed in order to effectively decrease bone fracture rate in kidney transplant recipients.
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Affiliation(s)
- Rubin Zhang
- Rubin Zhang, Kanwaljit K Chouhan, Section of Nephrology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States
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23
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Gurin L, Gohh R, Evangelista P. Pain syndrome with stress fractures in transplanted patients treated with calcineurin inhibitors. Clin Kidney J 2012; 5:13-6. [PMID: 26069740 PMCID: PMC4400457 DOI: 10.1093/ndtplus/sfr156] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Accepted: 10/13/2011] [Indexed: 11/21/2022] Open
Abstract
Bone disease remains a major cause of morbidity after renal transplantation. Post-transplant osseous complications include osteoporosis and osteonecrosis, both historically associated with glucocorticoids, and a newer syndrome of bone pain associated with calcineurin inhibitors. Calcineurin inhibitor-induced pain syndrome (CIPS) is a reversible etiology of lower extremity bone pain and bone marrow edema reported in patients receiving cyclosporine or tacrolimus after solid organ or bone marrow transplantation. While the syndrome’s pathophysiology is unclear, bone insufficiency and epiphyseal impaction may play a role. We review the literature on this increasingly important post-transplant entity and describe a case illustrating the syndrome’s key features.
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Affiliation(s)
- Lindsey Gurin
- Departments of Neurology and Psychiatry, New York University School of Medicine, New York, NY
| | - Reginald Gohh
- Division of Hypertension and Renal Disease, Department of Medicine, Alpert Medical School of Brown University, Providence, RI, USA
| | - Peter Evangelista
- Division of Musculoskeletal Radiology, Department of Diagnostic Imaging, Alpert Medical School of Brown University, Providence, RI, USA
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24
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Breitenstein A, Stumpe KDM, Gnannt R, Fehr T, Etter C. Calcineurin inhibitor-induced pain syndrome after kidney transplantation-a rare but disabling condition. NDT Plus 2010; 4:63-6. [PMID: 25984107 PMCID: PMC4421624 DOI: 10.1093/ndtplus/sfq172] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2010] [Revised: 09/07/2010] [Accepted: 09/09/2010] [Indexed: 11/15/2022] Open
Affiliation(s)
| | - Katrin D M Stumpe
- Department of Nuclear Medicine , University Hospital Zurich , Zurich , Switzerland
| | - Ralph Gnannt
- Institute of Diagnostic Radiology , University Hospital Zurich , Zurich , Switzerland
| | - Thomas Fehr
- Division of Nephrology , University Hospital Zurich , Zurich , Switzerland
| | - Christoph Etter
- Division of Nephrology , University Hospital Zurich , Zurich , Switzerland
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25
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Nair A, Simonetti M, Birsa N, Ferrari MD, van den Maagdenberg AMJM, Giniatullin R, Nistri A, Fabbretti E. Familial hemiplegic migraine Ca(v)2.1 channel mutation R192Q enhances ATP-gated P2X3 receptor activity of mouse sensory ganglion neurons mediating trigeminal pain. Mol Pain 2010; 6:48. [PMID: 20735819 PMCID: PMC2940876 DOI: 10.1186/1744-8069-6-48] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2010] [Accepted: 08/24/2010] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND The R192Q mutation of the CACNA1A gene, encoding for the α1 subunit of voltage-gated P/Q Ca2+ channels (Ca(v)2.1), is associated with familial hemiplegic migraine-1. We investigated whether this gain-of-function mutation changed the structure and function of trigeminal neuron P2X3 receptors that are thought to be important contributors to migraine pain. RESULTS Using in vitro trigeminal sensory neurons of a mouse genetic model knockin for the CACNA1A R192Q mutation, we performed patch clamp recording and intracellular Ca2+ imaging that showed how these knockin ganglion neurons generated P2X3 receptor-mediated responses significantly larger than wt neurons. These enhanced effects were reversed by the Ca(v)2.1 blocker ω-agatoxin. We, thus, explored intracellular signalling dependent on kinases and phosphatases to understand the molecular regulation of P2X3 receptors of knockin neurons. In such cells we observed strong activation of CaMKII reversed by ω-agatoxin treatment. The CaMKII inhibitor KN-93 blocked CaMKII phosphorylation and the hyperesponsive P2X3 phenotype. Although no significant difference in membrane expression of knockin receptors was found, serine phosphorylation of knockin P2X3 receptors was constitutively decreased and restored by KN-93. No change in threonine or tyrosine phosphorylation was detected. Finally, pharmacological inhibitors of the phosphatase calcineurin normalized the enhanced P2X3 receptor responses of knockin neurons and increased their serine phosphorylation. CONCLUSIONS The present results suggest that the CACNA1A mutation conferred a novel molecular phenotype to P2X3 receptors of trigeminal ganglion neurons via CaMKII-dependent activation of calcineurin that selectively impaired the serine phosphorylation state of such receptors, thus potentiating their effects in transducing trigeminal nociception.
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Affiliation(s)
- Asha Nair
- Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy
- Current Address: Institute for Molecules and Materials, University of Nijmegen, Toernooiveld 1, Nijmegen 6525 ED, The Netherlands
| | - Manuela Simonetti
- Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy
- Current Address: Pharmacology Institute, Faculty of Medicine, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Nicol Birsa
- Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy
| | - Michel D Ferrari
- Leiden University Medical Centre, Department of Neurology, 2300 RC Leiden, The Netherlands
| | - Arn MJM van den Maagdenberg
- Leiden University Medical Centre, Department of Neurology, 2300 RC Leiden, The Netherlands
- Leiden University Medical Centre, Department of Human Genetics, 2300 RC, Leiden, The Netherlands
| | - Rashid Giniatullin
- Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy
- Department of Neurobiology, A. I. Virtanen Institute, University of Eastern Finland, 70211 Kuopio, Finland
| | - Andrea Nistri
- Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy
| | - Elsa Fabbretti
- Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy
- University of Nova Gorica, SI-5000, Slovenia
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26
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Calcineurin-inhibitor-induced pain syndrome after bone marrow transplantation. J Anesth 2008; 22:61-3. [PMID: 18306017 DOI: 10.1007/s00540-007-0574-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2007] [Accepted: 09/03/2007] [Indexed: 10/22/2022]
Abstract
Calcineurin-inhibitor-induced pain syndrome (CIPS), a rare complication seen in patients with organ transplants, is associated with the use of calcineurin inhibitors (CIs) such as cyclosporine (CSP) and tacrolimus (FK). Patients with this syndrome usually present with severe leg pain. This case report demonstrates the successful pain control of this pain syndrome in a 42-year-old female patient who had been given CIs (FK and CSP) as an immunosuppressive agent after a bone marrow transplant. Twenty-one days after the transplantation, she complained of severe pain in her bilateral lower extremities; this lasted several weeks, and was resistant to ordinary analgesics such as intramuscular pentazocine, intravenous morphine, and even oral nifedipine, which is generally accepted as an effective analgesic agent for the pain in this syndrome. Due to the presence of allodynia, our patient's pain had neuropathic pain-like characteristics, unlike the pain in previously reported patients with other organ transplants. Her pain was successfully relieved by the administration of oral amytriptyline, clonazepam, oxycodone, and intravenous lidocaine, all of which ordinarily have an analgesic effect on neuropathic pain. CIPS in patients with hematopoietic stem cell transplants treated with FK may have a mechanism by which neuropathic pain may develop that is different from that in patients with other organ transplants.
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Ferrari U, Empl M, Kim KS, Sostak P, Förderreuther S, Straube A. Calcineurin Inhibitor‐Induced Headache: Clinical Characteristics and Possible Mechanisms. Headache 2005; 45:211-4. [PMID: 15836594 DOI: 10.1111/j.1526-4610.2005.05046.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To classify the headache syndromes under treatment with calcineurin inhibitors and to investigate whether the latter influence the nitric oxide production of human brain microvascular cells (HBMEC). BACKGROUND Single cases of cyclosporine-induced headaches have been reported. Since calcineurin inhibitors are known to influence the renal metabolism of NO, a key molecule in tension-type headache and migraine, we were interested whether calcineurin inhibitors might change NO metabolism in HBMEC as well. DESIGN AND METHODS Headache symptoms of 74 patients receiving cyclosporine and/or tacrolimus for organ transplantation were retrospectively assessed. Furthermore, the effect of cyclosporine and tacrolimus on nitric oxide production in human brain microvascular endothelial cells was investigated after incubation. RESULTS Only 18 of the 74 patients reported no headache 1-36 months after liver, lung, or bone-marrow transplantation, 28 reported a new headache, and 17 an increase in the frequency or intensity of a pre-existing headache. The headache was generally classified as migraine without aura (IHS 1.1) or migraine-like headache (IHS 1.6). Furthermore, we found significantly increased NO production after co-incubation of calcineurin inhibitors with human brain microvascular endothelial cells. CONCLUSION The pathophysiological mechanism of these headaches may be connected with an endothelial dysfunction in terms of increased production of NO.
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Affiliation(s)
- Uta Ferrari
- Klinikum Grosshadern, Department of Neurology, Munich, Germany
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