Clinical features and treatment of calcineurin inhibitor-induced pain syndrome in renal transplant recipients

TONG Ling; FAN Xing; YU Airong

doi:10.12206/j.issn.1006-0111.202101014

Volume 40 Issue 1

Jan. 2022

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TONG Ling, FAN Xing, YU Airong. Clinical features and treatment of calcineurin inhibitor-induced pain syndrome in renal transplant recipients[J]. Journal of Pharmaceutical Practice and Service, 2022, 40(1): 84-88. doi: 10.12206/j.issn.1006-0111.202101014

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TONG Ling, FAN Xing, YU Airong. Clinical features and treatment of calcineurin inhibitor-induced pain syndrome in renal transplant recipients[J]. Journal of Pharmaceutical Practice and Service, 2022, 40(1): 84-88. doi: 10.12206/j.issn.1006-0111.202101014

Clinical features and treatment of calcineurin inhibitor-induced pain syndrome in renal transplant recipients

doi: 10.12206/j.issn.1006-0111.202101014

TONG Ling^a
,,
FAN Xing^{b
,
,},
YU Airong^{a
,
,}

1.
Department of Clinical Pharmacy,
2.
Department of Nephrology, General Hospital of Central Theater Command of PLA, Wuhan 430070, China

Received Date: 2021-01-12
Rev Recd Date: 2021-05-18

Available Online: 2022-01-20

Publish Date: 2022-01-25

Abstract

Objective To understand the clinical features and therapeutic methods for calcineurin inhibitor-induced pain syndrome (CIPS) in kidney transplant recipients. Methods The related articles or abstracts from January 1991 to December 2020 were obtained by searching PubMed, Google Scholar, CNKI, Wanfang and VIP databases. The reviews, duplicate literatures and the articles involved in non-kidney transplant recipients were excluded. 11 full papers were included with 15 case reports. Results The average age of patients at the time of diagnosis of CIPS was (44.6±8.31) years, and the 53.3% of the patients was male. The average appearance time of CIPS was (2.42±3.07) months after kidney transplantation. CIPS mainly affected bilateral hands, elbows, wrists, knees, ankles, feet and back. The patients had normal or elevated trough concentrations of calcineurin inhibitors (CNIs) when CIPS occurred. Some patients had elevated alkaline phosphatase, parathyroid hormone, blood calcium, C-reactive protein levels, and abnormal phosphorus levels, while rheumatoid factor and uric acid levels were normal. CIPS symptoms in most patients disappeared with dose reduction of CNIs, change to different class of CNIs, pamidronate IV injection, pregabalin, calcium channel antagonists, etc. The average recovery time was (4.43±3.31) months. Conclusion The most effective treatment for CIPS is to reduce the dose of CNIs and replace immunosuppressants. Other treatments include GABA analogs, intravenous pamidronate, calcium channel blockers and conservative therapy.
- renal transplantation,
- calcineurin inhibitors,
- pain syndrome,
- clinical features,
- treatment

References

[1]	LUCAS V P, PONGE T D, PLOUGASTEL-LUCAS M L, et al. Musculoskeletal pain in renal-transplant recipients[J]. N Engl J Med,1991,325(20):1449-1450. doi: 10.1056/NEJM199111143252016
[2]	GROTZ W H, BREITENFELDT M K, BRAUNE S W, et al. Calcineurin-inhibitor induced pain syndrome (CIPS): a severe disabling complication after organ transplantation[J]. Transpl Int,2001,14(1):16-23. doi: 10.1111/j.1432-2277.2001.tb00004.x
[3]	ELDER G J. From marrow oedema to osteonecrosis: common paths in the development of post-transplant bone pain[J]. Nephrology (Carlton),2006,11(6):560-567. doi: 10.1111/j.1440-1797.2006.00708.x
[4]	MALAT G E, DUPUIS R E, KASSMAN B, et al. Tacrolimus-induced pain syndrome in a pediatric orthotopic liver transplant patient[J]. Pediatr Transplant,2002,6(5):435-438. doi: 10.1034/j.1399-3046.2002.02030.x
[5]	ELEFTHERIADIS T, ROUNTAS C, VLASSIS S, et al. Quiz: nine years of persistent, disabling foot pain in a kidney transplant recipient[J]. Am J Kidney Dis,2017,70(2):A13-A15. doi: 10.1053/j.ajkd.2017.04.015
[6]	GURIN L, GOHH R, EVANGELISTA P. Pain syndrome with stress fractures in transplanted patients treated with calcineurin inhibitors[J]. Clin Kidney J,2012,5(1):13-16. doi: 10.1093/ndtplus/sfr156
[7]	BREITENSTEIN A, STUMPE K D, GNANNT R, et al. Calcineurin inhibitor-induced pain syndrome after kidney transplantation-a rare but disabling condition[J]. NDT Plus,2011,4(1):63-66.
[8]	ISHIDA S, KATO M, FUJITA T, et al. Calcineurin inhibitor-induced pain syndrome in ABO-incompatible living kidney transplantation: a case report[J]. Transplant Proc,2017,49(1):163-166. doi: 10.1016/j.transproceed.2016.11.007
[9]	BORGHI TORZILLO M F, BAVCAR P, LUTFI R, et al. Post-transplant distal limb syndrome[J]. Medicina (B Aires),2017,77(1):40-42.
[10]	COATES P T, TIE M, RUSS G R, et al. Transient bone marrow edema in renal transplantation: a distinct post-transplantation syndrome with a characteristic MRI appearance[J]. Am J Transplant,2002,2(5):467-470. doi: 10.1034/j.1600-6143.2002.20512.x
[11]	VILLAVERDE V, CANTALEJO M, BALSA A, et al. Leg bone pain syndrome in a kidney transplant patient treated with tacrolimus (FK506)[J]. Ann Rheum Dis,1999,58(10):653-654.
[12]	COLLINI A, DE BARTOLOMEIS C, BARNI R, et al. Calcineurin-inhibitor induced pain syndrome after organ transplantation[J]. Kidney Int,2006,70(7):1367-1370. doi: 10.1038/sj.ki.5001833
[13]	UDOMKARNJANANUN S, TOWNAMCHAI N, VIROJANAWAT M, et al. An unusual manifestation of calcineurin inhibitor-induced pain syndrome in kidney transplantation: a case report and literature review[J]. Am J Case Rep,2018,19:442-446. doi: 10.12659/AJCR.908886
[14]	CHADHA Y, BRAHME S K, HUANG B K, et al. Calcineurin-inhibitor induced pain syndrome - Magnetic resonance imaging and scintigraphic findings illustrated through two cases[J]. Clin Imaging,2019,53:174-178. doi: 10.1016/j.clinimag.2018.10.022
[15]	CHAPIN R W, CHUA E, SIMMONS J, et al. Case report: imaging features in a renal transplant patient with calcineurin inhibitor-induced pain syndrome (CIPS)[J]. Skeletal Radiol,2013,42(9):1311-1315. doi: 10.1007/s00256-013-1616-5
[16]	SMITH H S. Calcineurin as a nociceptor modulator[J]. Pain Physician,2009,12(4):E309-E318.
[17]	HU Y M, CHEN S R, CHEN H, et al. Casein kinase II inhibition reverses pain hypersensitivity and potentiated spinal N-methyl-D-aspartate receptor activity caused by calcineurin inhibitor[J]. J Pharmacol Exp Ther,2014,349(2):239-247. doi: 10.1124/jpet.113.212563
[18]	CHEN S R, HU Y M, CHEN H, et al. Calcineurin inhibitor induces pain hypersensitivity by potentiating pre- and postsynaptic NMDA receptor activity in spinal cords[J]. J Physiol,2014,592(1):215-227. doi: 10.1113/jphysiol.2013.263814
[19]	TILLMANN F P, JÄGER M, BLONDIN D, et al. Post-transplant distal limb syndrome: clinical diagnosis and long-term outcome in 37 renal transplant recipients[J]. Transpl Int,2008,21(6):547-553. doi: 10.1111/j.1432-2277.2008.00668.x
[20]	TAŞOĞLU Ö, GÖKCAN H, DEMIR S Ö, et al. Pregabalin: a new adjunct in calcineurin inhibitor pain syndrome treatment[J]. Prog Transpl,2016,26(3):224-226. doi: 10.1177/1526924816654832

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通讯作者: 陈斌, [email protected]

1.
沈阳化工大学材料科学与工程学院沈阳 110142

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肾移植患者中19%～35%出现了肌肉骨骼疼痛，其中由钙调神经磷酸酶抑制剂（calcineurin inhibitors，CNIs）导致的一种双侧、对称性、难治性疼痛被称为钙调神经磷酸酶抑制剂致疼痛综合征（calcineurin inhibitor-induced pain syndrome，CIPS），最常累及双下肢。CIPS由Bouteiller等首次描述，并于1991年由Lucas等在肾移植患者中首次报道^[1]，最终由Grotz等在2001年命名为CIPS^[2]。近20年来，有关移植后疼痛综合征的报道不断出现，包括CIPS、无血管性坏死（AVN）以及反射性交感神经营养不良综合征（RSDS）等，其中CIPS越来越受到人们的关注。该综合征影响了1%～17%的肾、心脏、肺、肝脏、胰腺或骨髓移植患者^[3]，且均报道与他克莫司或环孢素有关，移植受者中环孢素致CIPS的发生率为1.5%～14%，而他克莫司致CIPS的发生率为2.2%^[4]。为了解肾移植受者中CIPS的临床特征及其治疗方法，本研究对目前已发表的病例报告进行了汇总和统计分析。

3. 讨论

在本研究中, 肾移植术后出现CIPS的患者无明显性别差异且为中青年人群, 其肾移植类型多为尸体肾移植, 原发病主要为IgA肾病、自身免疫性疾病和高血压。既往研究报道CIPS主要累及下肢, 本研究显示可出现CIPS症状的部位众多, 涉及双侧手、肘、腕、膝盖、脚踝、双足以及后背。CIPS多表现为神经性症状, 如异常性疼痛和电击样疼痛, 也有相关瘙痒的报道。没有营养性皮肤变化或血管舒缩不稳的迹象。体格检查通常是正常的。

本研究中CIPS出现的时间范围为肾移植后14 d至1年, 经治疗后缓解期最短为20 d, 最长可达1年。实验室检查提示发生CIPS时CNIs的谷浓度升高或正常, 部分患者的碱性磷酸酶、甲状旁腺激素、血钙、C反应蛋白水平升高, 血磷水平异常, 而类风湿因子、尿酸水平正常。CIPS已被证实可能发生在肝、肾移植以及干细胞移植中。CNIs阻断可下调背景电流的脊髓钾离子通道, 进而通过影响动作电位传播的速度来增强兴奋性信号传导^[16]。Grotz等提出了这样的假说, 即CNIs引起的血管紊乱导致骨髓血管通透性增加并伴有骨髓水肿, 后期报道的一些CIPS患者受累关节中示踪剂摄入增加和轻度骨髓水肿亦证实了这一假说。他克莫司可通过增加潜在的N-甲基-D-天冬氨酸受体(NMDAR)活性导致不受限制的伤害性输入, 并且其磷酸化状态由蛋白激酶和蛋白磷酸酶活性之间的平衡动态控制。酪蛋白激酶II的激活可增加NMDARs的磷酸化和活性, 而钙调磷酸酶可以负反馈调节大脑中NMDARs的磷酸化及其功能。尽管CNIs导致脊髓NMDAR活性增加的机制尚不完全清楚, 但在CIPS中, CNIs可能通过抑制钙调磷酸酶的活性, 使脊髓背角中NMDARs的磷酸化/去磷酸化周期转变为以磷酸化状态为主^[17]。初级感觉神经元和脊髓背角神经元的中央末端之间的第一感觉突触在感觉信息的传递和转换中起着重要作用。谷氨酸是一种重要的兴奋性神经递质, 而NMDARs在与背角疼痛传导相关的脊髓突触可塑性中起着关键作用^[18]。

针对CIPS的药物治疗中, 阿片类镇痛药如吗啡、芬太尼、羟考酮等通常对CIPS无效。非甾体类抗炎药可以缓解症状, 但会对肾功能产生不利影响。据报道, 核心减压可迅速改善短暂性骨髓水肿的症状, 但如果保守处理, CIPS和短暂性骨髓水肿通常会在2～4个月内改善。氯膦酸盐和降钙素的使用似乎可以通过抑制骨溶解来减轻疼痛。CNIs减量或停用也可以缓解疼痛症状。在许多情况下, CNIs交换(如从他克莫司更换为环孢素或从环孢素更换为他克莫司)是有效的。下肢疼痛时建议将腿抬高。使用不抑制细胞色素P450的钙通道拮抗剂似乎也能有效地降低骨内高压。前列环素类似物伊洛前列素可能至少在重症患者中是一种安全的治疗选择。在Tillmann等进行的一项原始研究中, 采用标准方案静注伊洛前列素治疗10名患者, 通过评分从1～10的视觉类似量表测量, 结果表明伊洛前列素可促进疼痛的缓解: 治疗前(5.6±1.5), 治疗后(2.1±1.3), P = 0.0004^[19]。Taşoğlu等的病例报告中首次描述了通常能有效用于神经性疼痛的γ-氨基丁酸(GABA)类似物, 如加巴喷丁或普瑞巴林。作者介绍了一名48岁接受了肝移植手术的男性患者, 该患者出现了双脚剧烈疼痛, 且疼痛程度逐渐增加, 有时甚至累及到膝盖。而给予普瑞巴林150 mg, 每天2次, 显著减轻了他的疼痛^[20]。尽管已描述了在使用双膦酸盐(30 mg)后, CIPS症状得到改善, 但目前对其有效性仍存在争议。本研究中76.9%(10/13)的肾移植受者通过将CNIs减量或将CNIs更换为同类药物中的另一种药物, 使CIPS症状得到了缓解, 其他缓解症状的方法还包括静脉注射帕米膦酸、使用普瑞巴林以及尼卡地平。而使用阿片类镇痛药、双磷酸盐、降钙素、氨氯地平或硝苯地平未能明显改善症状。

CIPS是移植受者中发生的一种难治性疼痛综合征, 受累部位广泛, 病程长短不一, 其发病机制仍有待进一步研究。CIPS的最有效治疗方法是减少CNIs的剂量和更换免疫抑制剂, 其他治疗方式包括GABA类似物、帕米膦酸钠静脉注射、钙通道阻滞剂和保守疗法等。

Reference (20)

[1]	LUCAS V P, PONGE T D, PLOUGASTEL-LUCAS M L, et al. Musculoskeletal pain in renal-transplant recipients[J]. N Engl J Med,1991,325(20):1449-1450.
[2]	GROTZ W H, BREITENFELDT M K, BRAUNE S W, et al. Calcineurin-inhibitor induced pain syndrome (CIPS): a severe disabling complication after organ transplantation[J]. Transpl Int,2001,14(1):16-23.
[3]	ELDER G J. From marrow oedema to osteonecrosis: common paths in the development of post-transplant bone pain[J]. Nephrology (Carlton),2006,11(6):560-567.
[4]	MALAT G E, DUPUIS R E, KASSMAN B, et al. Tacrolimus-induced pain syndrome in a pediatric orthotopic liver transplant patient[J]. Pediatr Transplant,2002,6(5):435-438.
[5]	ELEFTHERIADIS T, ROUNTAS C, VLASSIS S, et al. Quiz: nine years of persistent, disabling foot pain in a kidney transplant recipient[J]. Am J Kidney Dis,2017,70(2):A13-A15.
[6]	GURIN L, GOHH R, EVANGELISTA P. Pain syndrome with stress fractures in transplanted patients treated with calcineurin inhibitors[J]. Clin Kidney J,2012,5(1):13-16.
[7]	BREITENSTEIN A, STUMPE K D, GNANNT R, et al. Calcineurin inhibitor-induced pain syndrome after kidney transplantation-a rare but disabling condition[J]. NDT Plus,2011,4(1):63-66.
[8]	ISHIDA S, KATO M, FUJITA T, et al. Calcineurin inhibitor-induced pain syndrome in ABO-incompatible living kidney transplantation: a case report[J]. Transplant Proc,2017,49(1):163-166.
[9]	BORGHI TORZILLO M F, BAVCAR P, LUTFI R, et al. Post-transplant distal limb syndrome[J]. Medicina (B Aires),2017,77(1):40-42.
[10]	COATES P T, TIE M, RUSS G R, et al. Transient bone marrow edema in renal transplantation: a distinct post-transplantation syndrome with a characteristic MRI appearance[J]. Am J Transplant,2002,2(5):467-470.
[11]	VILLAVERDE V, CANTALEJO M, BALSA A, et al. Leg bone pain syndrome in a kidney transplant patient treated with tacrolimus (FK506)[J]. Ann Rheum Dis,1999,58(10):653-654.
[12]	COLLINI A, DE BARTOLOMEIS C, BARNI R, et al. Calcineurin-inhibitor induced pain syndrome after organ transplantation[J]. Kidney Int,2006,70(7):1367-1370.
[13]	UDOMKARNJANANUN S, TOWNAMCHAI N, VIROJANAWAT M, et al. An unusual manifestation of calcineurin inhibitor-induced pain syndrome in kidney transplantation: a case report and literature review[J]. Am J Case Rep,2018,19:442-446.
[14]	CHADHA Y, BRAHME S K, HUANG B K, et al. Calcineurin-inhibitor induced pain syndrome - Magnetic resonance imaging and scintigraphic findings illustrated through two cases[J]. Clin Imaging,2019,53:174-178.
[15]	CHAPIN R W, CHUA E, SIMMONS J, et al. Case report: imaging features in a renal transplant patient with calcineurin inhibitor-induced pain syndrome (CIPS)[J]. Skeletal Radiol,2013,42(9):1311-1315.
[16]	SMITH H S. Calcineurin as a nociceptor modulator[J]. Pain Physician,2009,12(4):E309-E318.
[17]	HU Y M, CHEN S R, CHEN H, et al. Casein kinase II inhibition reverses pain hypersensitivity and potentiated spinal N-methyl-D-aspartate receptor activity caused by calcineurin inhibitor[J]. J Pharmacol Exp Ther,2014,349(2):239-247.
[18]	CHEN S R, HU Y M, CHEN H, et al. Calcineurin inhibitor induces pain hypersensitivity by potentiating pre- and postsynaptic NMDA receptor activity in spinal cords[J]. J Physiol,2014,592(1):215-227.
[19]	TILLMANN F P, JÄGER M, BLONDIN D, et al. Post-transplant distal limb syndrome: clinical diagnosis and long-term outcome in 37 renal transplant recipients[J]. Transpl Int,2008,21(6):547-553.
[20]	TAŞOĞLU Ö, GÖKCAN H, DEMIR S Ö, et al. Pregabalin: a new adjunct in calcineurin inhibitor pain syndrome treatment[J]. Prog Transpl,2016,26(3):224-226.

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病例	症状表现	累及关节	症状出现时间
1	双足对称性的严重疼痛	双足	过去的9年 (发生在肾移植后不久)
2	双侧踝关节和膝盖疼痛，双侧下肢左下踝外侧踝乏力	膝盖，脚踝	第2次肾移植后6周
3	首先是左脚疼痛，然后是双脚（在脚趾两侧）和膝盖（在两个膝盖的外侧）进行性疼痛，患处伴有水肿	膝盖，双足	移植后2个月
4	高热，疲劳和关节疼痛	手肘，手腕，膝盖	移植后14 d
5	双脚突发严重的对称性疼痛，行走受限	双足	肾移植后1年
6	突发严重的双侧膝关节疼痛	膝盖	移植后第1个月
7	突发严重的双侧膝关节疼痛	膝盖	移植后第1个月
8	突发严重的双侧膝关节疼痛	膝盖	移植后第1个月
9	突发严重的双侧膝关节疼痛，双足严重的骨痛	膝盖，双足	移植后第1个月
10	膝部进行性双侧对称性疼痛且行走困难	膝盖	移植后2个月
11	运动时多个关节剧烈疼痛，并在移植后2个月使用拐杖走路	双手，膝盖，脚踝和双足	移植后1个月
12	双足疼痛，无法行走	双足	移植后6个月
13	从胸腔到腰骶的严重后背钝痛，疼痛评分为10/10。背部伸展使疼痛加重，背部弯曲和躺下缓解。坐位时，尾骨区疼痛加重；背部中线以外无疼痛辐射	后背	移植后43 d
14	双足和脚踝进行性疼痛	双足和脚踝	术后1个月
15	双侧足部疼痛和轻微的脚踝疼痛，最后延伸至膝盖；4个月后，疼痛变得难以忍受，手和肘部出现轻微疼痛	双足，脚踝，膝盖，手和肘部	肾移植后73 d

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Clinical features and treatment of calcineurin inhibitor-induced pain syndrome in renal transplant recipients

doi: 10.12206/j.issn.1006-0111.202101014

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