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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2021  |  Volume : 32  |  Issue : 6  |  Page : 1795-1799
Calcineurin Inhibitor-Induced Pain Syndrome: An Uncommon but a Debilitating Complication of Calcineurin Inhibitors Use

Department of Pancreas and Kidney Transplantation, Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, , SaudArabia

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Date of Web Publication27-Jul-2022


The outcomes of renal transplantation have improved significantly with the use of calcineurin inhibitors (CNI). However, this improvement comes at the price of side effects. CNI-induced pain syndrome (CIPS) is a benign but disabling painful syndrome. It particularly affects the lower limbs. We present the case of a young male renal transplant recipient. He presented with worsening bilateral lower limb pain four months after transplantation. Induction therapy was basiliximab. Tacrolimus, steroids, and mycophenolate mofetil constituted maintenance immunosuppressive therapy. Pain affected the ankles and toes bilaterally. It started gradually but progressed over four weeks. The relentless pain affected his mobility to an extent that he became wheel chair dependent. Pain was unresponsive to paracetamol and codeine. No formal psychiatry assessment was done but patient-reported depression symptoms related to his reduced mobility. On examination, he had bony tenderness over the affected areas with the good range of passive movements. Neurological and vascular examinations of lower limbs were unremarkable. Inflammatory and infective causes of joint pain were excluded. Magnetic resonance imaging (MRI) feet showed the features of bone marrow edema. He was diagnosed with CIPS. Immunosuppression was changed from tacrolimus to cyclosporine. Pregabalin was also introduced after the diagnosis. Symptoms improved gradually over a month. He started to walk with a stick initially and then without any aid. Renal transplant function remained stable throughout this period. MRI feet scan, five months after the symptoms showed resolution of the bone marrow edema. CIPS is an uncommon, benign but disabling complication of CNI. Recognizing it early could limit the burden of symptoms (both physical and psychological) and loss of productivity. The management of CIPS is not evidence based and further research is required in this therapeutic area.

How to cite this article:
Ullah A, Aly A, Ali T, Alahmadi I. Calcineurin Inhibitor-Induced Pain Syndrome: An Uncommon but a Debilitating Complication of Calcineurin Inhibitors Use. Saudi J Kidney Dis Transpl 2021;32:1795-9

How to cite this URL:
Ullah A, Aly A, Ali T, Alahmadi I. Calcineurin Inhibitor-Induced Pain Syndrome: An Uncommon but a Debilitating Complication of Calcineurin Inhibitors Use. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Sep 25];32:1795-9. Available from: https://www.sjkdt.org/text.asp?2021/32/6/1795/352443

   Introduction Top

Renal transplantation (RT) is the preferred choice of treatment in selected end-stage renal disease (ESRD) patients. The outcomes of RT have improved significantly with the use of calcineurin inhibitors (CNI).[1] However, it comes at the price of side effects. CNI-induced pain syndrome (CIPS) is a benign but disabling side effect.[2] We report a case of CIPS in a renal transplant recipient who fully recovered.

   Case Report Top

A 36-year-old male with ESRD due to unknown etiology received a living related RT from his sister. He received basiliximab (20 mg IV on day 0 and 4) as induction therapy. Maintenance therapy consisted of tacrolimus, mycophenolate mofetil, and prednisone. Tacrolimus levels in the first few weeks were high; however, acceptable levels were achieved by adjusting the dose [Figure 1]. He used amlodipine for blood pressure control. Sixteen weeks posttransplantation, he presented with gradual onset, dull bony pain in the ankle, metatarsals, and toes bilaterally. The pain was constant, worse on recumbency, relieved slightly by resting legs above the heart level. On examination, he had tenderness over the affected bones but no features of joint disease. Neurological and vascular examinations were unremarkable. Vasomotor or trophic skin changes were absent. Over the subsequent four weeks, his symptoms progressively worsened to the degree that he became a wheelchair user. Simple analgesia and codeine were ineffective in alleviating his symptoms.
Figure 1. Tacrolimus levels (ng/mL) before and at the time of symptoms presentation.

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X-rays of the feet showed peri-articular osteopenia at tarsometatarsal area bilaterally. A noncontrast magnetic resonance imaging (MRI) scan revealed bone marrow edema bilaterally in the inter-tarsal, tarsometatarsal and to a lesser extent metatarsophalangeal (MTP) joints. Small joint effusions were noted in the tarsometatarsal, MTP joints and right posterior subtalar recess. There were no features of fracture, osteomyelitis or avascular necrosis [Figure 2].
Figure 2. Magnetic resonance imaging foot scan showing bone marrow edema at presentation and resolution on repeat scan.

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Rheumatology review excluded infective and inflammatory joint diseases, and diagnosis of CIPS was made. CNI was not stopped due to the risk of rejection. However, the tacrolimus was replaced by cyclosporine as per rheumatology advice. Paracetamol and codeine were stopped due to lack of efficacy, and pregabalin 150 mg BD was commenced.

Symptoms improved gradually over the next four weeks. The patient started to walk with a stick initially and then unaided.

A follow-up MRI feet scan (5 months after the symptoms) revealed interval reduction in the bone marrow edema in tarsal and proximal metatarsal bones with residual edema in the talus. Effusions were resolved entirely [Figure 2].

Bone biomarkers and serum creatinine trends are summarized in [Table 1]. A week before his symptoms, rise in serum calcium level, with inappropriately high parathyroid hormone was noted. Hypercalcemia peaked at 2.9 mmol/L. Calcium + Vitamin D was discontinued, and cinacalcet 30 mg daily was commenced. Hypercalcemia improved gradually over eight weeks. Parathyroid sestamibi scan revealed two hyperactive nodules localized posterior to the left thyroid lobe.
Table 1. Bone and other relevant biomarkers.

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The authors obtained all appropriate consent forms from the patient for the publication of this case report.

   Discussion Top

Musculoskeletal symptoms are common after solid organ transplantation. Nineteen to thirty-five percent of renal transplant recipients report it.[3] CIPS is an uncommon benign but disabling side effect of CNI.

CNI-induced polyarticular pain was first reported by Bouteiller et al;[4] however, the term CIPS was first coined by Grotz et al in 2001.[5] The exact incidence of CIPS is unknown. It is reported to be 1%-17%.[6] Adults and children with a history of solid organ or hemopoietic stem cell transplants are affected.[7] Interestingly, CIPS is also reported in patients using CNI for inflammatory conditions, for example, Crohn’s disease[7] suggesting that CNI is an important etiologic factor for CIPS rather than the clinical setting. The topical use of CNIs (tacrolimus and pimecrolimus) is not associated with CIPS indicating that systemic exposure is necessary.[8],[9]

Clinically, CIPS presents with symmetrical bilateral pain, affecting distal extremities of lower limbs, i.e., knees, ankles, and feet. Although one case involving the spine was reported,[10] pain is usually dull and persistent. Some authors have described electric shocklike pain and allodynia.[11] Pain is exacerbated by walking or resting legs below the heart level. The severity of symptoms varies, but significant disability is reported as observed in our case.[12] The onset of symptoms is variable manifesting between three and 18 months after CNI exposure.[5] The symptoms improve gradually and could take up to 18 months to resolve. In some patients, symptoms did not resolve fully[13] and the condition recurred in two cases after full resolution.[2]

The exact pathophysiology of CIPS is unknown. The most supported hypothesis is that of CNI-induced intraosseous vasoconstriction. CNI causes vasocontraction by increasing endothelin/thromboxane and inhibiting K+ channels and nitric oxide synthase in the endothelial cells.[14],[15],[16] Intraosseous vasoconstriction results in hypoperfusion, marrow edema, and bone compartment syndrome. Similar pathological changes are seen in osteonecrosis.[4] Gauthier and Barbosa have reported CIPS cases progressing to osteonecrosis[6] pointing toward a common pathological process.

CNI also affects nociceptive pathways causing neuropathy. Two pores potassium (K2P) channels regulate neuronal excitability.

CNI inhibits K2P channels leading to enhanced neuronal excitability.[17] N-methyl D-aspartate and γ-aminobutyric acid (GABA) receptors are also modulated by CNI.[18] This could explain the benefits of GABA analogues in CIPS.

Inflammatory and rheumatological markers in blood are normal. Radiographs of the affected bones are either normal or may show mild osteoporosis/osteopenia. Technetium bone scan reveals increased tracer uptake in the affected bones and joints. MRI scan of the affected areas show bone marrow edema.[19] Sympathetic joint effusions are seen in some cases. Tillmann et al[2] observed a rise in serum alkaline phosphatase (ALP) concomitant or before the symptoms and concomitant rise in serum calcium level. We did not see a surge in ALP before or at the time of symptoms; however, serum calcium level increased a week before the symptoms in our case. ALP in our patient went up two months after symptoms manifestation.

The current management of CIPS is based on expert opinions due to dearth of evidence. Some cases resolve spontaneously; however, most cases responded to either reduction or withdrawal of CNIs. In our patient, symptoms were alleviated by replacing tacrolimus with cyclosporine. Interestingly, four cases in Tillmann et al[2] series did not improve with the conversion of cyclosporine to tacrolimus. Resting and leg elevation relieves the symptoms. Calcium-channel blockers, especially dihydropyridine derivatives, were helpful in some cases;[3] however, other reported equivocal results.[12] Taşoğlu et al achieved good results with pregabalin use in one case.[20] Simple analgesia and opioids are ineffective. Nonsteroidal anti-inflammatory agents are best avoided due to the risk of nephrotoxicity. The use of hyperbaric oxygen therapy,[2] calcitonin, and bisphosphonate is controversial.[19]

In conclusion, CIPS is a benign but debilitating side effect of CNI. Recognizing it early could limit the burden of symptoms and loss of productivity. Further research is required to inform the management of CIPS.

   References Top

Ponticelli C. Calcineurin-inhibitors in renal transplantation. Too precious to be abandoned. Nephrol Dial Transplant 2000; 15:1307-9.  Back to cited text no. 1
Tillmann FP, Jäger M, Blondin D, et al. Posttransplant distal limb syndrome: Clinical diagnosis and long-term outcome in 37 renal transplant recipients. Transpl Int 2008;21:547- 53.  Back to cited text no. 2
Sperschneider H, Stein G. Bone disease after renal transplantation. Nephrol Dial Transplant 2003;18:874-7.  Back to cited text no. 3
Bouteiller G, Lloveras JJ, Condouret J, Durroux R, Durand D. Painful polyarticular syndrome probably induced by cyclosporin in three patients with a kidney transplant and one with a heart transplant. Rev Rhum Mal Osteoartic 1989;56:753-5.  Back to cited text no. 4
Grotz WH, Breitenfeldt MK, Braune SW, et al. Calcineurin-inhibitor induced pain syndrome (CIPS): A severe disabling complication after organ transplantation. Transpl Int 2001;14:16- 23.  Back to cited text no. 5
Elder GJ. From marrow oedema to osteonecrosis: Common paths in the development of post-transplant bone pain. Nephrology (Carlton) 2006;11:560-7.  Back to cited text no. 6
Isaacs KL. Severe bone pain as an adverse effect of cyclosporin therapy for Crohn’s disease. Inflamm Bowel Dis 1998;4:95-7.  Back to cited text no. 7
Laboratories L. Protopic 0.1% Ointment 2018. Available at: https://www.medicines.org.uk/ emc/product/1608/smpc#UNDESIRABLE_EF FECTS. [Accessed on 20 June 2020].  Back to cited text no. 8
Mylan. Elidel 10 mg/g Cream 2013. Available at: https://www.medicines.org.uk/emc/product/ 4966/smpc#gref [Accessed on 20 June 2020].  Back to cited text no. 9
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. Am J Case Rep 2018;19:442-6.  Back to cited text no. 10
Noda Y, Kodama K, Yasuda T, Takahashi S. Calcineurin-inhibitor-induced pain syn-drome after bone marrow transplantation. J Anesth 2008;22:61-3.  Back to cited text no. 11
Breitenstein A, Stumpe KD, Gnannt R, Fehr T, Etter C. Calcineurin inhibitor-induced pain syndrome after kidney transplantation - A rare but disabling condition. NDT Plus 2011 ;4:63- 6.  Back to cited text no. 12
Fujii N, Ikeda K, Koyama M, et al. Calcineurin inhibitor-induced irreversible neuropathic pain after allogeneic hematopoietic stem cell transplantation. Int J Hematol 2006;83:459-61.  Back to cited text no. 13
Duncker DJ, van Zon NS, Pavek TJ, Herrlinger SK, Bache RJ. Endogenous adenosine mediates coronary vasodilation during exercise after K(ATP)+ channel blockade. J Clin Invest 1995;95:285-95.  Back to cited text no. 14
Masaki T. Possible role of endothelin in endothelial regulation of vascular tone. Annu Rev Pharmacol Toxicol 1995;35: 235-55.  Back to cited text no. 15
Kou R, Greif D, Michel T. Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor. Implications for the vascular responses to cyclosporin A. J Biol Chem 2002;277:29669-73.  Back to cited text no. 16
Goldstein SA, Bayliss DA, Kim D, Lesage F, Plant LD, Rajan S. International Union of Pharmacology. LV. Nomenclature and molecular relationships of two-P potassium channels. Pharmacol Rev 2005;57:527-40.  Back to cited text no. 17
Smith HS. Calcineurin as a nociceptor modulator. Pain Physician 2009;12:E309-18.  Back to cited text no. 18
Amiri F. Diagnosis and treatment of calcineurin inhibitor induced pain syn-drome in chronic kidney disease stage 5 transplantation. Indian J Transplant 2018; 12:125-35.  Back to cited text no. 19
  [Full text]  
Taşoğlu Ö, Gökcan H, Demir SÖ, Yenigün D, Akdoğan M, Kaçar S. Pregabalin: A new adjunct in calcineurin inhibitor pain syndrome treatment. Prog Transplant 2016;26:224-6.  Back to cited text no. 20

Correspondence Address:
Asad Ullah
Department of Pancreas and Kidney Transplantation, Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
, SaudArabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.352443

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