Colchicine: An Impressive Effect on Posttransplant Leak Syndrome and Renal Failure Enrico Cocchi, MD,a,b Federica Chiale, MD,a,b Bruno Gianoglio, MD,b Luca Deorsola, MD,c Carlo Pace Napoleone, MD,c Franca Fagioli, MD,d Licia Peruzzi, MDa,b

Capillary leak syndrome is a critical condition occasionally occurring abstract posttransplant and is characterized by acute endothelial hyperpermeability leading to systemic protein-rich fluid extravasation and consequent , hypoperfusion, and . Treatment is merely aUniversity of Turin, Turin, Italy; and bNephrology, Dialysis supportive and is based on osmotic drugs, , continuous renal and Transplantation Unit, cPediatric Cardiac Surgery Unit, replacement therapy, and surgical drainage. However, removal of the and dPediatric Onco-Hematology Unit, Stem Cell fl Transplantation and Cellular Therapy Division, Regina underlying in ammatory cause is mandatory to achieve stable resolution. Margherita Children’s Hospital, Turin, Italy Herein, we report the first successful treatment with colchicine in 2 life- Dr Cocchi conceptualized the study, drafted the threatening pediatric cases of capillary leak syndrome with renal failure initial manuscript, and reviewed and revised the occurring after transplant (heart and bone marrow) and unresponsive to any manuscript; Drs Chiale, Deorsola, Pace Napoleone, other line of therapy. Both cases were only palliated by supportive therapy Gianoglio, and Fagioli designed the data collection and revealed an impressively rapid response to colchicine both in terms of instruments, collected data, and reviewed and revised the manuscript; Dr Peruzzi was actively diuresis and clinical condition recovery, allowing for the cessation of renal involved in both cases’ management, conceptualized replacement therapy in a few hours. In both patients, colchicine was and designed the study, coordinated and supervised temporarily discontinued for transient leukopenia (attributed to an additive data collection, and critically reviewed the manuscript for important intellectual content; and effect with mycophenolate mofetil), resulting in extravasation, and renal all authors approved the final manuscript as failure recurrence was restored only after colchicine reintroduction. Although submitted and agreed to be accountable for all the association of colchicine with an immunosuppressive drug was formerly aspects of the work. contraindicated, no other adverse events were noted when using a minimized DOI: https://doi.org/10.1542/peds.2018-2820 dose. Both patients are now maintaining a good renal function without Accepted for publication Dec 18, 2018 recurrence of extravasation after 6 months of follow-up. In conclusion, this Address correspondence to Enrico Cocchi, MD, strikingly positive experience forces physicians to consider this old and cost- University of Turin, Nephrology, Dialysis and Transplantation Unit, Regina Margherita Children’s effective drug as a new, powerful rescue tool in such critical cases. Hospital, Piazza Polonia 94, Turin 10126, Italy. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Capillary leak syndrome (CLS) is for idiopathic pericarditis and proved Copyright © 2019 by the American Academy of characterized by massive protein-rich its efficacy in several inflammatory Pediatrics fluid extravasation secondary to diseases, including postsurgery FINANCIAL DISCLOSURE: The authors have indicated – endothelial hyperpermeability due to serositis and .7 9 they have no financial relationships relevant to this systemic inflammatory status.1 CLS Moreover, it has a safe profile with article to disclose. may be detectable in various diseases, minor gastrointestinal problems as FUNDING: No external funding. including autoinflammatory ones common adverse reactions, which POTENTIAL CONFLICT OF INTEREST: The authors have whose treatment relies on anti- usually resolve after drug indicated they have no potential conflicts of interest inflammatory drugs and colchicine.2–4 discontinuation, whereas other to disclose. Colchicine is a widely available, safe, more serious effects are rare. and low-cost drug that acts both as These characteristics make To cite: Cocchi E, Chiale F, Gianoglio B, et al. a spindle poison and as an anti- colchicine an attractive therapeutic Colchicine: An Impressive Effect on inflammatory agent.5–7 In recent years, tool for various inflammatory Posttransplant Capillary Leak Syndrome and Renal Failure. Pediatrics. 2019;143(5):e20182820 colchicine became the standard of care disorders.7

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 143, number 5, May 2019:e20182820 CASE REPORT CLS occasionally occurs in fibrosis (FibroScan 12 kPa, [eGFR] 48.9 mL/minute per 1.73 m2) a posttransplant setting in which fluid cooresponding to Metavir grade F4). and under maintenance therapy with overload and impaired fluid balance He received an orthotopic heart cyclosporin and prednisone. are strongly related with transplant with standard – Since HSCT, she presented with 3 AKI mortality.10 12 In fact, massive fluid thymoglobulin-steroid induction, episodes characterized by increased extravasation leads to peripheral tacrolimus, mycophenolate mofetil creatinine and C-reactive hypoperfusion and renal impairment, (MMF), and steroid maintenance. protein (CRP), bilateral pleural often resulting in prerenal acute Since day 1 posttransplant, he effusions requiring thoracentesis and kidney injury (AKI).13 In early phases, experienced severe fluid leakage up vacuum up to 20 days, ascites, and treatment is merely supportive and to 3000 to 4000 mL/day, initially diffuse peripheral . The based on reattracting fluids from limited to mediastinum and identified presentation was always dominated third space to effective circulating as lymph. After a few days of partial by respiratory distress and fever, volume (ECV) by using osmotic resolution, leakage became rapidly evolving to multiple effusions agents, such as albumin, followed by multisystemic (pleural, peritoneal, and AKI. The first 2 episodes (days 44 net fluid elimination with diuretics. and subcutaneous) with and 179) occurred during prednisone Nevertheless, when fluid accumulates a composition similar to plasma. tapering and were effectively in body cavities and interferes with controlled by intravenous vital organ function, a surgical He developed oligoanuric AKI, methylprednisolone pulses (2–5 drainage is mandatory.14,15 This requiring CRRT from the second mg/kg per dose). The third episode approach is normally sufficient to posttransplant day. (day 347) initially responded to support the patient until resolution of Because of persistent extravasation, methylprednisolone pulses (10 the extravasation-underlying cause. on day 59, thoracic duct ligation was mg/kg every other day) and MMF Nevertheless, in some critical cases, performed, which was partially (600 mg/m2), but subsequent extravasation severity and speed successful in reducing the mediastinal effusions and oliguria worsened until exceeds treatment efficiency, and AKI effusions (Fig 1). Nevertheless, CRRT requirement. progresses, requiring continuous oliguria progressed to anuria and renal replacement therapy (CRRT) to increased fluid overload (Fig 1) The severity of systemic effusion, fl ensure proper uid balance. In case of despite normal right and left despite increased immune fl persistence of the in ammatory noxa, ventricular function and renal suppression, led to a rescue attempt spontaneous resolution is rarely perfusion. Additional corticosteroid with colchicine. achievable, and clinical management pulses and anti-inflammatory drugs of the patients represents a difficult were unsuccessful. Progressive RESULTS challenge, especially in children. In decline of general conditions led to such cases, rescue treatments beyond a rescue attempt with colchicine on Colchicine Mechanism of Action on traditional care become necessary. day 97. Vascular Endothelial and Herein, we present our positive Extravasation experience with colchicine in 2 Patient 2 Colchicine’s precise impact on children who developed a severe CLS A 12-year-old girl affected by trisomy vasculature is still unknown, and rapidly evolving to anuric AKI after 21 and Tetralogy of Fallot corrected specific literature on the topic is heart and bone marrow transplant at 3 months developed an M6 acute lacking. that was unresponsive to any other myeloid leukemia at age 4 and acute In fact, although colchicine’s best- line of treatment. lymphoblastic leukemia at age 11. She known effect is arresting microtubule was effectively treated with polymerization at high dosage, it also chemotherapy and hematopoietic CASE PATIENTS exerts several anti-inflammatory stem cell transplant (HSCT) 7 effects on both and months later. Patient 1 endothelial cells through modulation A 17-year-old boy was born with an On day 23 posttransplant, she of VCAM-1, tumor necrosis factor a, univentricular heart treated by using developed oliguric AKI, which E-selectin, interleukin 1b, and NLRP3 pulmonary banding, gradually resolved after nephrotoxic inflammasome. However, no clear bidirectional Glenn, and extracardiac drug withdrawal (acyclovir, explanation of its effect on Fontan interventions in infancy, vancomycin, and amikacin), allowing extravasation is provided in the complicated by severe plastic for her to be discharged on day 31 literature.7,16,17 This effect may also bronchitis and Fontan-associated with mild renal impairment be attributable to its in vivo liver disease with advanced hepatic (estimated glomerular filtration rate antiapoptotic action, considering that

Downloaded from www.aappublications.org/news by guest on September 27, 2021 2 COCCHI et al FIGURE 1 The image represents the clinical course of the cases: eGFR (mL/minute per 1.73 m2). Red-shadowed area represents CRRT period, and green-shadowed area represents colchicine-treatment periods. Patient 1 starts from heart transplant (day 0) and shows clinic and laboratory trends. The plot clearly shows how thoracic duct ligation reduced drainage-measurable leaks but was ineffective in restoring diuresis and normal fluid balance. Colchicine initiation allowed for reaching an optimal diuresis and a good fluid balance with no leaks, temporarily interrupted by its discontinuation (day 127–day 132). It also shows that colchicine effectively suppressed inflammatory indices (sCRP). The red shadows in the plot illustrate CRRT. eGFR during CRRT is unreliable and therefore not represented. Patient 2 shows the clinic and laboratory course starting from admission for a third third-space AKI episode (day 0 on the plot corresponds to day 347 from HSCT). The panel clearly shows how colchicine initiation at first, and its dose increment later, allowed diuresis and eGFR restoration with normal fluid balance. It also shows recurrence of leaks and AKI after colchicine discontinuation and additional resolution with colchicine reintroduction. The plot shows how improved renal function may be the cause underlying different time response to colchicine as explained above and clearly visible from the eGFR curve trend. sCRP panel shows how colchicine allowed for stable remission of sCRP concentration. Diuresis is measured daily (mL/day). Leaks are the total daily fluid removal from drainages (mL/day). adm, hospital admission; colch, colchicine initiation; col_inc, incremented colchicine dose from 0.5 to 1 mg daily; CVVHDF, day with continuous veno-venous hemodiafiltration treatment; disch, discharge; I/O, daily fluid input-output balance (mL); sCRP, serum CRP concentration (mg/dL); TD lig, thoracic duct ligation; TX, heart transplant. endothelial cell apoptosis appears to persisted until Cardiac Function 18,19 play a role in CLS pathogenesis. extravasation resolution despite Both patients had normal cardiac Altogether, this multisite action may massive albumin supplementation function; patient 1 was affected by – reduce both endothelial permeability (1 2 g/kg per day) and highly severe mediastinal effusion requiring and extravasation of high–molecular caloric total parenteral nutrition. At drainage, whereas patient 2 had only weight molecules, such as albumin, the same time, in both patients, mild pericardial effusion. In both but additional studies are needed to persisted despite cases, cardiac function was monitored fl clarify the exact effect of colchicine on uid administration in accordance daily by using echocardiography vasculature. with the guidelines of during the acute extravasation management, requiring continuous phase, revealing normal ventricular Effects of Colchicine on endovenous sympathomimetic amine function and excluding a cardiac Hypoalbuminemia and Blood support in patient 1. etiology for such fluid overload. Pressure Both patients presented with Both albuminemia and blood massive hypoalbuminemia pressure normalized in a few days Effects of Colchicine on Diuresis and without albuminuria in addition after colchicine administration, Fluid Balance to hypotension, hemoconcentration, presumably through fluid The initial dose of colchicine was and generalized edema. compartment reequilibration (Fig 2). 10 µg/kg per day (0.5 mg/day)

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 143, number 5, May 2019 3 obtaining only a partial response and evolving into complete resolution after dose doubling (1 mg daily).

Inflammatory Markers Both patients had normalized serum CRP only after colchicine introduction (Fig 1), suggesting its capacity to interrupt the inflammatory mechanism behind the capillary leak, which was always associated with serum CRP increments but never associated with any evidence of infections. FIGURE 2 The figure summarizes the pathogenesis of the cases; fluid extravasation from ECV to third space, driven by inflammatory-based peripheral vasodilation, is initially compensated by a cardiac output Patient Discharge and Follow-up increment and diuresis reduction (compensation phase). When cardiac output increment reaches its physiologic limit, if extravasation continues, the ECV is gradually stolen by third space, renal Patients were discharged with perfusion is impaired (prerenal AKI), and diuresis decreases. In this uncompensated phase, diuresis colchicine maintenance at cannot be restored through diuretics administration because ECV is extremely reduced. In the same a minimized dose of 2.5 µ/kg per day manner, fluid removal (leaks curve in figure) is an additional extravasation of third space outside (0.125 mg/day) under strict follow- the body, but it does not lead to any ECV expansion. In this regard, leaks drainage and CRRT are of central importance in decongesting vital organs (such as heart, lungs, etc), but it is merely up. supportive. The combination of osmotic agents (such as albumin) and diuretics is generally ade- quate to counterbalance such extravasation during the time necessary to resolve the underlying Patient 1 was discharged on day 143 noxa. Nevertheless, in the presented cases, the extravasation-driving force was overwhelming, and after transplant with colchicine and no effective result was obtained until colchicine introduction, which interrupted the pathogenic chain and restored the physiologic status. tacrolimus without MMF nor steroids. Until now (day 320), no recurrence of extravasation and stable renal modulated in consideration of renal colchicine discontinuation due to function (eGFR 60 mL/minute per failure. transient leukopenia (interpreted as 1.73 m2) were achieved. additive effect with MMF), further ECV hypovolemia was extremely revealing its antiextravasation effect. Patient 2 was discharged on day 467 pronounced in both patients and only after HSCT and experienced fl partially responsive to uid In patient 1, recurrence was almost a transient central venous administration. After colchicine immediate, with pericardial and catheter–related on day 487. It administration, diuresis was restarted pleural effusions requiring drainage is noteworthy that during this in a few hours, and 48 hours later, within 5 days from colchicine episode, an initially mild bilateral fl a net-negative uid balance was discontinuation. pleural effusion without significant achieved (Fig 1), allowing for CRRT Patient 2 experienced bilateral diuresis impairment was controlled discontinuation. The end of the by using colchicine dose doubling “inflammatory crisis” was defined by pleural effusions, ascites, and AKI, requiring CRRT after a latency of without a need for additional massive in both patients, as steroids. is characteristic of CLS resolution.1 14 days. It is worth noting that CRRT could be Colchicine Reintroduction There are no clear indications for stopped after more than 3 months colchicine therapy duration. On the In both cases, colchicine was (day 108) in patient 1, when renal basis of actual experience from reintroduced after leukopenia failure was considered irreversible by inflammatory diseases, it can range recovery. In patient 1, this took place this time. from 1 to 18 months, depending on 8 days after withdrawal with patient response and adverse a strikingly rapid response similar to Extravasation Recurrence at effects.9,20 We will evaluate colchicine that observed after primary Suspension dose requirements through follow-up colchicine introduction. In both cases, systemic extravasation in both cases, and tapering will be with hypoalbuminemia, oliguria, and In patient 2, colchicine was attempted after 12 months, according fluid overload recurred shortly after reintroduced after 39 days, initially to patient status.

Downloaded from www.aappublications.org/news by guest on September 27, 2021 4 COCCHI et al Safety, Interaction, and Adverse immunosuppressive therapy and AKI REFERENCES Events at a reduced dose. 1. Siddall E, Khatri M, Radhakrishnan J. Parents gave informed consent to the To the best of our knowledge, this is Capillary leak syndrome: etiologies, colchicine treatment as a third-line the first report of a severe third-space pathophysiology, and management. rescue therapy to be considered as an AKI attributable to CLS in a transplant Kidney Int. 2017;92(1):37–46 extension of the approved pericardial setting effectively controlled with 2. Kallinich T, Haffner D, Niehues T, et al. effusion indication. colchicine. Colchicine use in children and adolescents with familial In case 1, a colchicine-tacrolimus This empirical observation in 2 Mediterranean fever: literature review interaction developed without impact different transplant settings and the and consensus statement. Pediatrics. on daily monitored tacrolimus absence of significant side effects 21 2007;119(2). Available at: www. levels. Colchicine was modulated in led physicians to consider colchicine pediatrics.org/cgi/content/full/119/2/ both cases according to the leukocyte as a useful option in posttransplant e474 count because of drug level CLS and renal failure in which 3. Hsu P, Xie Z, Frith K, et al. Idiopathic unavailability.22 Mild leukopenia was CRRT weaning is mandatory systemic capillary leak syndrome in initially observed in both cases, to ensure transplant success and children. Pediatrics. 2015;135(3). attributed to additive MMF effect, and patient survival without additional Available at: www.pediatrics.org/cgi/ resolved with colchicine and MMF morbidity. content/full/135/3/e730 discontinuation. No infections Additional exploration of the 4. Imazio M, Brucato A, Cemin R, et al; ICAP occurred in patient 1. Patient 2 has potential use of colchicine in Investigators. A randomized trial of transient central venous posttransplant systemic fluid effusion colchicine for acute pericarditis. N Engl catheter–related sepsis, which was is advocated. J Med. 2013;369(16):1522–1528 unrelated to leukopenia. 5. Leung YY, Yao Hui LL, Kraus VB. No other adverse effect was recorded. ACKNOWLEDGMENTS Colchicine–update on mechanisms of action and therapeutic uses. Semin We acknowledge the physicians and Arthritis Rheum. 2015;45(3):341–350 DISCUSSION nurses of the cardiac intensive care, 6. Chaldakov GN. Colchicine, Severe CLS leading to dialysis, onco-hematology, nutrition, a microtubule-disassembling drug, in a hemodynamically relevant third cardiology, psychology, and the therapy of cardiovascular diseases. space with anuria requiring CRRT rehabilitation units for the great Cell Biol Int. 2018;42(8):1079–1084 may represent a serious life- collaborative work and continuous 7. Martínez GJ, Celermajer DS, Patel S. The threatening event, especially within support to the patients and their NLRP3 inflammasome and the emerging the complex transplant setting. families, who always encouraged role of colchicine to inhibit us to try 1 additional rescue effort In our cases, CLS occurred under full atherosclerosis-associated and gave their consent for publication immune suppression and was inflammation. Atherosclerosis. 2018; of these data. We thank Gabriel unresponsive to any line of treatment, 269:262–271 Oniscu (Scottish Transplant Unit, whereas colchicine proved 8. Imazio M, Brucato A, Rovere ME, et al. Royal Infirmary of Edinburgh, a successful option. Colchicine prevents early postoperative Edinburgh, UK) for revising the pericardial and pleural effusions. Am Although primary pathogenic subsets article. Heart J. 2011;162(3):527–532.e1 might be conceivably different, both cases shared a similar course: 9. Alabed S, Cabello JB, Irving GJ, Qintar massive CLS with a rapid progression M, Burls A. Colchicine for pericarditis. ABBREVIATIONS Cochrane Database Syst Rev. 2014;(8): to anuric AKI requiring CRRT. Fluid CD010652 extravasation was interrupted only by AKI: acute kidney injury colchicine, resulting in renal CLS: capillary leak syndrome 10. Schroth M, Plank C, Meissner U, et al. perfusion and diuresis normalization. CRP: C-reactive protein Hypertonic-hyperoncotic solutions The colchicine effect was additionally CRRT: continuous renal improve cardiac function in children after open-heart surgery. Pediatrics. revealed by the extravasation relapse replacement therapy 2006;118(1). Available at: www. a few days after treatment was ECV: effective circulating volume pediatrics.org/cgi/content/full/118/1/ stopped and subsequent reversal eGFR: estimated glomerular fi e76 after its reintroduction. ltration rate HSCT: hematopoietic stem cell 11. Balakumar V, Murugan R, Sileanu FE, It is worth noting that, although transplant Palevsky P, Clermont G, Kellum JA. Both formerly contraindicated, the drug MMF: mycophenolate mofetil positive and negative fluid balance may was safely administered during be associated with reduced long-term

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 143, number 5, May 2019 5 survival in the critically ill. Crit Care 16. Paschke S, Weidner AF, Paust T, Marti O, 20. Pelliccia A, Corrado D, Bjørnstad HH, Med. 2017;45(8):e749–e757 Beil M, Ben-Chetrit E. Technical advance: et al. Recommendations for 12. De Corte W, Dhondt A, Vanholder R, inhibition of neutrophil chemotaxis by participation in competitive et al. Long-term outcome in ICU patients colchicine is modulated through sport and leisure-time physical with acute kidney injury treated with viscoelastic properties of subcellular activity in individuals with renal replacement therapy: compartments. J Leukoc Biol. 2013; cardiomyopathies, myocarditis – a prospective cohort study. Crit Care. 94(5):1091 1096 and pericarditis. Eur J Cardiovasc Prev Rehabil. 2006;13(6): 2016;20(1):256 17. Park YH, Wood G, Kastner DL, Chae JJ. 876–885 13. Ranucci M. Perioperative renal failure: Pyrin inflammasome activation and hypoperfusion during cardiopulmonary RhoA signaling in the autoinflammatory 21. Amanova A, Kendi Celebi Z, Bakar F, bypass? Semin Cardiothorac Vasc diseases FMF and HIDS. Nat Immunol. Caglayan MG, Keven K. Colchicine Anesth. 2007;11(4):265–268 2016;17(8):914–921 levels in chronic kidney 14. Porcel JM. Pleural effusions in acute 18. Kim S, Jung ES, Lee J, Heo NJ, Na KY, Han diseases and kidney transplant idiopathic pericarditis and postcardiac JS. Effects of colchicine on renal recipients using tacrolimus. – injury syndrome. Curr Opin Pulm Med. fibrosis and apoptosis in obstructed Clin Transplant. 2014;28(10):1177 2017;23(4):346–350 kidneys. Korean J Intern Med. 2018; 1183 33(3):568–576 15. Costanzo MR, Ronco C, Abraham WT, 22. Yousuf Bhat Z, Reddy S, Pillai U, Doshi et al. Extracorporeal ultrafiltration for 19. Assaly R, Olson D, Hammersley J, et al. M, Wilpula E. Colchicine-induced fluid overload in heart failure: current Initial evidence of endothelial cell myopathy in a tacrolimus-treated renal status and prospects for further apoptosis as a mechanism of systemic transplant recipient: case report and research. J Am Coll Cardiol. 2017; capillary leak syndrome. Chest. 2001; literature review. Am J Ther. 2016;23(2): 69(19):2428–2445 120(4):1301–1308 e614–e616

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Downloaded from www.aappublications.org/news by guest on September 27, 2021 Colchicine: An Impressive Effect on Posttransplant Capillary Leak Syndrome and Renal Failure Enrico Cocchi, Federica Chiale, Bruno Gianoglio, Luca Deorsola, Carlo Pace Napoleone, Franca Fagioli and Licia Peruzzi Pediatrics 2019;143; DOI: 10.1542/peds.2018-2820 originally published online April 18, 2019;

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