Colchicine: An Impressive Effect onPosttransplant Capillary LeakSyndrome and Renal FailureEnrico 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

abstractCapillary leak syndrome is a critical condition occasionally occurringposttransplant and is characterized by acute endothelial hyperpermeabilityleading to systemic protein-rich fluid extravasation and consequenthypovolemia, hypoperfusion, and acute kidney injury. Treatment is merelysupportive and is based on osmotic drugs, diuretics, continuous renalreplacement therapy, and surgical drainage. However, removal of theunderlying inflammatory cause is mandatory to achieve stable resolution.Herein, we report the first successful treatment with colchicine in 2 life-threatening pediatric cases of capillary leak syndrome with renal failureoccurring after transplant (heart and bone marrow) and unresponsive to anyother line of therapy. Both cases were only palliated by supportive therapyand revealed an impressively rapid response to colchicine both in terms ofdiuresis and clinical condition recovery, allowing for the cessation of renalreplacement therapy in a few hours. In both patients, colchicine wastemporarily discontinued for transient leukopenia (attributed to an additiveeffect with mycophenolate mofetil), resulting in extravasation, and renalfailure recurrence was restored only after colchicine reintroduction. Althoughthe association of colchicine with an immunosuppressive drug was formerlycontraindicated, no other adverse events were noted when using a minimizeddose. Both patients are now maintaining a good renal function withoutrecurrence of extravasation after 6 months of follow-up. In conclusion, thisstrikingly positive experience forces physicians to consider this old and cost-effective drug as a new, powerful rescue tool in such critical cases.

Capillary leak syndrome (CLS) ischaracterized by massive protein-richfluid extravasation secondary toendothelial hyperpermeability due tosystemic inflammatory status.1 CLSmay be detectable in various diseases,including autoinflammatory oneswhose treatment relies on anti-inflammatory drugs and colchicine.2–4

Colchicine is a widely available, safe,and low-cost drug that acts both asa spindle poison and as an anti-inflammatory agent.5–7 In recent years,colchicine became the standard of care

for idiopathic pericarditis and provedits efficacy in several inflammatorydiseases, including postsurgeryserositis and atherosclerosis.7–9

Moreover, it has a safe profile withminor gastrointestinal problems ascommon adverse reactions, whichusually resolve after drugdiscontinuation, whereas othermore serious effects are rare.These characteristics makecolchicine an attractive therapeutictool for various inflammatorydisorders.7

aUniversity of Turin, Turin, Italy; and bNephrology, Dialysisand Transplantation Unit, cPediatric Cardiac Surgery Unit,and dPediatric Onco-Hematology Unit, Stem CellTransplantation and Cellular Therapy Division, ReginaMargherita Children’s Hospital, Turin, Italy

Dr Cocchi conceptualized the study, drafted theinitial manuscript, and reviewed and revised themanuscript; Drs Chiale, Deorsola, Pace Napoleone,Gianoglio, and Fagioli designed the data collectioninstruments, collected data, and reviewed andrevised the manuscript; Dr Peruzzi was activelyinvolved in both cases’ management, conceptualizedand designed the study, coordinated and superviseddata collection, and critically reviewed themanuscript for important intellectual content; andall authors approved the final manuscript assubmitted and agreed to be accountable for allaspects of the work.

DOI: https://doi.org/10.1542/peds.2018-2820

Accepted for publication Dec 18, 2018

Address correspondence to Enrico Cocchi, MD,University of Turin, Nephrology, Dialysis andTransplantation Unit, Regina Margherita Children’sHospital, Piazza Polonia 94, Turin 10126, Italy. E-mail:enrico.cocchi@unito.it

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,1098-4275).

Copyright © 2019 by the American Academy ofPediatrics

FINANCIAL DISCLOSURE: The authors have indicatedthey have no financial relationships relevant to thisarticle to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors haveindicated they have no potential conflicts of interestto disclose.

To cite: Cocchi E, Chiale F, Gianoglio B, et al.Colchicine: An Impressive Effect onPosttransplant Capillary Leak Syndrome andRenal Failure. Pediatrics. 2019;143(5):e20182820

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CLS occasionally occurs ina posttransplant setting in which fluidoverload and impaired fluid balanceare strongly related withmortality.10–12 In fact, massive fluidextravasation leads to peripheralhypoperfusion and renal impairment,often resulting in prerenal acutekidney injury (AKI).13 In early phases,treatment is merely supportive andbased on reattracting fluids fromthird space to effective circulatingvolume (ECV) by using osmoticagents, such as albumin, followed bynet fluid elimination with diuretics.Nevertheless, when fluid accumulatesin body cavities and interferes withvital organ function, a surgicaldrainage is mandatory.14,15 Thisapproach is normally sufficient tosupport the patient until resolution ofthe extravasation-underlying cause.Nevertheless, in some critical cases,extravasation severity and speedexceeds treatment efficiency, and AKIprogresses, requiring continuousrenal replacement therapy (CRRT) toensure proper fluid balance. In case ofpersistence of the inflammatory noxa,spontaneous resolution is rarelyachievable, and clinical managementof the patients represents a difficultchallenge, especially in children. Insuch cases, rescue treatments beyondtraditional care become necessary.

Herein, we present our positiveexperience with colchicine in 2children who developed a severe CLSrapidly evolving to anuric AKI afterheart and bone marrow transplantthat was unresponsive to any otherline of treatment.

CASE PATIENTS

Patient 1

A 17-year-old boy was born with anuniventricular heart treated by usingpulmonary artery banding,bidirectional Glenn, and extracardiacFontan interventions in infancy,complicated by severe plasticbronchitis and Fontan-associatedliver disease with advanced hepatic

fibrosis (FibroScan 12 kPa,cooresponding to Metavir grade F4).He received an orthotopic hearttransplant with standardthymoglobulin-steroid induction,tacrolimus, mycophenolate mofetil(MMF), and steroid maintenance.

Since day 1 posttransplant, heexperienced severe fluid leakage upto 3000 to 4000 mL/day, initiallylimited to mediastinum and identifiedas lymph. After a few days of partialresolution, leakage becamemultisystemic (pleural, peritoneal,and subcutaneous) witha composition similar to plasma.

He developed oligoanuric AKI,requiring CRRT from the secondposttransplant day.

Because of persistent extravasation,on day 59, thoracic duct ligation wasperformed, which was partiallysuccessful in reducing the mediastinaleffusions (Fig 1). Nevertheless,oliguria progressed to anuria andincreased fluid overload (Fig 1)despite normal right and leftventricular function and renalperfusion. Additional corticosteroidpulses and anti-inflammatory drugswere unsuccessful. Progressivedecline of general conditions led toa rescue attempt with colchicine onday 97.

Patient 2

A 12-year-old girl affected by trisomy21 and Tetralogy of Fallot correctedat 3 months developed an M6 acutemyeloid leukemia at age 4 and acutelymphoblastic leukemia at age 11. Shewas effectively treated withchemotherapy and hematopoieticstem cell transplant (HSCT) 7months later.

On day 23 posttransplant, shedeveloped oliguric AKI, whichgradually resolved after nephrotoxicdrug withdrawal (acyclovir,vancomycin, and amikacin), allowingfor her to be discharged on day 31with mild renal impairment(estimated glomerular filtration rate

[eGFR] 48.9 mL/minute per 1.73 m2)and under maintenance therapy withcyclosporin and prednisone.

Since HSCT, she presented with 3 AKIepisodes characterized by increasedserum creatinine and C-reactiveprotein (CRP), bilateral pleuraleffusions requiring thoracentesis andvacuum up to 20 days, ascites, anddiffuse peripheral edema. Thepresentation was always dominatedby respiratory distress and fever,rapidly evolving to multiple effusionsand AKI. The first 2 episodes (days 44and 179) occurred during prednisonetapering and were effectivelycontrolled by intravenousmethylprednisolone pulses (2–5mg/kg per dose). The third episode(day 347) initially responded tomethylprednisolone pulses (10mg/kg every other day) and MMF(600 mg/m2), but subsequenteffusions and oliguria worsened untilCRRT requirement.

The severity of systemic effusion,despite increased immunesuppression, led to a rescue attemptwith colchicine.

RESULTS

Colchicine Mechanism of Action onVascular Endothelial andExtravasation

Colchicine’s precise impact onvasculature is still unknown, andspecific literature on the topic islacking.

In fact, although colchicine’s best-known effect is arresting microtubulepolymerization at high dosage, it alsoexerts several anti-inflammatoryeffects on both macrophages andendothelial cells through modulationof VCAM-1, tumor necrosis factor a,E-selectin, interleukin 1b, and NLRP3inflammasome. However, no clearexplanation of its effect onextravasation is provided in theliterature.7,16,17 This effect may alsobe attributable to its in vivoantiapoptotic action, considering that

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endothelial cell apoptosis appears toplay a role in CLS pathogenesis.18,19

Altogether, this multisite action mayreduce both endothelial permeabilityand extravasation of high–molecularweight molecules, such as albumin,but additional studies are needed toclarify the exact effect of colchicine onvasculature.

Effects of Colchicine onHypoalbuminemia and BloodPressure

Both patients presented withmassive hypoalbuminemiawithout albuminuria in additionto hypotension, hemoconcentration,and generalized edema.

Hypoalbuminemia persisted untilextravasation resolution despitemassive albumin supplementation(1–2 g/kg per day) and highlycaloric total parenteral nutrition. Atthe same time, in both patients,hypotension persisted despitefluid administration in accordancewith the guidelines of shockmanagement, requiring continuousendovenous sympathomimetic aminesupport in patient 1.

Both albuminemia and bloodpressure normalized in a few daysafter colchicine administration,presumably through fluidcompartment reequilibration (Fig 2).

Cardiac Function

Both patients had normal cardiacfunction; patient 1 was affected bysevere mediastinal effusion requiringdrainage, whereas patient 2 had onlymild pericardial effusion. In bothcases, cardiac function was monitoreddaily by using echocardiographyduring the acute extravasationphase, revealing normal ventricularfunction and excluding a cardiacetiology for such fluid overload.

Effects of Colchicine on Diuresis andFluid Balance

The initial dose of colchicine was10 µg/kg per day (0.5 mg/day)

FIGURE 1The image represents the clinical course of the cases: eGFR (mL/minute per 1.73 m2). Red-shadowed area represents CRRT period, and green-shadowedarea represents colchicine-treatment periods. Patient 1 starts from heart transplant (day 0) and shows clinic and laboratory trends. The plot clearlyshows how thoracic duct ligation reduced drainage-measurable leaks but was ineffective in restoring diuresis and normal fluid balance. Colchicineinitiation allowed for reaching an optimal diuresis and a good fluid balance with no leaks, temporarily interrupted by its discontinuation (day 127–day132). It also shows that colchicine effectively suppressed inflammatory indices (sCRP). The red shadows in the plot illustrate CRRT. eGFR during CRRT isunreliable 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, alloweddiuresis and eGFR restoration with normal fluid balance. It also shows recurrence of leaks and AKI after colchicine discontinuation and additionalresolution with colchicine reintroduction. The plot shows how improved renal function may be the cause underlying different time response to colchicineas 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.

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modulated in consideration of renalfailure.

ECV hypovolemia was extremelypronounced in both patients and onlypartially responsive to fluidadministration. After colchicineadministration, diuresis was restartedin a few hours, and 48 hours later,a net-negative fluid balance wasachieved (Fig 1), allowing for CRRTdiscontinuation. The end of the“inflammatory crisis” was defined bymassive polyuria in both patients, asis characteristic of CLS resolution.1

It is worth noting that CRRT could bestopped after more than 3 months(day 108) in patient 1, when renalfailure was considered irreversible bythis time.

Extravasation Recurrence atSuspension

In both cases, systemic extravasationwith hypoalbuminemia, oliguria, andfluid overload recurred shortly after

colchicine discontinuation due totransient leukopenia (interpreted asadditive effect with MMF), furtherrevealing its antiextravasation effect.

In patient 1, recurrence was almostimmediate, with pericardial andpleural effusions requiring drainagewithin 5 days from colchicinediscontinuation.

Patient 2 experienced bilateralpleural effusions, ascites, and AKI,requiring CRRT after a latency of14 days.

Colchicine Reintroduction

In both cases, colchicine wasreintroduced after leukopeniarecovery. In patient 1, this took place8 days after withdrawal witha strikingly rapid response similar tothat observed after primarycolchicine introduction.

In patient 2, colchicine wasreintroduced after 39 days, initially

obtaining only a partial response andevolving into complete resolutionafter dose doubling (1 mg daily).

Inflammatory Markers

Both patients had normalized serumCRP only after colchicine introduction(Fig 1), suggesting its capacity tointerrupt the inflammatorymechanism behind the capillary leak,which was always associated withserum CRP increments but neverassociated with any evidence ofinfections.

Patient Discharge and Follow-up

Patients were discharged withcolchicine maintenance ata minimized dose of 2.5 µ/kg per day(0.125 mg/day) under strict follow-up.

Patient 1 was discharged on day 143after transplant with colchicine andtacrolimus without MMF nor steroids.Until now (day 320), no recurrence ofextravasation and stable renalfunction (eGFR 60 mL/minute per1.73 m2) were achieved.

Patient 2 was discharged on day 467after HSCT and experienceda transient central venouscatheter–related sepsis on day 487. Itis noteworthy that during thisepisode, an initially mild bilateralpleural effusion without significantdiuresis impairment was controlledby using colchicine dose doublingwithout a need for additionalsteroids.

There are no clear indications forcolchicine therapy duration. On thebasis of actual experience frominflammatory diseases, it can rangefrom 1 to 18 months, depending onpatient response and adverseeffects.9,20 We will evaluate colchicinedose requirements through follow-upin both cases, and tapering will beattempted after 12 months, accordingto patient status.

FIGURE 2The 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 outputincrement and diuresis reduction (compensation phase). When cardiac output increment reachesits physiologic limit, if extravasation continues, the ECV is gradually stolen by third space, renalperfusion is impaired (prerenal AKI), and diuresis decreases. In this uncompensated phase, diuresiscannot be restored through diuretics administration because ECV is extremely reduced. In the samemanner, fluid removal (leaks curve in figure) is an additional extravasation of third space outsidethe body, but it does not lead to any ECV expansion. In this regard, leaks drainage and CRRT are ofcentral importance in decongesting vital organs (such as heart, lungs, etc), but it is merelysupportive. 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 underlyingnoxa. Nevertheless, in the presented cases, the extravasation-driving force was overwhelming, andno effective result was obtained until colchicine introduction, which interrupted the pathogenicchain and restored the physiologic status.

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Safety, Interaction, and AdverseEvents

Parents gave informed consent to thecolchicine treatment as a third-linerescue therapy to be considered as anextension of the approved pericardialeffusion indication.

In case 1, a colchicine-tacrolimusinteraction developed without impacton daily monitored tacrolimuslevels.21 Colchicine was modulated inboth cases according to the leukocytecount because of drug levelunavailability.22 Mild leukopenia wasinitially observed in both cases,attributed to additive MMF effect, andresolved with colchicine and MMFdiscontinuation. No infectionsoccurred in patient 1. Patient 2 hastransient central venouscatheter–related sepsis, which wasunrelated to leukopenia.

No other adverse effect was recorded.

DISCUSSION

Severe CLS leading toa hemodynamically relevant thirdspace with anuria requiring CRRTmay represent a serious life-threatening event, especially withinthe complex transplant setting.

In our cases, CLS occurred under fullimmune suppression and wasunresponsive to any line of treatment,whereas colchicine proveda successful option.

Although primary pathogenic subsetsmight be conceivably different, bothcases shared a similar course:massive CLS with a rapid progressionto anuric AKI requiring CRRT. Fluidextravasation was interrupted only bycolchicine, resulting in renalperfusion and diuresis normalization.The colchicine effect was additionallyrevealed by the extravasation relapsea few days after treatment wasstopped and subsequent reversalafter its reintroduction.

It is worth noting that, althoughformerly contraindicated, the drugwas safely administered during

immunosuppressive therapy and AKIat a reduced dose.

To the best of our knowledge, this isthe first report of a severe third-spaceAKI attributable to CLS in a transplantsetting effectively controlled withcolchicine.

This empirical observation in 2different transplant settings and theabsence of significant side effectsled physicians to consider colchicineas a useful option in posttransplantCLS and renal failure in whichCRRT weaning is mandatoryto ensure transplant success andpatient survival without additionalmorbidity.

Additional exploration of thepotential use of colchicine inposttransplant systemic fluid effusionis advocated.

ACKNOWLEDGMENTS

We acknowledge the physicians andnurses of the cardiac intensive care,dialysis, onco-hematology, nutrition,cardiology, psychology, andrehabilitation units for the greatcollaborative work and continuoussupport to the patients and theirfamilies, who always encouragedus to try 1 additional rescue effortand gave their consent for publicationof these data. We thank GabrielOniscu (Scottish Transplant Unit,Royal Infirmary of Edinburgh,Edinburgh, UK) for revising thearticle.

ABBREVIATIONS

AKI: acute kidney injuryCLS: capillary leak syndromeCRP: C-reactive proteinCRRT: continuous renal

replacement therapyECV: effective circulating volumeeGFR: estimated glomerular

filtration rateHSCT: hematopoietic stem cell

transplantMMF: mycophenolate mofetil

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DOI: 10.1542/peds.2018-2820 originally published online April 18, 2019; 2019;143;Pediatrics 

Napoleone, Franca Fagioli and Licia PeruzziEnrico Cocchi, Federica Chiale, Bruno Gianoglio, Luca Deorsola, Carlo Pace

and Renal FailureColchicine: An Impressive Effect on Posttransplant Capillary Leak Syndrome

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DOI: 10.1542/peds.2018-2820 originally published online April 18, 2019; 2019;143;Pediatrics 

Napoleone, Franca Fagioli and Licia PeruzziEnrico Cocchi, Federica Chiale, Bruno Gianoglio, Luca Deorsola, Carlo Pace

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