Bakker, Stephan J.L.

Berger, Stefan P.

Knoester, Marjolein

Kremer, Daan

Verschuuren, Erik A.M.

English

ARTS repository - University of Groningen

   University of GroningenSuccessful Kidney Transplantation Despite Ongoing Chronic Norovirus InfectionKremer, Daan; Berger, Stefan P.; Verschuuren, Erik A.M.; Bakker, Stephan J.L.; Knoester,MarjoleinPublished in:Kidney International ReportsDOI:10.1016/j.ekir.2023.11.028IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionVersion created as part of publication process; publisher's layout; not normally made publicly availablePublication date:2023Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Kremer, D., Berger, S. P., Verschuuren, E. A. M., Bakker, S. J. L., & Knoester, M. (2023). SuccessfulKidney Transplantation Despite Ongoing Chronic Norovirus Infection. Kidney International Reports.https://doi.org/10.1016/j.ekir.2023.11.028CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 01-02-2024NEPHROLOGY ROUNDSKidneySuccessful Kidney Transplantation DespiteOngoing Chronic Norovirus InfectionDaan Kremer1, Stefan P. Berger1, Erik A.M. Verschuuren2, Stephan J.L. Bakker1 andMarjolein Knoester31Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen,Groningen, The Netherlands; 2Department of Pulmonology and Tuberculosis, Lung Transplantation Program, University ofGroningen, University Medical Center Groningen, Groningen, The Netherlands; and 3Department of Medical Microbiology andInfection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsCorrespondence: Daan Kremer, Department of Internal Medicine, Division of Nephrology, University of Groningen, UniversityMedical Center Groningen, 9700 RB Groningen, The Netherlands. E-mail: d.kremer@umcg.nlReceived 19 October 2023; revised 23 November 2023; accepted 27 November 2023Kidney Int Rep (2023) -, -–-; https://doi.org/10.1016/j.ekir.2023.11.028ª 2023 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BYlicense (http://creativecommons.org/licenses/by/4.0/).KEYWORDS: Caliciviridae; gastroenteritis; immune system; lung transplantation; transplantation; transplant candidacyª 2023 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BYlicense (http://creativecommons.org/licenses/by/4.0/).Table 1. Teaching pointsWe report a first case of a safe and successful kidney transplantation in a patient with anongoing chronic norovirus infectionKey considerations in proceeding with the kidney transplantation, were the patient’sclinical stability despite the ongoing norovirus infection, and the fact that theimmunosuppression would remain unaltered after transplantationThis case establishes an important precedent, but we encourage the publication of othercases of transplantations in patients with ongoing norovirus infections, to guidedecision-making in such instances. After all, numbers of similar cases will increase,given the increasing numbers of patients receiving second or third organ transplants.INTRODUCTIONNorovirus infection is one of the leading causes ofacute gastroenteritis outbreaks worldwide.1 Nor-ovirus infections generally present as acute-onsetnausea, diarrhea, and abdominal discomfort, and arecleared within 3 days in approximately 85% of cases.1The illness rarely lasts longer than 1 week in immu-nocompetent patients.1 However, immunocompromisedpatients may develop chronic norovirus infections,suffering from relapsing and remitting episodes ofwatery diarrhea, unable to clear the virus.2 Chronicnorovirus infections can last for months, or even years,and can have considerable clinical consequences,including malnutrition, dehydration, alterations in thegastrointestinal barrier, and impaired graft outcome.3,4The clinical impact of chronic norovirus infectionsafter solid organ transplantation has been described inprevious studies.3,5 However, all reported casesconcern patients who had undergone a transplant inthe past and then encountered a chronic norovirusinfection. To our knowledge, there are no reports ofpatients with an ongoing chronic norovirus infectionundergoing a transplantation or retransplantation.Such cases will likely present more frequently in thefuture, and reporting of such cases is important tounderstand any potential posttransplant infectiousexacerbations and graft outcomes.In a search for precedents to aid in the decision-making process in such scenarios, we identified a pa-tient in our center who had undergone kidneyInternational Reports (2023) -, -–-transplantation while suffering from an ongoing,chronic norovirus infection. This patient is the subjectof the current report. Key teaching points of this caseare presented in Table 1.CASE PRESENTATIONThe patient was a 63-year old Caucasian female with ahistory of a bilateral lung transplantation because oflung emphysema. An overview of the patient’s med-ical history and ongoing medication is provided inTable 2. Four years after lung transplantation, thepatient started to experience watery diarrhea andabdominal discomfort. Microbiology analyses showedthe presence of fecal norovirus RNA (repeatedly typedby sequencing as norovirus GII.Pg). In the followingyears, the patient continued to experience gastroin-testinal discomfort and episodes of watery diarrhea,for which she intermittently used loperamide. Fecalnorovirus loads were monitored and showed ongoingfecal norovirus shedding for 5 years after onset.1Table 2. Overview of medical history and medication use prior tothe patient’s kidney transplantationMedicalhistory Condition TreatmentSurgical cholecystitis cholecystectomydiverticulitis Hartmann procedureMedical lung emphysema Bilateral lung transplantationComplication: acute tubular necrosis, severalhemodialysis sessions, after which stabilization ofkidney function (creatinine w160 mmol/l; eGFRw25 ml/min per 1.73 m2)calcineurin inhibitornephrotoxicityAs a result, progressive kidney disease, culminating inend-stage kidney disease and the decision to opt forpreemptive kidney transplantationMedicationuseMedication Dosagedarbepoetin alpha 30 mg once per 5 weeksazathioprine 50 mg once dailycalcium carbonate 500 mg once dailyalphacalcidol 0.25 mg once every 2 daysloperamide 2 mg once dailysodium bicarbonate 1000 mg 3 times dailyesomeprazole 40 mg once dailycotrimoxazole 240 mg once dailytacrolimus 1 mg twice dailyprednisolone 5 mg once dailyeGFR, estimated glomerular filtration rate.After transplantation, the patient repeatedly had normal IgG levels (>7 g/l) and besidesthe ongoing chronic norovirus infection, there were no clinical clues for primary im-munodeficiency disorders.NEPHROLOGY ROUNDS D Kremer et al.: Successful Transplantation Despite NorovirusAbsolute lymphocyte count in this period wasgenerally low to normal (mean: 1.2  0.4 billion/l).Figure 1. Overview of the trajectory of circulating creatinine concentratiovalues indicate higher viral loads) over time. Events of lung transplantationperiod of gastrointestinal complaints is visualized in light blue.All creatinine values are presented in the weeks before and after lungcirculating creatinine concentration measured in the outpatient setting isclarity.2Despite the ongoing norovirus infection, the patient’slung graft function and general physical conditionremained stable.In the following years, the patient developed kidneyfailure, which was attributed to posttransplant acutetubular necrosis and calcineurin inhibitor toxicity. Thetrajectories of creatinine, norovirus, and clinicalsymptoms are presented visually in Figure 1. The pa-tient was considered for a preemptive kidney trans-plantation. However, the question was raised aboutwhether the ongoing chronic norovirus infectionwould be a contraindication. Despite the lack of sci-entific support for this decision, the clinical teamdecided that the patient was eligible for kidneytransplantation. Key considerations were that the pa-tient had been clinically stable for years, despite herchronic norovirus infection. Moreover, immunosup-pressive therapy would remain unaltered after trans-plantation, because she already used triple-therapyimmunosuppression (prednisolone, tacrolimus, andazathioprine) with tacrolimus trough levels that werecompatible with those targeted early after kidneytransplantation. The planned kidney transplantationwas therefore not expected to exacerbate the ongoingnorovirus infection. The patient received standard in-duction therapy following local treatment protocols(including basiliximab 2 hours before and 4 days aftertransplantation).n (in black) and fecal norovirus cycle threshold value (in gray; lowerand kidney transplantation are represented by red vertical lines. Theand kidney transplantations, respectively. In other periods, only 1shown per 6 months during routine outpatient clinic visits to improveKidney International Reports (2023) -, -–-D Kremer et al.: Successful Transplantation Despite Norovirus NEPHROLOGY ROUNDSThe patient successfully underwent a living unre-lated kidney transplantation, with excellent graftfunction immediately after transplantation. Tripleimmunosuppression was continued with target tacro-limus trough levels between 7 and 9 mg/l, azathioprine,and a prednisolone taper. Measured tacrolimus troughconcentrations were similar in the 2 years before kid-ney transplantation, compared to the 2 years afterkidney transplantation (mean 7.4  1.4 mg/l vs. 7.2 1.1 mg/l), and lymphocyte count also remained stable(1.0  0.4 billion/l). Fecal norovirus load remainedstable in the first days after transplantation. Clinically,the patient’s stools remained unchanged in the firstmonths after transplantation, without any exacerba-tions of diarrhea or gastrointestinal discomfort.Approximately 10 weeks after kidney trans-plantation (i.e., approximately 9.5 years after lungtransplantation), the patient reported that the episodesof diarrhea and gastrointestinal discomfort had stoppedcompletely. In line with this, fecal viral load steadilydecreased in the years after transplantation. The epi-sodes of diarrhea and abdominal discomfort remainabsent, and kidney and lung graft function are stable todate (i.e., 4 years after kidney transplantation, 13 yearsafter lung transplantation).DISCUSSIONTo our knowledge, this is the first report of a suc-cessful (kidney) transplantation in a patient with anongoing, chronic norovirus infection. Notably, theprevalence of chronic norovirus infections in organtransplant recipients is substantial, and increasingnumbers of patients receive second or third organtransplants.3,6,7 Therefore, it appears likely thatincreasing numbers of similar cases of patients withongoing norovirus infections will be considered forkidney transplantation in the future. This report es-tablishes a precedent that may inform the decision-making process in such scenarios. However, thisconcerns a single case report which, in itself, isinsufficient to infer broader statements on safety inother patients.Norovirus infections have different clinical charac-teristics in immunocompromised hosts, compared toimmunocompetent hosts. In immunocompromised hosts,such as organ transplant recipients using immunosup-pressive therapy, norovirus prevalence is relativelyhigh, with cases presenting year-round rather than thewinter-peak that is typically observed in immunocom-petent hosts.2 Moreover, complications of norovirusinfections are more common and have larger clinicalimpact in immunocompromised hosts. For example,dehydration, malnutrition, and intestinal barrierKidney International Reports (2023) -, -–-dysfunction are much more common in immunocom-promised hosts; and can compromise graft and patientoutcome.5 Such severe complications were not observedin our patient, who remained clinically and physicallystable during the years of infection.Treatment options in patients with norovirus in-fections are primarily supportive, to prevent dehydra-tion. Antimotility agents such as loperamide can beconsidered, as was done in our patient. Successful treat-ment of norovirus infections in solid organ transplantrecipients using nitazoxanide or immunoglobulins hasbeen reported; however, results are inconsistent.2,4 Thereare suggestions that temporary discontinuation of pro-liferation inhibitors may help with norovirus clearance;however, this comes with a risk of eliciting graft rejec-tion.2,4 Interventional trials are needed to robustly eval-uate therapeutic treatment options. Meanwhile,supportive care is the only evidence-based treatment.2,4Literature on the duration of chronic norovirus in-fections in immunocompromised hosts is limited; how-ever, infections can last indefinitely.2 In our case, itstands out that the norovirus fecal load steadilydecreased after kidney transplantation, after an ongoinginfection with much higher viral loads for years.Although we cannot find reports of chronic norovirusinfections with kidney disease being the sole cause, it iswidely known that kidney failure is associated withimmunological dysfunction.8 During kidney failure,both antiinflammatory and proinflammatory cytokinescan accumulate due to uremic toxins, oxidative stress,and volume overload.8,9 It appears plausible that, in thereported case, the combination of kidney failure on topof the use of immunosuppressive medication led to thepatient’s initial incapacity to control the virus.Improvement of kidney function by the kidney trans-plantation may have sufficiently improved the patient’simmunological state, to allow her to decrease the viralload after years of infection despite the similar immu-nosuppressive regimen. However, the actual role ofkidney function in the decreasing viral load is strictlyhypothetical, because it may also have occurred inabsence of the performed kidney transplantation.In conclusion, this report describes a first case of asafe and successful kidney transplantation in a patientsuffering from a chronic norovirus infection. Westress the need for future reporting of similar cases,which can further inform clinicians in the decision-making process of patients with a chronic norovirusinfection who are being considered for organtransplantation.DISCLOSUREAll the authors declared no competing interests.3NEPHROLOGY ROUNDS D Kremer et al.: Successful Transplantation Despite NorovirusPATIENT CONSENTThe authors declare that they have obtained informedconsent from the patient discussed in the report.REFERENCES1. Dolin R. Noroviruses—challenges to control. N Engl J Med.2007;357:1072–1073. https://doi.org/10.1056/NEJMP0780502. Bok K, Green KY. Norovirus gastroenteritis in immunocom-promised patients. N Engl J Med. 2012;367:2126–2132. https://doi.org/10.1056/nejmra12077423. Westhoff TH, Vergoulidou M, Loddenkemper C, et al. ChronicNorovirus infection in renal transplant recipients. Nephrol DialTransplant. 2009;24:1051–1053. https://doi.org/10.1093/ndt/gfn6934. Nair SN, Bhaskaran A, Chandorkar A, Fontana L, Obeid KM.Noroviral diarrhea in solid organ transplant recipients: ananalysis of interventions and outcomes. Clin Transpl. 2023;37:e14855. https://doi.org/10.1111/CTR.1485545. Roos-Weil D, Ambert-Balay K, Lanternier F, et al. Impact ofNorovirus/Sapovirus-related diarrhea in renal transplant re-cipients hospitalized for diarrhea. Transplantation. 2011;92:61–69. https://doi.org/10.1097/TP.0B013E31821C93926. Halawa A. The third and fourth renal transplant; technicallychallenging, but still a valid option. Ann Transplant. 2012;17:125–132. https://doi.org/10.12659/AOT.8837037. Hirji SA, Castleberry AW, Castleberry AW, et al. Long termsurvival following kidney transplantation in previous lungtransplant recipients-an analysis of the UNOS registry. ClinTranspl. 2017;31. https://doi.org/10.1111/ctr.129538. Kato S, Chmielewski M, Honda H, et al. Aspects of immunedysfunction in end-stage renal disease. Clin J Am Soc Nephrol.2008;3:1526–1533. https://doi.org/10.2215/CJN.009502089. Stenvinkel P, Ketteler M, Johnson RJ, et al. IL-10, IL-6, andTNF-alpha: central factors in the altered cytokine network ofuremia–the good, the bad, and the ugly. Kidney Int.2005;67:1216–1233. https://doi.org/10.1111/J.1523-1755.2005.00200.XKidney International Reports (2023) -, -–-

Successful Kidney Transplantation Despite Ongoing Chronic Norovirus Infection

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Successful Kidney Transplantation Despite Ongoing Chronic Norovirus Infection

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