Onconephrology in Renal Transplant Patient: A Challenge for the Transplant Nephrologist

Posted on Scarica PDF

Enrico Sanna1, Ana Maria Manzione1, Silvia Mingozzi1, Luigi Biancone1

1 SC Nefrologia, Dialisi, Trapianto di Rene, Città della Salute e della Scienza di Torino, sede Molinette, Torino, Italia

Corresponding author:
Luigi Biancone
SC Nefrologia, Dialisi, Trapianto di Rene, Città della Salute e della Scienza di Torino, sede Molinette, Torino, Italia
Corso Bramante, 88/90
10126 Torino – Italia
Tel. 011-6336150
email: luigi.biancone@unito.it

 

Abstract

Onconephrology, an emerging field in modern medicine, is gaining importance due to its intricate challenges derived from the mixing field of tumorous and renal diseases. The growing incidence of tumors in transplant patients requires preventive strategies and accurate monitoring. Pre-transplant screening is crucial, focusing on subjects with oncological history. Post-transplant follow-up must be personalized, tailoring screenings for patients with cancer history. Immunosuppressive therapy, although essential to prevent organ rejection, represents a delicate balance between controlling the immune response and cancer risk management.
Immune checkpoint inhibitors emerge as a fascinating potential for cancer therapy, but their use in transplant patients requires caution and further research to carefully evaluate their safety and effectiveness, balancing potential benefits with actual risk of rejection. In summary, onconephrology is a growing field that requires an interdisciplinary approach and constant research, aimed at successfully addressing the complex challenges associated with oncological diseases in renal and transplant patients.

Keywords: Onconephrology, Kidney transplant, Immunosuppressive therapy, Immune check-point inhibitors

Sorry, this entry is only available in Italian.

Introduzione: l’onconefrologia e le sue prospettive

L’onconefrologia sta emergendo come una disciplina chiave nella medicina moderna, richiedendo specialisti in grado di gestire le complessità delle patologie tumorali e renali.

L’addestramento specifico è limitato, e c’è un’urgenza crescente di formare più onconefrologi per far fronte alla domanda in crescita. L’integrazione di onconefrologi in squadre multidisciplinari è fondamentale per affrontare le innumerevoli sfide legate ai pazienti oncologici con malattia renale, inclusi coloro che hanno ricevuto un trapianto di rene.

La precisione nell’applicazione delle terapie oncologiche richiede una formazione continua specifica, e l’onconefrologia deve essere inclusa nei programmi di formazione specialistica, per mantenere aggiornati i professionisti sulle cure nei pazienti oncologici nel complicato setting della nefrologia.

L’onconefrologia deve anche affrontare sfide come la mancanza di linee guida adeguate e lo sviluppo di nuovi strumenti diagnostici, inoltre la comunicazione tra oncologi e nefrologi risulta essenziale per migliorare i risultati dei pazienti e la gestione delle lesioni renali acute e croniche.

Le sfide poste da questa particolare categoria di pazienti possono essere superate attraverso la collaborazione interdisciplinare precoce e l’uso di criteri di classificazione universali. In definitiva, l’onconefrologia rappresenta un campo in evoluzione che richiede attenzione, formazione e collaborazione per affrontare efficacemente le complessità della gestione delle malattie oncologiche nei pazienti nefropatici e portatori di trapianto di rene.

 

Epidemiologia, mortalità e fattori di rischio del tumore nel paziente portatore di trapianto di rene

Il tumore è una delle principali cause di morte nei pazienti sottoposti a trapianto di rene [1, 2].

Negli studi internazionali, la popolazione dei trapiantati mostra un tasso standardizzato di incidenza (SIR) di neoplasia di 2-4 volte in più rispetto alla popolazione generale, seppur con enormi variabilità in base alla neoplasia considerata [3-9].

L’incidenza all’interno della popolazione trapiantata mostra poi un prevedibile incremento con il passare degli anni, arrivando ad oscillare tra il 10% ed il 15% a circa 15 anni dal trapianto [3, 4].

Risultati simili sono stati riscontrati anche nella popolazione italiana [5, 6]. Questi numeri sono destinati a crescere, anche in considerazione dell’aumento dell’aspettativa di vita dei pazienti trapiantati e della maggiore efficacia delle terapie antirigetto, che permette un incremento della vita media del trapianto e quindi della durata totale di immunosoppressione.

Come è prevedibile, il rischio di mortalità in questi pazienti è più elevato rispetto alla popolazione generale. I dati osservazionali hanno difatti dimostrato che i tassi di mortalità standardizzati sono almeno 1,8-2,5 volte più elevati rispetto alla popolazione generale corrispondente per età e sesso [10, 11]. Questo vale soprattutto per quanto riguarda i linfomi non Hodgkin, i tumori urogenitali ed il melanoma, patologie che mostrano un rischio complessivo di morte che supera di cinque-dieci volte quello di coloro che non hanno ricevuto un trapianto di rene [10].

Diversi fattori di rischio per malattia oncologica sono stati identificati nel paziente trapiantato. Questi possono riguardare il paziente (età anagrafica, etnia, stile di vita e fumo, malattia renale di base, storia di neoplasia, storia di abuso di analgesici, suscettibilità alle infezioni virali, fattori genetici) o possono essere fattori più propriamente trapiantologici (grado di compatibilità immunologica, valore di vPRA, terapia immunosoppressiva) [12-24].

La trasmissione di malignità dal donatore è un evento raro, con un’incidenza stimata tra lo 0,01% e lo 0,05%. Questo rischio varia in base al tipo di neoplasia [25-27]. Tuttavia bisogna evidenziare come il rischio di mortalità sia, in caso di trasmissione, particolarmente elevato, verificandosi in circa il 20% dei soggetti colpiti [26, 27], per cui una scrupolosa valutazione del potenziale donatore d’organo è essenziale per ridurre al minimo questo rischio.

 

Screening pre trapianto e timing di trapianto nel paziente con storia oncologica

Un accurato screening prima del trapianto è fortemente raccomandato dalle principali linee guida, considerando il maggior rischio oncologico evidenziato anche nei pazienti con ESRD, specialmente se sottoposti a terapia dialitica e per alcuni istotipi specifici [28-32].

In aggiunta, non è sempre del tutto chiaro quale sia il momento opportuno per sottoporre al trapianto renale coloro che hanno una storia oncologica, e questo è tuttora motivo di dibattito nella letteratura medica. Infatti, anche se il tumore è stato adeguatamente trattato, il beneficio di un trapianto deve essere bilanciato ad un rischio di una eventuale recidiva, da considerare specialmente in corso di immunodepressione. Diverse linee guida, come ad esempio quelle della KDIGO [28] o quelle di recente formulazione da parte di Al-Adra e colleghi [33], hanno cercato di mettere luce sulla questione.

Le linee guida di Al-Adra e colleghi sono state sviluppate attraverso un consensus conference nel 2019, che ha coinvolto specialisti trapiantologi ed oncologi.

La valutazione del rischio oncologico nel lavoro di Al-Adra si basa sulla stadiazione TNM (tumore, coinvolgimento dei linfonodi regionali, metastasi) unitamente a strumenti di recente sviluppo, come l’analisi dei marcatori tumorali e l’epigenetica.

In generale, i tempi di attesa dalla guarigione sono stati decisi in base alla stadiazione, alle caratteristiche biologiche del tumore e alla probabilità di recidiva. Di conseguenza, sono stati suggeriti tempi di attesa che variano dall’assenza di attesa a 2 anni per i tumori a basso grado, fino a 5 anni per quelli ad alto grado. Per procedere all’eventuale trapianto si è deciso di considerare come cut-off un tasso di sopravvivenza almeno del 80% a 5 anni.

Benché non esaustive, queste raccomandazioni trattano le patologie tumorali più comuni, offrendo così un orientamento al trapiantologo clinico. È importante però ricordare che tali indicazioni si basano principalmente su dati provenienti dalla popolazione generale, vista la limitata disponibilità di evidenze sulle popolazioni trapiantate.

 

Screening nel paziente già sottoposto a trapianto di rene

Come già detto, dopo il trapianto di rene il rischio di tumore è come minimo raddoppiato rispetto alla popolazione generale. Per tale ragione, lo screening in senso oncologico è di vitale importanza. Le raccomandazioni [34, 35] variano tra diverse società, ma in generale lo screening dovrebbe almeno seguire le indicazioni già formulate per la popolazione generale, con alcune importanti eccezioni.

Nello specifico, per i tumori della pelle e delle labbra (tumori cutanei non melanoma), il rischio è considerevolmente elevato [36-43], e la maggior parte degli autori consiglia una valutazione dermatologica annuale, in aggiunta ad un costante e scrupoloso automonitoraggio.

Per quanto riguarda i tumori urologici, non esistono linee guida chiare per lo screening del carcinoma a cellule renali nei reni nativi dopo il trapianto. Tuttavia, si suggerisce di sottoporre i pazienti con malattia cistica acquisita, pregresso carcinoma a cellule renali o abuso di analgesici a controlli ecografici periodici ogni 1-3 anni dopo il trapianto. Inoltre, i pazienti con ematuria di recente insorgenza dovrebbero essere valutati per escludere una eventuale neoplasia urologica.

Altri tumori che meritano un follow-up specifico rispetto alla popolazione generale sono i tumori associati alla relazione tra immunodepressione e virus oncogeni, specialmente HPV, EBV, HHV-8. Tra questi ricordiamo il carcinoma della cervice, il carcinoma anale, la sindrome linfoproliferativa post trapianto (PTLD), il sarcoma di Kaposi ed il già menzionato tumore cutaneo non melanoma.

Nella Tabella I è schematizzato il programma di monitoraggio oncologico del paziente adulto portatore di trapianto di rene adottato dalla Rete Nefrologica Piemonte – Valle d’Aosta e dal Centro trapianti di rene “A. Vercellone” della Città della salute e della scienza di Torino.

Il rapporto costo-efficacia di queste raccomandazioni è comunque oggetto di discussione [8, 43], soprattutto in Paesi che adottano politiche sanitarie differenti dalle nostre.

Infine, al di là delle raccomandazioni generali, è ruolo del nefrologo trapiantologo identificare i pazienti a maggior rischio, ed impostare uno screening oncologico adattato sul singolo paziente. Una rete integrata ed interdisciplinare è necessaria per assicurare una corretta gestione dei casi complessi, ed è in grado di ridurre la morbilità e la mortalità in questi pazienti.

Nella Figura 1 è schematizzata la rete interdisciplinare di assistenza al paziente adulto portatore di trapianto di rene della Città della Salute e della Scienza di Torino.

Tipo di Neoplasia

Accertamenti proposti
Mammella

Mammografia annuale/biennale.
 Cervice 

Citologico cervice ed esame pelvico annuale.
Prostata

Visita annuale (DRE) e PSA in >50 anni.
 Stomaco/Colon-retto

SOF annuale; se positivo: colonscopia; se colonscopia negativa: EGDS.
Epatocellulare (Cirrosi HCV/HBV relata o da altra causa)

ETG semestrale; a-FP semestrale.
Cute

Autoesame mensile; visita dermatologica annuale.
 Kaposi Sarcoma

Autoesame mensile; visita dermatologica annuale, HHV-8 DNA nei soggetti a rischio per regione geografica.
PTLD

EBV-DNA ogni 6-12 mesi, se viremia in incremento progressivo: valutazione ematologica (+ ETG stazioni linfonodali).
Renale (reni nativi)                        

ETG semestrale/annuale. Nei pazienti ADPKD: TC addome mdc biennale/RM senza mdc.
 Polmone

Rx torace annuale.
 Tiroide

ETG tiroide al II anno; successivamente triennale.
Tabella I. Programma di monitoraggio oncologico del paziente adulto portatore di trapianto di rene adottato dalla rete nefrologica Piemonte – Valle d’Aosta.
Figura 1. Rete interdisciplinare adottata dalla Città della Salute e della Scienza di Torino per l’assistenza al paziente adulto portatore di trapianto di rene.
Figura 1. Rete interdisciplinare adottata dalla Città della Salute e della Scienza di Torino per l’assistenza al paziente adulto portatore di trapianto di rene.

 

La terapia Immunosoppressiva

Il principale fattore oncogeno nel paziente portatore di trapianto è rappresentato dall’immunosoppressione [18], intesa come intensità, durata e carico cumulativo [19, 21, 44].

Questa aumenta il rischio tumorale riducendo la sorveglianza immunitaria, compromettendo i meccanismi di difesa contro virus oncogeni e cellule neoplastiche ed anche attraverso vie molecolari specifiche [20, 22-24].

L’importanza del carico totale di immunosoppressione nel rischio oncologico è stata inizialmente evidenziata da dati storici che hanno suggerito come i pazienti sottoposti a trapianto cardiaco mostravano una maggiore incidenza di tumori rispetto ai pazienti sottoposti a trapianto di rene [21, 44]. Studi simili hanno suggerito un rischio maggiore di malignità, in particolare di disturbi linfoproliferativi post-trapianto (PTLD), nei pazienti che hanno ricevuto terapia depletiva linfocitaria [45], ma non è chiaro se il rischio aumenti con l’aumentare delle dosi utilizzate all’induzione [46, 47].

Gli inibitori delle calcineurine, come il tacrolimus e la ciclosporina, sono associati a un aumento del rischio di malignità. Questi farmaci sembrano agire attraverso la produzione aumentata di citochine come il fattore di crescita trasformante (TGF)-beta, il fattore di crescita endoteliale vascolare (VEGF) e IL-6 [20, 22, 23, 48]. Inoltre, questi inibitori riducono la capacità di riparare i danni al DNA indotti dalle radiazioni, evento importante soprattutto nella patogenesi dei tumori della pelle [49]. Alcuni studi evidenziano come dosi di farmaco maggiori siano direttamente correlati ad un maggior rischio di tumore [50, 51].

Gli antimetaboliti come l’azatioprina sono stati implicati nello sviluppo di malignità post-trapianto, in particolare dei tumori della pelle non melanoma [18]. Questo trova le sue motivazioni nella capacità mutagena di questa molecola e soprattutto nella sua capacità di ridurre l’attività di riparazione delle mutazioni del DNA indotte dalle radiazioni contribuendo all’aumento dello sviluppo di instabilità del DNA microsatellite [52, 53]. A differenza dell’azatioprina, gli analoghi del micofenolato (Micofenolato Mofetile, MMF, e Acido Micofenolico, MPA) sembrano associarsi a un rischio di malignità post-trapianto inferiore, con possibili effetti antiproliferativi dovuti all’inibizione dell’enzima inosine monophosphate dehydrogenase [18, 54]. Tuttavia, studi di popolazione suggeriscono che la riduzione del rischio oncologico potrebbe ricondursi almeno in parte alla minor incidenza di rigetto acuto e alla conseguente minore necessità di aumentare le dosi di immunosoppressori [55].

L’utilizzo degli inibitori del mTOR sembra invece ridurre l’incidenza di malignità post-trapianto rispetto ad altri regimi immunosoppressori. Anche se è stato osservato un tasso di mortalità più elevato nei pazienti in trattamento con inibitori di mTOR (prevalentemente per infezioni ed eventi cardiovascolari [56, 57]), il rischio di malignità sembra diminuire con questi farmaci, probabilmente per la loro attività antiproliferativa ed anti-angiogenetica, attività particolarmente evidente contro i tumori cutanei non melanoma [5, 23, 56-65]. In effetti l’everolimus è utilizzato anche per trattare il tumore mammario recettore ormonale-positivo, i tumori neuroendocrini e il carcinoma a cellule renali. Tuttavia, è importante notare che tali farmaci sono associati a un aumento del rischio di rigetto rispetto agli inibitori delle calcineurine [65, 66].

Infine, il belatacept è stato associato a un rischio elevato di disturbi linfoproliferativi post-trapianto, specialmente con coinvolgimento del sistema nervoso centrale. Molti di questi casi si sono verificati in pazienti che erano sieronegativi per il virus di Epstein-Barr, motivo per cui il suo utilizzo in tali individui è sconsigliato [67, 68]. Un piccolo studio monocentrico sembra suggerire una riduzione del rischio oncogeno per quanto riguarda i tumori cutanei [69].

In caso di elevato rischio neoplastico o di effettiva diagnosi oncologica la riduzione della terapia immunodepressiva è quindi una delle prime contromisure che possono essere adottate. La riduzione dei livelli ematici target degli inibitori delle calcineurine, l’eventuale introduzione di un mTOR inibitore, la riduzione o la sospensione dei farmaci antimetaboliti (tra i quali bisognerebbe preferire il micofenolato mofetile o l’Acido micofenolico rispetto alla Azatioprina), la riduzione o la sospensione della terapia corticosteroidea, sono alcune delle contromisure che possono essere adottate. Casi particolarmente gravi potrebbero meritare riduzioni della terapia immunosoppressiva particolarmente aggressive, fino alla completa sospensione. Le principali linee guida internazionali rimangono tuttavia molto vaghe su come modificare la terapia immunodepressiva [34, 70], è ruolo del trapiantologo scegliere lo schema terapeutico ideale per il rischio oncologico del singolo paziente, sia in senso di prevenzione che in corso di terapia oncologica.

 

Inibitori del Checkpoint immunitario nel paziente portatore di trapianto di rene

Gli inibitori dei checkpoint immunitari (ICIs) hanno profondamente rivoluzionato l’approccio alla terapia oncologica, e le indicazioni per il loro utilizzo sono destinate ad estendersi ulteriormente [71]. Tuttavia, rimane ancora poco chiara la sicurezza e l’efficacia di questi farmaci nei pazienti sottoposti a trapianto di organo solido.

Il meccanismo d’azione di questi anticorpi monoclonali prevede infatti una stimolazione dell’attività immunitaria cellulo-mediata, al fine di eliminare le cellule neoplastiche. L’utilizzo di inibitori dei checkpoint immunitari nei pazienti con tumori avanzati che hanno ricevuto un trapianto potrebbe portare a miglioramenti nei risultati terapeutici, ma questo è evidentemente correlato ad un elevato rischio di rigetto [72-74].

Per i pazienti che hanno necessitato di terapie immunosoppressive, alcuni studi suggeriscono che l’efficacia degli inibitori dei checkpoint immunitari (ICI) non risulti eccessivamente influenzata [74-77]. Tuttavia, altri lavori indicano che l’uso precoce di corticosteroidi o l’adozione di terapie immunosoppressive insieme ai corticosteroidi siano associati ad esiti di sopravvivenza più sfavorevoli [78, 79]. Inoltre, nel valutare la possibilità di un nuovo trattamento con immunoterapia per pazienti che abbiano sperimentato eventi avversi immunomediati (irAE), l’uso simultaneo di terapie immunosoppressive è collegato a una ridotta efficacia dell’ICI. Per questo è comune pratica quella di ridurre o sospendere totalmente la terapia immunodepressiva in corso di terapia con questi farmaci, conferendo quindi un netto incremento del rischio di rigetto dell’allotrapianto.

Risultano in corso al momento attuale diversi trial clinici indirizzati proprio a chiarire la sicurezza e l’efficacia di questi farmaci nei pazienti portatori di trapianto di organo solido, alcuni dei quali mirano a valutarne gli outcome in seguito al mantenimento della terapia ID invariata (ACTRN12617000741381, NCT03816332, NCT04339062, NCT03966209, NCT04721132).

 

Conclusione

Non è un compito semplice quello di trovare il giusto equilibrio tra grado efficace di immunosoppressione e basso rischio oncologico. Questa è una sfida quotidiana per il nefrologo trapiantologo, che spesso deve adottare delle scelte terapeutiche di grande peso clinico in assenza di chiare indicazioni da parte delle linee guida. Sono quindi indispensabili ulteriori studi specificatamente rivolti alla popolazione trapiantata, che permettano una migliore comprensione del problema.

 

Bibliografia

  1. Riella LV. Understanding the causes of mortality post-transplantation – there is more than meets the eye. J Bras Nefrol. 2018 Apr-Jun;40(2):102-104. https://doi.org/10.1590/2175-8239-jbn-2018-0002-0003.
  2. Ying T, Shi B, Kelly PJ, et al. Death after Kidney Transplantation: An Analysis by Era and Time Post-Transplant. J Am Soc Nephrol. 2020 Dec;31(12):2887-2899. https://doi.org/10.1681/ASN.2020050566.
  3. Krynitz B, Edgren G, Lindelöf B, et al. Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008–a Swedish population-based study. Int J Cancer. 2013 Mar 15;132(6):1429-38. https://doi.org/10.1002/ijc.27765.
  4. Kasiske BL, Snyder JJ, Gilbertson DT, et al. Cancer after kidney transplantation in the United States. Am J Transplant. 2004 Jun;4(6):905-13. https://doi.org/10.1111/j.1600-6143.2004.00450.x.
  5. Piselli P, Serraino D, Segoloni GP, et al. Immunosuppression and Cancer Study Group. Risk of de novo cancers after transplantation: results from a cohort of 7217 kidney transplant recipients, Italy 1997-2009. Eur J Cancer. 2013 Jan;49(2):336-44. https://doi.org/10.1016/j.ejca.2012.09.013.
  6. Piselli P, Serraino D, Cimaglia C, et al. Italian Transplant and Cancer Cohort Study. Variation in Post-Transplant Cancer Incidence among Italian Kidney Transplant Recipients over a 25-Year Period. Cancers (Basel). 2023 Feb 20;15(4):1347. https://doi.org/10.3390/cancers15041347.
  7. Engels EA, Pfeiffer RM, Fraumeni JF Jr, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 2011 Nov 2;306(17):1891-901. https://doi.org/10.1001/jama.2011.1592.
  8. Asch WS, Bia MJ. Oncologic issues and kidney transplantation: a review of frequency, mortality, and screening. Adv Chronic Kidney Dis. 2014 Jan;21(1):106-13. https://doi.org/10.1053/j.ackd.2013.07.003.
  9. Dahle DO, Skauby M, Langberg CW, et al. Renal Cell Carcinoma and Kidney Transplantation: A Narrative Review. Transplantation. 2022 Jan 1;106(1):e52-e63. https://doi.org/10.1097/TP.0000000000003762.
  10. Au EH, Chapman JR, Craig JC, et al. Overall and Site-Specific Cancer Mortality in Patients on Dialysis and after Kidney Transplant. J Am Soc Nephrol. 2019 Mar;30(3):471-480. https://doi.org/10.1681/ASN.2018090906
  11. Acuna SA, Fernandes KA, Daly C, et al. Cancer Mortality Among Recipients of Solid-Organ Transplantation in Ontario, Canada. JAMA Oncol. 2016 Apr;2(4):463-9. https://doi.org/10.1001/jamaoncol.2015.5137.
  12. Webster AC, Craig JC, Simpson JM, et al. Identifying high risk groups and quantifying absolute risk of cancer after kidney transplantation: a cohort study of 15,183 recipients. Am J Transplant. 2007 Sep;7(9):2140-51. https://doi.org/10.1111/j.1600-6143.2007.01908.x.
  13. Kliem V, Thon W, Krautzig S, et al. High mortality from urothelial carcinoma despite regular tumor screening in patients with analgesic nephropathy after renal transplantation. Transpl Int. 1996;9(3):231-5. https://doi.org/10.1007/BF00335391.
  14. Kanaan N, Hassoun Z, Raggi C, et al. Long-term Outcome of Kidney Recipients Transplanted for Aristolochic Acid Nephropathy. Transplantation. 2016 Feb;100(2):416-21. https://doi.org/10.1097/TP.0000000000000941.
  15. Dantal J, Hourmant M, Cantarovich D, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet. 1998 Feb 28;351(9103):623-8. https://doi.org/10.1016/S0140-6736(97)08496-1.
  16. Lim WH, Chapman JR, Wong G. Peak panel reactive antibody, cancer, graft, and patient outcomes in kidney transplant recipients. Transplantation. 2015 May;99(5):1043-50. https://doi.org/10.1097/TP.0000000000000469.
  17. Hussain SK, Makgoeng SB, Everly MJ, et al. HLA and Risk of Diffuse Large B cell Lymphoma After Solid Organ Transplantation. Transplantation. 2016 Nov;100(11):2453-2460. https://doi.org/10.1097/TP.0000000000001025.
  18. Buell JF, Gross TG, Woodle ES. Malignancy after transplantation. Transplantation. 2005 Oct 15;80(2 Suppl):S254-64. https://doi.org/10.1097/01.tp.0000186382.81130.ba.
  19. Caforio AL, Fortina AB, Piaserico S, et al. Skin cancer in heart transplant recipients: risk factor analysis and relevance of immunosuppressive therapy. Circulation. 2000 Nov 7;102(19 Suppl 3):III222-7. https://doi.org/10.1161/01.cir.102.suppl_3.iii-222.
  20. Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature. 1999 Feb 11;397(6719):530-4. https://doi.org/10.1038/17401.
  21. Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet. 1993 Dec 18-25;342(8886-8887):1514-6. https://doi.org/10.1016/s0140-6736(05)80084-4.
  22. Shihab FS, Bennett WM, Isaac J, et al. Nitric oxide modulates vascular endothelial growth factor and receptors in chronic cyclosporine nephrotoxicity. Kidney Int. 2003 Feb;63(2):522-33. https://doi.org/10.1046/j.1523-1755.2003.00757.x.
  23. Guba M, Graeb C, Jauch KW, et al. Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation. Transplantation. 2004 Jun 27;77(12):1777-82. https://doi.org/10.1097/01.tp.0000120181.89206.54.
  24. Imao T, Ichimaru N, Takahara S, et al. Risk factors for malignancy in Japanese renal transplant recipients. Cancer. 2007 May 15;109(10):2109-15. https://doi.org/10.1002/cncr.22636.
  25. Myron Kauffman H, McBride MA, et al. Transplant tumor registry: donor related malignancies. Transplantation. 2002 Aug 15;74(3):358-62. https://doi.org/10.1097/00007890-200208150-00011.
  26. Desai R, Collett D, Watson CJ, et al. Cancer transmission from organ donors-unavoidable but low risk. Transplantation. 2012 Dec 27;94(12):1200-7. https://doi.org/10.1097/TP.0b013e318272df41.
  27. Xiao D, Craig JC, Chapman JR, et al. Donor cancer transmission in kidney transplantation: a systematic review. Am J Transplant. 2013 Oct;13(10):2645-52. https://doi.org/10.1111/ajt.12430.
  28. Chadban SJ, Ahn C, Axelrod DA, et al. KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation. Transplantation. 2020 Apr;104(4S1 Suppl 1):S11-S103. HTTPS://DOI.ORG/10.1097/tp.0000000000003136.
  29. Wong G, Staplin N, Emberson J, et al. Chronic kidney disease and the risk of cancer: an individual patient data meta-analysis of 32,057 participants from six prospective studies. BMC Cancer. 2016 Jul 16;16:488. https://doi.org/10.1186/s12885-016-2532-6.
  30. Shebl FM, Warren JL, Eggers PW, et al. Cancer risk among elderly persons with end-stage renal disease: a population-based case-control study. BMC Nephrol. 2012 Jul 26;13:65. https://doi.org/10.1186/1471-2369-13-65.
  31. Vajdic CM, McDonald SP, McCredie MR, et al. Cancer incidence before and after kidney transplantation. JAMA. 2006 Dec 20;296(23):2823-31. https://doi.org/10.1001/jama.296.23.2823.
  32. Inamoto H, Ozaki R, Matsuzaki T, et al. Incidence and mortality patterns of malignancy and factors affecting the risk of malignancy in dialysis patients. Nephron. 1991;59(4):611-7. https://doi.org/10.1159/000186652.
  33. Al-Adra DP, Hammel L, Roberts J, et al. Pretransplant solid organ malignancy and organ transplant candidacy: A consensus expert opinion statement. Am J Transplant. 2021 Feb;21(2):460-474. https://doi.org/10.1111/ajt.16318.
  34. Kasiske BL, Zeier MG, Chapman JR, et al; Kidney Disease: Improving Global Outcomes. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int. 2010 Feb;77(4):299-311. https://doi.org/10.1038/ki.2009.377.
  35. Kasiske BL, Vazquez MA, Harmon WE, et al. Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation. J Am Soc Nephrol. 2000 Oct;11 Suppl 15:S1-86.
  36. Ulrich C, Kanitakis J, Stockfleth E, et al. Skin cancer in organ transplant recipients–where do we stand today? Am J Transplant. 2008 Nov;8(11):2192-8. https://doi.org/10.1111/j.1600-6143.2008.02386.x.
  37. Park CK, Fung K, Austin PC, et al. Incidence and Risk Factors of Keratinocyte Carcinoma After First Solid Organ Transplant in Ontario, Canada. JAMA Dermatol. 2019 Sep 1;155(9):1041-1048. https://doi.org/10.1001/jamadermatol.2019.0692.
  38. Iannacone MR, Sinnya S, Pandeya N, et al; STAR Study. Prevalence of Skin Cancer and Related Skin Tumors in High-Risk Kidney and Liver Transplant Recipients in Queensland, Australia. J Invest Dermatol. 2016 Jul;136(7):1382-1386. https://doi.org/10.1016/j.jid.2016.02.804.
  39. Garrett GL, Blanc PD, Boscardin J, et al. Incidence of and Risk Factors for Skin Cancer in Organ Transplant Recipients in the United States. JAMA Dermatol. 2017 Mar 1;153(3):296-303. https://doi.org/10.1001/jamadermatol.2016.4920. Erratum in: JAMA Dermatol. 2017 Mar 1;153(3):357.
  40. Mittal A, Colegio OR. Skin Cancers in Organ Transplant Recipients. Am J Transplant. 2017 Oct;17(10):2509-2530. https://doi.org/10.1111/ajt.14382. Epub 2017 Sep 14.
  41. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003 Apr 24;348(17):1681-91. https://doi.org/10.1056/NEJMra022137.
  42. Greenberg JN, Zwald FO. Management of Skin Cancer in Solid-organ Transplant Recipients: A Multidisciplinary Approach. Dermatol Clin. 2011 Apr;29(2):231-41, ix. https://doi.org/10.1016/j.det.2011.02.004.
  43. Wong G, Chapman JR, Craig JC. Cancer screening in renal transplant recipients: what is the evidence? Clin J Am Soc Nephrol. 2008 Mar;3 Suppl 2(Suppl 2):S87-S100. https://doi.org/10.2215/CJN.03320807.
  44. Mihalov ML, Gattuso P, Abraham K, et al. Incidence of post-transplant malignancy among 674 solid-organ-transplant recipients at a single center. Clin Transplant. 1996 Jun;10(3):248-55.
  45. Cherikh WS, Kauffman HM, McBride MA, et al. Association of the type of induction immunosuppression with posttransplant lymphoproliferative disorder, graft survival, and patient survival after primary kidney transplantation. Transplantation. 2003 Nov 15;76(9):1289-93. https://doi.org/10.1097/01.TP.0000100826.58738.2B.
  46. Bustami RT, Ojo AO, Wolfe RA, et al. Immunosuppression and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant. 2004 Jan;4(1):87-93. https://doi.org/10.1046/j.1600-6135.2003.00274.x.
  47. Marks WH, Ilsley JN, Dharnidharka VR. Post-transplantation lymphoproliferative disorder in kidney and heart transplant recipients receiving thymoglobulin: a systematic review. Transplant Proc. 2011 Jun;43(5):1395-404. https://doi.org/10.1016/j.transproceed.2011.03.036.
  48. Maluccio M, Sharma V, Lagman M, et al. Tacrolimus enhances transforming growth factor-beta1 expression and promotes tumor progression. Transplantation. 2003 Aug 15;76(3):597-602. https://doi.org/10.1097/01.TP.0000081399.75231.3B.
  49. Herman M, Weinstein T, Korzets A, et al. Effect of cyclosporin A on DNA repair and cancer incidence in kidney transplant recipients. J Lab Clin Med. 2001 Jan;137(1):14-20. https://doi.org/10.1067/mlc.2001.111469.
  50. Dantal J, Hourmant M, Cantarovich D, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet. 1998 Feb 28;351(9103):623-8. https://doi.org/10.1016/S0140-6736(97)08496-1.
  51. Dharnidharka VR, Ho PL, Stablein DM, et al. Mycophenolate, tacrolimus and post-transplant lymphoproliferative disorder: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant. 2002 Oct;6(5):396-9. https://doi.org/10.1034/j.1399-3046.2002.00021.x.
  52. Swann PF, Waters TR, Moulton DC, et al. Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science. 1996 Aug 23;273(5278):1109-11. https://doi.org/10.1126/science.273.5278.1109.
  53. Offman J, Opelz G, Doehler B, et al. Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation. Blood. 2004 Aug 1;104(3):822-8. https://doi.org/10.1182/blood-2003-11-3938.
  54. O’Neill JO, Edwards LB, Taylor DO. Mycophenolate mofetil and risk of developing malignancy after orthotopic heart transplantation: analysis of the transplant registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006 Oct;25(10):1186-91. https://doi.org/10.1016/j.healun.2006.06.010.
  55. Robson R, Cecka JM, Opelz G, et al. Prospective registry-based observational cohort study of the long-term risk of malignancies in renal transplant patients treated with mycophenolate mofetil. Am J Transplant. 2005 Dec;5(12):2954-60. https://doi.org/10.1111/j.1600-6143.2005.01125.x.
  56. Dantal J, Morelon E, Rostaing L, et al; TUMORAPA Study Group. Sirolimus for Secondary Prevention of Skin Cancer in Kidney Transplant Recipients: 5-Year Results. J Clin Oncol. 2018 Sep 1;36(25):2612-2620. https://doi.org/10.1200/JCO.2017.76.6691.
  57. Knoll GA, Kokolo MB, Mallick R, et al. Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ. 2014 Nov 24;349:g6679. https://doi.org/10.1136/bmj.g6679.
  58. Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002 Feb;8(2):128-35. https://doi.org/10.1038/nm0202-128.
  59. Huber S, Bruns CJ, Schmid G, et al. Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis. Kidney Int. 2007 Apr;71(8):771-7. https://doi.org/10.1038/sj.ki.5002112.
  60. Campistol JM, Eris J, Oberbauer R, et al. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol. 2006 Feb;17(2):581-9. https://doi.org/10.1681/ASN.2005090993.
  61. Campistol JM, Gutierrez-Dalmau A, Torregrosa JV. Conversion to sirolimus: a successful treatment for posttransplantation Kaposi’s sarcoma. Transplantation. 2004 Mar 15;77(5):760-2. https://doi.org/10.1097/01.tp.0000115344.18025.0b.
  62. Kahan BD, Yakupoglu YK, Schoenberg L, et al. Low incidence of malignancy among sirolimus/cyclosporine-treated renal transplant recipients. Transplantation. 2005 Sep 27;80(6):749-58. https://doi.org/10.1097/01.tp.0000173770.42403.f7.
  63. Yanik EL, Siddiqui K, Engels EA. Sirolimus effects on cancer incidence after kidney transplantation: a meta-analysis. Cancer Med. 2015 Sep;4(9):1448-59. https://doi.org/10.1002/cam4.487.
  64. Yanik EL, Gustafson SK, Kasiske BL, et al. Sirolimus use and cancer incidence among US kidney transplant recipients. Am J Transplant. 2015 Jan;15(1):129-36. https://doi.org/10.1111/ajt.12969.
  65. Lim WH, Eris J, Kanellis J, et al. A systematic review of conversion from calcineurin inhibitor to mammalian target of rapamycin inhibitors for maintenance immunosuppression in kidney transplant recipients. Am J Transplant. 2014 Sep;14(9):2106-19. https://doi.org/10.1111/ajt.12795.
  66. Lim LM, Kung LF, Kuo MC, Huang AM, Kuo HT. Timing of mTORI usage and outcomes in kidney transplant recipients. Int J Med Sci. 2021 Jan 9;18(5):1179-1184. https://doi.org/10.7150/ijms.53655.
  67. Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010 Mar;10(3):535-46. https://doi.org/10.1111/j.1600-6143.2009.03005.x.
  68. Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and Long-Term Outcomes in Kidney Transplantation. N Engl J Med. 2016 Jan 28;374(4):333-43. https://doi.org/10.1056/NEJMoa1506027. Erratum in: N Engl J Med. 2016 Feb 18;374(7):698.
  69. Wang M, Mittal A, Colegio OR. Belatacept reduces skin cancer risk in kidney transplant recipients. J Am Acad Dermatol. 2020 Apr;82(4):996-998. https://doi.org/10.1016/j.jaad.2019.09.070.
  70. Bia M, Adey DB, Bloom RD, et al. KDOQI US commentary on the 2009 KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Kidney Dis. 2010 Aug;56(2):189-218. https://doi.org/10.1053/j.ajkd.2010.04.010.
  71. Bagchi S, Yuan R, Engleman EG. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annu Rev Pathol. 2021 Jan 24;16:223-249. https://doi.org/10.1146/annurev-pathol-042020-042741.
  72. Cui X, Yan C, Xu Y, et al. Allograft rejection following immune checkpoint inhibitors in solid organ transplant recipients: A safety analysis from a literature review and a pharmacovigilance system. Cancer Med. 2023 Mar;12(5):5181-5194. https://doi.org/10.1002/cam4.5394.
  73. Manohar S, Thongprayoon C, Cheungpasitporn W, et al. Systematic Review of the Safety of Immune Checkpoint Inhibitors Among Kidney Transplant Patients. Kidney Int Rep. 2019 Dec 7;5(2):149-158. https://doi.org/10.1016/j.ekir.2019.11.015.
  74. Rünger A, Schadendorf D, Hauschild A, et al. Immune checkpoint blockade for organ-transplant recipients with cancer: A review. Eur J Cancer. 2022 Nov;175:326-335. https://doi.org/10.1016/j.ejca.2022.08.010.
  75. Horvat TZ, Adel NG, Dang TO, et al. Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015 Oct 1;33(28):3193-8. https://doi.org/10.1200/JCO.2015.60.8448.
  76. Murakami N, Mulvaney P, Danesh M, et al; Immune Checkpoint Inhibitors in Solid Organ Transplant Consortium. A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant. Kidney Int. 2021 Jul;100(1):196-205. https://doi.org/10.1016/j.kint.2020.12.015.
  77. Carroll RP, Boyer M, Gebski V, et al. Immune checkpoint inhibitors in kidney transplant recipients: a multicentre, single-arm, phase 1 study. Lancet Oncol. 2022 Aug;23(8):1078-1086. https://doi.org/10.1016/S1470-2045(22)00368-0.
  78. Bai X, Hu J, Betof Warner A, et al. Early Use of High-Dose Glucocorticoid for the Management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti-PD-1 Monotherapy. Clin Cancer Res. 2021 Nov 1;27(21):5993-6000. https://doi.org/10.1158/1078-0432.CCR-21-1283.
  79. van Not OJ, Verheijden RJ, van den Eertwegh AJM, et al. Association of Immune-Related Adverse Event Management With Survival in Patients With Advanced Melanoma. JAMA Oncol. 2022 Dec 1;8(12):1794-1801. https://doi.org/10.1001/jamaoncol.2022.5041.

Immunosuppressive therapy reduction and early post-infection graft function in kidney transplant recipients with COVID-19

Posted on Scarica PDF

Gaetano Alfano

Gaetano Alfano1,2*, Francesca Damiano1*, Francesco Fontana1, Camilla Ferri3, Andrea Melluso3, Martina Montani3, Niccolò Morisi3, Lorenzo Tei3, Jessica Plessi3, Silvia Giovanella2,3, Giulia Ligabue3, Giacomo Mori2, Giovanni Guaraldi4, Riccardo Magistroni1,3, Gianni Cappelli1,3, Gabriele Donati1,3

1 Nephrology, Dialysis and Transplant Unit, University Hospital of Modena, Modena, Italy
2 Clinical and Experimental Medicine Ph.D. Program, University of Modena and Reggio Emilia, via del Pozzo 71, 41124 Modena, Italy
3 Surgical, Medical and Dental Department of Morphological Sciences, Section of Nephrology, University of Modena and Reggio Emilia, via del Pozzo 71, 41124 Modena, Italy
4 Clinic of Infectious Diseases, University Hospital of Modena, Modena, Italy
* both authors contributed equally as first author

Corresponding author:
Gaetano Alfano, MD
Surgical, Medical and Dental Department of Morphological Sciences, Section of Nephrology, University Hospital of Modena and Reggio Emilia, via del Pozzo, 71
41124 - Modena (Italy)
E-mail: gaetano.alfano@unimore.it
ORCID: 0000-0003-0591-8622

 

Abstract

Background: Kidney transplant (KT) recipients with COVID-19 are at high risk of poor outcomes due to the high burden of comorbidities and immunosuppression. The effects of immunosuppressive therapy (IST) reduction are unclear in patients with COVID-19.
Methods: A retrospective study on 45 KT recipients followed at the University Hospital of Modena (Italy) who tested positive for COVID-19 by RT-PCR analysis.
Results: The median age was 56.1 years (interquartile range,[IQR] 47.3-61.1), with a predominance of males (64.4%). Kidney transplantation vintage was 10.1 (2.7-16) years, and 55.6 % of patients were on triple IST before COVID-19. Early immunosuppression minimization occurred in 27 (60%) patients (reduced-dose IST group) and included antimetabolite (88.8%) and calcineurin inhibitor withdrawal (22.2%). After SARS-CoV-2 infection, 88.9% of patients became symptomatic and 42.2% required hospitalization. One patient experienced irreversible graft failure. There were no differences in serum creatinine level and proteinuria in non-hospitalized patients before and post-COVID-19, whereas hospitalized patients experienced better kidney function after hospital discharge (P=0.019). Overall mortality was 17.8%. without differences between full- and reduced-dose IST. Risk factors for death were age (odds ratio [OR]: 1.19; 95%CI: 1.01-1.39), and duration of kidney transplant (OR: 1.17; 95%CI: 1.01-1.35). One KT recipient developed IgA glomerulonephritis and two ones experienced symptomatic COVID-19 after primary infection and SARS-CoV-2 mRNA vaccine, respectively.
Conclusions: Despite the reduction of immunosuppression, COVID-19 affected the survival of KT recipients. Age of patients and time elapsed from kidney transplantation were independent predictors of death . Early kidney function was favorable in most survivors after COVID-19.

Keywords: COVID-19, kidney transplant, immunosuppressive therapy, graft function, proteinuria, mortality, transplant, SARS-COV-2, reinfection

Introduction

Since SARS CoV-2 infection was first identified in December 2019, the pandemic spread quickly around the world, with a disruptive impact on social and economic life. This virus yielded several new challenges to our healthcare systems that had to cope with an increased rate of morbidity and mortality among the most vulnerable populations [1]. Kidney transplant (KT) recipients are a subset of the population at high risk of severe COVID-19 due to the high burden of comorbidities and the cumulative side effects of immunosuppressive therapy (IST) [2]. Data collected so far show that transplant recipients are extremely susceptible to the SARS-CoV-2 infection, much more than the general population [3, 4]. The causes are multiple, but principally revolve around the use of long-term IST.

Despite the great emphasis on early IST reduction to face the potentially lethal consequences of COVID-19, no confirming data supports its beneficial effect in terms of survival or clinical manifestations. Additional uncertainty arises from the recent literature reporting that a tempered immune response is thought to prevent COVID‐19–induced systemic inflammatory syndrome. To date, data regarding early graft outcomes after COVID-19 are scarce [5]. It is worth noting that graft survival may be threatened by non-reversible episodes of kidney injury [6, 7]. Lastly, a concerning issue may be the hyporesponsiveness to anti-SARS-CoV-2 vaccination [8, 9]. Numerous studies have confirmed that KT recipients have a blunted immune response to mRNA vaccines [10]. Only 48% of patients were able to develop a protective serologic response to SARS-CoV-2 [11]. Caillard et al [12] reported that about one-third of kidney transplant patients had severe manifestations, including a fatal outcome, despite COVID-19 vaccination. This group of patients is therefore expected to remain vulnerable to the severe complications of COVID-19 until new strategies will be implemented to reduce the susceptibility of these subjects.

Considering all the uncertainties in the management of KT recipients and the high risk of severe COVID-19 manifestations within this cohort of patients, we report our experience in managing KT recipients with COVID-19. In particular, we focus on the impact of early IST reduction, and early graft function after the resolution of the infection.

 

Material and methods

Kidney transplant outpatient clinic

This kidney transplant outpatient clinic follows more than 500 KT recipients, including combined liver and pancreas-kidney transplantation. Outpatient service was delivered by a senior nephrologist with experience in kidney transplantation, one fellow and three nurses. A 24-h, 7/7 days per week service was available for KT recipients in case of kidney-related pathologic processes (anuria, fluid overload) or infections. This service was also offered to the subjects transplanted in our Center but living far away from it.

During COVID-19 all the patients were instructed to call the clinic in case of COVID-19 symptoms. Despite the reduction of non-essential healthcare services, our outpatient clinic continued to deliver care to KT recipients, adopting all the containment measures (triage at entry, masking, social distancing and hands hygiene) to prevent COVID-19 diffusion. A telephonic triage was performed for all patients before reaching the hospital to intercept paucisymptomatic patients.

Patients with symptoms were invited to perform nasal swabs using RT-PCR and were visited in a dedicated room to assess vital parameters and clinical conditions. According to the severity of the symptoms, patients were sent home or to the emergency room. To reduce the workload of the emergency room, patients were managed as outpatients unless they developed severe symptoms that required hospital admission. The monitoring of noncritical patients was mostly performed via phone calls and emails.

According to our internal protocol and taking into account the opinions of European experts [13, 14], immunosuppression was modulated as follow:

  • for asymptomatic or mild COVID-19 patients (i.e., mild upper respiratory and/or gastrointestinal symptoms, temperature <38°C without dyspnea) in triple therapy (calcineurin-inhibitors [CNI] + mycophenolate acid [MPA]/azathioprine [AZA] + steroids), MPA or AZA was withdrawn, and a dual therapy (CNI + steroid) was continued. If the patients were on dual therapy (CNI + mammalian target of rapamycin inhibitor [mTOR-i] or CNI + MPA), MPA/mTOR was withdrawn and replaced with a low dose of steroids (i.e., methylprednisolone 4 or 8 mg once-daily).
  • for moderate (signs and symptoms of lower respiratory disease or saturation of oxygen [SpO2] ≥94% on room air at sea level) and severe COVID-19 (SpO2 <94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen [PaO2/FiO2] <300 mm Hg, respiratory frequency >30 breaths per minute, or lung infiltrates >50%) all immunosuppressors, but steroids, were stopped. The prescription of anti-inflammatory and immunomodulant steroid therapy for symptomatic COVID-19 patients (dexamethasone at a dose of 6 mg once daily for up to 10 days) was not part of the anti-rejection therapy and was administered by COVID-19 experts.

COVID-19 population

The study population was comprised of kidney transplant recipients with COVID-19 with a complete follow-up, including death or discharge from hospital.

We retrospectively reviewed the electronic charts of all KT recipients with COVID-19 from March 7, 2020, to June 25, 2021. During this period we performed 144 nasopharyngeal swabs. The diagnosis of COVID-19 was performed through reverse transcriptase-polymerase chain reaction (RT-PCR) assay on a nasopharyngeal swab. We excluded patients aged <18 years. Kidney function was estimated by glomerular fraction rate (eGFR) using the CKD-EPI equation. Occasionally, some data were missing for patients admitted to a hospital located far from our Center.

This study has been authorized by the local Ethical Committee of Emilia Romagna (n. 839/2020). The study protocol complies with the guidelines for human studies and includes evidence that the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.

Statistical analysis

Baseline characteristics were described using median (interquartile range [IQR]) or frequencies, as appropriate. The chi-square or Fisher’s test, and student’s t-test were used to compare categorical and continuous variables between groups, respectively. Univariate and multivariate logistic regressions were performed to test the association between mortality and baseline patient characteristics. Variables that were significant on univariate analysis (P=<0.05) were entered into the multivariate model to identify independent predictors. Results were expressed as odds ratios (OR) and 95% confidence intervals (CI). Univariate and multivariate logistic regression analysis determined risk factors for death. A P value of <0.05 was considered statistically significant. All statistical analyses were performed using SPSS® statistical software.

 

Results

Characteristics of COVID-19 population

From the beginning of the COVID-19 pandemic in Italy, 45 KT recipients followed in our center contracted COVID-19. The demographic and clinical characteristics of these patients are detailed in Table I. This group of patients included two (4.4%) combined liver-kidney and one (2.2%) heart-kidney transplant recipient. Seven (15.5%) patients were hospitalized in another structure because they lived far from our Center.

Variable All patients
(n.=45)		 Reduced-dose IST
(n.=27)		 Full-dose IST
(n.=18)		 p-value
Age, year 56.1 (47.3-61.1) 55.9 (47.6-61.2) 56.1 (44.4-62) 0.85
Range 19.2-83.5 19.2-79.8 28.1-83.5
Males, n. (%) 29 (64.4) 18 (66.7) 110 (61.1) 0.75
Race/ethnicity 0.61
White, n. (%) 41 (91.1) 26 (92.6) 16 (88.9
Black, n. (%) 4 (8.9) 2 (7.4) 2 (11.1)
Transplant vintage, year 10.1 (2.7-16.01) 7.8 (2.4-15.2) 11.1 (4.7-21.1) 0.29
sCr pre-COVID-19, mg/dl 1.45 (1.18-1.84) 1.44 (1.18-1.81) 1.28 (1.14-1.82) 0.68
eGFR pre-COVID-19, ml/min 48.4 (36-64) 47.7 (35-64) 49.5 (38.6-67.9) 0.83
24-h proteinuria, mg/dl 87.4 (0.52-188.5) 72 (0.25-183) 145.5 (6.2-205) 0.69
Immunosuppressive therapy, n. (%)
CNI 39 (86.7) 24 (88.9) 15 (83.3) 0.67
mTOR-i 8 (17.8) 4 (14.8) 4 (22.2) 0.69
MPA 31 (68.9) 24 (88.9) 7 (38.9) 0.01
Steroid 36 (80) 23 (85.2) 13 (72.2) 0.44
IS regimen 0.001
Triple therapy 25 (55.6) 21 (77) 4 (22.2)
Double therapy 19 (42.2) 6 (22.2) 13 (72.2)
Monotherapy 1 (2.2) 0 (0) 1 (5.6)
Reduction IS therapy, n. (%) 27 (60) 27 (100) 0 (0) N/A
MPA withdrawal 24 (53.3) 24 (88.9) 0 (0) N/A
CNI or mTOR-i withdrawal 6 (13.3) 6 (22.2) 0 (0) N/A
Increase steroid 9 (5,4) 8 (29.6) 1 (5.6) 0.064
Comorbidities, n. (%)
HIV, HCV or HBV 6 (13.3) 3 (11.1) 3 (16.7) 0.65
Diabetes 5 (11.1) 4 (14.8) 1 (5.6) 0.63
Neoplasia 10 (22.2) 7 (25.9) 3 (16.7) 0.71
Graft rejection 4 (8.9) 1 (3.7) 3 (16.7) 0.13
CVD 12 (26.7) 7 (25.9) 4 (22.2) 77
Autoimmune disease 4 (8.9) 1 (3.7) 3 (16.7) 0.13
Previous severe infection 13 (28.9) 8 (29.6) 5 (27.7) 1
Symptomatic COVID-19, n. (%) 40 (88.9) 27 (100) 13 (72.2) 0.45
Hospitalization, n. (%) 19 (42.2) 14 (51.9) 5 (27.8) 0.13
Graft failure, n. (%) 1 (2.2) 1 (3.7) 0 (0) 1
ICU admission, n. (%) 9 (20) 4 (14.8) 5 (27.8) 0.28
Mortality, n (%) 8 (17.8) 4 (14.8) 4 (22.2) 0.69
Post-COVID-19 follow-up, day 70.5 (51-109) 76  (50.5-116.5) 69 (66-76) 0.57
Notes: eGFR denotes estimated glomerular filtration rate; CNI, calcineurin inhibitor; CVD, cardiovascular disease; HCV, hepatitis C; HBV, hepatitis B; IST, immunosuppressive therapy; MPA, mycophenolate acid; mTOR-I, mammalian target of rapamycin inhibitor; sCr, serum creatinine.
Table I:Demographics and clinical characteristics of KT recipients

The age of patients ranged from 19.2 to 83.5 years and the median was 56.1 (IQR, 47.3-61.1) years. COVID-19 was more prevalent in males than in females (64.4% vs 35.6%) and occurred after a median of 10.1 (2.7-16.01) years from transplantation.

Before the COVID-19 infection, serum creatine (sCr) was 1.45 (IQR 1.1-1.8) mg/dl corresponding to a median eGFR of 48.4 (IQR 36-64) ml/min. At the time of the COVID-19 diagnosis, more than half of the patients were in triple standard IST. Forty patients (88.9%) developed symptoms of COVID-19 and 19 of them (42.2%) required hospitalization. One patient returned to dialysis following acute kidney injury. Overall, nine patients (20%) were admitted to ICU for severe manifestations of COVID-91 and eight (17.8%) died.

Reduced- vs full-dose IST group

The entire population was subdivided into two groups: reduced-dose (n.=27; 60%) and full-dose IST (n.=18; 40%). There were no significative statistical differences in terms of demographic and clinical characteristics between the two groups. Statistical analysis detected significant differences in the prescription of IST. Patients who underwent reduction of immunosuppression (reduced-dose IST) were treated with a higher dose of IST before COVID-19; indeed, the rate of prescribed triple-drug IST was higher in this group than in full-dose IST patients (77% vs. 22.2%; P=<0.001).

In the reduced-dose IST group, MPA (88.8%) and CNI or mTOR-i (22.2%) were the most frequent discontinued agents. Conversely, the dose of steroids was increased in a third of patients and, in all of them, the administration of steroids changed from alternate days (methylprednisolone 2/0 or 4/0) to a daily regimen.

Hospitalization, ICU admission and death rate in patients who underwent IST reduction were 51.8%, 14.8% and 14.8%, respectively. However, despite IST reduction, hospitalization (P=0.13), ICU admission (P=0.28) and death (P=0.69) rates were not different from those of the full-dose IST group.

Outcomes of KT recipients with COVID-19

Univariate and multivariate logistic regression was performed to detect predictors of mortality (Table II). Multivariate analysis found that age (OR=1.19 [95%CI 1.01-1.39]; P=0.034) and years spent on immunosuppressive therapy (OR=1.17 [95%CI 1.01-1.35]; P=0.040) were associated with mortality in this group of patients.

Univariate Multivariate
Variable OR CI (95%) p-value OR CI (95%) p-value
Sex
Male 4.40 0.78 24.81 0.09  
Age (1-yr increase) 1.11 1.02 1.22 0.016 1.19 1.01 1.39 0.034
KT vintage (1-yr increase) 1.10 1.00 1.21 0.053 1.17 1.01 1.35 0.040
Steroid-based IST 1.93 0.21 18.08 0.56
Reduction IST 1.33 0.26 6.869 0.74
Increase of steroid 0.52 0.06 4.85 0.56
Triple IST 0.51 0.10 2.620 0.42
Double IST 1.96 0.38 10.026 0.42
GFR 0.99 0.95 1.026 0.57
GFR< 45ml/min 1.47 0.32 6.80 0.62
GFR 45-59 ml/min 0.68 0.15 3.16 0.62
sCr 1,33 0,26 6.87 0.73
Graft rejection 1.52 0.14 16.91 0.73
Autoimmune disease 0.00 0.00 0.99
HIV/HCV/HBV 2.58 0.38 17.43 0.33
Previous sever infection 0,73 0.13 4.19 0.72
Diabetes 1.11 0.11 11.49 0.93
Neoplasm 1.12 0.19 6.70 0.89
Cardiovascular disease 1.73 0.34 8.76 0.50
Notes: eGFR denotes estimated glomerular filtration rate; HCV, hepatitis C; HBV, hepatitis B; IST, immunosuppressive therapy; MPA, mycophenolate acid; mTOR-I, mammalian target of rapamycin inhibitor; sCr, serum creatinine.
Table II: Univariate and multivariate predictors of mortality through logistic regression analysis

Among the survivors (82.2%), one patient with a CKD stage 4 (GFR=20 ml/min) before SARS-CoV-2 infection developed irreversible graft failure requiring HD. One patient (2.7%) manifested de-novo proteinuria (4100 mg/die) after the resolution of COVID-19 and graft biopsy revealed IgA glomerulonephritis (the lack of data on the cause of CKD did not allow us to classify these histological findings as either de-novo or recurrent IgA glomerulonephritis). Lastly, one patient experienced symptomatic COVID-19 reinfection after the primary infection and another one following the SARS-CoV-2 mRNA vaccine. Early post-COVID-19 follow-up of 25 out of the 37 survivors showed that pre- and post-COVID variations of sCr, eGFR and 24-hour proteinuria were not statistically significant in outpatients after the resolution of COVID-19. A significantly lower sCr level (P=0.019) and eGFR (P=0.028) were measured after hospital discharge in hospitalized patients. No differences were noted in the level of daily proteinuria (Table III). The early follow-up of KT recipients after COVID-19 resolution did not show any new episodes of graft rejection.

Non-hospitalized patients Hospitalized patients
Pre-COVID-19 Post-COVID-19 p-value Pre-COVID-19 Post-COVID-19 p-value
sCr, mg/dl 1.31 (1.2-1.76) 1.33 (1.08- 1.7) 0.85 1.49 (1.1-1.8) 1.21 (0.9-2.1) 0.019
eGFR, ml/min 48.8 (40.5-62.1) 56.7 (41.5-67) 0.25 46.7 (36-64) 56.7 (41.5-67) 0.028
24-h proteinuria, mg/die 102 (6.2-205) 89.4 (37.2-246.4) 0.08 13(2.5-183) 44.7 (10.8-1141) 0.29
Notes: eGFR, estimated glomerular filtration rate; sCr, serum creatinine.
Table III: Early graft function post-COVID-19 in hospitalized and non-hospitalized KT recipients

 

Discussion

Numerous reports have alerted the scientific community regarding the unfavorable outcome of COVID-19 in patients with a reduced immune response [1, 15]. The results of this study confirmed that COVID-19 poses KT recipients at high risk of severe consequences.

In our cohort of KT recipients, COVID-19 carried with it a higher rate of symptoms, hospitalization and mortality compared to the general population [16, 17]. We found that in this cohort (45 KT recipients with COVID-19, median age 56.1), 40% of patients developed severe symptoms requiring hospitalization. Overall mortality was 17.8%, higher than the mortality reported in the general population, which ranges between 0.1-19.2% around the world and accounts for about 2.02% globally [18].

In an attempt to reconstitute the immune system against SAR-CoV-2 infection, we minimized the burden of IST in these patients. All KT recipients who communicated their COVID-19 positivity to our center, were advised to discontinue the antimetabolite agents (i.e., MFA or AZA) (88.9%) and CNI or m-TOR-i (22.2%). In the hospitalized patients, IST was further reduced or suspended, according to the clinical conditions of the patient. Nevertheless, hospitalization and death rates in the reduced-dose IST group were not dissimilar from the full-dose IST group.

At first glance, these results show that the reduction of immunosuppression did not confer any advantage in terms of patient survival. However, some considerations should be considered before drawing firm conclusions. Most patients who underwent IST reduction carried a significantly higher burden of IST compared to KT recipients whose therapy was left unmodified. The higher prevalence of triple-drug immunosuppressive regimen in patients who underwent IST minimization (77% vs. 22.2%; P=<0.001) has probably increased the vulnerability to COVID-19. Conversely, patients with a full-dose IST spent more time (11.2 vs 7.8 years) on kidney transplantation compared to the reduced-dose IST group. Lastly, we believe that the slight increase of steroid therapy (from alternate days to a daily administration) in the reduced-dose IST group (P=0.064) was too small to mitigate the inflammatory response driven by COVID-19.

Although the reduction of IST did not lead to a favorable outcome, it is worth mentioning that the overall mortality in our cohort was tendentially lower than that reported in other studies, where this approached up to 32.5% [19–26]. Our results are in line with the population-based data on 1013 KT recipients affected by COVID-19 collected by the French and Spanish national registries, which reported a 28-day mortality of 20% [27]. In Italy, Bossini et al. [24] reported a higher overall mortality rate (28%) during the first wave of COVID-19 in the city of Brescia. Similarly to our therapeutic strategy, they discontinued immunosuppression in all hospitalized patients and introduced or increased the dose of steroids. The causes underlying these different mortality rates are unknown. The different timing of enrollment made the two cohorts not perfectly comparable. All patients in the Brescia cohort were enrolled during the first wave of COVID-19 in Europe, in an overwhelmed and unprepared hospital setting, within a timespan characterized by a high rate of experimental regimens and relative side effects [28, 29]. Lastly, a lower median age (56.1 vs. 60 years) in our cohort of patients probably contributed to the better prognosis.

Multivariate analysis showed that the predictors of death were age and time elapsed on IST, in line with previous studies. Age is widely associated with COVID-19 severity and death in KT recipients [30, 31] as well as in the general population [32]. The Centers for Disease Control (CDC) claims that 8 out 10 COVID-19 deaths in the U.S. occurred in adults over 65 and that the risk of hospitalization and death increases enormously with age [33].

The effect of immunosuppression is still controversial in KT recipients [34]. Immunosuppression is known to dysregulate innate and adaptive immunity, exposing the patients to severe infections. On the other hand, severe COVID-19 infection has been associated with a dysregulated inflammatory response (IL-6, IL-1, and chemokines) leading to ARDS and sepsis. The new insights support a promising role of immunosuppressants (i.e., tocilizumab, steroid) in tempering the immune response of patients with severe manifestations of COVID-19 [35].

Lastly, we report a short-term good graft function in patients who survived COVID-19. These data indicate a stable early graft function (sCr and 24-hour proteinuria) in outpatients who were not hospitalized. Conversely, hospitalized KT recipients had a statistically significant improvement in renal function. As stated also by Dacina et al. [5], we speculate that lower sCr after SARS-CoV-2 is due to the minimization or withdrawn of CNI, a ‘drug holiday’ apparently without dire consequences in terms of graft rejection.

Finally, the limitations of the study should be enumerated. It is a retrospective study, with a small sample size and a short follow-up after COVID-19. The small number of patients and the short observation period may have reduced the probability to observe an underlying difference between these two groups. Long-term follow-up is required to verify if the early improvement of kidney function after COVID-19 is maintained in the survivors. Furthermore, we cannot exclude that, in some cases, the reduction of IST occurred with a short delay after the diagnosis of COVID-19; however, all patients with symptoms underwent nasopharyngeal swabs as fast as possible in an ambulatory setting.

 

Conclusion

In our cohort of patients, the reduction of immunosuppression did not decrease the risk of severe COVID-19 or death. COVID-19 was associated with hospitalization (42%), graft failure (2.2%), IgA glomerulonephritis (2.2%) and death (17.8%). Age and time elapsed from kidney transplantation were independent predictors of death in our patients. Short-term follow-up after COVID-19 showed an excellent graft function in most survivors. Primary infection or vaccination did not exclude the risk of SARS-CoV-2 infection in KT recipients.

 

Authorship credit

Conception: Gaetano Alfano and Francesca Damiano

Collection of data: Camilla Ferri, Francesco Giaroni, Andrea Melluso, Martina Montani, Niccolò Morisi, Lorenzo Tei, Jessica Plessi

Analysis and interpretation of data: Gaetano Alfano, Francesco Giaroni, Francesca Damiano

Drafting the article: Gaetano Alfano, Francesco Fontana, Silvia Giovanella, Giulia Ligabue, Giacomo Mori

Intellectual Contribution: Francesco Fontana Gianni Cappelli, Giovanni Guaraldi

Revising the article: Gianni Cappelli, Giovanni Guaraldi

Approval of the version to be published: all authors

 

Acknowledgments

Special thanks are due to Marco Ballestri, Elisabetta Ascione, Roberto Pulizzi and Francesca Facchini, skilled and experienced nephrologists involved in the “Kidney Transplant Program”, and to Laura Bonaretti and all nurses of the “Kidney Transplantation Outpatient Clinic” at the University Hospital of Modena for their precious support in managing KT recipients.

 

Bibliography

  1. Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020; 584:430-436. https://doi.org/10.1038/s41586-020-2521-4
  2. Khairallah P, Aggarwal N, Awan AA, et al. The impact of COVID-19 on kidney transplantation and the kidney transplant recipient – One year into the pandemic. Transpl Int Off J Eur Soc Organ Transplant 2021; 34:612–621. https://doi.org/10.1111/tri.13840
  3. Caillard S, Chavarot N, Francois H, et al. Is COVID-19 infection more severe in kidney transplant recipients? Am J Transplant 2021; 21:1295-1303. https://doi.org/10.1111/ajt.16424
  4. Fisher AM, Schlauch D, Mulloy M, et al. Outcomes of COVID-19 in hospitalized solid organ transplant recipients compared to a matched cohort of non-transplant patients at a national healthcare system in the United States. Clin Transplant 2021; 35. https://doi.org/10.1111/ctr.14216
  5. Elec AD, Oltean M, Goldis P, et al. COVID-19 after kidney transplantation: Early outcomes and renal function following antiviral treatment. Int J Infect Dis 2021; 104:426-432. https://doi.org/10.1016/j.ijid.2021.01.023
  6. Bajpai D, Deb S, Bose S, et al. Recovery of kidney function after AKI due to COVID-19 in kidney transplant recipients. Transpl Int Off J Eur Soc Organ Transplant 2021. https://doi.org/10.1111/tri.13886
  7. Alfano G, Giovanella S, Fontana F, et al. AKI in hospitalized patients with COVID-19: a single-center experience. G Ital Nefrol 2021; 38(5): 38-05-2021-02. https://giornaleitalianodinefrologia.it/2021/10/38-05-2021-02/
  8. Benotmane I, Gautier-Vargas G, Cognard N, et al. Weak anti–SARS-CoV-2 antibody response after the first injection of an mRNA COVID-19 vaccine in kidney transplant recipients. Kidney Int 2021; 99:1487-1489. https://doi.org/10.1016/j.kint.2021.03.014
  9. Alfano G, Fontana F, Mori G, et al. Seroconversion after COVID-19 vaccine in a dialysis patient on immunosuppressants. Clin Kidney J 2021. https://doi.org/10.1093/ckj/sfab065
  10. Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients. JAMA 2021; 325:2204. https://doi.org/10.1001/jama.2021.7489
  11. Benotmane I, Gautier-Vargas G, Cognard N, et al. Low immunization rates among kidney transplant recipients who received 2 doses of the mRNA-1273 SARS-CoV-2 vaccine. Kidney Int 2021; 99:1498-1500. https://doi.org/10.1016/j.kint.2021.04.005
  12. Caillard S, Chavarot N, Bertrand D, et al. Occurrence of severe COVID-19 in vaccinated transplant patients. Kidney Int 2021. https://doi.org/10.1016/j.kint.2021.05.011
  13. Tsalouchos A, Salvadori M. La pandemia del nuovo coronavirus 2019 ed il trapianto renale. G Clin Nefrol E Dialisi 2020; 32:60-63. https://doi.org/10.33393/gcnd.2020.2133
  14. Maggiore U, Abramowicz D, Crespo M, et al. How should I manage immunosuppression in a kidney transplant patient with COVID-19? An ERA-EDTA DESCARTES expert opinion. Nephrol Dial Transplant 2020; 35:899-904. https://doi.org/10.1093/ndt/gfaa130
  15. Myint PK, Carter B, Barlow-Pay F, et al. Routine use of immunosuppressants is associated with mortality in hospitalised patients with COVID-19. Ther Adv Drug Saf 2021; 12:2042098620985690. https://doi.org/10.1177/2042098620985690
  16. Cascella M, Rajnik M, Aleem A, et al. Features, Evaluation, and Treatment of Coronavirus (COVID-19). In: StatPearls. StatPearls Publishing, Treasure Island (FL): 2021.
  17. Mappe Coronavirus. https://mappe.protezionecivile.gov.it/it/mappe-emergenze/mappe-coronavirus (accessed 5 Jun 2021).
  18. COVID-19 Map. In: Johns Hopkins Coronavirus Resour. Cent. https://coronavirus.jhu.edu/map.html (accessed 1 Nov 2021).
  19. Pérez-Sáez MJ, Blasco M, Redondo-Pachón D, et al. Use of tocilizumab in kidney transplant recipients with COVID-19. Am J Transplant 2020; 20(11):3182-3190. https://doi.org/10.1111/ajt.16192
  20. Aziz H, Lashkari N, Yoon YC, et al. Effects of Coronavirus Disease 2019 on Solid Organ Transplantation. Transplant Proc 2020; 52:2642-2653. https://doi.org/10.1016/j.transproceed.2020.09.006
  21. Coll E, Fernández-Ruiz M, Sánchez-Álvarez JE, et al. COVID-19 in transplant recipients: The Spanish experience. Am J Transplant 2021; 21:1825-1837. https://doi.org/10.1111/ajt.16369
  22. Akalin E, Azzi Y, Bartash R, et al. Covid-19 and Kidney Transplantation. N Engl J Med 2020. https://doi.org/10.1056/NEJMc2011117
  23. Fernández-Ruiz M, Andrés A, Loinaz C, et al. COVID-19 in solid organ transplant recipients: A single-center case series from Spain. Am J Transplant 2020; 20:1849-1858. https://doi.org/10.1111/ajt.15929
  24. Bossini N, Alberici F, Delbarba E, et al. Kidney transplant patients with SARS‐CoV‐2 infection: the brescia renal COVID task force experience. Am J Transplant 2020. https://doi.org/10.1111/ajt.16176
  25. Cravedi P, Mothi SS, Azzi Y, et al. COVID-19 and kidney transplantation: Results from the TANGO International Transplant Consortium. Am J Transplant 2020; 20:3140-3148. https://doi.org/10.1111/ajt.16185
  26. Nair V, Jandovitz N, Hirsch JS, et al. COVID‐19 in kidney transplant recipients. Am J Transplant 2020. https://doi.org/10.1111/ajt.15967
  27. Jager KJ, Kramer A, Chesnaye NC, et al. Results from the ERA-EDTA Registry indicate a high mortality due to COVID-19 in dialysis patients and kidney transplant recipients across Europe. Kidney Int 2020; 98:1540-1548. https://doi.org/10.1016/j.kint.2020.09.006
  28. Gérard A, Romani S, Fresse A, et al. “Off-label” use of hydroxychloroquine, azithromycin, lopinavir-ritonavir and chloroquine in COVID-19: A survey of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers. Therapies 2020; 75:371-379. https://doi.org/10.1016/j.therap.2020.05.002
  29. Izcovich A, Siemieniuk RA, Bartoszko JJ, et al. Adverse effects of remdesivir, hydroxychloroquine, and lopinavir/ritonavir when used for COVID-19: systematic review and meta-analysis of randomized trials. Infectious Diseases (except HIV/AIDS) 2020. https://doi.org/10.1101/2020.11.16.20232876
  30. Coll E, Fernández-Ruiz M, Sánchez-Álvarez JE, et al. COVID-19 in transplant recipients: The Spanish experience. Am J Transplant 2021; 21:1825-1837. https://doi.org/10.1111/ajt.16369
  31. Oto OA, Ozturk S, Turgutalp K, et al. Predicting the outcome of COVID-19 infection in kidney transplant recipients. BMC Nephrol 2021; 22:100. https://doi.org/10.1186/s12882-021-02299-w
  32. Levin AT, Hanage WP, Owusu-Boaitey N, et al. Assessing the age specificity of infection fatality rates for COVID-19: systematic review, meta-analysis, and public policy implications. Eur J Epidemiol 2020; 35:1123-1138. https://doi.org/10.1007/s10654-020-00698-1
  33. Centers for Disease Control and Prevention. COVID-19 and Your Health. 2020. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/older-adults.html (accessed 27 May 2021).
  34. Chavarot N, Gueguen J, Bonnet G, et al. COVID‐19 severity in kidney transplant recipients is similar to nontransplant patients with similar comorbidities. Am J Transplant 2021; 21:1285-1294. https://doi.org/10.1111/ajt.16416
  35. Pérez-Sáez MJ, Blasco M, Redondo-Pachón D, et al. Use of tocilizumab in kidney transplant recipients with COVID-19. Am J Transplant 2020; 20:3182-3190. https://doi.org/10.1111/ajt.16192

Immunosuppression in kidney transplantation: a way between efficacy and toxicity

Posted on Scarica PDF

Giacomo Colussi

Costanza Casati, Alberto Menegotto, Maria Luisa Querques, Federica Ravera, Giacomo Colussi

S.C. Nefrologia, ASST-Grande Ospedale Metropolitano Niguarda, Milano

Corrispondenza:
Giacomo Colussi
S.C. Nefrologia, ASST Niguarda,
Piazza Ospedale Maggiore, 3
20162 Milano
Tel 02-6444 2521
Fax 02-6444 2909
e-mail: giacomo.colussi@ospedale niguarda.it

 

Abstract

Renal transplantation is the best treatment for patients with end-stage renal disease.

Over the last decades, the introduction of new immunosuppressive agents resulted into the reduction of the incidence of acute rejection and early graft loss. Despite this progress, there has been little improvement in the average life of the transplant.

The main reasons of late failure are patient’s death due to several complications (e.g. cancer, infectious or metabolic), and progressive deterioration of renal function caused by immunological and non-immunological factors.

The immunosuppressive therapy can be distinguished into two components: the induction therapy and the maintenance therapy. The former has the aim to implement intense and immediate immunosuppression. This therapy is mostly useful in transplant with high immunological risk, although it is correlated with an increased risk of cytopenias and viral infections.

The latter offers the rationale to prevent organ rejection and minimize drug toxicity. This is generally constituted by the association of two or three drugs with different mechanism of action.

The most common application of this scheme includes a calcineurin inhibitor in combination with an antimetabolite and a minimum dose of steroids.

Immunosuppressive therapy is also associated to an increased risk of infections and cancer development. For instance, each class of drugs is related to a different profile of toxicity.

The choice of treatment protocol should take into account the clinical characteristics of the donor and recipient. Furthermore, this treatment may change anytime when clinical conditions result into complications.

Key words: immunosuppressive protocols, immunosuppressive therapy, induction therapy, renal transplantation

Sorry, this entry is only available in Italian.

Introduzione

Il trapianto renale è la terapia che garantisce la maggior aspettativa di vita e la migliore qualità tra le terapie proponibili ai pazienti affetti da IRC terminale, con costi complessivamente ridotti rispetto alla dialisi [1–2–3–4].

Nelle ultime due decadi, grazie alla progressiva conoscenza dei meccanismi alla base della risposta immune all’innesto nell’organismo di cellule e tessuti eterologhi (attivazione e proliferazione dei linfociti T e B, citochine e chemochine di segnale, attivazione del complemento), sono entrati nella pratica clinica agenti immunosoppressori in grado di bloccare a vari livelli la cascata della risposta immune e di ridurre più efficacemente l’incidenza di rigetto acuto e di perdita precoce del graft.

Nonostante la riduzione del tasso dei rigetti acuti e di fallimento precoce, vi sono stati solo limitati progressi nell’allungamento della vita media del trapianto. Le principali cause di fallimento tardivo sono la morte del paziente con rene funzionante per complicanze infettive, tumorali o metaboliche, eventi cardiovascolari ed il progressivo deterioramento della funzione renale causato sia da fattori immunologici (rigetto cellulare tardivo, rigetto anticorpo-mediato, recidiva di nefropatia autoimmune) che da fattori non immunologici (nefrotossicità da CNI o altri farmaci, diabete, ipertensione arteriosa, invecchiamento dell’organo).
 

La visualizzazione dell’intero documento è riservata a Soci attivi, devi essere registrato e aver eseguito la Login con utente e password.