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Silvestre, Cristina (2016) Meccanismi di immunosorveglianza nella carcinogensei dei reni affetti da end-stage renal disease. [Tesi di dottorato]

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Abstract (inglese)

Background- Chronic kidney disease (CKD) and replacement therapies (dialysis or transplantation) increase the risk of native kidneys cancer. Acquired multicystic kidney disease in dialysis patients and immunosuppressive therapy in transplant recipients might be relevant factors for the development of renal cancer.
International guidelines do not clearly recommend specific screening protocols for these categories of patients, although the early diagnosis could lead to an excellent prognosis.
Objectives- To retrospectively analyze the cases of renal neoplasms of the native kidneys in chronic renal failure patients and renal transplant recipients that underwent nephrectomy at the Kidney and Pancreas Transplant Center at Hospital-University of Padua.
The histological type of the tumor, grading, stage at diagnosis and prognosis of these patients were evaluated and compared with the data reported in the literature in uremic patients and in the general population.
In the prospective phase of the study: the histopathological analysis and the flow cytometry of the kidneys have been addressed to study the expression of costimulatory molecules at the level of renal epithelial cells, to determine their function as non-professional APC (Antigen Presenting Cell). The activation status of intraepitelial lymphocyte population have been evaluated.
Methods- From April 2007 to June 2013, 18 patients with chronic kidney disease (CKD) and/or kidney transplant recipients underwent nephrectomy because of renal tumor at the Kidney and Pancreas Transplant Center at Hospital-University of Padua. Were analyzed: the cause of the CKD, the type of replacement therapy, the timing of kidney transplantation, immunosuppressive therapy, the histological type of the tumor, the Fuhrman grade, and patient outcomes.
Thereafter, between December 2014 and December 2015, 16 patients (5F/11M). were enrolled in the study. Indications for nephrectomy were: polycystic disease (APKD) 13 patients, suspected malignancy of the native kidney 3 patients, 1 patient underwent trasnsplantectomy of his kidney, performed for the detection of an aneurysm of the renal artery. Histological examination showed: neoplasms 2 cell carcinomas (Furhman Furhman 4 and 2 respectively), 1 papillary carcinoma
Results- The average age of the patients at the time of nephrectomy was 53.4 ± 11.2 years. Six patients were receiving dialysis (hemodialysis in 2 and 4 on peritoneal dialysis), while 12 patients had a kidney transplant and 1 had previously pancreas and kidney transplantation. One patient developed 2 bilateral metacronous neoplasia and 1 benign tumor. Histological examination showed 17 cases of malignancy (9 clear cell carcinomas and 8 papillary carcinomas) and 3 benign tumors (2 papillary adenoma and a renal oncocytoma). The stage at diagnosis was: in 16 cases T1, and in 1 case T2. All patients underwent nephrectomy: 12 laparoscopically, 5 with laparotomy and 2 by lombotomic approach. All patients were asymptomatic at diagnosis, which took place during ultrasound performed for other reasons and subsequently confirmed at the CT-scan with contrast and / or MRI. After a mean follow-up of 22 ± 20 months, two patients died of causes unrelated to renal cancer and there were no local or distant recurrence of the tumor, in the absence of adjuvant treatment.
The flow cytometry seems to show a greater expression of CD80, HLAABCm, HLAABCr; HLADRm and HLADRr; where HLAABCm and HLADRm represent the average intensity of fluorescence per cell, while HLAABCr and HLADRr represent the percentage of cells that exceed the gate and are therefore classified as positive. The expression of MCHC seems to increase in transplant recipient than in non-transplant patients; probably because immunosuppressive therapy, preventing rejection, leads an inhibition of T cell.
Conclusions- The diagnosis of kidney cancer which is carried out within the program of follow-up in kidney transplant patients and screening in uremic patients allows to detect cancer in its early stages, improving outcomes and reducing the need for adjuvant therapy.
The expression of costimulatory molecule CD80 in patients with renal carcinoma might suggest an activation of immunosurveillance in the carcinogenesis of the kidney. Further studies are needed to clarify the role of immunosuppressive therapy in the immunosurveillance.




Abstract (italiano)

Introduzione- L’insufficienza renale cronica (IRC) e specialmente la terapia sostitutiva (dialisi e trapianto), aumentano il rischio di riscontrare tumori dei reni nativi. I fattori che possono essere implicati sono la malattia renale multicistica acquisita nei dializzati e la terapia immunosoppressiva nei pazienti trapiantati.
Nelle linee guida internazionali mancano tuttavia delle chiare indicazioni sulla tipologia di screening a cui sottoporre questi pazienti , benché in caso di diagnosi precoce la prognosi di queste neoplasie possa risultare ottima.
Scopo dello studio- nella fase retrospettiva dello studio è stata analizzata la casistica di neoplasie renali dei reni nativi in pazienti affetti da insufficienza renale cronica e in pazienti trapiantati di rene e sottoposti a nefrectomia presso l’U.O.C. Trapianti di Rene e Pancreas dell’Azienda Ospedale-Università di Padova.
L’istotipo del tumore, il grading, lo stadio alla diagnosi e la prognosi di questa tipologia di pazienti sono stati valutati e confrontati con i dati riportati in letteratura relativi a pazienti uremici e nella popolazione generale.
Nella fase prospettica: l'analisi istopatologica e citofluorimetrica dei reni sono state indirizzate allo studio dell'espressione delle molecole di costimolazione a livello delle cellule epiteliali renali, per determinare la loro funzione di antigen presenting cell non professionali. Sono state inoltre analizzate le sottopopolazioni linfocitarie T residenti ed il loro stato di attivazione.
Materiali e metodi: Da Aprile 2007 a Giugno 2013, 18 pazienti affetti da IRC e/o trapiantati di rene sono stati sottoposti a nefrectomia per riscontro di neoplasia renale presso la U.O.C. Trapianti Rene e Pancreas dell’Azienda Ospedale- Università di Padova. Sono stati analizzati: la causa dell’IRC, il tipo di terapia sostitutiva, il timing del trapianto di rene, la terapia immunosoppressiva, l’istotipo della neoplasia, il grado Fuhrman, e l’outcome dei pazienti.
Successivamente tra dicembre 2014 e dicembre 2015, sono stati arruolati nello studio 16 pazienti (5F/11M). Le indicazioni all’intervento di nefrectomia sono state malattia policistica dell’adulto (APKD) 13 pazienti, sospetta neoplasia del rene nativo 3 pazienti, 1 paziente è stata sottoposta ed espianto di autotrapianto di rene, effettuato per il riscontro di un’aneurisma dell’arteria renale primitiva. Sono state riscontrate le seguenti neoplasie renali 2 carcinomi a cellule chiare (Furhman 4 e Furhman 2 rispettivamente), 1 carcinoma papillare.
Risultati- L’età media dei pazienti al momento della nefrectomia era 53.4±11.2 anni. Sei pazienti erano in trattamento dialitico (2 in emodialisi e 4 in dialisi peritoneale), mentre 11 pazienti erano trapiantati di rene e 1 era trapiantato di pancreas e rene. Un paziente ha presentato due neoplasie maligne bilaterali metacrone ed un tumore benigno. L’esame istologico ha evidenziato 17 casi di neoplasia maligna (9 carcinomi a cellule chiare e 8 carcinomi papillari) e 3 di tumore benigno (due adenomi papillari e un oncocitoma renale). Lo stadio alla diagnosi era: in 16 casi T1 ed in un caso T2. Tutti i pazienti sono stati sottoposti a nefrectomia: 12 per via laparoscopica, 5 per via laparotomica e 2 per via lombotomica. Tutti i pazienti erano asintomatici alla diagnosi, che è avvenuta in corso di ecografia eseguita per altre ragioni e successivamente confermata all’esame TAC con mezzo di contrasto e/o RM. Dopo un follow-up medio di 22±20 mesi, due pazienti sono deceduti per cause non collegate alla neoplasia renale e non si sono verificate recidive locali o a distanza della neoplasia, in assenza di trattamento adiuvante.
L’analisi puramente descrittiva della citofluorimetria sembra evidenziare una maggiore espressione di CD80, HLAABCm, HLAABCr; HLADRm e HLADRr; dove HLAABCm e HLADRm rappresentano l'intensità media della fluorescenza per cellula, mentre HLAABCr e HLADRr rappresentano la percentuale di cellule che superano il gate e sono quindi catalogate come positive. L’espressione di MCHC aumenta nei pazienti trapiantati rispetto ai non trapiantati in quanto il rene trapiantato sta esprimendo antigeni in modo non tollerigeno in quanto organo non self, la terapia immunosoppressiva determina un’inibizione del linfociti T a valle del CD80, impedendo il rigetto.
Conclusioni- La diagnosi delle neoplasie renali che viene effettuata nell’ambito di programma di follow-up nel paziente trapiantato di rene e di screening nel paziente uremico consente di individuare neoplasie in stadio precoce, migliorandone l’outcome e riducendo la necessità di terapie adiuvanti.
Sembra esserci un’attivazione nel processo di immunosorveglianza suggerito dall’ elevata espressione della molecola di costimolazione CD80 nei pazienti affetti da neoplasie renali.
Rimane da chiarire il ruolo della terapia immunosoppressiva nell’immunosorveglianza.

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Tipo di EPrint:Tesi di dottorato
Relatore:Valente, Marialuisa
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE CARDIOVASCOLARI
Data di deposito della tesi:26 Gennaio 2016
Anno di Pubblicazione:2016
Parole chiave (italiano / inglese):Immunosorveglianza, carcinogenesi, neoplasie renali; immunosurveillance, renal carcinoma
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/08 Anatomia patologica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Codice ID:9160
Depositato il:06 Ott 2016 17:22
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