ESPERIENZA DI RICERCA NELLE PATOLOGIE RARE NEFROLOGICHE Prof. Maurizio Salvadori Direttore S.O.D. Nefrologia dei Trapianti e Dialisi AOU Careggi Firenze

Patologie rare di interesse nefrologico Malattie cistiche renali: - ARPKD - Nefronoftisi - Rene a spugna midollare Tubulopatie Cistite interstiziale  Fibrosi retroperitoneale Amiloidosi Malattia di Anderson Fabry Sindrome di Alport Sclerosi Tuberosa Microangiopatia trombotica: -Sindrome emolitico-uremica -Porpora trombotica trombocitopenica Vasculiti paucimmuni: -Sindrome di Goodpasture -Granulomatosi di Wegener -Poliartrite microscopica Malattie del metabolismo degli aminoacidi: -Cistinuria Crioglobulinemia Porpora anafilattoide Malattia di Von Hippel Lindau

Malattie rare ancora non riconosciute Malattia membrane sottili Glomerulopatia immunotattoide Glomerulopatia fibrillare Glomerulonefrite membrano-proliferativa

Criticità Definizione non sempre univoca Scarso interesse scientifico Scarso interesse “industriale” Scarsa collaborazione dei clinici alla segnalazione ed alla “conoscenza” Inadeguatezza delle risorse da destinare alla ricerca ed alla assistenza

Farmaci orfani Farmaco non diffuso dall'industria farmaceutica per ragioni economiche ma che risponde a un bisogno di salute pubblica

Interesse industriale Terapie ad altissimo costo Per tutta la vita Agalsidase α Agalsidase β

Farmaci derivati da altre patologie Off label Rituximab Crioglobulinemia Vasculiti Anticorpi monoclonali Eculizimab Microangiopatia trombotica Inibitori del Proteosoma Bortezomib Amiloidosi ARPKD ? Sirolimus Inibitori mTOR Sclerosi tuberosa Everolimus

FUTURO Nuove conoscenze sulle malattie rare Nuovi e vecchi farmaci Ricerca ed applicazione

SCLEROSI TUBEROSA EVEROLIMUS AMILOIDOSI BORTEZOMIB ESPERIENZA TERAPEUTICHE INNOVATIVE S.O.D NEFROLOGIA DEI TRAPIANTI E DIALISI AOU CAREGGI FIRENZE CRIOGLOBULINEMIA MISTA ESSENZIALE TIPO II E III HCV CORRELATA RITUXIMAB INTERFERON RITUXIMAB MMF VASCULITI SCLEROSI TUBEROSA EVEROLIMUS AMILOIDOSI BORTEZOMIB

KIDNEY IN TUBEROUS SCLEROSIS COMPLEX

Renal involvement Angiomyolipomas Polycystic kidney disease Oncocitoma Carcinomas

Angiomyolipomas Different cell components can vary lesion to lesion One cell type can be dominant Epithelioid cells can exhibit: Mitotic activity Nuclear atypia Variable size Variable forms Often contain patches of smooth-muscle cells with nuclear atypia and mitotic figures Typically do not behave in a malignat fashion Very rarely can infiltrate the surrounding tissue Can be identified in liver, ovary, fallopian tube, spermatic cord, palate and colon Prevalence varies with age First detected during childhood and continues into adulthood. Commonly bilateral 85% revealed angiomyolipomas 1 80% of children developed renal lesions by age 10.5 years 2 75 % angiomyolipomas 17% renal cysts Increased in size and/or number in about 60% No gender predominance Often express receptors for estrogen and progesterone 1 Rakowski SK et al 2006. Kidney Int 70:1777-1782 2 Ewait DH et al 1998. J Urol 160:141-145

Angiomyolipomas Morbidities Acutely retroperitoneal hemorrhage Life-threatening Sudden and painful The risk is 25-50% Correlated with: Tumor size (> 3 cm) Micro or macroaneurysms size (>5 mm) Nephrectomy in unnecessary (risk of ESRD) Embolization is the preferred therapy Aggressive phenotype Rarely can recur after resection Metastasize Even be fatal Size greater than 8 cm More than 1 mitotic figure 50 high-power fields Evidence of necrosis Chronic kidney disease and ESRD Due to infiltration and coalescence Important to preserve renal function if at all possible Surgical approach is dangerous

Regulation of cell growth and proliferation by TSC Siroky BJ et al. (2009) Renal involvement in tuberous sclerosis complex and von Hippel–Lindau disease: shared disease mechanisms? Nat Clin Pract Nephrol doi:10.1038/ncpneph1032

BASALE 12 mesi

AMILOIDOSI