title: Saquinavir in steroid-dependent and -resistant nephrotic syndrome: a pilot study.
abstract: BACKGROUND
  Some difficult cases of idiopathic nephrotic syndrome (NS) have been treated with a HIV protease inhibitor provided with proteasome-inhibiting activity. The objective of this study was to limit nuclear factor κB (NF-κB) activation which is up-regulated in these patients, aiming at decreasing proteinuria and prednisone need.
  
  
  METHODS
  Ten cases with long-lasting (up to 15 years) history of NS with steroid dependence (six cases, of which three with secondary steroid resistance) or resistance to steroids (four cases) unsuccessfully treated with multiple immunosuppressive drugs, accepted a treatment with the protease inhibitor saquinavir. p50/p65 NF-κB nuclear localization and immunoproteasome/proteasome messenger RNA (mRNA) were monitored in peripheral blood mononuclear cells (PBMCs). The effects of saquinavir on NF-κB nuclear localization in cultured PBMCs and in immortalized human podocytes were assessed.
  
  
  RESULTS
  After a median follow-up of 14.7 months (6-68.7), 1/4 primary steroid-resistant NS (SRNS) and 5/6 steroid-dependent NS or secondary SRNS became infrequent (5) or frequent (1) relapsers, with 63% prednisone reduction (from 25.3 to 8.4 mg/kg/month, P = 0.015). Saquinavir was effective in association with low doses of calcineurin inhibitors (cyclosporine 2 mg/kg/day or tacrolimus 0.01-0.06 mg/kg/day). No side effects were observed apart from transitory mild diarrhoea. In PBMCs, NF-κB was down-regulated, while MECL-1 immunoproteasome/beta2 proteasome mRNA ratio was reversed to normal values. In culture, saquinavir blunted NF-κB activation in human podocytes and in PBMCs.
  
  
  CONCLUSIONS
  In this pilot study, a HIV antiprotease drug reduced proteinuria and had a steroid-sparing effect in some multidrug-resistant/-dependent NS. This observation warrants further investigation.
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, Regina Margherita University Hospital, Turin, Italy. rosanna.coppo@unito.it
authors.forename: Rosanna
authors.initials: R
authors.lastname: Coppo
authors.forename: Roberta
authors.initials: R
authors.lastname: Camilla
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Porcellini
authors.forename: Licia
authors.initials: L
authors.lastname: Peruzzi
authors.forename: Bruno
authors.initials: B
authors.lastname: Gianoglio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Amore
authors.forename: Valentina
authors.initials: V
authors.lastname: Daprà
authors.forename: Elisa
authors.initials: E
authors.lastname: Loiacono
authors.forename: Valentina
authors.initials: V
authors.lastname: Fonsato
authors.forename: Antonio
authors.initials: A
authors.lastname: Dal Canton
authors.forename: Ciro
authors.initials: C
authors.lastname: Esposito
authors.forename: Pasquale
authors.initials: P
authors.lastname: Esposito
authors.forename: Pier Angelo
authors.initials: PA
authors.lastname: Tovo
mesh_terms: D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D002648:Child; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009404:Nephrotic Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010865:Pilot Projects; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D011241:Prednisone / Q000627:therapeutic use*; D011507:Proteinuria / Q000517:prevention & control; D019258:Saquinavir / Q000494:pharmacology / Q000627:therapeutic use*; D013256:Steroids / Q000627:therapeutic use*; D016896:Treatment Outcome; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D017320:HIV Protease Inhibitors; D016328:NF-kappa B; D013256:Steroids; D019258:Saquinavir; D011241:Prednisone