Conversion from calcineurin inhibitors to sirolimus of recipients with chronic kidney graft disease grade iii for a period 2003-2011

• Published in: Vojnosanitetski pregled Vol. 70; no. 9; pp. 848 - 853
• Main Authors: Ignjatovic, Ljiljana, Hrvacevic, Rajko, Jovanovic, Dragan, Kovacevic, Zoran, Vavic, Neven, Rabrenovic, Violeta, Tomic, Aleksandar, Aleksic, Predrag, Draskovic-Pavlovic, Biljana, Dujic, Aleksandar, Karan, Zeljko, Maksic, Djoko
• Format: Journal Article
• Language: English
• Published: Serbia Ministry of Defence of the Republic of Serbia, University of Defence, Belgrade 01.09.2013
• Subjects: Adult; Azathioprine - therapeutic use; Biomarkers - blood; calcineurin; Calcineurin Inhibitors; chronic; Creatinine - blood; Cytomegalovirus Infections - epidemiology; Cytomegalovirus Infections - immunology; disease progression; Female; Follow-Up Studies; Glomerular Filtration Rate - drug effects; Graft Rejection - prevention & control; graft survival; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - therapeutic use; kidney failure; kidney transplantation; Kidney Transplantation - adverse effects; Male; Middle Aged; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - therapeutic use; Proteinuria - immunology; Renal Insufficiency, Chronic - drug therapy; Renal Insufficiency, Chronic - etiology; sirolimus; Sirolimus - administration & dosage; Sirolimus - therapeutic use; Time Factors; Treatment Outcome
• ISSN: 0042-8450; 2406-0720
• DOI: 10.2298/VSP1309848I

Background/Aim. Tremendous breakthrough in solid organ transplantation was made with the introduction of calcineurin inhibitors (CNI). At the same time, they are potentially nephrotoxic drugs with influence on onset and progression of renal graft failure. The aim of this study was to evaluate the outcome of a conversion from CNIbased immunosuppressive protocol to sirolimus (SRL) in recipients with graft in chronic kidney disease (CKD) grade III and proteinuria below 500 mg/day. Methods. In the period 2003-2011 24 patients (6 famale and 18 male), mean age 41 ? 12.2 years, on triple immunosuppressive therapy: steroids, antiproliferative drug [mycophenolate mofetil (MMF) or azathiopirine (AZA)] and CNI were switched from CNI to SRL and followe-up for 76 ? 13 months. Nine patients (the group I) had early postransplant conversion after 4 ? 3 months and 15 patients (the group II) late conversion after 46 ? 29 months. During the regular outpatient controls we followed graft function through the serum creatinine and glomerular filtration rate (GFR), proteinuria, lipidemia and side effects. Results. Thirty days after conversion, in all the patients GFR, proteinuria and lipidemia were insignificantly increased. In the first two post-conversion months all the patients had at least one urinary or respiratory infection, and 10 patients reactivated cytomegalovirus (CMV) infection or disease, and they were successfully treated with standard therapy. After 21 ? 11 months 15 patients from both groups discontinued SRL therapy due to reconversion to CNI (10 patients) and double immunosuppressive therapy (3 patients), return to hemodialysis (1 patient) and death (1 patient). Nine patients were still on SRL therapy. By the end of the follow-up they significantly improved GFR (from 53.2 ? 12.7 to 69 ? 15 mL/min), while the increase in proteinuria (from 265 ? 239 to 530.6 ? 416.7 mg/day) and lipidemia (cholesterol from 4.71 ? 0.98 to 5.61 ? 1.6 mmol/L and triglycerides from 2.04 ? 1.18 to 2.1 ? 0.72 mmol/L) were not significant. They were stable during the whole follow-up period. Ten patients were reconverted from SRL to CNI due to the abrupt increase of proteinuria (from 298 ? 232 to 1639 ? 1641/mg day in 7 patients), rapid growth of multiple ovarian cysts (2 patients) and operative treatment of persisted hematoma (1 patient). Thirty days after reconversion they were stable with an insignificant decrease in GFR (from 56.10 ? 28.09 to 47 ? 21 mL/min) and significantly improved proteinuria (from 1639 ? 1641 to 529 ? 688 mg/day). By the end of the follow-up these patients showed nonsignificant increase in the serum creatinine (from 172 ? 88 to 202 ? 91 mmol/L), decrease in GFR (from 56.10 ? 28.09 to 47 ? 21 mL/day) and increased proteinuria (from 528.9 ? 688 to 850 ? 1083 mg/min). Conclusion. In this small descriptive study, conversion from CNI to SRL was followed by an increased incidence of infections and consecutive 25-50% dose reduction in the second antiproliferative agent (AZA, MMF), with a possible influence on the development of glomerulopathy in some patients, which was the major reason for discontinuation of SRL therapy in the 7 (29%) patients. Nine (37.5%) of the patients experienced the greatest benefit of CIN to SRL conversion without serious post-conversion complications. Uvod/Cilj. Znacajan prodor u transplantaciji solidnih organa postignut je uvodjenjem kalcineurinskih inhibitora (KNI). Istovremeno, njihovi potencijalno nefrotoksicni efekti mogu da doprinesu nastanku i progresiji insuficijencije bubreznog grafta. Cilj ispitivanja bio je da se utvrdi ishod konverzije sa imunosupresivnih protokola baziranih na KNI na sirolimus (SRL) kod primalaca sa trecim stepenom hronicne bubrezne slabosti grafta i proteinurijom manjom od 500 mg/dan. Metode. U periodu od 2003. do 2011. 24 bolesnika (6 zena i 18 muskaraca), prosecne starosti 41 ? 12,2 godine, na trostrukoj imunosupresivnoj terapiji: steroidi, antiproliferativni lek [mekofenolat mofetil (MMF)/ azatioprin (AZA)] i KNI prevedeno je sa KNI na SRL i praceno 76 ? 13 meseci. Devet bolesnika (I grupa) prevedeno je rano, tokom prve postransplantacione godine (4 ? 3 meseca) i 15 kasno, nakon prve godine (46 ? 29 meseci). Tokom redovnih ambulantnih kontrola pratili smo funkciju grafta pracenjem vrednosti serumskog kreatinina, jacine glomerulske filtarcije (JGF), proteinurije i lipidemije. Rezultati. Tridesetog dana nakon konverzije kod svih bolesnika vrednosti JGF, proteinurije i lipidemije bile su neznato povecane. Tokom prva dva meseca svi bolesnici imali su makar jednu urinarnu ili respiratornu infekciju, a kod 10 bolesnika se reaktivirala citomegalovirusna infekcija/bolest, Bolesnici su uspesno izleceni standardnom terapijom. U preriodu od 21 ? 11 meseci kod 15 bolesnika iz obe grupe obustavljena je terapija SRL zbog: rekonverzije na KNI (10 bolesnika) ili dvostruke imunosupresivne terapije (3 bolesnika), vracanja na hemodijalizu (1 bolesnik) i smrti (1 bolesnik). Devet bolesnika bilo je i dalje na terapiji SRL. Do kraja pracenja oni su znatno popravili JGF (sa 53,2 ? 12,7 na 69 ? 15 mL/min), a neznatno povecali proteinuriju (sa 265 ? 239 na 530,6 ? 416,7 mg/dan) i lipidemiju (holesterol sa 4,71 ? 0,98 na 5,61 ? 1,6 mmol/L i trigliceride sa 2,04 ? 1,18 na 2,1 ? 0,72 mmol/L). Svi su bili stabilni tokom pracenja. Deset bolesnika vraceno je na KNI zbog naglog povecanja proteinurije, sa 298 ? 232 na 1639 ? 1641 mg/dan (7 bolesnika), brzog rasta multiplih ovarijalnih cista (2 bolesnika) i operativnog lecenja perzistentnog hematoma (1 bolesnik). Od rekonverzije do kraja pracenja bili su stabilni, ali sa neznatnim snizenjem JGF (sa 56,10 ? 28,09 na 47 ? 21 mL/min) i znacajno nizom proteinurijom (sa 1639 ? 1641 na 529 ? 688 mg/dan). Do kraja pracenja kod njih se neznatno povecala vrednost serumskog kreatinina (sa 172 ? 88 na 202 ? 91 mmol/L), smanjila vrednost JGF (sa 56,10 ? 28,09 na 47 ? 21 mL/min) i povecala proteinurija (sa 528,9 ? 688 na 850 ? 1083 mg/dan). Zakljucak. U ovom malom deskriptivnom ispitivanju prevodjenje sa KNI na SRL bilo je praceno vecom incidencijom infektivnih komplikacija, sto je uslovilo snizenje doze drugog antiproliferativnog leka (AZA ili MMF) za 25-50% i moguce imalo uticaj na pojavu glomerulopatije, koja je bila razlog za prekid terapije sirolimusom kod sedam (29%) bolesnika. Najvecu korist od konverzije sa CNI na SRL imalo je devet (37,5%) bolesnika koji nisu ispoljili znacajne komplikacije nakon konverzije.