Clinical and immunological follow-up of renal allograft recipients

Cilj: Kliničko i imunološko praćenje bolesnika s presađenim bubregom u KBC-u Rijeka te procjena imunosne reaktivnosti primatelja bubrežnog presatka, koji primaju anti-CD25 monoklonsko protutijelo daklizumab u sklopu standardnog imunosupresivnog protokola. Bolesnici i metode: Retrospektivna analiza obuhvaća kliničke podatke o 588 bolesnika, kojima je presađen bubreg u KBC-u Rijeka u proteklom gotovo 25-godišnjem razdoblju. Prospektivno randomizirano istraživanje obuhvaća primatelje bubrežnog presatka od 2006. do 2008. g. Iz ispitivanja su isključeni bolesnici s pozitivnim biljezima na hepatitis B ili C. Imunosna reaktivnost bolesnika određivana je analizom staničnog ciklusa limfocita periferne krvi, metodom protočne citometrije. Kontrolne skupine činili su zdravi darivatelji krvi i bolesnici na liječenju redovitom dijalizom. Rezultati: Kumulativno preživljavanje bolesnika i bubrežnih presadaka od 2001. do 2007. g. postalo je značajno bolje u odnosu na primatelje u razdoblju od 1985. do 1995. g. Tijekom 25-godišnjeg razdoblja, najčešći uzroci smrti bili su srčanožilne bolesti, infekcije i zloćudni tumori. Među zloćudnim tumorima najčešće se javljao karcinom kože, a potom karcinom bubrega i uretera. U bolesnika s endemskom nefropatijom nađena je visoka učestalost karcinoma prijelaznog epitela s lošom prognozom. Tijekom razdoblja praćenja zabilježen je porast prosječne starosne dobi bolesnika, značajan porast udjela muških primatelja bubrežnog presatka te značajno smanjenje učestalosti kroničnog glomerulonefritisa kao uzroka završnog bubrežnog zatajenja. Bolje preživljavanje presatka uočeno je u primatelja koji su bolovali od policistične bolesti bubrega, dok je značajno lošije bilo u slučaju primatelja ili darivatelja starijih od 50 g., te u muških primatelja nakon presađivanja bubrega od ženskih darivatelja. U prospektivnom dijelu ispitivanja, analizom staničnog ciklusa, uočeno je da tijekom prvih šest tjedana nakon presađivanja bubrega dolazi do postupnog pada proliferativnog odgovora limfocita T u odnosu na kontrolne skupine. Daklizumab je, ovisno o dozi, blokirao anti-CD3 potaknutu proliferaciju limfocita T te je doveo do naglog pada zastupljenosti IL-2 receptora na njihovoj membrani, dok je izražaj IL-2 receptora na stanicama NK varirao na niskoj razini. Uočen je i pad zastupljenosti ukupnih limfocita T, pomoćničkih i citotoksičnih stanica te limfocita B. U kasnijoj fazi, od 2.-6. tj. nakon presađivanja, zastupljenost ovih stanica se normalizirala. NK stanice su neposredno nakon presađivanja pokazale porast postotnog udjela, koji se u kasnijoj fazi ponovno normalizirao. Zaključak: Ovi rezultati predstavljaju značajan doprinos kliničkom praćenju bolesnika s bubrežnim presatkom i optimizaciji imunosupresivnog liječenja, s ciljem da se smanje neželjeni učinci prekomjerne imunosupresije i da se poboljša preživljavanje bolesnika i presatka.Aim: Clinical and immunological follow-up of renal allograft recipients in UHC Rijeka and estimation of the immune reactivity of patients receiving the anti-CD25 monoclonal antibody daclizumab, in combination with the standard immunosuppressive protocol. Patients and methods: Retrospectively, clinical data on 588 patients who received a renal allograft in UHC Rijeka over an almost 25 year period, were analyzed. The prospective randomized trial included recipients of renal allografts from 2006 until 2008. Excluded were patients with positive hepatitis B or C markers. The patients' immune reactivity was determined by analyzing the cell cycle of peripheral blood lymphocytes with flow-cytometry. Control groups were healthy blood donors and patients undergoing regular dialysis treatment. Results: Cummulative patient and graft survival of transplants performed during the period from 2001 until 2007 became significantly better than for kidney recipients in the period from 1985 until 1995. Over the 25 year period, most common causes of death were cardiovascular disease, infections and malignant tumors. The most common malignant tumor was skin cancer, followed by kidney and uretheral cancer. In patients with endemic nephropathy, a high incidence of urothelial cancer was observerd with a poor prognosis. During the follow-up period an increase in the patients' age average, a significant increase in the proportion of male renal allograft recipients and a significant decrease in the incidence of chronic glomerulonephritis as primary renal disease were observed. Recipients with polycystic kidney disease had better graft survival while the survival was significantly worse in case of recipients or donors age over 50 and in male recipients of kidneys from female donors. In the prospective part of the trial, cell cycle analysis showed a step-wise decrease of the proliferative response of T lymphocytes in comparison to the control groups during the first six weeks after renal transplantation. Daclizumab inhibited, dose-dependently, the anti-CD3 stimulated proliferation of lymphocytes T and lead to a sudden drop in the proportion of IL-2 receptors on their membrane, while the expression of IL-2 receptors on NK cells varied at a low level. A drop of the proportion of all T lymphocytes, both helper and cytotoxic cells as well as of B lymphocytes was observed. Over a period of two to six weeks after transplantation, the proportion of these cells normalized. NK cells showed a rise of their proportion immediately after engraftment, which normalized again in the latter phase. Conclusion: These results represent a valuable contribution for the clinical follow-up of renal transplant recipients and the optimization of immunosuppressive treatment, in order to minimize side effects of overimmunosuppression and to improve patients and graft survival