Immunosuppressive treatment for kidney transplantation

Razvoj novih imunosupresivnih lijekova i saznanja stečena primjenom različitih kombinacija ovih lijekova u imunosupresivnim protokolima dovela su do značajnog poboljšanja rezultata liječenja presađivanjem bubrega. Cilj imunosupresivnog liječenja smanjenje je neželjene imunosne aktivnosti, no ono često vodi u razvoj komplikacija kao što su infekcije, metabolički poremećaji, arterijska hipertenzija, tumori, te druge neželjene pojave. U ovom radu prikazani su mehanizmi djelovanja dostupnih imunosupresivnih lijekova, njihova primjena kod presađivanja bubrega i neželjena djelovanja. Imunosupresivni protokol koji se koristi u većine bolesnika obuhvaća inhibitor kalcineurina takrolimus ili ciklosporin, antimetabolit mikofenolat mofetil ili mikofenolnu kiselinu, i kortikosteroid. U ranom razdoblju nakon presađivanja za suzbijanje reakcije odbacivanja primjenjuje se jača imunosupresija pomoću većih doza imunosupresivnih lijekova ili dodavanjem indukcijskih agensa, monoklonskih ili poliklonskih antilimfocitnih protutijela. Uz navedene lijekove jednogodišnje preživljavanje bubrežnih presadaka iznosi više od 90 %, a učestalost akutnih reakcija odbacivanja do 15 %. U liječenju akutne reakcije odbacivanja posredovane stanicama primjenjuju se intravenski pulsne doze metilprednizolona, a rjeđe antilimfocitna protutijela. Za suzbijanje akutne humoralne reakcije odbacivanja, koju označava karakteristični patohistološki nalaz i dokaz donor-specifičnih protutijela u serumu primatelja, koriste se visoke doze intravenskih imunglobulina (IVIG) ili niske doze citomegalovirusnog hiperimunog globulina (CMVIG) u kombinaciji s plazmaferezom, do zadovoljavajućeg smanjenja titra antidonorskih protutijela. Rjeđe se primjenjuje imunoadsorpcija, rituksimab, alemtuzumab ili splenektomija. Ispitivanja imunosupresivnih tvari i njihovih mehanizama djelovanja dovela su do otkrića velikog broja potencijalnih lijekova, međutim, njihovoj primjeni u imunosupresivnom liječenju kod presađivanja bubrega moraju prethoditi velike randomizirane kontrolirane studije.The development of new immunosuppressive drugs and knowledge gained through their usage in different combinations in immunosuppressive protocols, has significantly improved results after renal transplantation. Immunosuppressive treatment aims at a reduction of unwanted immune activity, but complications often arise in the form of infections, metabolic disorders, arterial hypertension, tumors, and other side-effects. In this paper, we describe the mechanisms of action of available immunosuppressive drugs, their application for renal transplantation and their side-effects. In the majority of patients, the immunosuppressive protocol includes a calcineurin inhibitor, tacrolimus or cyclosporin, the antimetabolite mycophenolate mofetil or mycophenolic acid, and a corticosteroid. Early after transplantation, acute rejection is suppressed with higher doses of immunosuppressive drugs or an induction agent, monoclonal or polyclonal antilymphocytic antibodies. These drugs allow a one-year survival of renal allografts in over 90 % of cases, and an incidence of acute rejection reactions below 15 %. Acute cell-mediated rejection is treated with pulse doses of methylprednisolone intravenously, less often with antilymphocytic antibodies. Acute humoral rejection, characterized through specific pathohystologic changes and donor-specific antibodies in the recipient’s serum, is treated with high doses of intravenous immunoglobulines (IVIG) or low doses of cytomegalovirus hyperimmune globuline (CMVIG) together with plasmapheresis until a satisfactory reduction of anti-donor antibodies is obtained. Rarely, immunoadsorption, rituximab, alemtuzumab or splenectomy are applied. Investigations of immunosuppressive agents and their mechanisms of action have lead to the discovery of a large number of potential drugs. However, their application in the immunosupressive treament for renal transplantation has to be preceeded by large randomized controlled trials

Immunobiology of renal transplantation

Bubrežni presadak se u pravilu dobiva od genski neidentičnog darivatelja organa, što pobuđuje imunosni sustav primatelja na razvoj transplantacijske reakcije. Ova reakcija usmjerena je prvenstveno na strane MHC molekule, ali i na druge nepodudarne jake i slabe tkivne antigene. Intenzitet imunosnog odgovora određuju čimbenici darivatelja, prvenstveno izražaj nepodudarnih HLA antigena i prisustvo antigen predočnih stanica u presatku, dok je među čimbenicima primatelja najvažnija ranija senzibilizacija i razvoj protutijela na AB0 i HLA antigene. U ovom radu opisane su suvremene spoznaje o kliničkim značajkama i temeljnim imunosnim mehanizmima transplantacijske reakcije, koje čine osnovu za provođenje imunosupresivnog liječenja kod presađivanja bubrega.Renal transplants are usually received from geneically non-identical donors, which induces the recipient’s immune system to develop a transplantation reaction. This reaction is primarily directed against foreign MHC molecules, but also to other incompatible strong and weak tissue antigens. The intensity of the immune response depends on donor-dependent factors, primarily the expression of incompatible HLA antigens and the presence of antigen presenting cells in the allograft. Among recipient’s factors, the most important is an earlier sensitation and development of antibodies against AB0 and HLA antigens. In this paper we summarize the recent knowledge on clinical features and basic immune mechanisms of the transplantation reaction, which represents the basis for imunosuppressive treatment for renal transplantation

MFA11 (MFA 2011)

Catalogue of a culminating student exhibition held at the Mildred Lane Kemper Art Museum, May 6-Aug. 1, 2011. Content includes Introduction / Buzz Spector -- Patricia Olynyk -- Marshall N. Klimasewiski -- John Talbott Allen -- Meghan Bean -- Shira Berkowitz / Maggie Stanley Majors -- Darrick Byers, Bryce Olen Robinson -- Jisun Choi -- Zlatko Ćosić -- James R. Daniels -- Kara Daving -- Andrea Degener -- Kristin Fleischmann / Randi Shapiro -- William Frank / Lawrence Ypil -- Nicholas Kania -- Katherine McCullough -- Jordan McGirk / Aditi Machado -- Zachary Miller -- Esther Murphy / Maggie Stanley Majors -- Kathryn Neale -- Christopher Ottinger / Melissa Olson -- Maia Palmer -- Nicole Petrescu / Melissa Olson -- Lauren Pressler / Randi Shapiro -- Whitney Sage / Aliya A. Reich -- Donna Smith.https://openscholarship.wustl.edu/books/1005/thumbnail.jp

Immunosuppressive treatment for kidney transplantation

mmunosuppressive treatment minimizes unwanted immune reactivity, but it also leads to complications such as metabolic disorders, cardiovascular diseases and malignant tumours. In this paper we summarise the recent developments in action mechanisms of available immunosuppressive drugs and their usage for renal transplantation. These drugs act at various levels of lymphocytic activation and proliferation, and they may have additive or synergic effects when combined. In the majority of patients, the immunosuppressive protocol includes a calcineurin inhibitor (tacrolimus or cyclosporin), an antimetabolite (mycophenolate mofetil or mycophenolic acid) and a corticosteroid. Most patients also receive induction with monoclonal or polyclonal antilymphocytic antibodies. These immunosuppressive drugs allow a one-year survival of renal allografts in over 90% of cases and an incidence of acute rejection episodes below 15%. In most cases, acute cell-mediated rejection can be reversed with pulse doses of methylprednisolone; less often antilymphocytic antibodies must be applied. Acute humoral rejection can be suppressed with high doses of intravenous immunoglobulines or low doses of cytomegalovirus hyperimmune globuline, in combination with plasmapheresis, to obtain a satisfactory reduction of anti-donor antibodies. This treatment also allows renal transplantation for sensitised recipients, or transplantation against a positive cross match or AB0 incompatibility. Less often, immunoadsorption, alemtuzumab, rituximab or splenectomy are applied. New immunosuppressive drugs and protocols are currently under investigation. Immunosuppressive agents and methods targeting the induction of immune tolerance to the donor organ are especially promising

Complications after kidney transplantation

Za većinu bolesnika presađivanje bubrega najbolje je nadomjesno liječenje kod bubrežnog zatajenja, no ono je često povezano s razvojem komplikacija. Vodeći uzroci završnog zatajivanja bubrega (šećerna bolest, arterijska hipertenzija i ateroskleroza), starenje dijalitičke populacije te širenje kriterija za prihvaćanje sve većeg broja primatelja i darivatelja organa značajno povećavaju morbiditet. U prvoj godini nakon presađivanja bubrega najčešći su uzroci gubitka presatka akutno odbacivanje, arterijska tromboza, primarna afunkcija presatka i smrt, dok se nakon prve godine najviše presadaka gubi zbog smrti bolesnika s funkcionirajućim presatkom te kronične nefropatije presatka. Prema podacima našeg centra (KBC Rijeka), tijekom proteklog 25-godišnjeg razdoblja srčanožilne bolesti su uzrokovale smrt u 44,8 % primatelja, infekcije u 20,1 % i zloćudni tumori u 8,4 % slučajeva, s time da u 17,5 % primatelja nije bio poznat uzrok smrti. U ovom radu opisane su najčešće komplikacije nakon presađivanja bubrega, načini njihovog otkrivanja i liječenja. Reakcija odbacivanja presatka zauzima značajno mjesto među uzrocima kronične nefropatije i gubitka funkcije presatka. Akutna reakcija odbacivanja uz današnje imunosupresivno liječenje javlja se u manje od 15 % bolesnika i većinom ima asimptomatski tijek, a porast koncentracije serumskog kreatinina je kasni i nespecifični pokazatelj. Radi ranog otkrivanja reakcije odbacivanja te drugih uzroka oštećenja presatka ispituju se metode imunosnog praćenja koje, pored određivanja protutijela usmjerenih protiv stanica presatka i biljega stanične aktivacije, uključuju prikazivanje gena te određivanje bjelančevina i metabolita u krvi, mokraći i bioptatu presatka. Ove metode mogle bi omogućiti individualizaciju imunosupresivnog liječenja i pravodobno liječenje komplikacija, a time i poboljšanje rezultata liječenja presađivanjem bubrega.Renal transplantation is the best replacement therapy for renal failure in most patients, but it is often associated with development of complications. The leading causes of end-stage renal failure (diabetes mellitus, arterial hypertension and atherosclerosis), aging of the population undergoing dialysis and widening of the acceptance criterias for both recipients and donors, significantly increase morbidity. During the first year after transplantation, most grafts are lost due to acute rejection, arterial thrombosis, primary graft non-function and death. After the first year, most grafts are lost due to death from other causes, but with a functioning graft, and chronic allograft nephropathy. According to the data collected in our institution during the last twenty-five years, cardiovascular diseases caused death in 44.8 % recipients, infection in 20.1 % and malignant tumors in 8.4 %, while in 17.5 % of cases, the cause of death was unknown. This paper addresses the etiology of the most common complications after renal transplantation. Acute allograft rejection is a significant cause of chronic nephropathy and graft loss. With available immunosuppressive treatments, it occurs in less than 15 % of patients, it is frequently asymptomatic and a rise in serum creatinine is a late and nonspecific marker. For early diagnosis of rejection and causes of graft damage, several methods of immune monitoring are investigated, including not only the determination of antibodies against the allograft and markers of cell activation, but also gene profiling and determination of proteins and metabolites in blood, urine and biopsy specimens. These methods could allow individualised immunosuppressive treatments and timely treatment of complications, leading to an improvement of results after renal transplantation