GRAFT AND PATIENT SURVIVAL AFTER RENAL TRANSPLANTATION IN THE PERIOD FROM 1996-2017 IN MILITARY MEDICAL ACADEMY, BELGRADESERBIA

Introduction/Aim: Renal transplantation is the best and preferred way of treating patients with end-stage renal disease, as it offers improved survival and better quality of life in comparison to dialysis. The aim of this study is to show single-center results of the kidney allograft and patient survival during the period from 1996-2017. Methods: This is a retrospective, 22-year cohort study. Variables of interest were graft and patient survival in kidney transplanted patients. Age, gender, creatinine and induction therapy after transplantation were recorded in this group of patients as well. Results: Among 386 transplanted patiets, 316 patients had a living donor and 70 patients deceased donor. Preemptive renal transplantation is done in 29 or 7.5% patients and ABO-incompatible kidney transplantation in 21 or 5.4% patients. One-year, 5-year, 10-year and 20-year overall patient survival after kidney transplantation in the opserved group was 97.7%, 95.3%, 93.8% and 91.7%, respectively. One-year, 5-year, 10-year and 20-year graft survival in the our patinets were 93.8%, 85.5%, 78.5% and 73.3%, respectively. Conclusion: The outcome of graft and patient survival in Military Medical Academy kidney transplantation program are good and in the line with the most eminent world centers.


Introduction
Chronic kidney disease is an important health problem worldwide, since it is associated with increased risk of morbidity and mortality in this large group of population 1 . Renal transplantation is the best and preferred way of treating patients with end-stage renal disease, as it offers improved survival and better quality of life in comparison to dialysis 2, 3 .
In most transplantation centers, one-year kidney graft survival in the transplant patients with living-donor and deceased-donor is between 90-98% 4 . However, despite such good short-term results, the results of long-term graft survival are still unsatisfactory and have not been improved sufficiently over the last 20 years 5 . Data shows that hazard rates of graft failure at 10 years after transplantation is 64%, and terminal graft dysfunction is, by frequency, one of the 5 most common reasons for starting a chronic dialysis program in countries in which a large number of kidney transplants have been performed in the past period 6,7 . This fact represents a major health, social and economic problem. Factors that affect the graft survival are numerous and can be divided into immunological and nonimmunological 8 . Furthermore, results of graft and patient survival can also vary among individual regions due to the difference in certain patients and health care system characteristics, which may be important for the outcome of the transplantation.
The aim of this study is to show single-center results of the kidney allograft and patient survival during the period from 1996-2017.

Material and Methods
This is retrospective, 22-year cohort study during period from 1996 (when first kidney transplantation was performed in Military Medical Academy) till 2017. Study was performed in the Clinic of Nephrology and in the Center for Solid Organ Transplantation in Military Medical Academy, Belgrade. All patients who were transplated and regulary controled in our department were included in this study.
Variables of interest were graft and patient survival in kidney transplanted patients.
Age, gender, creatinine and induction therapy after transplantation were recorded in this group of patients as well. 6 Although it changed over time, standard imunosupressive protocol after kidney transplantation in our hospital included steroids (according to hospital practice); azathioprine until 1998, later replaced with micophenolat (mofetil and myfotic acid); and cyclospirine or tacrolimus (with C0 and C2 therapeutic monitoring for cyclosporine and C0 monitoring for tacrolimus). The mTor inhibitors were administered sporadically, initially as a replacement for calcineurin inhibitors (this practice was later stopped), in the cases of tumor formation after transplantation and, in recent years, in reduced doses with low doses of tacrolimus in some patients. During the last 10 years, patients were usually discarded from the hospital after kidney transplantation with steroids, micophenolat and tacrolimus.
In patients who are considered to have a higher immunological risk, after cadaveric transplantation and in the cases of delayed graft function, induction therapy was applied in the form of Anti-Tymocite globulin or IL-2 antagonist.
Complete statistical analysis was done with the statistical software package, PASW Statistics 18. Atribute variables were presented as frequency of certain categories, while statistical significance of differences was tested with the Chi-square test. Numerical variables were presented as mean with standard deviation, while statistical significance of differences was tested with the Mann-Whitney test or Independent samples t test (normal or not normal distribution). All the analyses were estimated at p<0.05 level of statistical significance. Unadjusted graft and patient survival was calculated using Kaplan-Meier plots and p-values derived from the univariate Log-rank test.
Principles of ICH Good Clinical Practice were strictly followed and ethical approval No. 01/31-01-13 from the ethics committee of the hospital was obtained for the study protocol No. 910-1.

Discussion
In our study, graft loss among living-donor and deceased-donor groups showed no significantly difference. In our study, one-year, 5-year, 10 Results of our study shows that the short and long term grafts and patient survival in our patients are comparable or even better in regard to results in the reputable centers worldwide. These results are particularly interesting because they include the beginnings of a kidney transplant program in our hospital 14 . Important reasons for this are, doubtless, skilled surgical techniques, reliable tissue typing, careful patient care and frequent controls, as well as contemporary immunosuppressive therapy 15,16 . However, certain demographic characteristics that may be somewhat specific and which may affect the results of transplantation should certainly be also mentioned. First of all, it can be concluded that patients in this study represent a rather typical sample of transplanted patients in our region: they are Caucasians (in our center was not African-American patients) and are relatively younger-age of patients at the time of transplantation were 44.5 years. Our patients were younger compared to patients in some other aereas 17 , and correspond to the average age of transplanted patients in other centers in Serbia 18 , as well as patients in our earlier study 19 . There were more men in the our group, which is also in line with our previous research 19 , but also with the experiences of other authors 4-6, 17, 18 .
Epidemiological data shows that chronic renal failure and uremia occur more frequently in males 8,20 . Comparison of men and women did not find a statistically significant difference in relation to age (p=0.604).
When analyzing our patients from the immune aspect, it can be concluded that their immunological risk were not high: the majority of transplants were made from a live donors. Kidney transplantation from a living donors certainly has its advantages-one of the most important is significantly shorter cold ischemia time and, consequently, lower incidence of delayed graft function and acute rejection which can results better long term graft survival 21 . In some patients kidney transplantations were performed pre-emptive, which can be associated with the better graft survival 21,23 . However, in our patients there was nevertheless a certain immunological risk: they were relatively young, and it is well known that these patients react immunologically stronger to the transplanted organ 24 . Also, in the majority of patients in Serbia, the cause of terminal renal insufficiency was immunological (chronic glomerulonephritis) 25 . Also, it should be noted that the shortage of organs and a higher number of transplantations from a living donor results in the acceptance of the so-called "border" living donors, that is, older donors with a greater number of comorbid conditions 26  year, and 91 and 83% after 9 years, respectively 30 . In our study, one-and 10 years patients with ABOi kidney transplant and allograft survival was 100.0% and 80.9%, and 90,5% and 71,4%, respectively. According to the conclusions from several transplant centers, this therapeutic option is acceptable for treating patients with end-stage renal disease 29 , although it has been shown that these patients receive higher doses of immunosuppressive therapy,which puts them at increased risk not only of early, but also of delayed complications. 30 Pre-emptive kidney transplantation is considered the best available form of renal replacement therapy 31 . This option is associated with improved patient and graft survival, better quality of life, and lower long-term medical costs compared with transplantation after dialysis initiation. In systematic literature review was shown that patient survival, graft survival and acute rejection rate were better in pre-emptive versus transplantation after start of dialysis 31 . In Australian study, the 5-year survival in the pre-emptive kidney transplantation group was 97% and 10-year survival 93% 32 , similar to our data. Therefore, pre-emptive transplantation should be the preferred modality of renal replacement therapy in patients who have a living donor 32 .

Conclusion
The outcome of graft and patient survival in Military Medical Academy kidney transplantation program are good and in the line with the most eminent world centers.
Further studies are needed which will more in detail clarify the influence of different factors on graft and patient survival in our patients.

Acknowledgment
The authors are in a position to present the basic and current results of the kidney transplant program at the Military Medical Academy. However, we owe special gratitude to our teachers, former heads of clinics of nephrology, center for kidney transplantation, vascular surgery, urology, immunology, radiology, neurology, anesthesiology, infectious diseases, cardiology, pulmology, endocrinology, microbiology, pharmacology, pharmacy as well as other branches and services without whose active participation and help such 11 complex and multidisciplinary field such as kidney transplantation would not be possible.
Also, we feel the greatest gratitude to a great number of our colleagues, medical technicians and other medical staff who participated in the transplant program with great desire and dedication from the very beginning to the present. Their number exceeded the possibility of individual enumeration in this paper. All these people had a pioneering vision of the importance of kidney transplantation and have enabled these results with their commitment, faith, knowledge and care for each patient. The possibility of safe and routine performance of the kidney transplantations in our hospital presently stands on their shoulders. Online First September, 2020.