Tacrolimus Utilization and Expenditure in Serbia.

BACKGROUND: Increasing immunosuppressant consumption and expenditure is a quite a challenge in transplantation medicine. The aim of the study was to characterize the utilization and expenditure of tacrolimus, backbone, and standard of care in immunosuppression regimen in Serbian solid organ transplant recipients. METHODS: This study was performed as retrospective cross-sectional study during a 3-year period (from 2013 to 2015) in Serbia. The Anatomical Therapeutic Chemical Classification/Defined Daily Doses (ATC/DDD) international system was used for consumption evaluation. RESULTS: Two hundred and sixty-nine patients were transplanted in Serbia from 2013 to 2015 (185 recipients from deceased donors and 84 recipients from living donors). Total number of deceased donors in this period was 81. The consumption of tacrolimus increased (from 0.051 DDD/1,000 inhabitants/day to 0.069 DDD/1,000 inhabitants/day in 2013 and 2015, respectively). The total cost of tacrolimus was also increased; from 1,206,816€ to 1,483,472€ in 2013 and 2015, respectively. On the other hand, the number of all new solid organ transplants (from deceased and living donors) per million population per year was decreased from 17.39 to 10.02, from 2013 to 2015, respectively. CONCLUSION: In spite downward trend in the number of solid organ transplants, tacrolimus consumption and expenditure in the examined 3-year period in Serbia increased. Since tacrolimus is a high-cost and life-preserving drug, its increasing utilization and expenditure will most likely continue consuming an enhancing share of Serbian pharmaceutical expenditure, as well as its health care, as a whole.

Aortobifemoral reconstruction and renal transplantation in a patient with abdominal aortic aneurysm and occlusion of iliac arteries: A case report.

Introduction: Aortoiliac occlusive disease and abdominal aortic aneurysm in patients with renal insufficiency on hemodialysis can significantly influence the success of renal transplantation. In the recent past, advanced atherosclerosis was considered as contraindication for renal transplantation. Complicated creation of vascular anastomoses and progression of occlusive or aneurysmal disease were the main reasons. Case report: We presented a 52-year-old man with a 5-year history of end-stage renal disease on haemodialysis. The patient was previously excluded from renal transplantation program because of severe aortoiliac atherosclerosis and abdominal aortic aneurysm. Resection of abdominal aortic aneurysm with occlusion of the iliac arteries and reconstruction with aortobifemoral synthetic grafts was performed and followed by cadaveric renal transplantation. Conclusion: Advanced atherosclerotic disease in aortoiliac segment requires elective vascular surgical reconstruction, as part of preparation for renal transplantation in patients with end-stage renal disease.

Economic Evaluation of Pharmacogenetic Tests in Patients Subjected to Renal Transplantation: A Review of Literature.

Renal transplantation is the treatment of choice for the patients with end-stage renal failure. Genetic factors, among others, can influence variability in response to immunosuppressive drugs. Nowadays, due to restrictive health resources, the question arises whether routine pharmacogenetic analyses should be done in the renal transplant recipients or not. The aim of this literature review was to present the up-to-date information considering the economic feasibility of pharmacogenetic testing in patients subjected to renal transplantation. The organization United Network for Organ Sharing in the US estimated that total costs per renal transplant concerning these analyses were $334,300 in 2014. Pharmacogenetic testing prior to treatment initiation could be helpful to predict and assess treatment response and the risks for adverse drug reactions. This kind of testing before treatment initiation seems to be one of the most promising applications of pharmacokinetics. Although pharmacogenetic tests were found to be a cost-effective or cost-saving strategy in many cases, some authors represent another opinion. However, if the real costs of renal transplantation are recognized, the application of these tests in the standard daily practice could be considered more realistic, which additionally emphasizes the importance of future studies assessing their cost effectiveness.

The distribution of genetic polymorphism of CYP3A5, CYP3A4 and ABCB1 in patients subjected to renal transplantation.

Background/Aim: Polymorphisms of genes which encode transporter P-glycoprotein and most important enzymes for tacrolimus pharmacokinetics can have significant influence reflecting on blood concentrations of this drug. The aim of this study was to examine the distribution of polymorphisms of CYP3A5, CYP3A4 and ABCB1 genes in patients subjected to renal transplantation, for the first time in our transplantation center. Methods: The research was designed as a prospective cross-sectional study which included 211 patients subjected to renal transplantation in the Centre for Solid Organ Transplantation of the university tertiary health care hospital, Military Medical Academy, Belgrade, Serbia. Patients of both genders, 22−69-year-old, Caucasians, subjected to immunosuppressive regimen, including tacrolimus, were recruited for the study. CYP3A5 6986A>G (the *3 or *1, rs776746), CYP3A4 - 392A>G (the *1 or *1B, rs2740574) and ABCB1 3435C>T (rs1045642) genotypes were determined by TaqMan® SNP genotyping assays. Restults: Most of our patients (94.8%) had functional CYP3A4 enzyme, while 87.7% of all the patients had diminished CYP3A5 enzymatic activity. On the other hand, about one third of them, 31.3%, had functional ABCB1 transporter. Conclusion: A total of 84.8% of our patients were found to express both the CYP3А5*3*3 genotype (associated with diminished CYP3А5 enzymatic activity) and CYP3А4*1*1/*1*1B (associated with functional CYP3А4 enzymatic activity), while out of all the patients with diminished CYP3A5 enzymatic activity, 68.7% had diminished activity of ABCB1 transporter. However, further studies are necessary in order to show the influence of these genetic polymorphisms on tacrolimus blood concentrations in patients after renal transplantation.

Tacrolimus concentration/dose ratio as a therapeutic drug monitoring strategy: the influence of gender and comedication.

UNLABELLED: BACKGROUND/AIM. A combination of tacrolimus and other drugs such as corticosteroids has been commonly used immunosuppressive regimens. On the other hand, there is a growing body of evidence that male and female may differ in their response to the equal drug treatment. The aim of the study was to estimated the use of tacrolimus concentration/dose (C/D) ratio for the assessment of the influence of gender differences and comedication on tacrolimus exposure in renal transplant recipients. METHODS. This prospective case series study included 54 patients, in which the unit of monitoring was outpatient examination (1,872) of the renal transplant patients. The patients were monitored in the period 2010-2014, starting one month after the transplantation. Tacrolimus trough concentrations (TTC) were measured by chemiluminescence microparticles immunoassay. RESULTS. TTC and the tacrolimus C/D ratio were significantly lower in the females comparing with the males. Contrary to the males, in the females a significant increase of the tacrolimus daily dose (TDD) per body weight and TTC, along with the corticosteroid dose increase, was not accompanied by any significant changes in the tacrolimus C/D ratio; in different corticosteroid doses faster elimination of tacrolimus was found with the exception of the doses > 0.25 mg/kg. In the patients treated with proton pump inhibitors, mainly with pantoprazole TDD per body weight and TTC were significantly higher, while the tacrolimus C/D ratio was significantly lower compared to the patients without this treatment. In the patients treated with calcium channel blockers, TDD per body weight was significantly lower (particularly with amlodipine). while the tacrolimus C/D ratio was higher compared to the patients who were not treated by them. CONCLUSION: A lower tacrolimus exposure was detected in females in comparison to males. When gender differences were considered in the context of different corticosteroid doses, faster elimination of tacrolimus in the females was also seen, with the exception of the doses > 0.25 mg/kg. Tacrolimus exposure in the pantoprazole-treated patients was significantly less expressed, while in patients treated with CCB amplodipine the tacrolimus C/D ratio was significantly higher in comparison with the patients not treated with them.

Specificities of transplantation of kidneys procured from donors with situs inversus totalis--a case report and review of the literature.

INTRODUCTION: Situs inversus totalis (SIT) represents a total vertical transposition of the thoracic and abdominal organs which are arranged in a mirror image reversal of the normal positioning. We presented a successful pre-dialysis kidney transplantation from a living sibling donor with SIT and the longest donor follow-up period, along with analysis of the reviewed literature. CASE REPORT: The pair for pre-dialysis kidney transplantation included a 68-year-old mother and 34-year-old daughter at low immunological risk. Comorbid- ities evidenced in kidney donors with previously diagnosed SIT, included moderate arterial hypertension and borderline blood glucose level. Explantation of the left donor kidney and its placement into the right iliac fossa of the recipient were performed in the course of the surgical procedure. A month after nephrectomy, second degree renal failure was noticed in the donor. A 20-month follow-up of the donor's kidney and graft in the recipient proved that their functions were excellent. CONCLUSION: In donors with previously di- agnosed SIT the multidisciplinary approach, preoperative evaluation of the patient and detection of possible vascular anomalies are required to provide maximum safety for the donor.

The influence of comedication on tacrolimus blood concentration in patients subjected to kidney transplantation: a retrospective study.

Tacrolimus is an immunosuppressant used for the prevention of kidney allograft rejection. The effects of comedication on tacrolimus trough concentrations (TTC) in kidney transplant recipients, subjected to basic immunosuppressant regime consisting of tacrolimus, corticosteroids and mycophenolate mofetil were investigated. This retrospective case series study involved 208 of these patients, with the outpatient examination recorded in the database of patients, at the unit of monitoring, with a total of 5,011 such examinations. Binary logistic regression analysis has shown that calcium channel blockers, diuretics and proton pump inhibitors (PPIs) significantly affected TTC (p < 0.001). PPIs significantly increased the number of examinations in which the TTC were in the recommended therapeutic range (from 5 to 15 ng/ml), as well as over the therapeutic range (p < 0.0001). When calcium channel blockers were added to PPIs, even more pronounced effect was obtained in comparison to triple-drug therapy only (p < 0.0001). In case a diuretic was given with a PPI, a significantly increased number of examinations with subtherapeutic TTC was observed when compared with PPI only (p = 0.0203). The combination of calcium channel blockers, diuretics and PPIs resulted in the number of examinations with TTC in the recommended therapeutic range not being different from the number of examinations with TTC in the triple-drug therapy only (p = 0.3829). ß-adrenergic antagonists can be administered without fear of affecting the tacrolimus optimal therapeutic concentrations. This was confirmed with all combinations of the examined drugs used in patients subjected to kidney transplantation concomitantly with ß blockers.

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

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 CNI-based 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.

Percutaneous transluminal renal angioplasty application effect on renal function in patients with renal artery stenosis - a case report on 4 patients.

INTRODUCTION: Renal artery stenosis (RAS) is narrowing of one or both renal arteries or their branches. Clinically sig nificant stenosis involves narrowing of the lumen, which is approximately 80%. The two most common causes of its occurrence are atherosclerosis and fibromuscular dyspla sia. Percutaneous transluminal renal angioplasty (PTRA) with stent implantation is an effective treatment modality that leads to lower blood pressure and improvement of kidney function. CASE REPORT: We presented 4 patients with significant stenosis of one or both renal arteries fol lowed by the development of arterial hypertension and re nal insufficiency. The causes of RAS were atherosclerosis in two patients and fibromuscular dysplasia in one patient. One of the patients had renal artery stenosis of trans planted kidney that developed 9 month after transplanta tion. In all the patients, in addition to clinical signs, dop pler screening suspected the existence of significant renal artery stenosis. The definitive diagnosis was made by ap plying computed tomographic angiography (CTA) of renal arteries in 3 of the patients and in 1 patient by percutaneus selective angiography. All the patients were treated by ap plication of PTRA with stent implantation followed by improvement/normalization of blood pressure and kidney function. CONCLUSION: Application of PTRA with stent implantation is an effective treatment of significant steno sis of one or both renal arteries followed by renal insuffi ciency.

Living unrelated donor kidney transplantation--a fourteen-year experience.

BACKGROUND: In countries without a national organization for retrieval and distribution of organs of the deceased donors, problem of organ shortage is still not resolved. In order to increase the number of kidney transplantations we started with the program of living unrelated - spousal donors. The aim of this study was to compare treatment outcome and renal graft function in patients receiving the graft from spousal and those receiving ghe graft from living related donors. METHOD: We retrospectively identified 14 patients who received renal allograft from spousal donors between 1996 and 2009 (group I). The control group consisted of 14 patients who got graft from related donor retrieved from the database and matched than with respect to sex, age, kidney disease, immunological and viral pretransplant status, the initial method of the end stage renal disease treatment and ABO compatibility. In the follow-up period of 41 +/- 38 months we recorded immunosuppressive therapy, surgical complications, episodes of acute rejection, CMV infection and graft function, assessed by serum creatinine levels at the beginning and in the end of the follow-up period. All patients had pretransplant negative cross-match. In ABO incompatible patients pretransplant isoagglutinine titer was zero. RESULTS: The patients with a spousal donor had worse HLA matching. There were no significant differences between the groups in surgical, infective, immunological complications and graft function. Two patients from the group I returned to hemodialysis after 82 and 22 months due to serious comorbidities. CONCLUSION: In spite of the worse HLA matching, graft survival and function of renal grafts from spousal donors were as good as those retrieved from related donors.

Our first experiences in applying an original method for removal of ABO-isoagglutinins in ABO-incompatible kidney recipients.

BACKGROUND/AIM: Due to improved methods for removal of ABO isoagglutinins and novel immunosuppressive protocols, short and long-term outcome in blood group incompatible is similar to blood group compatible kidney transplantation. The aim of this study was to determine the efficacy of our original method for removal of ABO isoagglutinins from the blood in ABO-incompatible kidney allograft recipients. METHOD: Between 2006 and 2008 twelve patients were transplanted from ABO incompatible living donors. Titers of ABO isoagglutinins were 4-128 (IgG). Immunosuppressive therapy started 14 days before kidney transplantation with rituximab, followed by a triple therapy (prednisone + tacrolimus + mycophenolate mofetil) and the first plasma exchange (PE) procedure, in which one plasma volume was substituted with albumin and saline on day 7 before transplantation. For selective extracorporeal immunoadsorption, the removed plasma was mixed with donor blood type filtered red blood cells, centrifuged and the supernatant separated and preserved. In the next PE procedure, the removed plasma was replaced with immunoadsorbed plasma, and so on. Titers of ABO agglutinins, renal allograft function and survival were followed-up. RESULTS: The pre-transplant treatment consisting of 1-5 PE procedures and immunosuppressive therapy resulted in target ABO agglutinins titers below 4. During a 10-24 month follow-up three patients had an early acute rejection, one patient acute rejection and hemolytic anemia, two patients surgical complications and one of them lost his graft. In the post-transplant period, the titers of ABO antibodies remained below 4. All the patients had stable kidney allograft function with mean serum creatinine +/- SD of 129 +/- 45 micromol/l at the end of the study. CONCLUSION: Our method for removal of ABO antibodies was effective in a limited series of patients and short-term follow-up.

[Efficacy of therapeutic monitoring of cyclosporine through C2 and AUC(0-4) during the first 24 months following kidney transplantation].

BACKGROUND/AIM: Cyclosporine (CyA) therapeutic drug monitoring (TDM) through the measurement of drug concentration in blood two hours after the administration (C2), and/or according to the calculated value of the area under the concentration-time curve during the first four hours following administration (AUC(0-4)) shows favourable correlation with clinical manifestations in patients with kidney transplantation (Tx). The aim of this study was to analyze clinical efficiency and usability of TDM CyA through C2 and AUC(0-4) in the group of our kidney transplanted patients during the first 24 months following Tx. METHODS: The study included 50 patients who had undergone kidney Tx using living donors at the Clinic of Nephrology Military Medical Academy, from 1996 to 2003. The first group (group C2) consisted of 25 patients in whom CyA dose was adjusted according to the target C2 and AUC(0-4) (calculated by the regression formula based on C1, C2 and C3), while the second group (group CO) consisted of 25 "historical" patients in whom the dose of this drug was adjusted according to CO. RESULTS: On the 6th day the average daily dose of CyA in the group C2 was 10.1 +/- 0.8 mg/kg, while in the group CO it was 7.6 +/- 1.6 (p < 0.05). One month following the Tx, daily drug doses were quite similar in the two observed groups (6.2 mg/kg in CO and 6.6 mg/kg in group C2, p = NS). In the group C2, target C2/AUC(0-4) (C2 1700 ng/ml, AUC(0-4) 4400 ng h/ml) on the sixth day was achieved in 36.3%, and on day 14 in 76% of the patients. The target AUC(0-4), in relation with C2, in each observed time interval was reached in the higher number of patients. Maximum CyA concentrations in the group C2 were registered 2 hours following the administration (C2), when compared with the concentrations registered after the first and the third hour (C1 and C3). In relation with C1 and C3, C2 concentration correlated most favorably with AUC(0-4), both on the 6th (r = 0.85) and on the 9th day (r = 0.87). During the first three months following the Tx, in the group CO, 10 episodes (40%) of acute cell rejection (AR) were registered, while in the group C2, two episodes (8%, p = 0.07) were registered; in the observed period covering the first two years, a total of 13 (52%) AR episodes in the group CO and 5 AR episodes (20%) in the group C2 (p = 0.03) were registered. All of five episodes of steroid resistant AR were registered in the group CO. In the group C2, all five patients with AR had lower C2 during AR: the average C2 at the moment of AR was 933.8 ng/ml, and in the patients without rejections was 1364.2 ng/ml (p = 0.008). In the same group, the average C0 at the moment of AR was 263.2 ng/ml, and 240.0 ng/ml (p = 0.486) in the patients without AR. In the C0 group, average C0 concentration at the moment of AR was 227.1 ng/ml, while in the patients without AR it was 227.7 ng/ml (p = 0.95). Totally 68% of the patients showed signs of acute CyA nephrotoxicity during the first year in the group C2, and 52% in the group CO (p = 0.38). In seven patients (28%) of the group C2 and six patients of the group C0 (24%, p = 0.96) in the first two years following Tx, administration of CyA was interrupted due to nephrotoxicity. Overall graft function was good in both groups during the period of two years. One graft was lost in the group CO due to chronic allograft nephropathy. The patients in the group C2 had better early and the same late graft function. Five patients in the group C2 who did not reach the target C2/AUC during the first 30 days, did not have more AR or worse graft function, comparing with the patients who reached the target concentrations. CONCLUSION: In the patients with CyA TDM through with the C2 and AUC(0-4), AR frequency was considerably lower, and AR episodes had a milder flow than in those with CyA TDM through the CO. The drug concentration in blood two hours after administration (C2) was a good predictor of acute graft rejection, while CO failed to point to the patients with the insufficient drug concentration. Higher drug doses were administered in the group C2 during the first month following Tx, and these patients did not show significantly higher frequency of acute nephrotoxicity and more frequent requirement of the drug use interruption. Graft function in both groups was good during the period of two years. CyA dose determination through C2 and AUC(0-4) is efficient TDM method, relatively simple for use in day to day clinical practice.

[Ten year experience in kidney transplantation in patients undergoing peritoneal dialysis (1996-2006)].

INTRODUCTION: Kidney transplantation is nowadays considered the most sophisticated method of treatment of chronic terminal renal insufficiency. The advancement in surgical technique and the use of new immunosuppressive medications provide a longer survival period of both the patient and the graft. MATERIAL AND METHODS: The objective of this paper is a retrospective presentation of the ten-year monitoring of kidney transplantation in patients undergoing peritoneal dialysis performed at the Military Medical Academy. RESULTS AND DISCUSSION: During that period, 32 patients underwent the transplantation (18 men and 14 women of the average age of 32.48+/-2.1). The total of 34 transplantations were performed, out of which 2 were retransplantations. Patient monitoring period was 7-92 months. The immunosuppressive therapy was quadrupled in 17 (50%) patients and tripled in 17 (50%) of them. The loss of the graft in the early period following the transplantation occurred in 5 (15.6%) patients due to trombosis a. renalis, out of whom two were retransplantation cases. Registered surgical vascular complications included 5 (15.6%) bleeding, 4 (12.5%) hematomes and 6 (18.7%) lymfocells. Delayed graft function occurred in 5 (14.7%) and acute rejection in 7 (20.5%) patients while the disease reccured in 2 patients. As for the complications, rejection without the loss of graft was registered in 4 (12.5%) pts, ureter stenosis in 3 (8.82%) pts, bacterial infections in 4 (12.5%) pts and reactivation of CMV infections in 9 (26.4%) pts. Our patients are observed for the maintenance of stable medium volume of serum creatinine (which is 123.6 +/-10.2 umol/l in the early stage and 133.24+/-11.1 umol/l in the end of the monitoring period as well as the medium volume of clearence creatinine (which is 64.80+/-3.5 ml/min at the early phase of monitoring period and 69.47+/-3.3 ml/min. in the end). CONCLUSION: Our group of renal transplantation patients, undergoing peritoneal dialysis was with stable renal function registered through the monitoring period.