Comparison of accepted and unaccepted living kidney donors: one-center experience.

BACKGROUND: Kidney transplantation from living donors (LD) has stagnated in many countries. This study aimed to check whether correction of LD selection practice could increase the number of kidney transplantations. METHODS: From January 2003 to December 2012, 241 potential adult LD were evaluated in our hospital. Outcome (mortality and end-stage renal disease-ESRD) of accepted LD (182) was compared with unaccepted (59) donors. RESULTS: Mortality of LD was comparable with that for the standardized Serbian population (SMR = 1.104; 95% CI (0.730-1.606). Among evaluated potential LD, almost every fourth had been unaccepted, but reasons were modifiable in 42.4% of them. In pre-donation period unaccepted donors were significantly older, measured glomerular filtration rate was lower, with higher 15-year and lifelong projected ESRD risks than accepted donors. Despite this, ten years outcome of both groups LD was similar: none of LD developed ESRD, 9.8% of accepted and 11.8% of unaccepted LD died (p = .803). CONCLUSIONS: During an average of 101 months of follow-up mortality of accepted LD did not differ significantly as compared to the age standardized Serbian population and none of them developed ESRD. In examination of potential LD, the use of accurate and precise methods for kidney function estimation and the evaluation of risk for ESRD and mortality as well as treatment of modifiable contraindications for kidney donation are necessary.

Exploring Sirolimus Pharmacokinetic Variability Using Data Available from the Routine Clinical Care of Renal Transplant Patients - Population Pharmacokinetic Approach.

BACKGROUND: Due to wide intra- and inter-individual pharmacokinetic variability and narrow therapeutic index of sirolimus, the therapeutic drug monitoring (TDM) of sirolimus with detailed biochemical and clinical monitoring is necessary for dose individualization in kidney transplant patients. The purpose of the study was to explore and identify factors that contribute to pharmacokinetic variability by developing and validating a population model using routine TDM data and routinely monitored biochemical and clinical parameters. METHODS: The data obtained by routine monitoring of 38 patients over a period of one year from the sirolimus treatment initiation, were collected from patients' records. Population analysis was performed using the software NONMEM®. The validity of the model was tested by the internal and external validation techniques. RESULTS: The pharmacokinetic variability was partially explained with patient's age and liver function. CL/F was found to decrease with age. According to the developed model, sirolimus CL/F decreases by, in average, 37% in patients with aspartate aminotransferase (AST) greater than 37 IU/L. The internal and external validation confirmed the satisfactory prediction of the developed model. CONCLUSIONS: The population modeling of routinely monitored data allowed quantification of the age and liver function influence on sirolimus CL/F. According to the final model, patients with compromised liver function expressed via AST values require careful monitoring and dosing adjustments. Proven good predictive performance makes this model a useful tool in everyday clinical practice.

Population Pharmacokinetic Approach of Immunosuppressive Therapy in Kidney Transplant Patients.

Immunosuppressive therapy is the cornerstone of successful kidney transplantation. Frequently used immunosuppressives are cyclosporine, tacrolimus, sirolimus and mycophenolic acid. These drugs have narrow therapeutic index and show high pharmacokinetic variability. In order to maintain the balance between efficacy and safety, dosing is based on measured drug concentrations. Proper identification, quantification and understanding the sources of variability in measured concentrations facilitate routine dose adjustment in clinical practice. Classical pharmacokinetic studies have limited use in transplant patients attributable to design with intense sampling in a small, relatively homogenous population, and identification of only single variability factor per study. Population approach is a powerful tool for analysing sparse data, identifying factors that influence drug pharmacokinetics and estimating variability. In this report we reviewed available population pharmacokinetic models for cyclosporine, tacrolimus, sirolimus and mycophenolic acid in adult kidney transplant patients. The major focus was to describe various demographic factors, biochemical parameters, genetic polymorphisms of metabolic enzymes and transporters and drug-drug interactions, which have been identified as an important concern of pharmacokinetic variability in kidney transplant patients.

Cystatin C and serum creatinine as predictors of kidney graft outcome.

PURPOSE: Serum cystatin C (Cys C) was evaluated as a predictor of kidney graft failure progression, and its predictive ability was compared to other markers of graft function. METHODS: The following kidney graft markers were determined in 91 patients who came for regular checkups of kidney graft function to our outpatient service in February 2008: Cys C, serum creatinine (sCr), 24-h proteinuria and 24-h urinary creatinine clearance (CCr). Glomerular filtration rate (eGFR) was estimated using sCr-based and Cys C formula. Patients were regularly monitored until February 2013 or to graft failure. RESULTS: During follow-up, graft failure occurred in 21 recipients. The Cys C ≥2.65 mg/l discriminated patients with and without graft failure (sensitivity of 80.95% and specificity of 92.86%). According to c statistic, the highest performance was achieved for Cys C (0.874). In addition, Cys C area under the curve (AUC) was significantly better than CCr AUC (p = 0.007), 24-h proteinuria AUC (p = 0.03), eGFR estimated by the chronic kidney disease epidemiology collaboration (EPI) AUC (p = 0.05), but not better than sCr or eGFR AUCs calculated by other formulas. In the multivariable model, sCr, CCr, Cys C and eGFRs were predictors of graft failure. Combination of Cys C, sCr and logarithm of 24 h proteinuria (0.883) or Cys C, CCr and logarithm of 24-h proteinuria (0.884) had the highest AUC for predicting graft outcome that exceed insignificantly Cys C or sCr areas. CONCLUSIONS: The most reliable predictors of graft outcome were Cys C, sCr and proteinuria. Because Cys C is unavailable in many transplant centers, from the practical point of view, sCr remains the most sensitive predictor of graft outcome.

Total plasma protein effect on tacrolimus elimination in kidney transplant patients--population pharmacokinetic approach.

Data from routine therapeutic drug monitoring of 105 adult kidney transplant recipients were used for population pharmacokinetic analysis which was performed using a non-linear mixed-effects modeling. The effect of demographic and clinical factors on tacrolimus clearance was evaluated. Following the initiation of treatment with tacrolimus, the results of our study indicate a decrease of the drug clearance on day 15, 1 and 6 months after transplantation for 4.4%, 6.3% and 10.92%, respectively. Our model suggests a negative correlation between tacrolimus clearance and haematocrit. According to final model, clearance decreases with increasing of aspartate aminotransferase. Our results demonstrated that CL/F increases with patients' weight. This study reveals incensement for 10.4% in tacrolimus clearance with alteration of patients' minimal measured total protein levels to upper normal range. The findings of this study explore various factors of tacrolimus pharmacokinetic variability and point out a relationship between tacrolimus clearance and total plasma protein. Developed model demonstrates the feasibility of estimation of individual tacrolimus clearance and may allow rational individualization of tacrolimus dosing in kidney transplant patients.

Malignant disease in renal transplant recipients--our experience.

Kidney transplantation is a treatment of choice for patient with end stage renal disease. Chronic renal failure is characterized with weak cellular and humoral immunity. In our paper we present our experience with presence of malignancy in renal transplant patients. Urology clinic in Belgrade transplanted 411 patients over the period of 16 years. Living donor transplantation was performed for 272 and cadaveric kidney transplant for 139 patients. In the postoperative follow up, malignancies were diagnosed in 7 of the transplanted patients. Three patients developed basal cell skin carcinoma, one was diagnosed with adenocarcinoma of the transplanted kidney, one developed transitional cell carcinoma of the bladder and testicular tumors were diagnosed in two patients. Postoperative immunosuppressive therapy usually double or triple when patients are in the immunological high risk group. Incidence of malignancy according to big health centers is around 1 in every 1000 transplanted patients. It is also noted the rise of incidence of malignancies in transplanted patient in over 50%.

[Bilateral tumors of the upper urothelium].

INTRODUCTION: The incidence of tumors of the upper urothelium is high in our country, apart from their relation to specific regions (BEN and PBEN) and their frequent bilateralism. Bilateral forms are present in significant percentage and are followed, in most cases, by renal failure, which speaks in favor of conservative surgery, if possible. OBJECTIVE: The aim of the study was to present epidemiological, pathoanatomical and clinical characteristics of bilateral tumors of the upper urothelium and evaluate the results of their treatment. METHOD: Our retrospective study analyzed 12 patients with bilateral tumors of the upper urothelium who were treated in the period from 1992 to 1996, according to their epidemiological, clinical, pathoanatomical and pathohistological characteristics, type of surgical treatment and relevant success. RESULTS: In the observed period, bilateral tumors of the upper urothelium were found in 8.2% of our patients. In the group of 12 patients, 5 females and 7 males, 11 cases were from the region of Balkan Endemic Nephropathy (BEN). Renal failure was recorded in high percentage (66%). Radical surgical treatment--total nephroureterectomy was performed in 9 kidney units, and conservative operation in 15 units. Relapse significantly depended on tumor stage and grade, not on type of surgical treatment in the majority of cases. Five-year survival was 58.33%; major cause of death was associated with further evolution of tumor, recurrence and tumor dissemination, respectively, while renal failure complications were the cause of death in one case. CONCLUSION: The success of treatment mainly depends on tumor stage and grade and not on type of surgical method in conservative treatment, but renal failure and its complications are an important risk factor in these patients.

Factors associated with hyperhomocysteinemia after renal transplantation.

Recent studies show that clinically stable renal transplant recipients have an increased prevalence of hyperhomocysteinemia (hyperHcy), but the mechanism of this disorder has not yet been elucidated. The aim of the present study was to evaluate the factors associated with hyperHcy after a successful renal transplantation. In 106 stable renal transplant recipients, total serum Hcy level (tHcy), folate, total protein, serum creatinine concentration, creatinine clearance, lipid status, body weight (BW), body mass index (BMI), and body fat (BF) were determined. The mean doses of cyclosporine, prednisolone, and azathioprine (mg/kg/day) were recorded. The mean serum tHcy level was significantly higher in renal transplant patients than in healthy controls (22.02 +/- 8.02 versus 13.0 +/- 3.3 micromol/ L; p < 0.001), and the incidence of patients with hyperHcy was 82%. Comparison of the group of 20 patients with tHcy level <15 micromol/L and the group of 86 patients with tHcy level >15 micromol/L revealed that the latter was significantly older, heavier, had been longer on dialysis before renal transplantation, and had older donors and poorer renal graft function. Significant correlation was found between tHcy level and recipient age, dialysis duration, BW, creatinine clearance, serum creatinine, and folate concentration. However, multivariate analysis indicated that creatinine clearance (p = 0.025) and BW (p = 0.03) were the only determinants of elevated total Hcy level in renal transplant recipients. HyperHcy persists after successful kidney transplantation in the majority of renal transplant recipients, and its appearance is primarily associated with creatinine clearance and body weight.

[Evaluation of the rate of progression of chronic renal transplant rejection using the proliferating cell nuclear antigen ]. / Procena brzine progresije hronicnog odbacivanja transplantisanog bubrega pomocu nuklearnog antigena proliferacije celija.

UNLABELLED: Since the introduction of kidney transplantation, the short-term patient and graft survival have been progressively improving, but the long-term graft survival and half-life of transplants have not. Beyond doubt, chronic rejection (CR) remains the major cause of chronic graft failure and is responsible for the loss over 10 years of 50% of grafts. (1-4). CR is characterized clinically by proteinuria, hypertension and declining renal function, and pathologically by arteriosclerosis, glomerulosclerosis and interstitial fibrosis. The progressive morphological changes of glomerular, vascular and tubulointerstitial (TIN) compartments in renal allografts experiencing chronic rejection correlate directly with declining renal function and the eventual graft loss [5]. In consideration of this fact and using proliferating cell nuclear antigen (PCNA) as a marker of cell proliferation, a retrospective analysis of renal allograft biopsies was carried out with the aim to determine whether quantification of the cell proliferation activity in three tissue compartments may be used as a prognostic index of CR progression. SUBJECTS AND METHODS: Clinical course and biopsy specimens of 27 patients with clinically and morphologically confirmed (Banff schema) diagnosis of CR were retrospectively evaluated. Patients were transplanted between 1988 and 1994 at our Institute and regularly followed-up for at least 2 years after transplantation (14 patients), or till haemodialysis has been resumed (11 patients) or till death (2 patients). The progression rate of renal graft function deterioration was estimated by slopes of regression lines obtained by plotting 1/sCr vs time. According to the progression rate after biopsy patients were divided into two groups: fast progression group (10 patients) and slow progression group (17 patients). Immunosuppressive regimens included induction with anti-lymphocyte globulin followed with cyclosporine, steroids and azathioprine. Immunohistochemistry. Sections of formalin-fixed, paraffinembedded tissue were stained for PCNA with monoclonal mouse anti-proliferating cell nuclear antigen (clone PC 10, Dako) as follows in ref. [6]. PCNA immunoreactivity of smooth muscle cells and lymphocytes in vascular intima, lymphocytes in TIN and glomerular mesangium proliferation was assessed by semiquantitative scoring (scale 0-3). Normal tonsil was used as a positive control. Differences between groups were evaluated using Student's t-test. Pearson's correlation test was used to study the relationship between variables. P values < 0.05 were considered as significant. RESULTS: Data on patients are presented in Table 1. The only statistical difference was in progression of chronic graft failure presented by regression lines obtained by plotting 1/sCr vs time. PCNA protein expressions in vascular, glomerular and TIN compartments for both groups are presented in Figs. 1-3.. PC 10 immunoreactivity was confined to the nucleus. The pattern of staining was granular or diffuse. Individual values of the scores of PCNA immunoreactivity in different tissue compartments for the groups examined are presented in Tables 2 and 3. Comparison of the means of PCNA immunoreactivity scores in different tissue compartments of fast and slow progression group showed that cells proliferation in glomerular, TIN and vascular compartments are significantly higher in the fast than in the slow progression group (Table 4). Besides, significant positive correlation was found between the slopes of the regression lines plotting 1/sCr vs. time and cells proliferation scores for all compartments (Table 5). DISCUSSION: Chronic graft failure may occur due to CR, cyclosporine nephrotoxicity, repeated acute rejection, recurrent glomerular diseases, surgical and urological complications, but CR was recognized as the most common cause of chronic graft failure and renal graft loss [7]. Progression of renal disease reflects the interactive effects of changes in the structure and function. This notion has been examined many times in the native kidneys by studies correlating glomerular filtration rate with architectural deterioration in the glomerular or interstitial compartment [8-10]. Meanwhile, the similar studies in human renal allograft are scarce. Increased PCNA immunodetection in glomerular cells as well as in interstitial infiltrates was described in acute and chronic renal graft rejection and diagnostic value of this finding was analyzed [12, 15]. Similarly, PCNA was often examined immunohistochemically in lymphoma and solid tumours as a marker of cell proliferation, but its reliability as a prognostic factor was also evaluated [18-20]. In the present study the prognostic value of PCNA expression in different tissue compartments of renal grafts experiencing CR was examined for the first time. The present study revealed that two groups examined with the different chronic graft failure progression rate as the main difference had significantly different proliferation of cells in glomerular, TIN and vascular compartments. PCNA immunoreactivity scores in these three compartments were significantly higher in the fast than in slow progression group. The significant positive correlation between the slope of the regression line plotting 1/sCr vs. time and cell proliferation in glomerular, TIN and vascular compartments was also found. Therefore, it was suggested that the measurement of PCNA expression in renal graft tissue might be used as a prognostic index.

Co-morbidity and kidney graft failure-two main causes of malnutrition in kidney transplant patients.

BACKGROUND: Malnutrition is very frequent in chronic renal failure but, after successful kidney transplantation, body weight gain is common and is widely investigated, while malnutrition after transplantation is underestimated. In the present study, the prevalence of malnutrition in kidney transplant patients and the factors which might contribute to its development are analysed. METHOD: In a population of 452 kidney transplant patients followed-up regularly at our department, body mass index (BMI) was determined. Out of this population, 47 patients (18 females, aged 13-54 years, post-transplantation period 6-180 months) were randomly selected for more detailed examination of their nutritional status using anthropometry (body weight, the mid-arm muscle circumference, skinfold thickness, BMI) as well as biochemical parameters (serum protein, albumin, cholesterol, red blood cell count). Co-morbidity of the selected patients was assessed using the Index of Coexistent Diseases. RESULTS: Among 452 kidney transplant patients, 15% had a BMI of <21 kg/m(2), 45% had a BMI of 21-25 kg/m(2), and 40% had a BMI >25 kg/m(2). After more accurate assessment of nutritional status of the selected 47 patients, a comparison between those who were malnourished (11 patients) and those who were well nourished (20 patients) was made. No significant difference was found in age at transplantation, pre-transplantation time on dialysis, donor origin, early post-transplant course, immunosuppressive therapy, number of rejection episodes or post-transplant period between these two groups. However, malnutrition appeared significantly more frequently in females, and malnourished patients had significantly higher serum creatinine levels. Co-morbidity conditions, assessed by the Index of Disease Severity and Index of Physical Impairment combined peak scores resulting in the final Index of Coexistent Disease, were more frequent and more severe in malnourished patients as compared with well-nourished patients. CONCLUSION: In a population of kidney transplant patients regularly followed-up at our clinic, 15% had malnutrition. Malnutrition is more frequent in females, but kidney graft failure and co-morbidity had a significant role in its development.