Leszek Domański

Experience With Autosomal Dominant Polycystic Kidney Disease in Patients Before and After Renal Transplantation : A 7-Year Observation

OBJECTIVE Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the presence of multiple cysts in both kidneys. Symptoms of the disease may arise either from the presence of cysts or from increasing loss of kidney function. First symptoms usually appear in the third decade of life: lumbar pain, urinary tract infections, arterial hypertension, or renal colic due to cyst rupture or coexistent nephrolithiasis. An early diagnosis, male gender, large kidneys by sonography, arterial hypertension, hematuria, and urinary tract infections are predictive factors of a faster progression of the disease. Our aim was to establish the indications for nephrectomy among symptomatic ADPKD patients before kidney transplantation and to assess the risks of posttransplantation complications among ADPKD patients without nephrectomy. PATIENTS AND METHODS The observed group consisted of 183 patients with ADPKD among whom 50 (27.3%) underwent kidney transplantation during a 7-year observation period (2000-2007). Among those subjects were 3 groups: (I) nephrectomy preceding transplantation; (II) nephrectomy during kidney transplantation; and (III) without nephrectomy. RESULTS Among group I before transplantation we observed: arterial hemorrhage, wound infections, and splenectomy 4 weeks after ADPKD nephrectomy; afterward we observed: urinary tract infections and contralateral cyst infection. Among group II we only observed 1 case of wound infection. Among group III we observed: ascending urinary tract infections, cyst infections, and cyst hemorrhage. Cyst hemorrhage and cyst infections led mainly to ADPKD kidney nephrectomy. During the observation time, 80.95% of grafts were functioning. CONCLUSIONS Unilateral nephrectomy is a well-founded preliminary surgical treatment before kidney transplantation. Bilateral nephrectomy before or during transplantation eliminates ADPKD complications and does not significantly increase general complications. The greatest numbers of complications and of graft losses were observed among the group without pretransplantation nephrectomy.

CYP3A5 and CYP3A4, but not ABCB1 polymorphisms affect tacrolimus dose-adjusted trough concentrations in kidney transplant recipients

BACKGROUND Tacrolimus (TAC), acting as a calcineurin inhibitor, is an immunosuppressant widely used after kidney transplantation. TAC requires blood concentration monitoring due to large interindividual variability in its pharmacokinetics and a narrow therapeutic index. Since genetic factors are considered responsible for a part of the observed pharmacokinetic variability, hereby SNPs within the CYP3A4, CYP3A5 and ABCB1 genes in kidney transplant patients of Polish Caucasian origin were investigated. PATIENTS & METHODS A total of 241 patients treated with TAC through the first year after kidney transplantation were genotyped for the presence of common SNPs: rs776746:A>G (CYP3A5*3), rs35599367:C>T (CYP3A4*22), rs2740574:A>G (CYP3A4*1B) and rs1045642:C>T (ABCB1 3435C>T) using TaqMan(®) assays. RESULTS CYP3A5 expressers received significantly higher weight-adjusted TAC doses, and were characterized by markedly lower C0 and dose adjusted C0 values in the course of treatment. CYP3A4*1B was significantly associated with TAC pharmacokinetics in univariate analysis. Impact of the CYP3A4*22 allele was significant only at particular time points, that is, 3 months after transplantation, with marginal significance 6 months after transplantation. The ABCB1 genotype did not influence TAC pharmacokinetics. Multivariate analysis of all the studied loci demonstrated that only the CYP3A5*1 (starting from month 1) and CYP3A4*22 alleles (at 3 and 6 months) were independent predictors of TAC dose-adjusted C0. CONCLUSION Our results confirm the impact of the CYP3A4*22 allele on TAC pharmacokinetics, as a second significant genetic factor (in addition to the CYP3A5*1 allele) influencing TAC dose-adjusted blood concentrations in kidney transplant recipients.

Clinical analysis of perioperative complement activity during ischemia/reperfusion injury following renal transplantation.

BACKGROUND AND OBJECTIVES The complement cascade seems to be an important mediator modulating renal ischemia/reperfusion injury. This study analyzed whether significant changes occur in the levels of a terminal panel of complement molecules (C3a, C5a, and C5b-9/membrane attack complex) during the early phase of human kidney allograft reperfusion and evaluated the potential association of these changes with clinical post-transplant graft function in kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Seventy-five renal transplant recipients undergoing transplantation between 2004 and 2006 were enrolled in the study and divided into early, slow, and delayed graft function groups. Blood samples were collected perioperatively during consecutive minutes of allograft reperfusion from the renal vein. Levels of complement molecules were measured using ELISA. RESULTS Analysis revealed no significant changes in C3a and C5a levels throughout reperfusion. The main complement molecule that was significantly associated with post-transplant graft function was C5b-9/membrane attack complex; throughout the reperfusion period, perioperative levels of C5b-9/membrane attack complex were around two to three times higher in delayed graft function patients than early and slow graft function individuals (P<0.005). In addition, C5b-9/membrane attack complex levels had a relatively high clinical sensitivity and specificity (70%-87.5%) for the prediction of early and long-term (1 year) post-transplant allograft function. CONCLUSIONS This clinical study supports a role for the complement cascade in delayed graft function development. However, additional studies are needed to elucidate the exact mechanisms responsible for this phenomenon. In addition, perioperative measurements of C5b-9/membrane attack complex are highlighted as promising potential clinical markers of post-transplant renal allograft function.

Elements of Mediterranean diet improve oxidative status in blood of kidney graft recipients

Patients were fully informed as to the study objectives and benefits, and provided written consent prior to enrolment. The study protocol was approved by the Committee on Human Research at the Pomeranian Medical University, Szczecin, Poland. An intensification of free-radical reactions may contribute to accelerated atherosclerosis in kidney graft recipients. We examined the effect of a Mediterranean-type diet (MD) on the oxidative status of the plasma and erythrocytes of kidney graft recipients. Two patient groups were formed: a study group consuming the MD diet and a control group with a low-fat diet. C-reactive protein levels in plasma, oleic acid C18 : 1n-9 and linoleic acid C18 : 2n-6 concentrations in triacylglycerols were determined. To determine the oxidative status, we measured the concentrations of alpha-tocopherol in plasma, the content of thiobarbituric acid-reactive species (TBARS) in plasma and erythrocytes, and the activities of superoxide dismutase, catalase and glutathione peroxidase in erythrocytes. In the MD group, the activities of erythrocyte enzymes changed significantly: those of superoxide dismutase increased (P<0.001 after 6 months), catalase decreased (P<0.001 after 6 months) and glutathione peroxidase decreased (P<0.05 after 2 months). The oleic acid content of triacylglycerols was increased (P<0.006) whereas that of linoleic acid was decreased (P<0.00005), alpha-tocopherol levels remaining unchanged. TBARS in plasma were decreased after 6 months of MD (P<0.05). No significant correlations were observed between TBARS, oleic acid, linoleic acid and alpha-tocopherol levels in plasma. MD appears to protect the erythrocytes against the action of free radicals, as reflected in the modified activities of some enzymes regulating the oxidative status of these blood cells.

Autosomal Dominant Polycystic Kidney Disease Is Not a Risk Factor for Post-transplant Diabetes Mellitus. Matched-pair Design Multicenter Study

BACKGROUND Post-transplant diabetes mellitus (PTDM) is a relatively common complication of kidney transplantation. The aim of our work was to compare the incidence of PTDM in kidney transplant recipients with and without autosomal dominant polycystic kidney disease (ADPKD) in a matched-pair design study. METHODS In total, 98 pairs of graft recipients, all of Caucasian origin and who received a kidney from the same cadaveric donor, were included in the study. The following clinical data were collected for statistical analysis: age, body mass index (BMI) before transplant, length and type of dialysis treatment, residual diuresis, and cold and warm graft ischemia time. Diabetes was diagnosed based on American Diabetes Association (ADA) criteria. RESULTS Incidence of PTDM was 19.4% in the ADPKD group and 18.4% in the non-ADPKD group, with no significant differences between groups. Multivariate logistic regression analysis of the PTDM risk in the ADPKD group including age, gender, BMI, and dialysis time as independent variables indicated that only higher residual diuresis is a significant independent risk factor (OR = 5.64 per every L/24 h, 95% CI = 1.31-24.33, p = 0.017). Similarly, logistic regression analysis adjusted for age and gender in the non-ADPKD group has shown that significant independent risk factors are BMI (OR = 1.30 per every kg/m(2), 95% CI = 1.06-1.59, p = 0.0094), longer dialysis time prior to transplant (OR = 1.036 per each month, 95% CI = 1.004-1.070, p = 0.025), and a history of arterial hypertension (OR = 9.09, 95% CI = 1.20-68.66, p = 0.030). CONCLUSIONS In this paired analysis, our results suggest that diagnosis of ADPKD does not increase risk of PTDM.

Association between the perioperative antioxidative ability of platelets and early post-transplant function of kidney allografts: a pilot study.

Background Recent studies have demonstrated that the actions of platelets may unfavorably influence post-transplant function of organ allografts. In this study, the association between post-transplant graft function and the perioperative activity of platelet antioxidants was examined among kidney recipients divided into early (EGF), slow (SGF), and delayed graft function (DGF) groups. Methodology/Principal Findings Activities of superoxide dismutase, catalase, glutathione transferase (GST), glutathione peroxidase, and glucose-6-phosphate dehydrogenase (G6P) were determined and levels of glutathione, oxidized glutathione, and isoprostane were measured in blood samples collected immediately before and during the first and fifth minutes of renal allograft reperfusion. Our results demonstrated a significant increase in isoprostane levels in all groups. Interestingly, in DGF patients, significantly lower levels of perioperative activity of catalase (p<0.02) and GST (p<0.02) were observed. Moreover, in our study, the activity of platelet antioxidants was associated with intensity of perioperative oxidative stress. For discriminating SGF/DGF from EGF, sensitivity, specificity, and positive and negative predictive values of platelet antioxidants were 81–91%, 50–58%, 32–37%, and 90–90.5%, respectively. Conclusions During renal transplantation, significant changes occur in the activity of platelet antioxidants. These changes seem to be associated with post-transplant graft function and can be potentially used to differentiate between EGF and SGF/DGF. To the best of our knowledge, this is the first study to reveal the potential protective role of platelets in the human transplantation setting.

Activity of CuZn-superoxide dismutase, catalase and glutathione peroxidase in erythrocytes in kidney allografts during reperfusion in patients with and without delayed graft function.

Abstract:  Background:  Generation of reactive oxygen species (ROS) is the main mechanism involved in the ischemic/reperfusion damage of the transplanted organ. Oxygen burst is a trigger for complex biochemical events leading to generation of oxygenated lipids and changes in microcirculation. Many markers have been researched to prove the presence of ROS in the transplanted tissue. Some of them, like superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) are considered to play a major role in graft protection against oxygen stress during reperfusion.

Is it possible to predict the early post-transplant allograft function using 20-HETE measurements? A preliminary report

20‐HydroxyEicosaTetraEnoic (20‐HETE) acid is an arachidonic acid metabolite that is generated via cytochrome P450 enzymes, and according to the findings from recent studies, may be involved in the pathogenesis of ischemia–reperfusion injury. The aim of this study was to: examine the dynamics of 20‐HETE changes during the first 5 min of allograft reperfusion, and analyze whether the observed changes are associated with post‐transplant graft function. Sixty‐nine renal transplant recipients were divided, according to their outcome, into early, slow and delayed graft function (EGF, SGF, DGF) group. Blood samples were collected directly before and during the first 5 min of allograft reperfusion. 20‐HETE concentrations were measured using ELISA. The results demonstrated significant differences in the concentrations and in the dynamics of 20‐HETE changes between patients with immediate graft function, and individuals with allograft activation problems. The sensitivity, specificity, positive and negative predictive value of 20‐HETEΔ(5‐0) parameter in discriminating EGF and SGF from DGF were 69%, 54%, 74% and 48% respectively. Therefore, our results demonstrated that the dynamics of 20‐HETE changes, which occurs during early phase of allograft reperfusion, is associated with early post‐transplant graft function and also highlighted 20‐HETE as a novel clinical marker of post‐transplant allograft function.

Histopathologic evaluation of pretransplantation biopsy as a factor influencing graft function after kidney transplantation in 3-year observation.

BACKGROUND Many factors affect long-term results in kidney transplantation including histologic damage as a independent predictor, eg, chronic allograft dysfunction (CAD) in protocol biopsies and age-dependent lesions. Histopathologic findings correlate with the incidence of delayed graft function, eventual renal function, and allograft survival, allowing a rather precise prediction of graft outcomes. PATIENTS AND METHODS We analyzed 92 thick-needle preimplantation renal biopsies and 29 from grafts after explantation. They had been preserved in 4% formalin and immersed in paraffin. Evaluable specimens contained ≥10 glomeruli and ≥2 arterial cross-sections. We analyzed tubulitis, intensity of acute tubular necrosis (ATN), inflammatory infiltration, glomerulonephritis, arterial hyalinization, arteritis, fibrosis, tubular atrophy, arterial intimal fibrosis, increased mesangial matrix, and glomerulosclerosis percentage, although for comparative analysis not only optimal ones were taken into consideration. Over postoperative time, we analyzed patient condition, urine output, serum concentrations of creatinine, urea, uric acid, and ions as well as necessity for postoperative dialysis, ie, delayed graft function (DGF). During the 3-year observation we analyzed living recipients, graft loss, death with a functioning graft, incidence of dysfunction (CAD), and acute rejection episodes (ARE). RESULTS We observed significant correlations between immediate graft function (IGF) and lack of ATN in the pretransplantation biopsy. The presence of ATN significantly correlated with DGF and primary graft non-function. There was no correlation between renal function and arterial hyalinization or fibrosis, inflammatory infiltration, and tubular atrophy. Over postoperative time we observed significant correlations between IGF and the lack of interstitial fibrosis as well as significantly lower levels of creatinine, urea, and potassium as well as greater urine output early after transplantation. IGF correlated with shorter time to reach a creatinine level of 2 mg/dL, lower concentrations of creatinine, urea, and potassium, as well as greater diuresis during the first 5 days. In addition, lower creatinine and urea concentrations after 1 month and of urea at 6 and 36 months were associated with IGF. Female recipients showed lower concentration of creatinine over 3 months, of urea during the 1st day, and of potassium at 1 month; however, thereafter the differences were not significant. Better function of the right kidney was observed. The presence of severe ATN (ATN III) correlated with lower creatinine concentrations at 6 months and urea after 3 years. The presence of hyalinization in biopsies correlated with higher concentrations of urea at 1 year and of borderline significance after 3 years; surprisingly, potassium concentrations were lower after 2 and 3 years. The presence of inflammatory infiltrates correlated with higher creatinine concentrations after 1 and 3 years; similar correlations, albeit of borderline significance, were observed in tubular atrophy. Interstitial fibrosis correlated with creatinine concentrations during 10 days after the operation and after 12 months, also with potassium concentrations 5 days after the operation. Borderline correlations were observed between donor age and creatinine concentration in the first day after the operation, after 6 months, and time to achieve a creatinine concentration of 2 mg/dL. We observed that biopsies with greater numbers of glomeruli correlated with better graft function, namely, lower creatinine concentrations after 5 days as well as at 1 and 6 months, as well as lower urea concentrations after 5 days and 6 months. We also observed differences in renal function depending on gender. The presence of acute tubular necrosis, arterial fibrosis and a lack of inflammatory infiltration in pretransplantation biopsy correlated with worse late renal function. Explantation biopsies showed signs of CAD in 66.4% and histologic features of ARE in 38.51%.

Polymorphisms of superoxide dismutase, glutathione peroxidase and catalase genes in patients with post-transplant diabetes mellitus.

BACKGROUND AND AIMS Post-transplant diabetes mellitus (PTDM) is a metabolic disorder that develops in response to a relative insulin deficiency in patients after organ transplantation treated with immunosuppressive drugs. Several studies have suggested that oxidative stress may be associated with diabetes and its complications. The aim of this study was to examine the association of polymorphisms in superoxide dismutase, catalase and glutathione peroxidase genes with PTDM in patients after kidney transplantation. METHODS The study included 159 patients receiving kidney transplants. PTDM was diagnosed in 21 patients. RESULTS Analyzing the C599T (Pro200Leu) polymorphism in the GPX1 gene PTDM was diagnosed in 8.45% of patients with CC genotype, 13.43% with CT and in 28.57% with TT. Allele T was significantly more frequent among patients with PTDM compared to patients without PTDM (OR = 2.14, 95% CI = 1.11-4.12, p = 0.024). There were no associations between SOD1, SOD2 and CAT polymorphisms and PTDM. CONCLUSIONS The present results suggest that Pro200Leu polymorphism of the GPX1 gene may be associated with the risk of PTDM development in renal graft recipients.