Kazimierz Ciechanowski

Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation

There is increasing interest in tacrolimus‐minimization regimens. ASSET was an open‐label, randomized, 12‐month study of everolimus plus tacrolimus in de‐novo renal‐transplant recipients. Everolimus trough targets were 3–8 ng/ml throughout the study. Tacrolimus trough targets were 4–7 ng/ml during the first 3 months and 1.5–3 ng/ml (n = 107) or 4–7 ng/ml (n = 117) from Month 4. All patients received basiliximab induction and corticosteroids. The primary objective was to demonstrate superior estimated glomerular filtration rate (eGFR; MDRD‐4) at Month 12 in the tacrolimus 1.5–3 ng/ml versus the 4–7 ng/ml group. Secondary endpoints included incidence of biopsy‐proven acute rejection (BPAR; Months 4–12) and serious adverse events (SAEs; Months 0–12). Statistical significance was not achieved for the primary endpoint (mean eGFR: 57.1 vs. 51.7 ml/min/1.73 m2), potentially due to overlapping of achieved tacrolimus exposure levels (Month 12 mean ± SD, tacrolimus 1.5–3 ng/ml: 3.4 ± 1.4; tacrolimus 4–7 ng/ml: 5.5 ± 2.0 ng/ml). BPAR (months 4–12) and SAE rates were comparable between groups (2.7% vs. 1.1% and 58.7% vs. 51.3%; respectively). Everolimus‐facilitated tacrolimus minimization, to levels lower than previously investigated, achieved good renal function, low BPAR and graft‐loss rates, and an acceptable safety profile in renal transplantation over 12 months although statistically superior renal function of the 1.5–3 ng/ml tacrolimus group was not achieved. (ClinicalTrials.gov: NCT00369161) is registered at http://www.clinicaltrials.gov.

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.

Sarcopenia: a major challenge in elderly patients with end-stage renal disease.

Sarcopenia is a condition of multifaceted etiology arising in many elderly people. In patients with chronic kidney, the loss of muscle mass is much more intensive and the first signs of sarcopenia are observed in younger patients than it is expected. It is associated with the whole-body protein-energy deficiency called protein-energy wasting (PEW). It seems to be one of the major factors limiting patients autonomy as well as decreasing the quality of life. If it cannot be treated with the simple methods requiring some knowledge and devotion, we will fail to save patients who die due to cardiovascular disease and infection, despite proper conduction of renal replacement therapy. Many factors influencing the risk of sarcopenia development have been evaluated in number of studies. Many studies also were conducted to assess the efficacy of different therapeutic strategies (diet, physical activity, hormones). Nevertheless, there is still no consensus on treatment the patients with PEW. Therefore, in the paper we present the reasons and pathophysiology of sarcopenia as an important element of protein energy wasting (PEW) in elderly patients suffering from chronic kidney disease. We also analyze possible options for treatment according to up-to-date knowledge.

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.

Platelets arachidonic acid metabolism in patients with essential hypertension.

Arachidonic acids (AA) metabolites, eicosanoids, exert a tremendous influence on circulatory and vascular homeostasis, and in humans are generated by many organs and cell types. In this study we wanted to verify whether platelets AA metabolism play a significant role in pathogenesis of essential hypertension (EH). Participants were divided into the study (EH) and the control group. Plasma and urine concentrations of isoprostanes (8-iPF2α-III) and thromboxane B2 (TxB2) were determined using the ELISA method. The levels of 5- and 12-hydroxyeicosatetraenoic (HETE) acids, generated by platelets, were analysed using RP-HPLC. In a suspension of not stimulated and AA-stimulated platelets TxB2 level was statistically lower in the study than in the control group (p < 0.0001 and 0.001 respectively). The concentration of 12-HETE was significantly elevated in EH patients compared to the control group; however, only in the non-stimulated conditions (p < 0.05). Plasma and urine F2-isoprostanes levels were significantly higher in hypertensive individuals than in the control group (p < 0.00002 and p < 0.01 respectively). Moreover, EH patients excreted more TxB2 in urine than normotensive individuals (p < 0.05). Our results highlight the mutual connections between the platelets AA metabolism and indicate its possible role in the pathogenesis of arterial hypertension. Moreover, we hypothesize that platelets AA metabolism may exert a pro-atherosclerotic effect. Finally, we suggest the use of (5-HETE+12-HETE)/TxB2 parameter in further studies.

Oxidative Stress and Antioxidative Enzyme Activities in Chronic Kidney Disease and Different Types of Renal Replacement Therapy

The incidence and diagnosis of chronic kidney disease (CKD) is on the rise all over the world. CKD is related to ageing of the society and high morbidity due to lifestyle diseases like diabetes, atherosclerosis, and hypertension. CKD is associated with increased oxidative stress generated by uremic toxicity, chronic inflammatory state, lack of vitamins and microelements, parenteral iron administration, and dialysis procedure itself. In terms of cellular physiology, erythrocytes and blood platelets in particular have effective enzymatic and non-enzymatic antioxidative system. The most efficient enzymatic antioxidants include superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase. Glutathione is the leading non-enzymatic free radical scavenger. In CKD, antioxidative defense is impaired and the abnormal activity of the enzymes and glutathione concentration is described in literature. The imbalance between the formation of reactive oxygen species and antioxidative system efficiency takes part in the pathogenesis of cardiovascular complications. It contributes to increased morbidity and mortality in patients with CKD. The severity of these processes depends on the type of renal replacement therapy; haemodialysis (HD) is more predisposing to such disorders than peritoneal dialysis (PD), or even conservative treatment. This can influence the outcome and the possibility of kidney transplantation. Moreover, the early function of kidney allograft seems to be dependent on perioperative antioxidative ability of platelets, which can play a potential protective role in kidney transplantation.

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.

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.

Novel Once-Daily Extended-Release Tacrolimus Versus Twice-Daily Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year Results of Phase 3, Double-Blind, Randomized Trial

BACKGROUND 1-year data from this trial showed the noninferiority of a novel once-daily extended-release tacrolimus (LCPT; Envarsus XR) to immediate-release tacrolimus (IR-Tac) twice daily after kidney transplantation. STUDY DESIGN Final 24-month analysis of a 2-armed, parallel-group, randomized, double-blind, double-dummy, multicenter, phase 3 trial. SETTING & PARTICIPANTS 543 de novo kidney recipients randomly assigned to LCPT (n=268) or IR-Tac (n=275); 507 (93.4%) completed the 24-month study. INTERVENTION LCPT tablets once daily at 0.17 mg/kg/d or IR-Tac twice daily at 0.1 mg/kg/d; subsequent doses were adjusted to maintain target trough ranges (first 30 days, 6-11 ng/mL; thereafter, 4-11 ng/mL). The intervention was 24 months; the study was double blinded for the entirety. OUTCOMES & MEASUREMENTS Treatment failure (death, transplant failure, biopsy-proven acute rejection, or loss to follow up) within 24 months. Safety end points included adverse events, serious adverse events, new-onset diabetes, kidney function, opportunistic infections, and malignancies. Pharmacokinetic measures included total daily dose (TDD) of study drugs and tacrolimus trough levels. RESULTS 24-month treatment failure was LCPT, 23.1%; IR-Tac, 27.3% (treatment difference, -4.14% [95% CI, -11.38% to +3.17%], well below the +10% noninferiority criterion defined for the primary 12-month end point). Subgroup analyses showed fewer treatment failures for LCPT versus IR-Tac among black, older, and female recipients. Safety was similar between groups. From month 1, TDD was lower for LCPT; the difference increased over time. At month 24, mean TDD for LCPT was 24% lower than for the IR-Tac group (P<0.001), but troughs were similar (means at 24 months: LCPT, 5.47 ± 0.17 ng/mL; IR-Tac, 5.8 ± 0.30 ng/mL; P=0.4). LIMITATIONS Trial participant eligibility criteria may limit the generalizability of results to the global population of de novo kidney transplant recipients. CONCLUSIONS Results suggest that once-daily LCPT in de novo kidney transplantation has comparable efficacy and safety profile to that of IR-Tac. Lower TDD reflects LCPTs improved bioavailability and absorption.

Does Glucose in Dialysis Fluid Protect Erythrocytes in Patients with Chronic Renal Failure

Background/Aims: The aim of this study was to assess the multifaceted influence of glucose present in dialyzing fluid on erythrocytes of patients with chronic renal failure (CRF) undergoing regular hemodialysis. Methods: A group of 44 subjects with CRF undergoing regular hemodialysis was studied. Two tests were used: osmotic fragility and resistance to the hemolytic agent saponin. The total content of isoprostane 8-iso-prostaglandin F2α type III (8-iPF2α-III) in plasma and erythrocyte’s membrane were determined by the ELISA method. Results: The presence of glucose in the dialysate is associated with lower intravascular hemolysis markers and high total 8-iPF2α-III concentrations in plasma. Conclusion: The presence of glucose in dialyzing fluid could protect erythrocytes. It limits hemolysis in patients with CRF, but, on the other hand, increases the oxidative processes. This kind of treatment along with other therapeutic intervention such as administration of antioxidants (e.g. α-tocopherol, ascorbic acid, N-acetylcysteine) could improve the condition of erythrocytes and outcome in CRF.