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Trial Registration: PEP Study: Ethics committee N° 393/2004, EudraCT 2004-004209-98. PEP-X Study: Ethics committee amendment application N° 154/01/2008. ClinicalTrials.gov NCT03751332., Competing Interests: This commercial affiliation (in the form of salaries from Astellas Pharma Inc. for MP, research/travel funds for MR, and an unrestricted grant for GSP) does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products.

Background: The multidrug resistance 1 gene (ABCB1) encodes P-glycoprotein (PGP), mainly expressed in the liver and engaged in metabolism of drugs including the immunosuppressant tacrolimus (TAC). ABCB1 single nucleotide polymorphisms (SNP) may significantly alter pharmacokinetics and influence TAC concentrations of kidney transplant recipients (KTR)., Methods: The genotype distribution of ABCB1 1236C>T, 2677G>T/A and 3435C>T was investigated among 96 Austrian KTR who were converted from cyclosporin to TAC. Dose adjusted TAC trough levels and L/D ratios were assessed at week 1, 2, 4, and 8, and month 3, 12, and 24, and the influence of ABCB1 genotypes on dose adjusted TAC trough levels and level to dose (L/D) ratios were analyzed., Results: The genotype distributions for ABCB1 1236C>T were CC 36.4%, CT 5.2%, TT 58.3%, for ABCB1 2677G>T/A GA 2%, GG 63.5%, GT 20.8%, TA 1%, TT 12.5%, and for ABCB1 3435C>T CC 20.8%, CT 7.2%, TT 71.8%. Dose adjusted TAC trough levels and L/D ratios were independent of ABCB1 genotypes except for ABCB1 1236C>T at a single time point (week 2: 0.02599 [CC] vs. 0.05704 [CT] vs. 0.03218 [TT]; p = 0.024)., Conclusions: Serial analyses of TAC trough levels revealed no significant association with important ABCB1 genotypes among stable long-term Austrian KTR.

Background: Tacrolimus (TAC) to ciclosporin A (CSA) conversion studies in stable kidney transplant recipients have reported varying effects on graft function. Here we study graft function (eGFR) trajectories using linear mixed models, which provide effect estimates on both slope and baseline level of GFR and offer increased statistical power., Methods: Secondary analysis of a randomized controlled trial of CSA treated kidney transplant recipients with stable graft function assigned to receive 0.1 mg/kg/day TAC (target 5-8 ng/ml) or to continue CSA based immunosuppression (target 70-150 ng/ml) at a 2:1 ratio. Renal graft function was estimated via the MDRD (eGFRMDRD) and CKD-EPI (eGFRCKD-EPI) formulas., Results: Forty-five patients continued CSA and 96 patients were converted to TAC with a median follow up of 24 months. Baseline demographics (except for recipient age) including native kidney disease, transplant characteristics, kidney graft function, medication use and comorbid conditions did not differ between groups. In respect to long-term renal graft function, linear mixed models showed significantly improved eGFR trajectories (eGFRMDRD: p<0.001, eGFRCKD-EPI: p<0.001) in the TAC versus CSA group over 24 months of follow up. Estimated eGFRCKD-EPI group differences between TAC and CSA were -3.49 (p = 0.019) at 3 months, -5.50 (p<0.001) at 12 months, and -4.48 ml/min/1.73m2 (p = 0.003) at 24 months of follow up. Baseline eGFR was a significant predictor of eGFR trajectories (eGFRMDRD: p<0.001, eGFRCKD-EPI: p<0.001). Significant effects for randomization group were evident despite short-term trough levels in the supratherapeutic range (27% (n = 26) of TAC patients at week one). Median TAC trough levels were within target range at week 4 after conversion., Conclusion: Conversion of CSA treated kidney transplant recipients with stable graft function to TAC (target 5-8 ng/ml) showed significantly improved long-term eGFR trajectories when compared to CSA maintenance (target 70-150 ng/ml)., Trial Registration: ClinicalTrials.gov NCT00182559 EudraCT identifier: 2004-004209-98.

Background: Autosomal-dominant polycystic kidney disease (ADPKD) is a hereditary illness that causes renal tubular epithelial cells to form cysts that proliferate and destroy renal tissue. This usually leads to a decline in renal function, and often to terminal kidney failure, with need for renal replacement therapy. There is currently no causative therapy. The mammalian target of rapamycin (mTOR) inhibitor sirolimus (SIR) is an immunosuppressant with strong antiproliferative effects, and is potentially able to stop or reduce cyst growth and preserve renal function in ADPKD. Continuous mTOR exposure results in a loss of its antiproliferative effects on renal tubular cells. With a half-life of roughly 60 hours, pulsed (weekly) administration of SIR may be an effective way to reduce cyst growth and preserve excretory renal function in ADPKD., Methods/design: The Vienna RAP Study is a randomized, double-blind, placebo-controlled trial, funded by the Anniversary Fund of the Oesterreichische Nationalbank. We will investigate the effects of a weekly dose of 3 mg SIR on kidney function in 34 patients with advanced ADPKD, compared to a placebo equivalent in 34 patients with advanced ADPKD, over 24 months. The primary endpoint is creatinine level (less or equal than 1.5-fold increase in serum creatinine without initiation of dialysis over two years) and dialysis, renal transplantation, or death. The secondary endpoints are safety, change in proteinuria (as indicated by albumin/creatinine- and protein/creatinine ratio, respectively), and creatinine clearance., Discussions: The Vienna RAP Study is, to the best of our knowledge, the first study to investigate the effects of a pulsed (weekly) dose of SIR on renal function in ADPKD., Trial Registration: This trial was registered with EudraCT (identifier: 2012-000550-60 (EU)) on 27 November 2013 and with ClinicalTrials.gov (identifier: NCT02055079 (USA)) on 3 February 2014.

Background: Endothelial progenitor cell (EPC) counts are proposed surrogate markers for vascular function and cardiovascular risk. The effect of tacrolimus (TAC) on EPC is unknown., Methods: In this randomized controlled trial, we assigned 148 stable long-term kidney transplant recipients (KTR) to maintaining ciclosporin (CSA) or to commencing TAC-based immunosuppression at a 2:1 ratio. EPC counts (CD34/KDR) after 24 months were defined as primary endpoint., Results: The intent-to-treat analysis included 141 KTR (estimated glomerular filtration rate, 46.7 [40.1-61.8] mL/min per 1.73 m). Median (interquartile range [IQR]) EPC counts at baseline and month 24 were 6 (2-9) and 3 (1-9) cells and 4 (2-8) and 2 (0-5) cells per 5×10 mononuclear cells in CSA and TAC, respectively. Median (IQR) circulating angiogenic cells at baseline and month 24 were 28 (10.7-57) and 44.33 (14.6-59.8) cells and 22 (10.8-41) and 21 (9.7-49.5) cells per high-power field in CSA and TAC, respectively. Median (IQR) endothelial cell colony-forming units count per well at baseline and month 24 were 10.5 (3.3-34.3) and 4.38 (1.7-26.5) in CSA and significantly declined from 9.31 (1.8-29.3) to 4.13 (1.1-9.5) in TAC (P=0.003). There were no cardiovascular events in either group., Conclusion: Although late conversion from CSA to TAC appears safe in KTR, conversion to TAC has no favorable effect on EPC. Low EPC levels are associated with a higher risk of subsequent cardiovascular events and are therefore of prognostic value. Their trend to decline over time deserves further examination.

Unlabelled: Renal transplant recipients are at increased risk of developing invasive pneumococcal diseases but may have poor response to the 23-valent pneumococcal polysaccharide vaccine (PPV). It may be possible to enhance immunogenicity by priming with 7-valent pneumococcal conjugate vaccine (7vPnC) and boosting with PPV 1 year later. In a randomized single-blind, controlled study, adult recipients of renal transplants received either 7nPVC or PPV followed by PPV 1 year later. The vaccine response was defined as 2-fold increase in antibody concentration from baseline and an absolute post-vaccination values ≥1 µg/ml. The primary endpoint was vaccine response of the primed group (7vPnC/PPV) compared with single PPV vaccination. Antibody concentrations for 10 serotypes were measured at baseline, 8 weeks after first vaccination, before second vaccination, and 8 weeks after second vaccination. Of 320 screened patients, 80 patients were randomized and 62 completed the study. Revaccination with PPV achieved no significant increase of immune response in the 7vPnC/PPV group compared with the single PPV recipients A response to at least 1 serotype was seen in 77.1% of patients who received 7vPnC and 93.1% of patients who received PPV (P = 0.046). After second vaccination response to at least 1 serotype was seen in 87.5% patients of 7vPnC/PPV group and 87.1% patients of PPV group (non significant p). The median number of serotypes eliciting a response was 3.5 (95% CI 2.5-4.5) in the 7vPnC/PPV group versus 5 (95% CI 3.9-6.1) in the PPV group (non-significant p). Immunogenicity of pneumococcal vaccination was not enhanced by the prime-boost strategy compared with vaccination with PPV alone. Administration of a single dose of PPV should continue to be the standard of care for adult recipients of renal transplants., Trial Registration: EudraCT 2007-004590-25.

Background and Objectives: Dialysis patients are at high risk for low-trauma bone fracture. Bone density measurements using dual-energy x-ray absorptiometry (DXA) do not reliably differentiate between patients with and without fractures. The aim of this study was to identify differences in bone microarchitecture between patients with and without a history of fracture using high-resolution peripheral quantitative computed tomography (HR-pQCT)., Design, Setting, Participants, & Measurements: Seventy-four prevalent hemodialysis patients were recruited for measurements of areal bone mineral density (aBMD) by DXA and bone microarchitecture by HR-pQCT. Patients with a history of trauma-related fracture were excluded. Forty healthy volunteers served as controls. Blood levels of parathyroid hormone, vitamin D, and markers of bone turnover were determined., Results: Dialysis patients, particularly women, had markedly impaired bone microarchitecture. Patients with fractures had significantly reduced cortical and trabecular microarchitecture compared with patients without fractures. aBMD tended to be lower in patients with fractures, but differences were statistically not significant. The strongest determinant of fracture was the HR-pQCT-measured trabecular density of the tibia, which also had the highest discriminatory power to differentiate patients according to fracture status. Radial DXA had a lower discriminatory power than trabecular density., Conclusions: Bone microarchitecture is severely impaired in dialysis patients and even more so in patients with a history of fracture. HR-pQCT can identify dialysis patients with a history of low-trauma fracture.

In humans, the hepatic end product of purine metabolism is uric acid. Serum uric acid levels physiologically and gradually rise during human lifetime. Hyperuricemia also arises from excess dietary purine or ethanol intake, decreased renal excretion of uric acid, tumor lysis in lymphoma, leukemia or solid tumors, and sometimes pharmacotherapy. The definition of hyperuricemia is currently arbitrary. Hyperuricemia is associated with chronic kidney disease, arterial hypertension, coronary artery and heart disease, cerebrovascular disease and diabetes mellitus. Xanthine oxidase, a hepatic enzyme, catalyzes the production of uric acid, nitric oxide, and reactive oxygen species, which potentially damage deoxyribonucleic acid, ribonucleic acid and proteins, inactivate enzymes, oxidize amino acids and convert poly-unsaturated fatty acids to lipids. This is believed to contribute to atherosclerosis, endothelial dysfunction, renovascular hypertension, and cardiovascular disease. Xanthine oxidase inhibition efficiently blocks uric acid generation, and this improves glomerular filtration rates, systemic blood pressure, and cerebro-cardiovascular outcomes. Here, data from animal, in vivo, retro- and prospective, and interventional studies are reported.

At present, solid organ transplantation relies on chronic immunosuppression. Calcineurin inhibitors (CNIs) still remain one of the most important components in current immunosuppressive regimens. However, life-long immunosuppression of transplant recipients is associated with high costs for the individual, health-care systems, and society. Hence, there is an urgent need of generic drugs that have the potential to exert equivalent therapeutic efficacy at a lower cost. Here, we report our findings of the conversion of 59 stable long-term kidney graft recipients from cyclosporine A (CsA) Neoral to CsA Neoimmun/Equoral. All patients displayed a continuous stable graft function after conversion for a follow-up period of 6 months, and no major side effects associated with the use of CsA Neoimmun/Equoral were observed. Also, CsA dose and trough levels did not differ after conversion to CsA Neoimmun/Equoral. These data indicate that conversion of long-term kidney graft recipients from CsA Neoral to CsA Neoimmun/Equoral is safe and effective, making this specific CsA generic a viable option for CNI therapy in stable renal transplant patients.

Chronic kidney disease (CKD) and end stage renal disease (ESRD) are severe medical conditions, increasing threats to human health and socio-economic burdens in industrialized countries. CKD is assessed by an estimation of the glomerular filtration rate (eGFR). ESRD is an indication for renal replacement therapy by either dialysis or kidney-transplantation. Major risk factors for CKD are arterial hypertension, hyperglycemia and hyperlipidemia. The multifactorial pathogenesis of CKD and ESRD offers various therapeutic interventions: treatment of the underlying disease, anti-hypertensive therapy, glycemic control and anti-diabetic therapy, anti-proteinuric therapy, renoprotection, and life style management. Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) lower the systemic blood-pressure, reduce proteinuria and may slow or even halt the deterioration of renal function. Alert glycemic control is important to avoid or protract diabetic nephropathy. Restricted protein intake, cessation of cigarette smoking and chronic analgesic-abuse may also prevent the progression of chronic nephropathy.

Background: The effect of serum prolactin levels on the response to erythropoiesis-stimulating agents (ESA) in patients on chronic hemodialysis is unknown., Methods: We included 111 stable hemodialysis patients in this study and examined the association of serum prolactin concentrations with the response to ESA. Accordingly we implemented an ESA index as a measure of therapeutic efficacy. The two outcomes of this cohort study were the association of prolactin concentrations with response to ESA, both at baseline (cross-sectional component) and after 1-year of follow-up (prospective component), and the presence of macroprolactin., Results: Two male patients, but none of the female patients, had serum prolactin concentrations within the reference range. Following precipitation with polyethylene glycol (PEG), 17 males (25.4%) and 9 females (20.6%) had serum prolactin concentrations within the reference range. Females had somewhat higher levels than males: 39.8 (IQR 32.3-64.5) versus 27.8 (IQR 23.4-47.8) ng/ml (p = 0.003). The ratio of prolactin(PEG)/prolactin(Native) was greater than 0.60 in 103 patients (92.8%), thus excluding significant amounts of macroprolactin. From uni- and multivariate analyses we did not find associations of serum prolactin concentrations with a response to ESA either at baseline or at follow-up., Conclusions: From this prospective study we provide evidence that elevated serum prolactin levels are not related to the presence of macroprolactin in chronic hemodialysis patients. Furthermore, serum prolactin concentrations are not associated with the response to erythropoietic therapy in these individuals., (Copyright 2007 S. Karger AG, Basel.)