36 results on '"Oberbauer R."'
Search Results
2. A paired-kidney allocation study found superior survival with HLA-DR compatible kidney transplants in the Eurotransplant Senior Program.
- Author
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de Fijter J, Dreyer G, Mallat M, Budde K, Pratschke J, Klempnauer J, Zeier M, Arns W, Hugo C, Rump LC, Hauser I, Schenker P, Schiffer M, Grimm MO, Kliem V, Olbricht CJ, Pisarski P, Banas B, Suwelack B, Hakenberg O, Berlakovich G, Schneeberger S, van de Wetering J, Berger S, Bemelman F, Kuypers D, Heidt S, Rahmel A, Claas F, Peeters P, Oberbauer R, Heemann U, and Krämer BK
- Subjects
- Humans, Aged, Cohort Studies, HLA-DR Antigens, Kidney, Tissue Donors, Histocompatibility Testing, Graft Survival, Kidney Transplantation adverse effects, Tissue and Organ Procurement
- Abstract
The Eurotransplant Senior Program (ESP) has expedited the chance for elderly patients with kidney failure to receive a timely transplant. This current study evaluated survival parameters of kidneys donated after brain death with or without matching for HLA-DR antigens. This cohort study evaluated the period within ESP with paired allocation of 675 kidneys from donors 65 years and older to transplant candidates 65 years and older, the first kidney to 341 patients within the Eurotransplant Senior DR-compatible Program and 334 contralateral kidneys without (ESP) HLA-DR antigen matching. We used Kaplan-Meier estimates and competing risk analysis to assess all cause mortality and kidney graft failure, respectively. The log-rank test and Cox proportional hazards regression were used for comparisons. Within ESP, matching for HLA-DR antigens was associated with a significantly lower five-year risk of mortality (hazard ratio 0.71; 95% confidence interval 0.53-0.95) and significantly lower cause-specific hazards for kidney graft failure and return to dialysis at one year (0.55; 0.35-0.87) and five years (0.73; 0.53-0.99) post-transplant. Allocation based on HLA-DR matching resulted in longer cold ischemia (mean difference 1.00 hours; 95% confidence interval: 0.32-1.68) and kidney offers with a significantly shorter median dialysis vintage of 2.4 versus 4.1 yrs. in ESP without matching. Thus, our allocation based on HLA-DR matching improved five-year patient and kidney allograft survival. Hence, our paired allocation study suggests a superior outcome of HLA-DR matching in the context of old-for-old kidney transplantation., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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3. Optimum timing of antithymocyte globulin in relation to adoptive regulatory T cell therapy.
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Muckenhuber M, Mucha J, Mengrelis K, How C, Reindl-Schwaighofer R, Heinzel A, Kainz V, Worel N, Berlakovich G, Edinger M, Oberbauer R, and Wekerle T
- Subjects
- Humans, Graft Rejection, Immunosuppression Therapy, Immunosuppressive Agents therapeutic use, T-Lymphocytes, Regulatory, Clinical Trials as Topic, Antilymphocyte Serum, Kidney Transplantation
- Abstract
Reducing the recipient's T cell repertoire is considered to increase the efficacy of regulatory T cell (Treg) therapy. This necessitates timing the administration of antithymocyte globulin (ATG) early enough before adoptive cell therapy (ACT) so that residual serum ATG does not deplete the transferred Tregs. The optimum time point in this regard has not been defined. Herein, we report the effects of residual serum ATG on the viability of an in vitro expanded Treg cell product used in a clinical trial of ACT in kidney transplant recipients (NCT03867617). Patients received ATG monotherapy (either 6 or 3 mg/kg body weight) without concomitant immunosuppression 2 to 3 weeks before transplantation and Treg transfer. An anti-ATG immunoglobulin G (IgG) immune response was elicited in all patients within 14 days. In turn, the elimination of total and Treg-specific ATG was accelerated substantially over control patients receiving the same dose of ATG with concomitant immunosuppression. However, ATG serum concentrations of <1 μg/mL, which had previously been reported as subtherapeutic threshold, triggered apoptosis of Tregs in vitro. Therefore, ATG levels need to decline to lower levels than those previously thought for efficacious Treg transfer. In 5 of 6 patients, such low levels of serum ATG considered safe for Treg transfer were reached within 2 weeks after ATG administration., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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4. Prediction models for living organ transplantation are poorly developed, reported, and validated: a systematic review.
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Haller MC, Aschauer C, Wallisch C, Leffondré K, van Smeden M, Oberbauer R, and Heinze G
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- Humans, Prognosis, Tissue Donors, Kidney Transplantation
- Abstract
Objective: To identify and critically appraise risk prediction models for living donor solid organ transplant counselling., Study Design and Setting: We systematically reviewed articles describing the development or validation of prognostic risk prediction models about living donor solid organ (kidney and liver) transplantation indexed in Medline until April 4, 2021. Models were eligible if intended to predict, at transplant counselling, any outcome occurring after transplantation or donation in recipients or donors. Duplicate study selection, data extraction, assessment for risk of bias and quality of reporting was done using the CHARMS checklist, PRISMA recommendations, PROBAST tool, and TRIPOD Statement., Results: We screened 4691 titles and included 49 studies describing 68 models (35 kidney, 33 liver transplantation). We identified 49 new risk prediction models and 19 external validations of existing models. Most models predicted recipients outcomes (n = 38, 75%), e.g., kidney graft loss (29%), or mortality of liver transplant recipients (55%). Many new models (n = 46, 94%) and external validations (n = 17, 89%) had a high risk of bias because of methodological weaknesses. The quality of reporting was generally poor., Conclusion: We advise against applying poorly developed, reported, or validated prediction models. Future studies could validate or update the few identified methodologically appropriate models., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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5. Nephrologists' Perspectives on Gender Disparities in CKD and Dialysis.
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Tong A, Evangelidis N, Kurnikowski A, Lewandowski M, Bretschneider P, Oberbauer R, Baumgart A, Scholes-Robertson N, Stamm T, Carrero JJ, Pecoits-Filho R, and Hecking M
- Abstract
Introduction: Globally, there are more women with chronic kidney disease (CKD), yet they comprise only 40% of patients receiving kidney replacement therapy by dialysis. We aimed to describe the perspectives of nephrologists on gender disparities in access to care and outcomes in CKD and dialysis., Methods: We conducted semistructured interviews with 51 nephrologists (28, 55% women) from 22 countries from October 2019 to April 2020. Transcripts were analyzed thematically., Results: We identified 6 themes. Related to women were primary commitment to caregiving (with subthemes of coordinating care, taking charge of health management, deprioritizing own health, centrality of family in decision-making); vigilance and self-reliance (diligence and conscientiousness, stoicism and tolerating symptoms, avoiding burden on family, isolation and coping alone); and stereotyping, stigma, and judgment (body image, dismissed as anxiety, shame and embarrassment, weakness and frailty). Related to men was protecting masculinity (safeguarding the provider role, clinging to control, self-regard, and entitled). Decisional power and ownership included men's dominance in decision-making and women's analytical approach in treatment decisions. Inequities compounded by social disadvantage (financial and transport barriers, without social security, limited literacy, entrenched discrimination, vulnerability) were barriers to care for women, particularly in socioeconomically disadvantaged communities., Conclusion: Nephrologists perceived that women with CKD faced many challenges in accessing care related to social norms and roles of caregiving responsibilities, disempowerment, lack of support, stereotyping by clinicians, and entrenched social and economic disadvantage. Addressing power differences, challenging systemic patriarchy, and managing unconscious bias may help to improve equitable care and outcomes for all people with CKD., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)
- Published
- 2021
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6. Trajectories of glomerular filtration rate and progression to end stage kidney disease after kidney transplantation.
- Author
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Raynaud M, Aubert O, Reese PP, Bouatou Y, Naesens M, Kamar N, Bailly É, Giral M, Ladrière M, Le Quintrec M, Delahousse M, Juric I, Basic-Jukic N, Gupta G, Akalin E, Yoo D, Chin CS, Proust-Lima C, Böhmig G, Oberbauer R, Stegall MD, Bentall AJ, Jordan SC, Huang E, Glotz D, Legendre C, Montgomery RA, Segev DL, Empana JP, Grams ME, Coresh J, Jouven X, Lefaucheur C, and Loupy A
- Subjects
- Glomerular Filtration Rate, Humans, Prospective Studies, Kidney Failure, Chronic diagnosis, Kidney Failure, Chronic surgery, Kidney Transplantation adverse effects
- Abstract
Although the gold standard of monitoring kidney transplant function relies on glomerular filtration rate (GFR), little is known about GFR trajectories after transplantation, their determinants, and their association with outcomes. To evaluate these parameters we examined kidney transplant recipients receiving care at 15 academic centers. Patients underwent prospective monitoring of estimated GFR (eGFR) measurements, with assessment of clinical, functional, histological and immunological parameters. Additional validation took place in seven randomized controlled trials that included a total of 14,132 patients with 403,497 eGFR measurements. After a median follow-up of 6.5 years, 1,688 patients developed end-stage kidney disease. Using unsupervised latent class mixed models, we identified eight distinct eGFR trajectories. Multinomial regression models identified seven significant determinants of eGFR trajectories including donor age, eGFR, proteinuria, and several significant histological features: graft scarring, graft interstitial inflammation and tubulitis, microcirculation inflammation, and circulating anti-HLA donor specific antibodies. The eGFR trajectories were associated with progression to end stage kidney disease. These trajectories, their determinants and respective associations with end stage kidney disease were similar across cohorts, as well as in diverse clinical scenarios, therapeutic eras and in the seven randomized control trials. Thus, our results provide the basis for a trajectory-based assessment of kidney transplant patients for risk stratification and monitoring., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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7. Response to: "Biostatistics pitfalls: Lessons learned from analysis of medical data" by Yin et al.
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Reindl-Schwaighofer R, Heinzel A, Heinze G, Kammer M, and Oberbauer R
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- Allografts, Cohort Studies, Humans, Prospective Studies, Biometry, Biostatistics
- Published
- 2020
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8. Integrative analysis of prognostic biomarkers derived from multiomics panels helps discrimination of chronic kidney disease trajectories in people with type 2 diabetes.
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Kammer M, Heinzel A, Willency JA, Duffin KL, Mayer G, Simons K, Gerl MJ, Klose C, Heinze G, Reindl-Schwaighofer R, Hu K, Perco P, Eder S, Rosivall L, Mark PB, Ju W, Kretzler M, McCarthy MI, Heerspink HL, Wiecek A, Gomez MF, and Oberbauer R
- Subjects
- Aged, Bayes Theorem, Biomarkers blood, Case-Control Studies, Female, Humans, Male, Middle Aged, Diabetes Mellitus, Type 2 complications, Glomerular Filtration Rate, Hepatitis A Virus Cellular Receptor 1 blood, Natriuretic Peptide, Brain blood, Peptide Fragments blood, Renal Insufficiency, Chronic blood
- Abstract
Clinical risk factors explain only a fraction of the variability of estimated glomerular filtration rate (eGFR) decline in people with type 2 diabetes. Cross-omics technologies by virtue of a wide spectrum screening of plasma samples have the potential to identify biomarkers for the refinement of prognosis in addition to clinical variables. Here we utilized proteomics, metabolomics and lipidomics panel assay measurements in baseline plasma samples from the multinational PROVALID study (PROspective cohort study in patients with type 2 diabetes mellitus for VALIDation of biomarkers) of patients with incident or early chronic kidney disease (median follow-up 35 months, median baseline eGFR 84 mL/min/1.73 m
2 , urine albumin-to-creatinine ratio 8.1 mg/g). In an accelerated case-control study, 258 individuals with a stable eGFR course (median eGFR change 0.1 mL/min/year) were compared to 223 individuals with a rapid eGFR decline (median eGFR decline -6.75 mL/min/year) using Bayesian multivariable logistic regression models to assess the discrimination of eGFR trajectories. The analysis included 402 candidate predictors and showed two protein markers (KIM-1, NTproBNP) to be relevant predictors of the eGFR trajectory with baseline eGFR being an important clinical covariate. The inclusion of metabolomic and lipidomic platforms did not improve discrimination substantially. Predictions using all available variables were statistically indistinguishable from predictions using only KIM-1 and baseline eGFR (area under the receiver operating characteristic curve 0.63). Thus, the discrimination of eGFR trajectories in patients with incident or early diabetic kidney disease and maintained baseline eGFR was modest and the protein marker KIM-1 was the most important predictor., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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9. The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population.
- Author
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Stapleton CP, Heinzel A, Guan W, van der Most PJ, van Setten J, Lord GM, Keating BJ, Israni AK, de Borst MH, Bakker SJL, Snieder H, Weale ME, Delaney F, Hernandez-Fuentes MP, Reindl-Schwaighofer R, Oberbauer R, Jacobson PA, Mark PB, Chapman FA, Phelan PJ, Kennedy C, Sexton D, Murray S, Jardine A, Traynor JP, McKnight AJ, Maxwell AP, Smyth LJ, Oetting WS, Matas AJ, Mannon RB, Schladt DP, Iklé DN, Cavalleri GL, and Conlon PJ
- Subjects
- Adult, Europe epidemiology, Female, Follow-Up Studies, Genome-Wide Association Study, Glomerular Filtration Rate, Graft Rejection epidemiology, Graft Rejection genetics, Graft Survival, Humans, Kidney Failure, Chronic genetics, Kidney Failure, Chronic surgery, Kidney Function Tests, Living Donors statistics & numerical data, Male, Middle Aged, Postoperative Complications epidemiology, Postoperative Complications genetics, Prognosis, Retrospective Studies, Risk Factors, Transplant Recipients statistics & numerical data, Genetic Markers, Genetic Variation, Graft Rejection diagnosis, Kidney physiopathology, Kidney Transplantation adverse effects, Postoperative Complications diagnosis, Risk Assessment methods
- Abstract
Genetic variation across the human leukocyte antigen loci is known to influence renal-transplant outcome. However, the impact of genetic variation beyond the human leukocyte antigen loci is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with posttransplant eGFR at different time-points, out to 5 years posttransplantation. We conducted GWAS meta-analyses across 10 844 donors and recipients from five European ancestry cohorts. We also analyzed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with nontransplant eGFR, on posttransplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1-year posttransplant. Thirty-two percent of the variability in eGFR at 1-year posttransplant was explained by our model containing clinical covariates (including weights for death/graft-failure), principal components and combined donor-recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR posttransplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a posttransplant context. Despite PRS being a significant predictor of eGFR posttransplant, the effect size of common genetic factors is limited compared to clinical variables., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)
- Published
- 2019
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10. Steroid pretreatment of organ donors does not impact on early rejection and long-term kidney allograft survival: Results from a multicenter randomized, controlled trial.
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Reindl-Schwaighofer R, Kainz A, Jelencsics K, Heinzel A, Berlakovich G, Remport Á, Heinze G, Langer R, and Oberbauer R
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- Adult, Biopsy, Female, Glomerular Filtration Rate, Humans, Incidence, Inflammation, Male, Methylprednisolone administration & dosage, Middle Aged, Multivariate Analysis, Proportional Hazards Models, Tissue Donors, Tissue and Organ Procurement, Treatment Outcome, Graft Rejection prevention & control, Graft Survival, Kidney Transplantation, Steroids therapeutic use
- Abstract
Steroid pretreatment of deceased donors reduces inflammation in allografts and is recommended by organ procurement guidelines. The impact on long-term graft outcome, however, remains elusive. In this multicenter randomized controlled trial, 306 deceased donors providing organs for 455 renal transplant recipients were randomized to 1000 mg of methylprednisolone or placebo prior to organ procurement (ISRCTN78828338). The incidence of biopsy-confirmed rejection (Banff>1) at 3 months was 23 (10%) in the steroid group and 26 (12%) in the placebo group (P = .468). Five-year functional graft survival was 84% and 82% for the steroid group and placebo group, respectively (P-value = .941). The hazard ratio of functional graft loss was 0.90 (95% confidence interval 0.57-1.42, P = .638) for steroid vs placebo in a multivariate Cox model. We did not observe effect modification by any of the predictors of graft survival and treatment modality. A robust sandwich estimate was used to account for paired grafts of some donors. The mean estimated GFR at 5 years was 47 mL/min per 1.73 m
2 in the steroid group and 48 mL/min per 1.73 m2 in the placebo group (P = .756). We conclude that steroid pretreatment does not impact on long-term graft survival. In a donor population with higher risk of delayed graft function, however, repetitive and higher doses of steroid treatment may result in different findings., (© 2019 The Authors American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)- Published
- 2019
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11. Contribution of non-HLA incompatibility between donor and recipient to kidney allograft survival: genome-wide analysis in a prospective cohort.
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Reindl-Schwaighofer R, Heinzel A, Kainz A, van Setten J, Jelencsics K, Hu K, Loza BL, Kammer M, Heinze G, Hruba P, Koňaříková A, Viklicky O, Boehmig GA, Eskandary F, Fischer G, Claas F, Tan JC, Albert TJ, Patel J, Keating B, and Oberbauer R
- Subjects
- Adult, Antibodies immunology, Case-Control Studies, Female, Genome-Wide Association Study, Graft Rejection immunology, HLA Antigens immunology, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Outcome Assessment, Health Care, Polymorphism, Single Nucleotide, Proportional Hazards Models, Prospective Studies, Tissue Donors, Allografts immunology, Graft Rejection epidemiology, Graft Survival, Histocompatibility Testing statistics & numerical data, Kidney Transplantation statistics & numerical data
- Abstract
Background: The introduction of HLA matching of donors and recipients was a breakthrough in kidney transplantation. However, half of all transplanted kidneys still fail within 15 years after transplantation. Epidemiological data suggest a fundamental role of non-HLA alloimmunity., Methods: We genotyped 477 pairs of deceased donors and first kidney transplant recipients with stable graft function at three months that were transplanted between Dec 1, 2005, and April 30, 2015. Genome-wide genetic mismatches in non-synonymous single nucleotide polymorphisms (nsSNPs) were calculated to identify incompatibilities in transmembrane and secreted proteins. We estimated the association between nsSNP mismatch and graft loss in a Cox proportional hazard model, adjusting for HLA mismatch and clinical covariates. Customised peptide arrays were generated to screen for antibodies against genotype-derived mismatched epitopes in 25 patients with biopsy-confirmed chronic antibody-mediated rejection., Findings: 59 268 nsSNPs affecting a transmembrane or secreted protein were analysed. The median number of nsSNP mismatches in immune-accessible transmembrane and secreted proteins between donors and recipients was 1892 (IQR 1850-1936). The degree of nsSNP mismatch was independently associated with graft loss in a multivariable model adjusted for HLA eplet mismatch (HLA-A, HLA-B, HLA-C, HLA-DP, HLA-DQ, and HLA-DR). Each increase by a unit of one IQR had an HR of 1·68 (95% CI 1·17-2·41, p=0·005). 5-year death censored graft survival was 98% in the quartile with the lowest mismatch, 91% in the second quartile, 89% in the third quartile, and 82% in the highest quartile (p=0·003, log-rank test). Customised peptide arrays verified a donor-specific alloimmune response to genetically predicted mismatched epitopes., Interpretation: Genetic mismatch of non-HLA haplotypes coding for transmembrane or secreted proteins is associated with an increased risk of functional graft loss independently of HLA incompatibility. As in HLA alloimmunity, donor-specific alloantibodies can be identified against genotype derived non-HLA epitopes., Funding: Austrian Science Fund, WWTF (Vienna Science and Technology Fund), and Ministry of Health of the Czech Republic., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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12. Allograft and patient survival after sequential HSCT and kidney transplantation from the same donor-A multicenter analysis.
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Eder M, Schwarz C, Kammer M, Jacobsen N, Stavroula ML, Cowan MJ, Chongkrairatanakul T, Gaston R, Ravanan R, Ishida H, Bachmann A, Alvarez S, Koch M, Garrouste C, Duffner UA, Cullis B, Schaap N, Medinger M, Sørensen SS, Dauber EM, Böhmig G, Regele H, Berlakovich GA, Wekerle T, and Oberbauer R
- Subjects
- Adolescent, Adult, Allografts, Case-Control Studies, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Immunosuppressive Agents therapeutic use, Kidney Failure, Chronic therapy, Male, Middle Aged, Prognosis, Risk Factors, Survival Rate, Transplantation, Homologous, Young Adult, Graft Survival, Hematopoietic Stem Cell Transplantation mortality, Kidney Failure, Chronic mortality, Kidney Transplantation mortality, Living Donors supply & distribution
- Abstract
Tolerance induction through simultaneous hematopoietic stem cell and renal transplantation has shown promising results, but it is hampered by the toxicity of preconditioning therapies and graft-versus-host disease (GVHD). Moreover, renal function has never been compared to conventionally transplanted patients, thus, whether donor-specific tolerance results in improved outcomes remains unanswered. We collected follow-up data of published cases of renal transplantations after hematopoietic stem cell transplantation from the same donor and compared patient and transplant kidney survival as well as function with caliper-matched living-donor renal transplantations from the Austrian dialysis and transplant registry. Overall, 22 tolerant and 20 control patients were included (median observation period 10 years [range 11 months to 26 years]). In the tolerant group, no renal allograft loss was reported, whereas 3 were lost in the control group. Median creatinine levels were 85 μmol/l (interquartile range [IQR] 72-99) in the tolerant cohort and 118 μmol/l (IQR 99-143) in the control group. Mixed linear-model showed around 29% lower average creatinine levels throughout follow-up in the tolerant group (P < .01). Our data clearly show stable renal graft function without long-term immunosuppression for many years, suggesting permanent donor-specific tolerance. Thus sequential transplantation might be an alternative approach for future studies targeting tolerance induction in renal allograft recipients., (© 2018 The Authors American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)
- Published
- 2019
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13. A randomized controlled trial of alanyl-glutamine supplementation in peritoneal dialysis fluid to assess impact on biomarkers of peritoneal health.
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Vychytil A, Herzog R, Probst P, Ribitsch W, Lhotta K, Machold-Fabrizii V, Wiesholzer M, Kaufmann M, Salmhofer H, Windpessl M, Rosenkranz AR, Oberbauer R, König F, Kratochwill K, and Aufricht C
- Subjects
- Aged, Austria, Biomarkers analysis, Cross-Over Studies, Female, Humans, Male, Middle Aged, Peritoneum drug effects, Peritoneum pathology, Peritonitis diagnosis, Peritonitis etiology, Proof of Concept Study, Prospective Studies, Treatment Outcome, Dialysis Solutions chemistry, Dipeptides administration & dosage, Kidney Failure, Chronic therapy, Peritoneal Dialysis adverse effects, Peritonitis prevention & control
- Abstract
In early clinical testing, acute addition of alanyl-glutamine (AlaGln) to glucose-based peritoneal dialysis (PD) fluids restored peritoneal cellular stress responses and leukocyte function. This study was designed to test the effect of extended treatment with AlaGln-supplemented PD fluid on biomarkers of peritoneal health. In a double-blinded, randomized crossover design, stable PD patients were treated with AlaGln (8 mM) or placebo added to PD fluid for eight weeks. As primary outcome measures, dialysate cancer-antigen 125 (CA-125) appearance rate and ex vivo stimulated interleukin-6 (IL-6) release were assessed in peritoneal equilibration tests. In 8 Austrian centers, 54 patients were screened, 50 randomized, and 41 included in the full analysis set. AlaGln supplementation significantly increased CA-125 appearance rate and ex vivo stimulated IL-6 release. AlaGln supplementation also reduced peritoneal protein loss, increased ex vivo stimulated tumor necrosis factor (TNF)-α release, and reduced systemic IL-8 levels. No adverse safety signals were observed. All 4 peritonitis episodes occurred during standard PD fluid treatment. A novel AlaGln-supplemented PD fluid improves biomarkers of peritoneal membrane integrity, immune competence, and systemic inflammation compared to unsupplemented PD fluid with neutral pH and low-glucose degradation. A phase 3 trial is needed to determine the impact of AlaGln supplementation on hard clinical outcomes., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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14. Functional Fc gamma receptor gene polymorphisms and donor-specific antibody-triggered microcirculation inflammation.
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Arnold ML, Kainz A, Hidalgo LG, Eskandary F, Kozakowski N, Wahrmann M, Haslacher H, Oberbauer R, Heilos A, Spriewald BM, Halloran PF, and Böhmig GA
- Subjects
- Adult, Cross-Sectional Studies, Female, Follow-Up Studies, GPI-Linked Proteins genetics, Genotype, Graft Rejection etiology, Graft Survival, Humans, Inflammation etiology, Kidney Failure, Chronic genetics, Kidney Failure, Chronic surgery, Male, Microcirculation, Middle Aged, Postoperative Complications, Prognosis, Risk Factors, Tissue Donors, Graft Rejection diagnosis, Inflammation diagnosis, Isoantibodies adverse effects, Kidney Transplantation adverse effects, Polymorphism, Genetic, Receptors, IgG genetics
- Abstract
Fc-dependent effector mechanisms may contribute to antibody-mediated rejection (ABMR), and distinct gene polymorphisms modifying the function of Fc gamma receptors (FcγRs) may influence the capability of donor-specific antibodies (DSAs) to trigger inflammation. To evaluate the relevance of functional FcγR variants in late ABMR, 85 DSA-positive kidney allograft recipients, who were recruited upon antibody screening of 741 prevalent patients, were genotyped for polymorphisms in FcγRIIA (FCGR2A-H/R
131 ; rs1801274), FcγRIIIA (FCGR3A-V/F158 ; rs396991), and FcγRIIIB (FCGR3B-neutrophil antigen 1 ([NA1]/NA2; rs35139848). Individuals with high-affinity FCGR3A-V158 alleles (V/V158 or V/F158 ) showed a higher rate (and extent) of peritubular capillaritis (ptc) in protocol biopsies than homozygous carriers of the lower-affinity allele (ptc score ≥1: 53.6% vs 25.9%; P = .018). Associations were independent of C1q-binding to DSA or capillary C4d. In parallel, there was a trend toward increased macrophage- and injury-repair response-associated transcript subsets. Kidney function over 24 months, however, was not different. In support of a functional role of FcγRIIIA polymorphism, NK92 cells expressing FCGR3A-V158 produced >2 times as much interferon gamma upon incubation with HLA antibody-coated cells as those expressing FCGR3A-F158 . FcγRIIA and FcγRIIIB polymorphisms were not associated with allograft morphology. Our data suggest that the presence of high-affinity FcγRIIIA variants may favor DSA-triggered microcirculation inflammation., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)- Published
- 2018
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15. Strategies for long-term preservation of kidney graft function.
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Wekerle T, Segev D, Lechler R, and Oberbauer R
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- Donor Selection, Graft Rejection etiology, Graft Rejection prevention & control, Humans, Kidney Failure, Chronic etiology, Kidney Failure, Chronic mortality, Graft Survival, Kidney Failure, Chronic surgery, Kidney Transplantation
- Abstract
Kidney transplantation has become a routine procedure in the treatment of patients with kidney failure, and requires collaboration of experts from different disciplines, such as nephrology, surgery, immunology, pathology, infectious disease medicine, cardiology, and oncology. Grafts can be obtained from deceased or living donors, with different logistical requirements and implications for long-term graft patency. 1-year graft survival rates are greater than 95% in many centres but improvement of long-term function remains a challenge. New developments in molecular immunology and computational biology have increased precision of donor and recipient matching of HLA and non-HLA compatibility. Individual omics-wide molecular diagnostics, extracorporeal therapies, and drug developments allow for precise individual decision making and treatment. Tolerance induction by mixed chimerism without toxic conditioning and with a low risk of graft versus host disease is a visionary but realistic goal. Some of these innovations are already used in modern transplant centres and will allow advancement in long-term allograft preservation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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16. miR-182-5p Inhibition Ameliorates Ischemic Acute Kidney Injury.
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Wilflingseder J, Jelencsics K, Bergmeister H, Sunzenauer J, Regele H, Eskandary F, Reindl-Schwaighofer R, Kainz A, and Oberbauer R
- Subjects
- Animals, Biopsy, Cells, Cultured, Disease Progression, Gene Expression Regulation drug effects, Humans, Ischemia pathology, Kidney blood supply, Kidney drug effects, Kidney metabolism, Kidney pathology, Male, Mice, Inbred C57BL, MicroRNAs metabolism, Oligonucleotides, Antisense pharmacology, Rats, Sprague-Dawley, Reperfusion Injury genetics, Reperfusion Injury pathology, Reproducibility of Results, Sus scrofa, Acute Kidney Injury genetics, Acute Kidney Injury pathology, Ischemia genetics, MicroRNAs antagonists & inhibitors
- Abstract
Acute kidney injury (AKI) remains a major clinical event with high mortality rates. We previously identified renal miR-182 as the main driver of post-transplantation AKI. Therefore, we tested the causal inference of miR-182 by inhibiting its renal expression in vivo. In 45 rats AKI was induced by right nephrectomy and contralateral clamping of the renal pedicle for 40 minutes. Systemically administered antisense oligonucleotide (ASO) inhibited miR-182 in the kidneys up to 96 hours. The maximum creatinine elevation was on day 2 after injury (mg/dL; median and interquartile range): ASO 2.5mg/kg: 1.9 (1.3; 3.2), ASO 25mg/kg: 2.8 (0.7; 5.0), mismatch oligonucleotide (MM) 25mg/kg: 5.7 (5,0; 5.8), saline: 4.4 (3.5; 5.8) (P = 0.016, analysis of variance). Blinded semiquantitative histologic evaluation of renal biopsies showed better preserved morphology in both ASO groups than saline- and MM-treated kidneys (median and interquartile range of overall injury scores): ASO both concentrations 1 (1, 1), saline 3 (3, 3) and MM 3 (3, 3) (P< 0.001, analysis of variance). ASO facilitated cell proliferation, metabolism, and angiogenesis on a genome-wide level. ASO when applied in normothermic kidney machine perfusion reduced renal miR-182 expression by more than two magnitudes. In summary, we showed that in vivo inhibition of miR-182 by ASO improved kidney function and morphology after AKI. This technique may be applicable to reduce the high rate of AKI in the human renal transplantation setting., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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17. Introducing the Wiley Transplant Peer Review Network.
- Author
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Kirk AD, Malchesky PS, Shapiro R, Webber SA, Hirsch HH, Marty FM, Oberbauer R, Wekerle T, Bühler LH, Labbate A, Perry K, and Wielgus J
- Subjects
- Authorship, Editorial Policies, Humans, Organ Transplantation standards, Peer Review, Research, Periodicals as Topic, Professional Review Organizations
- Published
- 2016
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- View/download PDF
18. Molecular diagnostics identifies risks for graft dysfunction despite borderline histologic changes.
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Hrubá P, Brabcová I, Gueler F, Krejčík Z, Stránecký V, Svobodová E, Malušková J, Gwinner W, Honsová E, Lodererová A, Oberbauer R, Zachoval R, and Viklický O
- Subjects
- Adult, Aged, Asymptomatic Diseases, Biopsy, Early Diagnosis, Female, Gene Expression Profiling, Gene Expression Regulation, Genetic Predisposition to Disease, Graft Rejection physiopathology, Humans, Kidney physiopathology, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Phenotype, Polymerase Chain Reaction, Predictive Value of Tests, Reproducibility of Results, Retrospective Studies, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Genetic Markers, Graft Rejection genetics, Graft Rejection pathology, Kidney pathology, Kidney Transplantation adverse effects, Molecular Diagnostic Techniques
- Abstract
The significance of borderline changes in kidney allograft biopsies is widely debated. To help resolve this, we studied differences in intrarenal gene expression patterns between early clinical and 3-month protocol biopsies, all of which had borderline histologic changes. The gene expression profiles in training set of patients by microarray analysis and data were validated in a larger cohort using RT-qPCR. There was greater expression of immunity- and inflammation-related genes in the early clinical biopsies compared to the 3-month protocol biopsies with borderline changes. In early clinically manifested borderline changes, graft deterioration within 24 months due to chronic rejection was associated with increased activation of immune, defense, and inflammatory processes. Regression modeling identified higher donor age and expression of macrophage receptor CLEC5A as risk factors for progression. In the 3-month protocol biopsies with borderline changes, graft dysfunction was associated with increased expression of fibrinogen complex transcripts. The discrimination power of fibrinogen was confirmed by cross-validation on two independent cohorts. Thus, our study highlights variations in gene expression between clinical and subclinical borderline changes despite similar histological findings. The data also support a recommendation for frequent patient monitoring, especially in those with borderline changes who received grafts from older donors.
- Published
- 2015
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19. Modifiable lifestyle and social factors affect chronic kidney disease in high-risk individuals with type 2 diabetes mellitus.
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Dunkler D, Kohl M, Heinze G, Teo KK, Rosengren A, Pogue J, Gao P, Gerstein H, Yusuf S, Oberbauer R, and Mann JF
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- Aged, Albuminuria epidemiology, Alcohol Drinking epidemiology, Anxiety economics, Diabetic Nephropathies physiopathology, Disease Progression, Educational Status, Female, Glomerular Filtration Rate, Humans, Male, Middle Aged, Motor Activity, Renal Insufficiency, Chronic physiopathology, Risk Factors, Smoking epidemiology, Stress, Psychological epidemiology, Diabetes Mellitus, Type 2 epidemiology, Diabetic Nephropathies epidemiology, Life Style, Renal Insufficiency, Chronic epidemiology, Social Support
- Abstract
This observational study examined the association between modifiable lifestyle and social factors on the incidence and progression of early chronic kidney disease (CKD) among those with type 2 diabetes. All 6972 people from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) with diabetes but without macroalbuminuria were studied. CKD progression was defined as decline in GFR of more than 5% per year, progression to end-stage renal disease, microalbuminuria, or macroalbuminuria at 5.5 years. Lifestyle/social factors included tobacco and alcohol use, physical activity, stress, financial worries, the size of the social network and education. Adjustments were made for known risks such as age, diabetes duration, GFR, albuminuria, gender, body mass index, blood pressure, fasting plasma glucose, and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers use. Competing risk of death was considered. At study end, 31% developed CKD and 15% had died. The social network score (SNS) was a significant independent risk factor of CKD and death, reducing the risk by 11 and 22% when comparing the third to the first tertile of the SNS (odds ratios of CKD 0.89 and death 0.78). Education showed a significant association with CKD but stress and financial worries did not. Those with moderate alcohol consumption had a significantly decreased CKD risk compared with nonusers. Regular physical activity significantly decreased the risk of CKD. Thus, lifestyle is a determinant of kidney health in people at high cardiovascular risk with diabetes.
- Published
- 2015
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- View/download PDF
20. The effect of steroid pretreatment of deceased organ donors on liver allograft function: a blinded randomized placebo-controlled trial.
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Amatschek S, Wilflingseder J, Pones M, Kainz A, Bodingbauer M, Mühlbacher F, Langer RM, Gerlei Z, and Oberbauer R
- Subjects
- Adult, Aged, Female, Graft Rejection, Humans, Male, Middle Aged, Transplantation, Homologous, Adrenal Cortex Hormones pharmacology, Liver Transplantation, Tissue Donors
- Abstract
Background & Aims: Brain death-associated inflammatory response contributes to increased risk of impaired early liver allograft function, which might be counterbalanced by steroid pretreatment of the organ donor. The aim of this randomized controlled trial was to elucidate whether steroid pretreatment of liver donors improves early liver allograft function, prevents rejection and prolongs survival., Methods: A placebo-controlled blinded randomized clinical trial was performed in three different centers in Austria and Hungary between 2006 and 2008. Ninety deceased organ donors received either 1000 mg of methylprednisolone or placebo 6h before recovery of organs. The primary end point was the concentration slope of transaminases within the first week. The secondary end point included survival and biopsy-confirmed acute rejection (BCAR) within 3 years after transplantation., Results: Of the 90 randomized donors, 83 recipients were eligible for study. The trajectories of ALT and AST were not different between treatments (p=0.40 and p=0.13, respectively). Eight subjects died in the steroid and 13 in the placebo group within 3 years after engraftment (RR=0.63 95% CI [0.29,1.36], p=0.31). Eleven recipients experienced biopsy-confirmed rejection (BCAR) in the steroid and 11 in the placebo group (RR=1.02 95% CI [0.50,2.10], p=1.00). No effect modification could be identified in the predefined strata of donor age, sex, cold ischemic time, and cause of donor death., Conclusions: Steroid pretreatment of organ donors did not improve outcomes after liver transplantation., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Published
- 2012
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21. The case: hemolysis and acute renal failure. Babesiosis.
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Blum S, Gattringer R, Haschke E, Walochnik J, Tschurtschenthaler G, Lang F, and Oberbauer R
- Subjects
- Aged, Animals, Babesia isolation & purification, Babesiosis blood, Erythrocytes parasitology, Erythrocytes pathology, Humans, Male, Parasitemia blood, Parasitemia diagnosis, Parasitemia parasitology, Acute Kidney Injury blood, Acute Kidney Injury etiology, Babesiosis complications, Babesiosis diagnosis, Hemolysis
- Published
- 2011
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22. A single nucleotide polymorphism at chromosome 2q21.3 (LCT -13910C>T) associates with clinical outcome after allogeneic hematopoietic stem cell transplantation.
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Hauser H, Zach O, Krieger O, Kasparu H, Koenig J, Girschikofsky M, Oberbauer R, and Lutz D
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- Acute Disease, Adult, Alleles, Female, Genotype, Graft vs Host Disease enzymology, Graft vs Host Disease genetics, Graft vs Host Disease immunology, Graft vs Host Disease microbiology, Humans, Intestines enzymology, Intestines immunology, Intestines microbiology, Lactase genetics, Male, Middle Aged, Prognosis, Risk Factors, Tissue Donors, Transplantation, Homologous, Chromosomes, Human, Pair 2 genetics, Hematopoietic Stem Cell Transplantation adverse effects, Polymorphism, Single Nucleotide
- Abstract
A single nucleotide polymorphism (SNP) responsible for lactase persistence (LCT -13910C>T) changes intestinal microflora. Considering the influence of bacterial microflora on various immune effects, we tested DNA from 111 recipients/donors and analyzed whether this SNP interferes with survival and the incidence of acute graft-versus-host disease (aGVHD) after allogeneic hematopoetic stem cell transplantations (HSCT). Median overall survival (OS) was significantly longer when donors had a CC genotype (not reached after 133 vs 11.1 months, P = .004). Multivariate analysis identified a donor T allele (hazard ratio 2.63, 95% confidence interval 1.29-5.33, P = .008) as independent risk factor for death. Surprisingly, recipient genotypes did not influence outcome and there were no differences regarding aGVHD. Transplantation-related mortality (TRM), relapse and pneumonia were significantly less frequent in patients with CC donors. These findings add to the growing list of non-HLA polymorphisms with impact on outcome after allogeneic HSCT.
- Published
- 2008
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23. Prophylactic bisphosphonate treatment prevents bone fractures after liver transplantation.
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Bodingbauer M, Wekerle T, Pakrah B, Roschger P, Peck-Radosavljevic M, Silberhumer G, Grampp S, Rockenschaub S, Berlakovich G, Steininger R, Klaushofer K, Oberbauer R, and Mühlbacher F
- Subjects
- Biomarkers blood, Bone Density drug effects, Female, Humans, Liver Transplantation mortality, Male, Middle Aged, Prospective Studies, Survival Analysis, Zoledronic Acid, Bone Density Conservation Agents therapeutic use, Diphosphonates therapeutic use, Fractures, Bone epidemiology, Fractures, Bone prevention & control, Imidazoles therapeutic use, Liver Transplantation adverse effects, Postoperative Complications prevention & control
- Abstract
A randomized controlled prospective open-label single center trial was performed. At the time of transplantation patients were randomly assigned to one of two treatment arms: The study group of 47 patients received zoledronic acid (ZOL, 8 infusions at 4 mg during the first 12 months after LT), calcium (1000 mg/d) and vitamin D (800 IE/d). The control group consisted of 49 patients who received calcium and vitamin D at same doses (CON). The incidence of bone fractures or death was predefined as the primary endpoint. Secondary endpoints included bone mineral density (BMD), serum biochemical markers of bone metabolism, parameters of trabecular bone histomorphometry and mineralization density distribution (BMDD). Patients were followed up for 24 months. Analysis was performed on an intention-to-treat basis. The primary endpoint fracture or death was reached in 26% of patients in the ZOL group and 46% in the CON group (p = 0.047, log rank test). Densitometry results were different between the groups at the femoral neck at 6 months after LT (mean+/-SD BMD ZOL: 0.80 +/- 0.19 g/cm2 vs. CON: 0.73 +/- 0.14 g/cm2, p = 0.036). Mixed linear models of biochemical bone markers showed less increase of osteocalcin in the ZOL group and histomorphometry and BMDD indicated a reduction in bone turnover. Prophylactic treatment with the bisphosphonate zoledronic acid reduces bone turnover and fractures after liver transplantation.
- Published
- 2007
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24. A "weight-listing" paradox for candidates of renal transplantation?
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Schold JD, Srinivas TR, Guerra G, Reed AI, Johnson RJ, Weiner ID, Oberbauer R, Harman JS, Hemming AW, and Meier-Kriesche HU
- Subjects
- Adolescent, Adult, Aged, Body Weight, Female, Humans, Kidney Failure, Chronic surgery, Male, Middle Aged, Proportional Hazards Models, Retrospective Studies, Treatment Outcome, Body Mass Index, Kidney Failure, Chronic mortality, Kidney Transplantation, Waiting Lists, Weight Loss
- Abstract
Research suggests that end-stage renal disease patients with elevated body mass index (BMI) have superior outcomes on dialysis. In contrast, low and high BMI patients represent the highest risk cohorts for kidney transplant recipients. The important question remains concerning how to manage transplant candidates given the potentially incommensurate impact of BMI by treatment modality. We conducted a retrospective analysis of waitlisted and transplanted patients in the United States from 1990 to 2003. We constructed Cox models to evaluate the effect of BMI on mortality of waitlisted candidates and identified risk factors for rapid weight change. We then assessed the impact of weight change during waitlisting on transplant outcomes. Decline in BMI on the waiting list was not protective for posttransplant mortality or graft loss across BMI strata. Substantial weight loss pretransplantation was associated with rapid gain posttransplantation. The highest risk for death was among listed patients with low BMI (13-20 kg/m(2), adjusted hazard ratio = 1.47, p < 0.01). Approximately one-third of candidates had a change in BMI category prior to transplantation. While observed declines in BMI may be volitional or markers of disease processes, there is no evidence that candidates have improved transplant outcomes attributable to weight loss. Prospective trials are needed to evaluate the efficacy of weight loss protocols for candidates of kidney transplantation.
- Published
- 2007
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- View/download PDF
25. Gene expression profiles of human proximal tubular epithelial cells in proteinuric nephropathies.
- Author
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Rudnicki M, Eder S, Perco P, Enrich J, Scheiber K, Koppelstätter C, Schratzberger G, Mayer B, Oberbauer R, Meyer TW, and Mayer G
- Subjects
- Aged, Apoptosis genetics, Bone Morphogenetic Protein 7, Bone Morphogenetic Proteins metabolism, Case-Control Studies, Cell Adhesion genetics, Cell Cycle Proteins metabolism, Cell Differentiation genetics, Cell Proliferation, Female, Gene Expression Profiling, Humans, Immunologic Factors metabolism, Kidney Diseases genetics, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Proteinuria genetics, Signal Transduction genetics, Thrombospondins metabolism, Transcription Factors metabolism, Transforming Growth Factor beta metabolism, Epithelial Cells metabolism, Kidney Diseases metabolism, Kidney Tubules, Proximal metabolism, Proteinuria metabolism
- Abstract
In kidney disease renal proximal tubular epithelial cells (RPTEC) actively contribute to the progression of tubulointerstitial fibrosis by mediating both an inflammatory response and via epithelial-to-mesenchymal transition. Using laser capture microdissection we specifically isolated RPTEC from cryosections of the healthy parts of kidneys removed owing to renal cell carcinoma and from kidney biopsies from patients with proteinuric nephropathies. RNA was extracted and hybridized to complementary DNA microarrays after linear RNA amplification. Statistical analysis identified 168 unique genes with known gene ontology association, which separated patients from controls. Besides distinct alterations in signal-transduction pathways (e.g. Wnt signalling), functional annotation revealed a significant upregulation of genes involved in cell proliferation and cell cycle control (like insulin-like growth factor 1 or cell division cycle 34), cell differentiation (e.g. bone morphogenetic protein 7), immune response, intracellular transport and metabolism in RPTEC from patients. On the contrary we found differential expression of a number of genes responsible for cell adhesion (like BH-protocadherin) with a marked downregulation of most of these transcripts. In summary, our results obtained from RPTEC revealed a differential regulation of genes, which are likely to be involved in either pro-fibrotic or tubulo-protective mechanisms in proteinuric patients at an early stage of kidney disease.
- Published
- 2007
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26. Developments in clinical islet, liver thoracic, kidney and pancreas transplantation in the last 5 years.
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Feng S, Barr M, Roberts J, Oberbauer R, and Kaplan B
- Subjects
- Graft Survival, Humans, Kidney Transplantation immunology, Survival Rate, Time Factors, Kidney Transplantation methods, Liver Transplantation methods, Pancreas Transplantation methods
- Abstract
Although organ transplantation has matured into a proven therapy for end-stage organ failure, the many notable developments of the past 5 years speak to the multitude of remaining challenges. Two new procedures, islet transplantation and adult-to-adult living donor liver transplantation, have emerged to enlarge our therapeutic armamentarium for Type 1 diabetes mellitus and end-stage liver disease, respectively. In cardiac transplantation, the acceptance of ventricular assist devices as destination therapy is a notable event in light of critical shortage of deceased donor organs. Both liver and lung allocation policies have made a dramatic paradigm shift away from waiting time toward the survival benefit of transplantation. Finally, primary threats to post-transplant longevity have gained an increasing share of the spotlight. Recognition of the impact of renal insufficiency for all nonrenal transplant recipients, of recurrent hepatitis C virus for liver recipients, and of accelerated vasculopathy for cardiac have identified novel end points for clinical trials.
- Published
- 2006
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27. Transcriptional response in the unaffected kidney after contralateral hydronephrosis or nephrectomy.
- Author
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Hauser P, Kainz A, Perco P, Bergmeister H, Mitterbauer C, Schwarz C, Regele HM, Mayer B, Meyer TW, and Oberbauer R
- Subjects
- Animals, Carrier Proteins genetics, Insulin-Like Growth Factor II genetics, Kidney surgery, Male, Nephrectomy, Rats, Rats, Sprague-Dawley, Transcription Factors genetics, Ureteral Obstruction genetics, Ureteral Obstruction physiopathology, Hydronephrosis genetics, Hydronephrosis physiopathology, Kidney physiology, Oligonucleotide Array Sequence Analysis, Transcriptional Activation physiology
- Abstract
Background: Unilateral loss of kidney function is followed by compensatory contralateral growth. The early, genome-wide transcriptional response of the untouched kidney to unilateral ureteral obstruction (UUO) or unilateral nephrectomy is unknown., Methods: Twelve adult male Sprague-Dawley rats were subjected to UUO and twelve rats to unilateral nephrectomy. At time points 12, 24, and 72 hours after insult four rats each were sacrificed and the contralateral kidney harvested for genome-wide gene expression analysis, transcription factor analysis, and histomorphology., Results: Microarray studies revealed that the majority of differentially expressed transcripts were suppressed in UUO and unilateral nephrectomy compared to control kidneys. The function of these suppressed genes is predominantly growth inhibition and apoptosis suggesting a net pro-hypertrophic response. Insulin-like growth factor-2 (IGF-2)-binding protein was one of the few activated genes. We observed a distinctly different molecular signature between UUO and unilateral nephrectomy at the three time points investigated. The early response in UUO rats suggests a counterbalance to the nonfiltering kidney by activation of transport pathways such as the aquaporins. Unilateral nephrectomy kidneys, on the other hand, respond immediately to contralateral nephrectomy by activation of cell cycle regulators such as the cyclin family. Several genes with weakly defined function were found to be associated with either UUO or unilateral nephrectomy. Transcription factor analysis of the identified transcripts suggests common regulation at least of some of these genes. All kidneys showed normal histology., Conclusion: Release of growth inhibition by nephrectomy leads to immediate cell cycle activation after unilateral nephrectomy, whereas UUO kidneys counterbalance filtration failure by activation of several transporters.
- Published
- 2005
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28. Calcineurin inhibitor withdrawal from sirolimus-based therapy in kidney transplantation: a systematic review of randomized trials.
- Author
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Oberbauer R
- Subjects
- Humans, Randomized Controlled Trials as Topic, Calcineurin Inhibitors, Graft Rejection drug therapy, Immunosuppressive Agents therapeutic use, Kidney Transplantation, Sirolimus therapeutic use
- Published
- 2005
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29. Alterations in gene expression in cadaveric vs. live donor kidneys suggest impaired tubular counterbalance of oxidative stress at implantation.
- Author
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Kainz A, Mitterbauer C, Hauser P, Schwarz C, Regele HM, Berlakovich G, Mayer G, Perco P, Mayer B, Meyer TW, and Oberbauer R
- Subjects
- Cadaver, Gene Expression Profiling, Humans, Kidney Glomerulus physiology, Living Donors, Oligonucleotide Array Sequence Analysis, Promoter Regions, Genetic, Gene Expression physiology, Kidney physiology, Kidney Transplantation, Oxidative Stress, Transplants
- Abstract
Recipients of live donor transplant kidneys (LIV) exhibit a significantly longer allograft half-life compared with cadaveric donor organs (CADs). The reasons are incompletely understood. Therefore this study sought to elucidate the genome-wide gene expression profiles in microdissected transplant kidney biopsies obtained from five cadaveric and five matched live donors before transplantation. cDNA microarrays were used to determine the transcripts in isolated glomeruli (G) and the tubulointerstitial (TI) compartment. Data were subjected to hierarchical clustering, maxT adjustment and a jackknife procedure to ensure robustness of reported findings; validation was performed by independent analysis of split biopsies and TaqMan-PCR. One hundred and thirteen sequences representing 62 unique genes (17 redundant features), and 34 ESTs separated G from TI. No difference in gene expression was found in G between LIV and CAD kidneys, but nine genes (two represented twice) and three ESTs were abundantly expressed in the CAD TI compared with LIV. The main biological function of these genes is counter regulation of oxidative stress. Promoter analysis of significant features suggested coregulated gene groups. These data suggest that CAD kidneys exhibit a distinctly different set of transcripts in the TI compartment but not in the G compartment when compared with LIV kidneys.
- Published
- 2004
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30. Nonsustained effect of short-term bisphosphonate therapy on bone turnover three years after renal transplantation.
- Author
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Schwarz C, Mitterbauer C, Heinze G, Woloszczuk W, Haas M, and Oberbauer R
- Subjects
- Acute Disease, Biomarkers, Bone Density drug effects, Calcification, Physiologic drug effects, Graft Rejection metabolism, Humans, Osteoblasts metabolism, Osteoclasts metabolism, Zoledronic Acid, Chronic Kidney Disease-Mineral and Bone Disorder drug therapy, Chronic Kidney Disease-Mineral and Bone Disorder metabolism, Diphosphonates administration & dosage, Femur metabolism, Imidazoles administration & dosage, Kidney Transplantation
- Abstract
Background: We recently showed that two doses of 4 mg of zoledronic acid (ZOL) ameliorated the bone loss and improved bone histology within the first six months after kidney transplantation. The aim of the present study was to evaluate whether this early short-term intervention exhibited a sustained bone-sparing effect., Methods: A homogenous group of 20 de novo renal transplant recipients were equally randomized to two infusions of 4 mg of ZOL or placebo at two weeks and three months after engraftment. Patients were followed up for three years by sequential determination of bone densitometry and specific biochemical markers., Results: From month six to three years after transplantation, both treatment groups exhibited an improvement of bone mineralization. Femoral neck bone mineral density z-scores increased statistically significantly from -1.3 (2.6) to -0.2 (3.6) in the placebo group and from -1.6 (2.9) to -1.2 (1.9) in the ZOL group (median, range). Biochemical parameters of osteoblast activity such as osteocalcin and bone-specific alkaline phosphatase did not increase significantly in both groups. Osteoprotegerin, a marker of osteoclast inhibition, was significantly elevated over the first six months in the ZOL group, but decreased to similar levels, as in the placebo group, over the next two and a half years. Other markers of osteoclast activity such as c-telopeptide of type 1 collagen, calcitonin, and intact parathyroid hormone were not different between six months and three years in either group., Conclusion: The early bone-sparing effect of short-term ZOL therapy confers no sustained benefit versus placebo at three year post-transplantation.
- Published
- 2004
- Full Text
- View/download PDF
31. Zoledronic acid to prevent bone loss in the first 6 months after renal transplantation.
- Author
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Haas M, Leko-Mohr Z, Roschger P, Kletzmayr J, Schwarz C, Mitterbauer C, Steininger R, Grampp S, Klaushofer K, Delling G, and Oberbauer R
- Subjects
- Biomarkers, Bone Density drug effects, Calcium metabolism, Female, Femur Neck metabolism, Humans, Lumbar Vertebrae metabolism, Male, Middle Aged, Postoperative Complications drug therapy, Postoperative Complications prevention & control, Zoledronic Acid, Chronic Kidney Disease-Mineral and Bone Disorder drug therapy, Chronic Kidney Disease-Mineral and Bone Disorder prevention & control, Diphosphonates therapeutic use, Imidazoles therapeutic use, Kidney Transplantation
- Abstract
Background: Bisphosphonates can prevent bone mineral density loss after renal transplantation, but their effect on trabecular mineralization and bone morphology, two key factors of bone stability, remains unknown., Methods: In a 6-month, randomized, placebo-controlled study, 20 kidney transplant recipients received either 4 mg zoledronic acid or placebo twice within 3 months after engraftment. At transplantation and after 6 months, mean trabecular calcium concentration and trabecular morphometry were measured in bone biopsies. Bone mineral density (BMD) of the femoral neck and the lumbar spine were evaluated by dual-energy x-ray absorptiometry, and serum biochemical markers of bone metabolism were determined monthly., Results: Trabecular calcium content increased significantly in the zoledronic acid group, but remained unchanged in the placebo group. BMD at femoral neck showed no change in the zoledronic acid group, but decreased in the placebo group. BMD of the lumbar spine was increased in the zoledronic acid group without change in the placebo group. High-turnover bone disease resolved similarly in both groups, as evidenced by a significant decrease of eroded bone surface, osteoclast and osteoblast surface. Serologic markers of bone formation and resorption were significantly lower in zoledronic acid-treated patients throughout the study. Kidney transplant function was stable after zoledronic acid therapy., Conclusions: Our results show that administration of zoledronic acid improves the calcium content of cancellous bone after kidney transplantation. The beneficial effect of bisphosphonate therapy is further evidenced by an increase of lumbar spine BMD, and stabilization of femur BMD.
- Published
- 2003
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32. Pimecrolimus identifies a common genomic anti-inflammatory profile, is clinically highly effective in psoriasis and is well tolerated.
- Author
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Rappersberger K, Komar M, Ebelin ME, Scott G, Burtin P, Greig G, Kehren J, Chibout SD, Cordier A, Holter W, Richter L, Oberbauer R, Stuetz A, and Wolff K
- Subjects
- Adult, Dose-Response Relationship, Drug, Double-Blind Method, Female, Follow-Up Studies, Gene Expression Profiling, Humans, Male, Middle Aged, Psoriasis genetics, Psoriasis immunology, Recurrence, Tacrolimus adverse effects, Tacrolimus pharmacokinetics, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Psoriasis drug therapy, Tacrolimus analogs & derivatives, Tacrolimus therapeutic use
- Abstract
The ascomycin macrolactam pimecrolimus is a novel inflammatory cytokine release inhibitor that so far has not been administered systemically to humans. In this phase I/II randomized double-blind, placebo-controlled, multiple rising dose proof of concept study psoriasis patients were treated with oral pimecrolimus or placebo. Gene profiling identified a common genomic profile with a downregulation of genes associated with inflammation but no changes in gene expression linked to drug-related side-effects. A steady state of pimecrolimus was reached after 5-10 d, Cmax, and area under the curve (0-24) was 54.5 ng per ml and 589.9 ng h per ml, respectively, at steady state at the highest dose. There was clear clinical efficacy in patients receiving 20 mg pimecrolimus twice daily and 30 mg twice daily with a reduction of Psoriasis Area and Severity Index by 60% and 75%, respectively. Histopatho logically and immunopathologically there was a reversion of the psoriatic phenotype towards normal. There were no notable clinical, laboratory, kidney function, or immunologic side-effects. We conclude that pimecrolimus taken orally is highly effective in a concentration-dependent manner in patients with psoriasis and on a short-term basis it is well tolerated and this is confirmed by its pharmacogenomic profile. The latter also indicates that pimecrolimus should be equally effective in other inflammatory skin diseases.
- Published
- 2002
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33. Regulation of renal tubular cell apoptosis and proliferation after ischemic injury to a solitary kidney.
- Author
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Oberbauer R, Schwarz C, Regele HM, Hansmann C, Meyer TW, and Mayer G
- Subjects
- Animals, Cell Division, Male, Proliferating Cell Nuclear Antigen analysis, Proto-Oncogene Proteins analysis, Proto-Oncogene Proteins c-bcl-2 analysis, Proto-Oncogene Proteins c-bcl-2 genetics, RNA, Messenger analysis, Rats, Rats, Sprague-Dawley, bcl-2-Associated X Protein, bcl-X Protein, Apoptosis, Ischemia pathology, Kidney blood supply, Kidney Tubules pathology
- Abstract
The time course and regulation of apoptosis and cellular regeneration after 30 minutes of acute ischemic injury to a single kidney was elucidated in rats at five time points over 20 weeks. The fraction of apoptotic cells was most prominent at 1 day after the insult in the distal tubule (8% +/- 4% vs 0% +/- 0%, acute renal failure [ARF] vs sham, respectively) and was still elevated at 7 days (2% +/- 2% vs 0% +/- 0%). At that time, the whole kidney mRNA expression of the apoptosis inhibitory genes bcl-xL and bcl-2, as well as that of the apoptosis promotor bax, was significantly reduced. Immunohistochemistry of kidney specimen showed suppression of bcl-2 in the distal tubule but up-regulation in the proximal tubule, whereas bax protein was more strongly expressed in the distal tubule. Cellular proliferation started at day 1 and continued over the following 20 weeks, leading to severe tubular dilation and kidney failure. These data indicate that differential regulation of bcl-2 family members contributes to the early apoptotic clearance of lethally injured tubular epithelial cells after ischemic injury to a solitary kidney.
- Published
- 2001
- Full Text
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34. Effect of anticoagulation on blood membrane interactions during hemodialysis.
- Author
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Hofbauer R, Moser D, Frass M, Oberbauer R, Kaye AD, Wagner O, Kapiotis S, and Druml W
- Subjects
- Adult, Blood Coagulation drug effects, Cell Adhesion drug effects, Erythrocytes ultrastructure, Female, Humans, Kidney Failure, Chronic blood, Male, Materials Testing, Membranes, Artificial, Microscopy, Electron, Scanning, Middle Aged, Sodium Citrate, Thrombosis drug therapy, Thrombosis prevention & control, Anticoagulants administration & dosage, Citrates administration & dosage, Dalteparin administration & dosage, Heparin, Low-Molecular-Weight administration & dosage, Kidney Failure, Chronic therapy, Renal Dialysis
- Abstract
Background: Adequate anticoagulation is a precondition to prevent extracorporeal blood clotting and to improve biocompatibility during hemodialysis. In this study, we performed a morphologic analysis by using scanning electron microscopy to compare three modes of anticoagulation-conventional unfractionated heparin (UFH), low molecular weight heparin (LMWH; dalteparin sodium), or sodium citrate during hemodialysis-on membrane-associated coagulation activation., Methods: Fifteen patients on regular hemodialysis therapy were investigated. Five patients received UFH, five patients LMWH, and five patients sodium citrate as an anticoagulant during a standardized hemodialysis protocol using a single-use polysulfone capillary dialyzer. Membrane-associated clotting was evaluated using a scanning electron microscope. A dialyzer clotting score was used for quantitative description of coagulation activation on membrane segments., Results: Using UFH as an anticoagulant revealed the most pronounced cell adhesion and thrombus formation and the highest dialyzer clotting score (11.5 +/- 1.3 of a maximal 20 points). LMWH had a lower dialyzer clotting score than UFH (10.4 +/- 1.2 of 20 points). During the use of sodium citrate, a negligible thrombus formation and the lowest dialyzer clotting score (1.6 +/- 0.6 of 20 points, P < 0.05) were observed., Conclusion: The results of this investigation indicate that using sodium citrate as an anticoagulant during hemodialysis induces a lower activation of coagulation than both conventional and fractionated heparin, which might contribute to an improvement of biocompatibility of hemodialysis extracorporeal circulation.
- Published
- 1999
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35. Low dose angiotensin converting enzyme inhibition and glomerular permselectivity in renal transplant recipients.
- Author
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Borchhardt K, Haas N, Yilmaz N, Oberbauer R, Schmidt A, Barnas U, and Mayer G
- Subjects
- Blood Pressure, Creatinine blood, Creatinine urine, Dextrans pharmacokinetics, Female, Glomerular Filtration Rate, Hemodynamics drug effects, Humans, Kidney Glomerulus blood supply, Male, Renal Circulation, Renin-Angiotensin System drug effects, Angiotensin-Converting Enzyme Inhibitors administration & dosage, Graft Survival drug effects, Kidney Glomerulus metabolism, Kidney Transplantation, Lisinopril administration & dosage
- Abstract
In this study, we determined the fractional clearance of neutral polydisperse dextrans (theta D) and monodisperse dextran sulfate (theta DS) to describe glomerular size and charge selectivity in 25 renal transplant recipients with proteinuria. Thirteen were treated with low dose lisinopril for six months (group 1) and 12 patients without ACE inhibitor therapy formed group 2. Mean arterial blood pressure was stable (group 1, 112 +/- 4; group 2, 109 +/- 2 mm Hg at baseline and after 6 months) whereas creatinine clearance, glomerular filtration rate and renal plasma flow decreased nonsignificantly but were comparable at any time. Lisinopril treatment lowered filtration fraction (22 +/- 2 vs. 19 +/- 2%, P = 0.07) whereas no change was seen in group 2 (20 +/- 2%). The fractional protein excretion (mg urinary protein per day/ml creatinine clearance per day) was stable in group 1, but significantly increased in group 2. The same pattern was found for theta D larger than 56 A. theta DS was stable and consistently elevated in both groups at any time. We conclude that low dose ACE inhibitor treatment in proteinuric renal transplant recipients stabilizes glomerular size selectivity independently of its systemic hemodynamic effects.
- Published
- 1997
- Full Text
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36. Renal uptake of an 18-mer phosphorothioate oligonucleotide.
- Author
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Oberbauer R, Schreiner GF, and Meyer TW
- Subjects
- Animals, Autoradiography, Base Sequence, Biological Transport, Active, Genetic Therapy, Infusions, Intravenous, Kidney ultrastructure, Kinetics, Male, Microscopy, Electron, Molecular Sequence Data, Oligodeoxyribonucleotides administration & dosage, Oligodeoxyribonucleotides genetics, Oligonucleotides, Antisense therapeutic use, Polydeoxyribonucleotides administration & dosage, Polydeoxyribonucleotides genetics, Polydeoxyribonucleotides pharmacokinetics, Rats, Rats, Sprague-Dawley, Tissue Distribution, Kidney metabolism, Oligodeoxyribonucleotides pharmacokinetics
- Abstract
Renal uptake of a 35S labeled 18-mer phosphorothioate oligodeoxynucleotide (molecular wt approximately 6,000) was evaluated following intravenous infusion into rats. The kidneys contained 21 +/- 3% of the infused dose at five hours after infusion and 3 +/- 1% of the infused dose at four days after infusion. The concentration of oligonucleotide was greater in the kidney than in the liver, spleen, or plasma at both intervals. Urine excretion of oligonucleotide label averaged 17 +/- 1%, 35 +/- 5%, and 64 +/- 3% of the infused dose at five hours, one day, and four days after infusion. Electrophoresis (PAGE) showed that oligonucleotide was retained in the kidney was the intact 18-mer at both five hours and four days after infusion, while full size oligonucleotide was not found in the urine at either interval. Light microscopic autoradiography showed that oligonucleotide uptake was most prominent in the early proximal tubule. Electron microscopic autoradiography indicated that oligonucleotide was not confined to the brush border or endocytic-lysosomal pathway. Micropuncture studies showed that the tubule fluid to plasma concentration ratios of oligonucleotide label averaged 7 +/- 3% in Bowman's space and 6 +/- 2% in the distal tubule. Despite restriction of filtration by plasma protein binding, as indicated by the low Bowman's space to plasma concentration ratio, the calculated tubular reabsorption rate for oligonucleotide was sufficient to account for the large amount of oligonucleotide found in the kidney after intravenous infusion. These results indicate that the proximal tubule plays a prominent role in the disposition of intravenously infused oligonucleotide, and raise the possibility that oligonucleotides could exert antisense effects in this nephron segment.
- Published
- 1995
- Full Text
- View/download PDF
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