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Biomedical subjects

Bryan N Becker

Publications and source records attributed to Bryan N Becker.

At least 19 recordsLinked to original sources
PubMed2006

Noninvasive assessment of early kidney allograft dysfunction by blood oxygen level-dependent magnetic resonance imaging.

BACKGROUND: Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) is a noninvasive method to assess tissue oxygen bioavailability, using deoxyhemoglobin as an endogenous contrast agent. We hypothesized that BOLD-MRI could accurately discriminate different types of rejection early after kidney transplantation. METHODS: Twenty-three patients underwent imaging in the first four months posttransplant. Five had normal functioning transplants and 18 had biopsy-proven acute allograft dysfunction (acute tubular necrosis [ATN, n=5] and acute rejection [n=13] including borderline rejection: n=3; IA rejection: n=4; IIA rejection: n=6: C4d(+) rejection: n=9). RESULTS: Mean medullary R2* (MR2*) levels (a measure directly proportional to tissue deoxyhemoglobin levels) were significantly higher in normal functioning allografts (R2*=24.3/s+/-2.3) versus acute rejection (R2*=16.6/s+/-2.1) and ATN (R2*=20.9/s+/-1.8) (P<0.05). The lowest MR2* levels were observed in acute rejection episodes with vascular injury i.e. IIA and C4d (+). Similarly, the lowest medullary to cortical R2* ratios (MCR2*) were present in allografts with IIA (1.24+/-0.05) and C4d(+) rejection (1.26+/-0.06). ROC curve analyses suggested that MR2* and MCR2* values could accurately discriminate acute rejection in the early posttransplant period. CONCLUSIONS: BOLD-MRI demonstrated significant changes in medullary oxygen bioavailability in allografts with biopsy-proven ATN and acute rejection, suggesting that there may be a role for this noninvasive tool to evaluate kidney function early after transplantation.

Adult↗
PubMed2006

Preemptive transplantation for patients with diabetes-related kidney disease.

BACKGROUND: Preemptive kidney transplantation (PreKT) before initiation of chronic dialysis has been examined recently with favorable results as the most effective treatment for kidney failure. Given that few of these studies are disease specific, the present analyses investigated the outcomes of PreKT by transplantation option and diabetes type. METHODS: The impact of PreKT on posttransplantation mortality and graft failure was examined in 23 238 adults with type 1 and type 2 diabetes mellitus (DM), receiving either living or deceased donor kidneys or undergoing simultaneous pancreas-kidney (SPK) transplantation between January 1, 1997, and December 31, 2002. RESULTS: The PreKTs were provided to 14.4% of patients with type 1 DM and 6.7% of patients with type 2 DM. Cox regression models were used to estimate the effect of PreKT on the adjusted risk ratio (RR) of graft failure and mortality. After adjusting for multiple factors, PreKT in this era was associated with lower RR of mortality only among type 1 and type 2 diabetic recipients of transplants from living donors and SPK transplant recipients with type 1 DM (RR, 0.50-0.65; P<.007 for each). The effect on graft failure was less pronounced, significant only for preemptive SPK transplant recipients (RR, 0.79; P=.01 vs nonpreemptive SPK transplant recipients). CONCLUSIONS: These analyses suggest that PreKT has significant benefits for subsets of patients with types 1 and 2 DM and end-stage renal disease. It also suggests a time trend toward less benefit from preemptive transplants from deceased donors in more recent years compared with the early 1990s. This observation and the discrepancies between RR of graft loss and RR of mortality deserve further study.

Adolescent↗
PubMed2006

In-center hemodialysis patients' use of the internet in the United States: a national survey.

BACKGROUND: Education is critical to help patients with chronic kidney disease self-manage their illness by thoroughly understanding their treatment options, medications, diet and fluids, and symptoms. METHODS: This study assesses in-center hemodialysis patients' use of the Internet in general and for health information seeking, both independently and by proxy-asking a family member or friend. Patients (n = 1,804) were recruited from 37 randomly selected dialysis clinics in 18 End-Stage Renal Disease Networks. Respondents completed a survey in English or Spanish. RESULTS: Across the entire sample, 34.7% had used the Internet themselves compared with 38% of disabled Americans. Internet use was more likely among patients who were younger, non-Hispanic, from the Southeast or Texas, and more highly educated. Median education level of English-reading respondents was 12th grade. Their total Internet health information use was 43.5% (24.7% independently, 18.8% by proxy). Median education level of Spanish-reading respondents was 6th grade; their total Internet health information use was only 25.5% (8.5% independently, 17% by proxy). Reasons for not using the Internet related more to not having access to a computer or knowledge (70.4%) than to lack of interest (21.3%). CONCLUSION: Alerting patients to Internet access at public libraries or providing a computer in dialysis clinic waiting rooms may help overcome this barrier. Proxy use may extend the reach of the Internet to patients who do not have access on their own.

Adolescent↗
PubMed2005

Prevention of chronic allograft nephropathy with vitamin D.

Chronic allograft nephropathy (CAN) is the leading cause of late allograft loss in kidney transplantation. Interstitial fibrosis and glomerulosclerosis are characteristic of CAN. Transforming growth factor beta-1 (TGFbeta-1) is associated with both of these histologic findings in the transplant setting. Recent studies have suggested that vitamin D signaling pathways may interact with and regulate TGFbeta-1 mediated events. We examined the efficacy of 1,25-dihydroxyvitamin D(3), the active metabolite of vitamin D [1,25-(OH)(2)D(3)], the active metabolite of vitamin D, as monotherapy to prolong allograft survival and preserve renal function in a rat model of CAN, the Fisher 344 to Lewis model. Recipients went without treatment or were treated with cyclosporine A (CSA; 10 days) or 1,25(OH)(2)D(3) (1000, 500 or 250 ng/kg/day). Grafts were harvested at the time of rejection or at 24 weeks post-transplant. A portion of the graft was processed for histology and immunohistochemistry and a second portion was analyzed for protein expression by western blotting. Not only did 1,25-(OH)(2)D(3) treatment significantly prolong graft survival, but it also prevented histological changes associated with CAN. 1,25-(OH)(2)D(3) treatment significantly decreased Smad 2 expression. This TGFbeta signaling molecule is likely involved in fibrosis. Moreover, 1,25-(OH)(2)D(3) treatment increased Smad 7 expression, an important feedback molecule in the TGFbeta-1 signaling pathway. This suggests that 1,25-(OH)(2)D(3) interacts with TGFbeta-1 in limiting histological injury in this model of CAN. Furthermore, 1,25-(OH)(2)D(3), treatment increased expression of matrix metalloproteinase 2 (MMP-2), thus directly affecting levels of another important matrix molecule. Taken together our data suggests that 1,25-(OH)(2)D(3) mitigates CAN in this model by altering TGFbeta-1 and matrix-regulating molecules.

Animals↗
PubMed2005

ATR blockade reduces IFN-gamma production in lymphocytes in vivo and in vitro.

BACKGROUND: Type 1 angiotensin II (Ang II) receptor (AT(1)R) signaling induces proinflammatory responses. Recent studies suggest that T lymphocytes express AT(1)R; yet the effects of Ang II binding to AT(1)R on T cells are poorly understood. We examined the effect of AT(1)R blockade on release of the proinflammatory cytokine, interferon-gamma (IFN-gamma) by human lymphocytes in vivo and in vitro. METHODS: We used an AT(1)R blocker losartan in a randomized clinical trial in kidney transplant recipients over a 12-month period [AT(1)R blocker (N= 11) and control (N= 10)]. Peripheral blood lymphocytes, isolated from both cohorts, were analyzed by enzyme-linked immunosorbent spot assays (ELISPOT) analyses and real-time reverse transcription-polymerase chain reaction (RT-PCR) to enumerate IFN-gamma producing T cells and IFN-gamma mRNA levels. The effects of AT(1)R blockade in vitro were assessed using human alloreactive T cells and an IFN-gamma producing human cytotoxic T-lymphocyte line. Alloreactive T cells were treated with losartan or candesartan and enzyme-linked immunosorbant assay (ELISA) was used to measure IFN-gamma protein release. The cytotoxic T-lymphocyte line also was AT(1)R blocker-treated prior to determining IFN-gamma producing cells by intracellular cytokine staining. RESULTS: The AT(1)R blocker cohort had a significant decrease in IFN-gamma producing peripheral blood lymphocytes (P< or = 0.05 for each time point) and IFN-gamma mRNA levels (P= 0.01 vs. control patients). Losartan also decreased IFN-gamma production (P < 0.001) in purified alloreactive T cells in vitro as did candesartan. Moreover, Ang II amplified IFN-gamma generation (P < 0.05) in alloreactive T cells while AT(1)R blocker treatment inhibited Ang II's effect (P < 0.04). AT(1)R blocker treatment furthermore also inhibited IFN-gamma production in the cytotoxic T-lymphocyte line. CONCLUSION: AT(1)R blockers may have a clinically relevant immunomodulatory role by blocking IFN-gamma production in T cells.

Adult↗
PubMed2005

Functionally significant renal allograft rejection is defined by transcriptional criteria.

Renal allograft acute cellular rejection (ACR) is a T-cell mediated disease that is diagnosed histologically. However, many normally functioning allografts have T-cell infiltrates and histological ACR, and many nonimmune processes cause allograft dysfunction. Thus, neither histological nor functional criteria are sufficient to establish a significant rejection, and the fundamental features of clinical rejection remain undefined. To differentiate allograft lymphocyte infiltration from clinically significant ACR, we compared renal biopsies from patients with ACR to patients with: sub-clinical rejection (SCR, stable function with histological rejection); no rejection; and nontransplanted kidneys. Biopsies were compared histologically and transcriptionally by RT-PCR for 72 relevant immune function genes. Neither the degree nor the composition of the infiltrate defined ACR. However, transcripts up-regulated during effector T(H)1 T-cell activation, most significantly the transcription factor T-bet, the effector receptor Fas ligand and the costimulation molecule CD152 clearly (p = 0.001) distinguished the patient categories. Transcripts from other genes were equivalently elevated in SCR and ACR, indicating their association with infiltration, not dysfunction. Clinically significant ACR is not defined solely by the magnitude nor composition of the infiltrate, but rather by the transcriptional activity of the infiltrating cells. Quantitative analysis of selected gene transcripts may enhance the clinical assessment of allografts.

Adult↗
PubMed2005

Assessment of acute renal transplant rejection with blood oxygen level-dependent MR imaging: initial experience.

PURPOSE: To prospectively assess the oxygenation state of renal transplants and determine the feasibility of using blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging to differentiate between acute tubular necrosis (ATN), acute rejection, and normal function. MATERIALS AND METHODS: This HIPAA-compliant study had institutional human subjects review committee approval, and written informed consent was obtained from all patients. BOLD MR imaging was performed in 20 patients (age range, 21-70 years) who had recently received renal transplants. Six patients had clinically normal functioning transplants, eight had biopsy-proved rejection, and six had biopsy-proved ATN. R2* (1/sec) measurements were obtained in the medulla and cortex of transplanted kidneys. R2* is a measure of the rate of signal loss in a specific region and is related to the amount of deoxyhemoglobin present. Statistical analysis was performed by using a two-sample t test. Threshold R2* values were identified to discriminate between transplanted kidneys with ATN, those with acute rejection, and those with normal function. RESULTS: R2* values for the medulla were significantly lower in the acute rejection group (R2* = 15.8/sec +/- 1.5) than in normally functioning transplants (R2* = 23.9/sec +/- 3.2) and transplants with ATN (R2* = 21.3/sec +/- 1.9). The differences between the acute rejection and normal function groups (P = .001), as well as between the acute rejection and ATN groups (P < .001), were significant. Acute rejection could be differentiated from normal function and ATN in all cases by using a threshold R2* value of 18/sec. R2* values for the cortex were higher in ATN (R2* = 14.2/sec +/- 1.4) than for normally functioning transplants (R2* = 12.7/sec +/- 1.6) and transplants with rejection (R2* = 12.4/sec +/- 1.2). The difference in R2* values in the cortex between ATN and rejection was statistically significant (P = .034), although there was no threshold value that enabled differentiation of all cases of ATN from cases of normal function or acute rejection. CONCLUSION: R2* measurements in the medullary regions of transplanted kidneys with acute rejection were significantly lower than those in normally functioning transplants or transplants with ATN. These results suggest that marked changes in intrarenal oxygenation occur during acute transplant rejection.

Adult↗
PubMed2004

Intrathymic injection of anti-Fas monoclonal antibody prolongs murine non-vascularized cardiac allograft survival.

Fas is a pro-apoptotic molecule involved in activation-induced cell-death of T lymphocytes, central and peripheral tolerance and immune privilege. We sought to determine the role of Fas in the thymus after organ transplantation. Heterotopic non-vascularized heart transplants from C3H mice were placed in C57Bl/6 recipients. A hamster anti-mouse anti-Fas mAb (JO2) was injected in the thymus of allograft recipients at the time of transplant. Results were compared with intrathymic injections of hamster IgG (HIgG), anti-FasL, as well as surgical thymectomy or intraperitoneal or intravenous injections of JO2 as controls. Intrathymic injection of 5 microg JO2 induced massive thymocyte apoptosis and enhanced allograft survival compared to HIgG (median graft survival 16 days vs 12.5 days, respectively, P=0.01). The effect was receptor and ligand specific. Intraperitoneal or intravenous injections of JO2 did not prolong graft survival. Thymocyte apoptosis was confirmed in vitro, in vivo and in situ. In the thymus, double positive immature CD4+8+ thymocytes were most susceptible to Fas-induced apoptosis. Our data shows that specific modulation of Fas pathways in the thymus at the time of transplant improves modestly but significantly murine heterotopic non-vascularized cardiac allograft survival and is associated with apoptosis of immature CD4+8+ thymocytes.

Animals↗
PubMed2004

Campath-1H in renal transplantation: The University of Wisconsin experience.

BACKGROUND: Immune cell depletion is known to prevent renal allograft rejection and injury. We evaluated the humanized monoclonal antibody Campath-1H (alemtuzumab; ILEX Oncology, San Antonio, Texas) in renal transplant recipients for its safety and efficacy in preventing rejection when used in combination with a calcineurin inhibitor, mycophenolate mofetil, and low-dose steroid therapy. METHODS: One hundred twenty-six consecutive renal allograft recipients received 2 doses of Campath-1H antibody on days 0 and 1. Outcomes were compared to patients who received an anti-CD25 antibody (n=799), Thymoglobulin (n=160), or other antibody treatment (n=156) in combination with a calcineurin inhibitor, mycophenolate mofetil, and higher dose steroids. RESULTS: The Campath-1H group overall experienced less rejection than the other 3 groups (P=.037). Patients with delayed graft function experienced less rejection with Campath-1H than control groups (P=.0096) and improved graft survival (P=.0119). There was no difference in infection or malignancies between the 4 groups. CONCLUSIONS: Campath-1H was well tolerated in renal transplant patients and led to significant reductions in incidence of rejection. Patients with delayed graft function experienced significantly improved graft survival.

Adult↗
PubMed2004

Superior long-term results of simultaneous pancreas-kidney transplantation from pediatric donors.

The shortage of cadaveric donors for simultaneous pancreas-kidney transplantation has prompted the use of cadaveric organs from pediatric donors. The long-term outcome and its impact on overall long-term survival are unknown. A total of 680 recipients receiving cadaver Simultaneous pancreas-kidney (SPK) transplantation from pediatric and adult donors between July 1986 and September 2001 were analyzed and compared. Ten-year kidney and pancreas graft survival for SPK transplantation from donors aged <18 years (n = 142) were 80% and 72%, respectively, compared to 61% pancreas and kidney graft survival from donors > or =18 years of age (n = 538; p = 0.03 and 0.05, respectively). Five years post-transplant, blood glucose, HbA1c and creatinine clearance were significantly better in recipients from pediatric donors (85.3 +/- 13 mg/dL, 5.5 +/- 3.5% and 65.6 +/- 16 mL/min, respectively), compared to recipients from adult donors (95.1 +/- 29 mg/dL, 5.9 +/- 3.5% and 58.3 +/- 17 mL/min; p = 0.001, 0.01 and 0.002, respectively). Causes of graft failure for kidney and pancreas transplants were similar between the two groups. No statistically significant difference was observed in patient survival between recipients from pediatric donors compared to adult donors (85% vs. 76%, p = 0.29). When recipients of SPK from pediatric donors were stratified according to age (3-11 years and 12-17 years) and compared, no difference in kidney or pancreas graft survival was observed (kidney 76.4% vs. 81.3%, p = 0.15; pancreas 75% vs. 76%, p = 0.10, respectively). Pediatric donors represent a valuable source of organs, providing excellent short- and long-term outcomes. Wide utilization of pediatric organs will substantially increase the donor pool.

Adolescent↗
PubMed2004

Evaluation of eHealth web sites for patients with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) affects up to 19.2 million Americans, and untreated kidney disease can progress to kidney failure. Patient education is an important part of slowing disease progression, but the ability of health professionals to provide this education is limited by time constraints. To date, there have been no systematic evaluations of CKD eHealth Web sites. METHODS: Seven nonproprietary and 4 proprietary Web sites geared toward educating patients with CKD were identified by using the Internet to search for the terms "chronic kidney disease," "kidney disease," and "chronic renal failure." Web sites were evaluated according to (1) compliance with the principles of the Health on the Net (HON) Foundation Code of Conduct and (2) reading grade level. RESULTS: Nonproprietary sites were in compliance with an average of 5.2 principles, with a range of 3 to 8. Average compliance of proprietary Web sites with the HON Code of Conduct principles was 3.12, with a range of 2 to 4 (P = 0.021). Of nonproprietary Web sites, average reading grade level assessed by the Fry Readability Scale was greater than grade 14, with a range from grade 11 through graduate school. Of proprietary sites, average readability was grade 11, with a range from grades 7 through 16 (P = 0.575). CONCLUSION: The Internet has the potential to be a very powerful educational tool for patients with CKD. However, many easily accessed CKD public health Web sites do not comply with accepted standards for health Web sites and are written using language beyond the general public's reading comprehension.

Adult↗
PubMed2004

Epithelial cell polarity and improved early outcomes in delayed graft function: a pilot study of polyclonal vs monoclonal antibodies.

BACKGROUND: Polyclonal antibody preparations contain antibodies that bind not only to molecules on circulating lymphocytes but also to other sites that bear similar antigens. We hypothesized that this extra-antibody effect would increase the number of intact tubular epithelial cells in organs at high risk for delayed graft function (DGF). METHODS: We used immunohistochemistry to examine serial biopsy samples (time 0 and 7-10 days after transplantation) in 18 kidney transplant recipients with DGF. These individuals received either polyclonal rabbit antithymocyte sera or a monoclonal humanized anti-CD25 antibody as induction immunosuppression. We also examined their early clinical course over 6 months. RESULTS: Individuals treated with the polyclonal preparation demonstrated greater preservation of kidney epithelial cell polarity manifested by more intense and more localized basolateral distribution of E-cadherin (P = 0.016), beta-catenin (P = 0.008) and Na-K ATPase (P = 0.02). These individuals were also more likely to maintain greater estimated glomerular filtration rates (eGFRs) at follow-up than patients treated with an anti-CD25 monoclonal antibody (6 month eGFR polyclonal: 55.5+/-7.12 ml/min vs monoclonal: 43.33+/-6.48 ml/min; P = 0.002). CONCLUSION: Though a pilot study, these data suggest that a purified polyclonal antibody preparation may help conserve functional kidney mass during DGF with potential benefits on transplant function overall.

Adult↗
PubMed2004

Donor genomics influence graft events: the effect of donor polymorphisms on acute rejection and chronic allograft nephropathy.

BACKGROUND: Organs procured from deceased donors emanate from individuals with diverse genetic backgrounds. Donor organs, therefore, may vary in their response to injury and immune stimuli in a genetically determined manner. We assessed polymorphisms from 244 renal allograft donors to better understand the impact of donor polymorphisms on selected transplant outcomes. METHODS: Donor genomic DNA restriction fragment length polymorphisms were assayed for evidence of common cytokine [interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-alpha, TGF-beta, interferon (IFN)-gamma] and chemokine (CCR2, CCR5) polymorphisms. Associations between donor polymorphisms and graft events were determined using chi-square, linear regression, and Kaplan-Meier analyses. RESULTS: Several genotypic polymorphisms demonstrated a modest association with acute rejection, including the transforming growth factor (TGF)-beta T/C codon 10 (P= 0.027) and the CCR5 G/A 59029 (P= 0.039) genes by chi-square analysis. Notably, the presence of the T allele in the IFN-gamma gene (+874) demonstrated a highly significant association with biopsy-proven chronic allograft nephropathy (P < 0.008). This association remained highly significant in a multiple linear regression model that incorporated biopsy-proven acute rejection as a covariate. CONCLUSION: These data suggest that many of the donor polymorphisms studied in this analysis may influence a recipient's immune response to a renal allograft. However, their greatest impact may be demonstrated in long-term outcomes.

Acute Disease↗
PubMed2004

Rituximab as treatment for refractory kidney transplant rejection.

Recent studies have shown that a high density of CD 20+ cells are seen in patients who have steroid-resistant rejection episodes. Rituximab is a high-affinity CD-20 specific antibody that inhibits B-cell proliferation while inducing cellular apoptosis. Thus, it is a rational choice for therapy in transplantation to abrogate B-cell-mediated events. Twenty-seven patients were diagnosed with biopsy-confirmed rejection manifested by thrombotic microangiopathy and/or endothelialitis between 2/99 and 2/02 at our institution. These individuals were treated with a single dose of rituximab, in addition to other therapies, in an effort to reverse their rejection episodes. Twenty-four received additional steroids while 22 of the 27 patients were also treated with plasmapheresis and antithymocyte globulin (ATG). Only three patients experienced graft loss not associated with patient death during the follow-up period (605 +/- 335.3 days). In the 24 successfully treated patients, the serum creatinine at the time of initiating rituximab therapy was 5.6 +/- 1.0 mg/dL and decreased to 0.95 +/- 0.7 mg/dL at discharge. The addition of rituximab may improve outcomes in severe, steroid-resistant or antibody-mediated rejection episodes after kidney transplantation.

Adolescent↗
PubMed2004

The type 1 angiotensin II receptor tail affects receptor targeting, internalization, and membrane fusion properties.

Endocytosis modulates cell responses by removing and recycling receptors from the cell surface. Type I angiotensin II receptors (AT1R) are somewhat unique in that they are expressed at apical (AP) and basolateral (BL) membranes in proximal tubule cells and both receptor sites undergo endocytosis. We analyzed AT1R cytoplasmic (-COOH) tail deletion mutants to determine whether classic AT1R endocytosis motifs functioned similarly in polarized cells and simultaneously altered receptor properties. Serially truncating the AT1R tail had little effect on AP/BL AT1R distribution as determined by 125I-angiotensin II binding in LLCPK(Cl4) cells transfected with an AT1R transcript. AP AT1R expression required the proximal 12 amino acids in the AT1R-COOH tail. Deleting all but the proximal 12 aa of the AT1R-COOH tail (T316L mutant) decreased AP AT1R internalization at 20 min (17 +/- 6%; p < 0.05 versus full-length; n = 5) and inhibited AP AT1R-stimulated arachidonic acid release (counts released per milligram of protein at 20 min: full-length, 18,762 +/- 4018; T316L, 2430 +/- 1711; n = 4; p < 0.02). Endosomal fusion assays were performed using peptide sequences of regions in the AT1R tail involved in endocytosis (YFLQLLKYIPP [LL] and LSTKMSTLSY [STL]). Peptide STL significantly inhibited endosomal fusion (22 +/- 10% of control; n = 5; p < 0.05 versus positive control). Peptide LL had no significant inhibitory effect. AT(1)R in polarized cells contain dominant endocytosis signals but these motifs do not correlate with AP or BL AT1R expression. Moreover, peptide sequences within the AT1R-COOH tail necessary for endocytosis also modulate endosomal fusion properties.

Amino Acid Sequence↗