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Biomedical subjects

W Harmon

Publications and source records attributed to W Harmon.

At least 19 recordsLinked to original sources
PubMed2006

Decreased risk of renal allograft thrombosis associated with interleukin-2 receptor antagonists: a report of the NAPRTCS.

Graft thrombosis is the most common cause of first year graft failure in pediatric renal transplantation. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database was analyzed for cases of graft failure due to thrombosis among patients transplanted from 1998 to 2004. The impact of interleukin-2 (IL-2) receptor antagonists as induction therapy was determined. There were a total of 51 graft failures due to thrombosis among the 2750 reported renal transplants (1.85%) (95% CI (1.39%, 2.41%)). This represents the most common cause of graft loss during the first year post-transplant accounting for 35% of first year losses and 18% of all graft losses. The incidence of thrombosis among patients who received IL-2 receptor antibodies was 1.07% (12/1126) compared to 2.40% (39/1624) among patients who did not (OR 0.44, 95% CI 0.23, 0.84, p = 0.014). Use of IL-2 receptor blockade was the only significant prognostic factor in a multivariate model with previously identified risk factors. Analysis of NAPRTCS data found that the use of IL-2 receptor antibodies as induction therapy is associated with a significantly decreased risk of graft failure due to thrombosis. This provocative finding requires further investigation to determine whether thrombotic failure can be decreased by this therapeutic strategy.

Adolescent↗
PubMed2001

Hounsfield unit density in the determination of urinary stone composition.

OBJECTIVES: Noncontrast computed tomography (NCCT) has emerged as the diagnostic study of choice in the evaluation of acute flank pain. Recent in vitro studies have suggested that NCCT can be used to predict the composition of urinary stones on the basis of differences in radiodensity (measured in Hounsfield units, HUs). We sought to determine whether the analysis of in vivo urinary stones seen on NCCT could predict their composition. METHODS: Between March 1997 and August 1999, 100 pure stones from patients seen at the Wilford Hall Medical Center in San Antonio, Texas were submitted for analysis. All had been visualized by NCCT before stone passage or retrieval. A General Electric High-Speed Advantage CT scanner evaluated most of these patients by a "flank pain protocol" (ie, helical technique with breath-holding at 120 kV, 200 mA with 5 mm collimation). Each scan was interpreted by one of two staff radiologists who measured the HUs for each stone. A statistical comparison was made between the stone composition and radiodensity. To allow for subsequently observed increases in radiodensity with increasing stone size regardless of composition, the HU value was divided by each stone's largest transverse diameter in millimeters to give the HU density. A statistical comparison was then made between stone composition and HU density. RESULTS: No significant difference was noted between the HU values of calcium oxalate and calcium phosphate stones, and thus they were analyzed collectively as "calcium stones." When the HU values of calcium (n = 87), uric acid (n = 7), struvite (n = 4), and cystine (n = 2) stones were compared, the overlap of ranges precluded accurate identification, and the mean HU values were not significantly different from one another. There was less overlap noted when comparing the HU densities of the stones studied, and no noncalcium stone had an HU density greater than 76 HU/mm. Using one-way analysis of variance, significant differences were noted between the mean HU density of calcium (105 +/- 43) and uric acid (50 +/- 24) stones (P = 0.006). A trend toward significance was found between the mean HU density of the calcium and struvite stones (53 +/- 28, P = 0.073). No significant differences were found among the other stones. CONCLUSIONS: HU density compared with the HU value alone better characterized differences in radiodensities among urinary stones; calcium stones can be distinguished from uric acid stones on the basis of this value. However, neither the HU density nor the mean HU value was able to identify urinary stones in vivo.

Analysis of Variance↗
PubMed2000

Consensus statement on the live organ donor.

OBJECTIVE: To recommend practice guidelines for transplant physicians, primary care providers, health care planners, and all those who are concerned about the well-being of the live organ donor. PARTICIPANTS: An executive group representing the National Kidney Foundation, and the American Societies of Transplantation, Transplant Surgeons, and Nephrology formed a steering committee of 12 members to evaluate current practices of living donor transplantation of the kidney, pancreas, liver, intestine, and lung. The steering committee subsequently assembled more than 100 representatives of the transplant community (physicians, nurses, ethicists, psychologists, lawyers, scientists, social workers, transplant recipients, and living donors) at a national conference held June 1-2, 2000, in Kansas City, Mo. CONSENSUS PROCESS: Attendees participated in 7 assigned work groups. Three were organ specific (lung, liver, and kidney) and 4 were focused on social and ethical concerns (informed consent, donor source, psychosocial issues, and live organ donor registry). Work groups' deliberations were structured by a series of questions developed by the steering committee. Each work group presented its deliberations to an open plenary session of all attendees. This information was stored and shaped into a statement circulated electronically to all attendees for their comments, and finally approved by the steering committee for publication. The term consensus is not meant to convey universal agreement of the participants. The statement identifies issues of controversy; however, the wording of the entire statement is a consensus by approval of all attendees. CONCLUSION: The person who gives consent to be a live organ donor should be competent, willing to donate, free from coercion, medically and psychosocially suitable, fully informed of the risks and benefits as a donor, and fully informed of the risks, benefits, and alternative treatment available to the recipient. The benefits to both donor and recipient must outweigh the risks associated with the donation and transplantation of the living donor organ.

Health Status↗
PubMed1999

Regional heparinization via simultaneous separation and reaction in a novel Taylor-Couette flow device.

The development of a safe and efficient bioreactor design has remained a challenge for the clinical application of immobilized enzymes. Specifically, the use of immobilized heparinase I has been the target of many studies to make heparin anticoagulation therapy safer for the critically ill patient with kidney failure or heart disease. We have investigated the use of Taylor-Couette flow for a novel type of bioreactor. In a previous study, we showed that the fluidization of agarose immobilized heparinase within Taylor vortices in whole blood can lead to extensive blood damage in the form of cell depletion and hemolysis. Based on these findings, we designed and developed a reactor, referred to as vortex-flow plasmapheretic reactor (VFPR), that incorporated plasmapheresis and fluidization of the agarose in the reactive compartment, separate from the whole-blood path. In the present study, immobilized heparinase I was tested as a means of achieving regional heparinization of a closed circuit. This is a method in which heparin is infused into the extracorporeal circuit predialyzer and neutralized postdialyzer. Saline studies were performed with an immobilized heparinase I-packed bed and with the VFPR. An in vitro feasibility study was performed with the VFPR using human blood. The VFPR achieved heparin conversions of 44 +/- 0.5% and 34 +/- 2% in saline and blood, respectively. In addition, the VFPR caused no blood damage. We report a novel method to achieve fluidization which depended on secondary, circumferencial flow, and was independent of the primary flow through the device.

Biocompatible Materials↗
PubMed1999

Investigation of a whole blood fluidized bed Taylor-Couette flow device for enzymatic heparin neutralization.

The use of clinical bioreactors will increase as more therapeutic proteins are being cloned, expressed, and produced at a reduced cost. The proposed use of an immobilized heparinase I reactor to make heparin anticoagulation a safer therapy is an example of how the specificity and high activity of an enzyme could be incorporated into a system to ultimately benefit a patient. However, the development of a safe and efficient bioreactor is important for the use of immobilized heparinase I and other therapeutic proteins designed for use in medical extracorporeal procedures. This study examined the possibility of using Taylor-Couette flow and "flow-induced" recirculation of the agarose beads as a way to fluidize agarose-bound heparinase in whole blood. Heparinase I was immobilized onto agarose beads via cyanogen bromide activation. A reactor based on Taylor-Couette flow was designed and modified with a tangential recirculation line. The reactor was tested for efficacy and safety in vitro in human blood. Visualization studies in water and 42% glycerol were used to determine the minimum rotation rate for efficient fluidization. The strategic placement of the recirculation line allowed recirculation of the agarose without the use of an external pump. The device removed 90% of the heparin activity within 2 min from 450 cc of human blood at a blood flow rate of 100 mL/min. Furthermore, the device maintained inlet and outlet clotting times of 269 +/- 10 and 235 +/- 6 s, respectively, demonstrating the potential for regional heparinization. Blood damage was a function of gel volume fraction and rotation rate of the inner cylinder. Hemolysis of the red cells is an important issue when Taylor vortices are combined with macroscopic solid particles such as agarose beads. A modified Taylor-Couette flow device was developed to treat whole blood and operational criteria were established to minimize hemolysis.

Bioreactors↗
PubMed1999

Ex vivo evaluation of a Taylor-Couette flow, immobilized heparinase I device for clinical application.

Efficient and safe heparin anticoagulation has remained a problem for continuous renal replacement therapies and intermittent hemodialysis for patients with acute renal failure. To make heparin therapy safer for the patient with acute renal failure at high risk of bleeding, we have proposed regional heparinization of the circuit via an immobilized heparinase I filter. This study tested a device based on Taylor-Couette flow and simultaneous separation/reaction for efficacy and safety of heparin removal in a sheep model. Heparinase I was immobilized onto agarose beads via cyanogen bromide activation. The device, referred to as a vortex flow plasmapheretic reactor, consisted of two concentric cylinders, a priming volume of 45 ml, a microporous membrane for plasma separation, and an outer compartment where the immobilized heparinase I was fluidized separately from the blood cells. Manual white cell and platelet counts, hematocrit, total protein, and fibrinogen assays were performed. Heparin levels were indirectly measured via whole-blood recalcification times (WBRTs). The vortex flow plasmapheretic reactor maintained significantly higher heparin levels in the extracorporeal circuit than in the sheep (device inlet WBRTs were 1. 5 times the device outlet WBRTs) with no hemolysis. The reactor treatment did not effect any physiologically significant changes in complete blood cell counts, platelets, and protein levels for up to 2 hr of operation. Furthermore, gross necropsy and histopathology did not show any significant abnormalities in the kidney, liver, heart, brain, and spleen.

Acute Kidney Injury↗
PubMed1999

Mycophenolate mofetil in pediatric renal transplantation.

The use of mycophenolate mofetil (MMF) in adult renal transplantation has been associated with significantly decreased incidence of acute rejection. However, limited data are available for children after renal transplantation. A total of 67 patients undergoing renal transplantation at the University of Alabama at Birmingham, AL, USA and Children's Hospital of Boston, MA, USA were enrolled into the Cooperative Clinical Trials in Pediatric Transplantation randomized controlled trial of induction with OKT3 vs. i.v. cyclosporin A (CsA) at the time of transplantation. The first 31 patients entered were begun on azathioprine (AZA), 2 mg/kg on the first post-operative day. The subsequent 36 patients were begun on MMF, 1000 mg/m2/d. Other maintenance immunosuppression included oral CsA and Prednisone. Biopsy confirmation was obtained for all suspected rejection episodes. Glomerular filtration rate (GFR) was calculated using the Schwartz formula. Data were analyzed using Kaplan Meier survival curves and compared using log-rank tests. At the time of analysis, 52 patients (mean age 10.1 +/- 5 yr) had completed at least 12 months and 15 others had completed at least 6 months of follow-up post-transplantation. Of these, there were 39 male/28 female; 48 white/15 black/4 other; 49 living donor/18 cadaver donor. There were no significant differences in the incidence of rejection episodes, number of rejection episodes, the GFR at 6 and 12 months, allograft, or patient survival between patients receiving MMF vs. AZA. We could demonstrate no significant differences in these outcomes based on sex, race or induction therapy, leading to the conclusion that pediatric patients treated under a consistent protocol in two institutions have no improvement in short-term allograft outcome with the addition of MMF therapy.

Adolescent↗
PubMed1998

Increased CD40 ligand gene expression during human renal and murine islet allograft rejection.

BACKGROUND: The interaction between CD40 and its ligand CD40L is essential for the development and maintenance of vigorous immunity. We have sought to determine: (i) whether a heightened level of CD40L transcripts is evident during acute allograft rejection and (ii) the kinetics of CD40L gene expression during allograft rejection. METHODS: By using quantitative reverse transcriptase-assisted polymerase chain reaction techniques, we found that heightened CD40L gene expression is a correlate of acute human renal allograft rejection (P<0.01). RESULTS: In a murine model of MHC-mismatched islet allografts, our results showed that CD40L transcripts were rarely detected at day 2 after transplantation, but were remarkably heightened at day 5 after transplantation. The transcript levels then steadily increased and peaked at the time of rejection. CONCLUSION: These data suggest that therapy aimed at blocking the CD40 to CD40L interaction should be applied during the immediate posttransplant period.

Animals↗
PubMed1997

Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction.

BACKGROUND: It has been suggested that T cells primed by processed donor major histocompatibility complex antigen (the "indirect" pathway of allorecognition) may be responsible for mediating chronic allograft rejection. The purpose of this study was to develop a clinically useful assay to study the occurrence of indirect allorecognition during chronic rejection in humans. METHODS: A panel of 20 mer peptides corresponding to the hypervariable regions of HLA-DRB1*0101, DRB1*1501, and DRB1*0301 were synthesized. Lymphocytes obtained from renal allograft recipients were cocultured with these peptides. Proliferation was assayed by DNA incorporation of [3H]thymidine, and positive proliferation was defined by a statistically significant increase in counts per minute over background with a minimum stimulation index of 2. The precursor frequency of allopeptide reactive T cells was determined by limiting dilution analysis. RESULTS: Lymphocytes from 82% of patients who were mismatched for at least one of the three DR molecules and had chronic allograft dysfunction specifically proliferated to the mismatched allopeptides (n=11). Proliferation was seen in only 6% of control subjects (2/33, P<0.0001). The proliferative response was low grade and was best detected on day 7-8 of culture in vitro. The precursor frequency of peptide-specific T cells was more than 10-fold higher compared with controls (P<0.001). CONCLUSIONS: These data demonstrate for the first time that T cells of patients with chronic graft dysfunction are primed to recognize and respond to specific donor-derived major histocompatibility complex allopeptides. Our results support the hypothesis that T cells primed via the indirect pathway of allorecognition may be important mediators of chronic rejection and provide the rationale to develop specific therapeutic strategies to prevent or interrupt this process.

Adult↗
PubMed1997

Quantitative detection of immune activation transcripts as a diagnostic tool in kidney transplantation.

Procedures to diagnose renal allograft rejection depend upon detection of graft dysfunction and the presence of a mononuclear leukocytic infiltrate; however, the presence of a modest cellular infiltrate is often not conclusive and can be detected in non-rejecting grafts. We have pursued a molecular approach utilizing reverse transcription (RT)-PCR to test the diagnostic accuracy of multiple immune activation gene analysis as means to diagnose renal allograft rejection. The magnitude of intragraft gene expression of 15 immune activation genes was quantified by competitive RT-PCR in 60 renal allograft core biopsies obtained for surveillance or to diagnose the etiology of graft dysfunction. Results were compared with a clinicopathological analysis based upon the histological diagnosis (Banff criteria) and the response to antirejection treatment. During acute renal allograft rejection intragraft expression of the interleukin (IL)-7 (P < 0.001), IL-10 (P < 0.0001), IL-15 (P < 0.0001), Fas ligand (P < 0.0001), perforin (P < 0.0001), and granzyme B (P < 0.0015), but not IL-2, interferon gamma, or IL-4, genes is significantly heightened. Amplified RANTES and IL-8 gene transcripts are sensitive but nonspecific markers of rejection. A simultaneous RT-PCR evaluation of perforin, granzyme B, and Fas ligand identifies acute rejection, including cases with mild infiltration, with extraordinary sensitivity (100%) and specificity (100%). Effective antirejection therapy results in a rapid down-regulation of gene expression. The combined analysis of Fas ligand, perforin, and granzyme B gene expression by quantitative RT-PCR provides a reliable tool for diagnosis and follow-up of acute renal allograft rejection. Its accuracy and a potential rapid application within few hours suggest its use in the clinical management of renal transplant patients.

Adult↗
PubMed1997

Renal transplantation in children from 1987-1996: the 1996 Annual Report of the North American Pediatric Renal Transplant Cooperative Study.

The 1996 Annual Report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) summarizes data voluntarily collected from 130 centers on 4329 children and adolescent patients who received renal transplants on or after January 1, 1987. This report updates information on transplants; data on dialysis and chronic renal insufficiency have, for the first time, been reported separately (in submission). The NAPRTCS registry shows that the majority of pediatric renal transplants are performed in children above 6 years of age (73%). The most frequent diagnoses include obstructive uropathy (16%), aplastic/hypoplastic/dysplastic kidneys (16%), and focal segmental glomerulosclerosis (12%). Pre-emptive transplantation was performed in 24% of patients. Triple drug maintenance therapy with prednisone, cyclosporine and azathioprine was used by >70% of all transplant recipients throughout 7 years of follow-up. Fifty-six per cent of transplant recipients were rehospitalized during months 1-5 (51% live donor (LD), 62% cadaver donor (CD)), with rejection and infection as the main causes. In the period 30-35 months post-transplant, 19-22% of patients (163 LD, 185 CD) were rehospitalized. The median time to the first rejection was 46 days for CD transplants and 377 days for LD grafts (p<.001). Six-year graft survival rates were 73% and 56% for LD grafts and CD grafts, respectively (p<.001). The overall growth deficit was constant over a period of 60 months. However, children transplanted under 5 years of age reduce their height deficit by about one-third compared to an increase in height deficit of up to 22% for older children. The NAPRTCS data analysis also demonstrates a delay in first rejection episodes in LD compared to CD transplants, and a steady improvement in CD graft survival over the past 5 years in pediatric transplant recipients.

Adolescent↗
PubMed1995

Analysis of rejection outcomes and implications--a report of the North American Pediatric Renal Transplant Cooperative Study.

For this study, we analyzed the role of rejection in graft failure in children. Rejection results were examined after 3004 pediatric renal transplants (1367 living donor, 1637 cadaver source). A total of 3453 (1298 living donor, 2155 cadaver source) rejection episodes have occurred, for rejection ratios of .95 for living donor and 1.32 for cadaver source transplants, with a constant difference of 18% points after four months, in the percentage of patients ever experiencing a rejection. Rejection results were examined by patient age (0-1 vs. 2-5 vs. 6-12 vs. > or = 13). Rejection ratios, annualized rejection frequency, time to first rejection, and mean number of rejections for patients with rejection were not elevated in the younger patients. However, for the initial rejection episode, recipients less than six years of age had significantly (P < .001) poorer outcome from the rejection episode with an increased risk of graft failure in both donor source groups. This age effect on rejection outcome is only seen with the first rejection episode and is not observed with subsequent rejection episodes.

Adolescent↗
PubMed1995

Steady improvement in renal allograft survival among North American children: a five year appraisal by the North American Pediatric Renal Transplant Cooperative Study.

From 1987 through 1994, the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) has enrolled 1641 cadaver donor transplants. For this study, we have analyzed one and two year graft survival by annual cohorts for the years 1987 through 1991. For the 1987 cohort one and two year graft survival was 72% and 65%, respectively, and for the 1991 cohort it was 83% and 78%, respectively. Using a proportional hazards model, and comparing the 1987 cohort to the 1991 cohort, the relative risk for graft failure was 1.40 (P = 0.02). Analysis of practice patterns revealed the following changes which may have been associated with this improved graft survival: (1) use of T cell induction antibody, 38% in 1987 and 67% in 1991 (P < or = 0.001); (2) the increased use of cyclosporine (CsA) post-transplant: in 1987, 87% were maintained on CsA at day 30 compared to 97% in 1991 (P < 0.001); (3) the mean higher daily maintenance CsA dose at 12 months post-transplant which in 1987 was 6.5 mg/kg compared to 7.5 mg/kg in 1991 (P = 0.03); (4) the decreased use of random transfusions, 54% receiving > 5 transfusions in 1987 compared to 37% in 1991 (P < 0.001); and (5) decreased use of younger cadaver donors between 1987 and 1991 (P < 0.001).

Antibodies, Monoclonal↗
PubMed1994

Posttransplant deaths and factors that influence the mortality rate in North American children.

Of 2457 patients in the North American Pediatric Renal Transplant Cooperative Study registry who were followed for 5481 patient-years after the index transplantation, we observed 136 deaths, for an average annual rate of 24.8 deaths per 1000 patient-years. Death resulted primarily from infection (n = 55, 40%), cardiovascular causes (n = 28, 21%), hemorrhage (n = 16, 12%), and malignancies (n = 9, 7%). Cadaver-donor source was associated with greater mortality (6.7%) than a living-donor source (4.0%) (P < 0.005). Recipients aged 0-1, 2-5, 6-12, and 13-17 years old had mortality rates of 17.5, 8.0, 3.6, and 4.5%, respectively (P < .001). Mortality rates increased substantially when examined by recipient and cadaver donor ages (mortality rates of up to 45%), the greater the concordance between young donor and recipient ages. Interestingly, acute tubular necrosis and graft failure less than 30 days after transplantation (GH30) were each associated with markedly elevated mortality rates. (The risk ratio for ATN was 3.1 [P < 0.001] and for GF30 it was 6.4 [P < 0.001].) Mortality after transplantation was also affected by the underlying renal disease, with high mortality rates observed for oxalosis (n = 21, 33.3%), congenital nephrotic syndrome (n = 79, 15.2%), pyelo/interstitial nephritis (n = 54, 11.1%), and Drash syndrome (n = 14, 21.4%). When the joint effect of these risk factors was examined in a Cox proportional hazards model, young recipient age (0-1 years old) and GF30 were significant (P < .001) risk factors of mortality for recipients of living-donor organs. For recipients of cadaver kidneys, young recipient age--0-1 years old (P < .001) and 2-5 years old (P = .002)--ATN (P = .029), and GF30 (P < .001) were all significant risk factors. Recipient age is the major determinant of increased mortality after renal transplantation. Avoidance of acute tubular necrosis by reducing cold time and preventing early graft failure by better matching techniques in this vulnerable population may improve the mortality rate.

Adolescent↗
PubMed1994

Cyclosporin A inhibits CD40 ligand expression in T lymphocytes.

The ligand for CD40 is expressed on activated T lymphocytes and delivers contact-dependent activation signals to B lymphocytes. The mechanisms regulating CD40 ligand gene expression are largely unknown. Optimal expression of CD40 ligand required activation of protein kinase C and a rise in intracellular calcium concentration. CD40 ligand expression was inhibited by pretreatment of T cells with cyclosporin A. Cyclosporin A analogues inhibited CD40 ligand expression with a potency mirroring the ability of each compound to inhibit calcineurin activity, indicating that calcineurin plays a key role in CD40 ligand gene expression. Cyclosporin A inhibited IL-4-driven CD40 ligand-dependent IgE isotype switching in PBMC but did not inhibit IgE synthesis induced by CD40 mAb plus IL-4. PBMC derived from transplant patients receiving cyclosporin A failed to express CD40 ligand upon stimulation. These results suggest that patients receiving cyclosporin A may be deficient in CD40 ligand-dependent T cell help.

Adolescent↗
PubMed1993

Factors predictive of sustained growth in children after renal transplantation. The North American Pediatric Renal Transplant Cooperative Study.

To ascertain growth and rehabilitation of children after transplantation, the North American Pediatric Renal Transplant Cooperative Study collected growth data on renal transplant recipients. From January 1987 through December 1990, a total of 1553 children with one or more transplants were entered into the study by its 75 participating centers. Of these, the first 300 children with a functioning graft and 2 years of linear growth data form the cohort for this study. For the total cohort of 300 patients, the mean (+/- SEM) baseline height z score was -2.41 +/- 0.09, and the change in z score determined after 2 years was 0.18 +/- 0.06 (p < 0.01). Children in the age group from birth to 1 year had the maximal deficit and had the maximal improvement in z score, gaining about 1 SD (p < 0.01). For the 2- to 5-year-old group, the change in z score was about 0.5 SD (p < 0.001). No improvement in z score was noted for children 6 to 17 years of age. Each increase in serum creatinine concentration of 90 mumol/L (1 mg/dl) was associated with -0.17 decrease in the z score (p < 0.001). Gender, donor source, history of previous transplantation, and prior dialysis were not associated with a significant change in the z score; thus the increased rate of growth during the first 2 post-transplantation years occurred mainly in subjects less than 6 years of age.

Adolescent↗