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D J Norman

Publications and source records attributed to D J Norman.

At least 19 recordsLinked to original sources
PubMed2006

Cardiovascular events following renal transplantation: role of traditional and transplant-specific risk factors.

Cardiovascular mortality is increased in transplant recipients. However, studies including non-fatal events are critical to assess the burden of disease and to identify novel risk factors. We described the incidence of fatal and non-fatal events, and explored associations and interactions among traditional and transplant-specific risk factors and cardiovascular events (CVE) in a cohort of 922 patients transplanted between 1993 and 1998. One hundred and seventy-six patients experienced 201 CVE (111 cardiac, 48 cerebrovascular, 42 peripheral-vascular). Most CVE were non-fatal. Factors associated with cardiac events were (adjusted hazard ratios) tobacco (3.53; P<0.001), obesity (2.92; P<0.001), diabetes (2.63; P<0.001), multiple rejections (2.19; P=0.008), prior CVE (2.0; P=0.004), dialysis >1 year (1.91; P=0.007), and overweight status (1.68; P=0.04); with cerebrovascular events: diabetes and peritoneal dialysis (11.95; P<0.001), age >45 (6.77; P<0.001), diabetes (4.87; P<0.001), prior CVE (3.73; P<0.001), creatinine >141 micromol/l (3.16; P=0.001), peritoneal dialysis (3.06; P=0.027), and obesity (0.32; P=0.046); with peripheral-vascular events: diabetes (8.48; P<0.001), tobacco and cytomegalovirus (3.88; P<0.001), age >45 (2.31; P=0.019), and prior CVE (2.25; P=0.016); with mortality: tobacco and deceased-donor (3.52; P<0.001), age >45 (1.81; P=0.002), diabetes (1.76; P=0.002), pulse pressure (1.64; P=0.029), prior CVE (1.52; P=0.04), and dialysis >1 year (1.47; P=0.04). The majority of CVE post-transplant were non-fatal. Previous CVE was strongly associated with CVE post-transplant. Interactions among transplant-specific and traditional risks impacted significantly the incidence of CVE. Modifiable factors such as duration of dialysis, deceased-donor transplantation, and acute rejection should be viewed as cardiovascular risks.

Adolescent↗
PubMed2000

Phase I trial of HuM291, a humanized anti-CD3 antibody, in patients receiving renal allografts from living donors.

BACKGROUND: HuM291 is a humanized anti-CD3 monoclonal antibody engineered to reduce binding to Fcgamma receptors and complement fixation. HuM291 has a long serum half-life and mediated profound depletion of circulating T cells in chimpanzees; HuM291 also has significantly less mitogenic and cytokine-releasing activity than OKT3 in vitro. METHODS: A phase I dose-escalation study was conducted in 15 end-stage renal disease patients scheduled for renal allografts from living donors. Patients received one i.v. HuM291 injection before transplantation. Five doses were tested: 0.015 microg/kg, 0.15 microg/kg, 0.0015 mg/kg, 0.0045 mg/kg, and 0.015 mg/kg. Patients were followed for adverse events, laboratory abnormalities, serum cytokine levels, pharmacokinetics, and CD2+, CD3+, CD4+, and CD8+ T cell counts. RESULTS: HuM291 was well tolerated; most adverse events were mild to moderate in severity and included headache, nausea, chills, and fever. These occurred within the first few hours after HuM291 administration, resolved within 24 to 48 hr, and were likely related to cytokine release. In general, peak tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 levels were detected 1 to 6 hr postdosing only at the three highest doses and were generally undetectable by 24-hr postdosing. Serious adverse events possibly related to HuM291 included clotting of a fistula (two patients), chemical cellulitis (one patient), and increased serum creatinine/decreased hematocrit (one patient). At doses > or = 0.0015 mg/kg (0.1 mg/70 kg), HuM291 induced rapid, marked depletion of peripheral T cells within 2 hr; duration of T cell depletion was dose dependent. At the two highest dose levels, T cells remained depleted for approximately 1 week. CONCLUSIONS: A single HuM291 dose rapidly depleted circulating T cells in a dose-dependent manner and was associated with only mild to moderate symptoms of cytokine release.

Adult↗
PubMed2000

Valaciclovir prophylaxis of cytomegalovirus infection and disease in renal transplantation: an economic evaluation.

BACKGROUND: Cytomegalovirus (CMV) disease is a major cause of morbidity and mortality in solid organ transplant patients and is associated with large additional healthcare expenditures. An economic evaluation of valaciclovir CMV prophylaxis in a renal transplant population is reported. METHODS: Medical resource use data were collected alongside a multicenter multinational randomized, placebo-controlled, double-blind trial of valaciclovir CMV prophylaxis in renal transplantation. Patients were stratified into donor seropositive/recipient sero-negative (D+R-) and recipient seropositive (R+) groups. Patients were followed-up 6 months posttransplant. A cost-effectiveness analysis from the perspective of the French health care system was performed using the number of cases of CMV disease avoided at 6 months as the clinical endpoint. RESULTS: Resource use was significantly increased among patients who developed CMV disease compared to those who did not develop disease. In the high risk D+R- group, valaciclovir prophylaxis was associated with an average of 5.5 fewer inpatient hospital days (P < OR =0.05) and with significantly lower use of other healthcare resources. In the R+ group, valaciclovir prophylaxis prevented cases of CMV disease at a marginally greater mean cost per patient compared with placebo. For D+R- patients valaciclovir prophylaxis was therefore an economically superior strategy, resulting in fewer cases of CMV disease and lower total mean healthcare expenditures. CONCLUSIONS: Valaciclovir CMV prophylaxis in renal transplantation is a more cost-effective therapy compared with placebo, in the high-risk D+R- patient population. For the R+ group, the incremental cost per case of CMV disease was modest.

Acyclovir↗
PubMed2000

Reversible acute renal allograft dysfunction due to gabapentin.

BACKGROUND: The use of gabapentin as an effective analgesic agent for neuropathic pain has expanded considerably. Its lack of both anticholinergic side effects and interference with the metabolism of drugs via the cytochrome P450 pathway make it especially useful for transplant recipients. METHODS AND RESULTS: We describe the case of a renal transplant recipient with a long-term stable functioning allograft who developed reversible acute renal dysfunction after beginning gabapentin therapy for chronic pain due to diabetic neuropathy. CONCLUSIONS: We suggest that gabapentin may cause acute renal dysfunction by a mechanism involving renal afferent vasoconstriction. Caution should be employed when considering the use of gabapentin in transplant recipients, especially when combined with other agents that may potentiate renal vasoconstriction.

Acetates↗
PubMed1999

Renal transplantation across the ABO barrier using A2 kidneys.

BACKGROUND: The waiting list for cadaveric kidney transplantation has continued to grow, and with the relative scarcity of cadaver donors, the median waiting time for patients in the United States increased to 824 days in 1994. The median waiting times for patients with blood groups B or O were 1329 and 1007 days, respectively. Allocation of blood group A2 kidneys (20% of group A) to blood group O and B patients expands their potential donor pool and shortens their waiting time for a kidney transplantation. METHODS: Between May 1991 and June 1998, we transplanted 15 A2 kidneys into 6 blood group O and 9 blood group B patients. Anti-A isoagglutinins were measured before transplantation, and patients with anti-A1 titers > or = 1:8 underwent plasmapheresis (PP). RESULTS: One patient with high titer anti-A antibodies, who did not receive PP, lost her allograft because of hyperacute rejection. Allograft function was excellent in the remaining 14 patients, with a mean serum creatinine level of 1.7 (+/-0.89) mg/dl at 1 month and 1.3 (+/-0.34) mg/dl at 1 year. The actuarial 1-year graft survival rate was 93.3+/-6.4% and the patient survival rate was 100%. CONCLUSION: We conclude that the allocation of blood group A2 kidneys for blood group O and B recipients is a practical way to expand the donor pool for these transplant candidates. PP may be important for reducing the levels of anti-A1 and anti-A2 antibodies and for reducing the risk of hyperacute rejection. Splenectomy seems to be unnecessary.

ABO Blood-Group System↗
PubMed1999

HLA-identical sibling renal transplantation--a 21-yr single-center experience.

Human lymphocyte antigen (HLA)-identical sibling organs offer the best long-term outcomes for recipients of a renal transplant apart from an identical twin. Unlike cadaveric transplants, however, factors that affect long-term survival of these immunologically privileged grafts are not well described. We reviewed 108 HLA-identical transplants performed at our institution between January 1977 and February 1993. Variables chosen for graft survival analysis were: gender, age and ABO blood type of donors and recipients, panel reactivity antibodies (PRA), blood transfusions prior to transplant, pregnancies, and the underlying renal disease. Additionally, incidence of acute rejection (AR), timing of AR, serum creatinine levels at 1 wk and at 1 yr, and presence of hypertension were included in the analysis. Mean follow-up was 130.9 +/- 58.2 months (range 38-250 months). Actual 5-yr patient and graft survivals were 92 and 88%, respectively. Thirty-eight grafts were lost, and 22 recipients died during the observation period. Death was the main cause of graft failure. Cardiac events accounted for the majority of deaths. AR occurred in 46% and repeated rejections in 11% of recipients. Actuarial graft survival at 10 yr was poorer for patients with any AR (69%), and significantly worse with repeated AR (33%), compared to patients without AR (86%), p = 0.001). Sixty percent of all rejections and 88% of the first rejections occurred in the first 60 d post-transplantation. The first AR that occurred after 60 d was associated with poor graft survival (49 vs. 70%, p = 0.04). Recipients with renal diseases with potential to recur (membranous glomerulonephritis (MGN), membrano-proliferative glomerulonephritis (MPGN), focal and segmental glomerulonephritis (FSGN), polyarteritis nodosa (PAN), rapid progressive glomerulonephritis (RPGN), Henoch-Schoenlein purpura (HSP), diabetes mellitus (DM), interstitial nephritis, systemic lupus erythematosus (SLE) and chronic glomerulonephritis (CGN)) faired worse as a group than recipients with hypertensive nephrosclerosis (HTN), autosomal dominant polycystic kidney disease (ADPKD), Alport's, reflux or congenital dysplasia (68 vs. 96% at 10 yr, p = 0.0009). Poor patient survival was seen in diabetics (71 vs. 88% at 10 yr, p = 0.01). There was a trend to poorer graft survival in diabetic recipients when compared to non-diabetics (65 vs. 81% at 10 yr, p = 0.054). Elevated creatinine at 1 yr was associated with worse graft survival. Likewise, the magnitude of creatinine increase during the first year directly correlated with the risk of graft loss. Hypertensive patients were more likely to lose their grafts than normotensive recipients (72 vs. 86%, p = 0.04). Pre-transplant blood transfusion, pregnancy, and PRA level were not associated with increased graft failure or AR. Graft survival was not affected by gender, age, or ABO blood type of donors or recipients. In conclusion, better prevention and treatment of AR, hypertension, and cardiac disease should improve graft and patient survival. Close attention to recurrence of disease and subtle changes in the creatinine level during the first year might dictate early diagnostic and, hopefully, therapeutic interventions.

ABO Blood-Group System↗
PubMed1999

Factors in cardiac risk stratification of candidates for renal transplant.

BACKGROUND: Renal transplant candidates are at high risk of fatal and nonfatal cardiac events. METHODS: This study evaluated five clinical risk factors--age at least 50 years, insulin-requiring diabetes mellitus, angina, congestive heart failure and an abnormal electrocardiogram (ECG) (excluding left ventricular hypertrophy)--that had been used in the first tier of a two-tiered prospectively applied risk stratification algorithm. RESULTS: Using multiple logistic regression analysis, age at least 50 years, abnormal ECG, and diabetes mellitus were independently predictive of cardiac death. Of the two remaining clinical risk factors, the presence of angina had independent predictive value for nonfatal cardiac events (myocardial infarction, coronary angioplasty, bypass surgery, and unstable angina). The independent predictive value of congestive heart failure approached statistical significance. CONCLUSION: Clinical risk-factor analysis is helpful in identifying renal transplant candidates at high risk for fatal or nonfatal cardiac events.

Algorithms↗
PubMed1998

Efficacy and safety of low molecular weight heparin in renal transplantation.

BACKGROUND: Deep venous thrombosis (DVT) is a common problem with potentially devastating results in patients undergoing major surgical procedures. Certain renal transplant recipients are particularly at risk for allograft loss as a consequence of renal vein and artery thrombosis. Over the past few years, low molecular weight heparin has been well established as an accepted modality of treatment and prophylaxis of DVT. The efficacy and safety of low molecular weight heparin in the prophylaxis of DVT following renal transplantation in adults has not previously been reported. METHODS: Dalteparin was administered to 120 adult renal transplant recipients postoperatively at the Oregon Health Sciences University. RESULTS: No patient developed allograft arterial or venous thrombosis. One patient developed subclavian vein thrombosis. No bleeding complications were encountered, and side effects were very minimal. CONCLUSION: Prophylaxis with dalteparin is an effective and safe modality for the prevention of thrombosis in adult patients undergoing renal transplantation.

Adolescent↗
PubMed1998

Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation.

BACKGROUND: Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS: A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS: A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS: Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.

Acute Disease↗
PubMed1998

Squamous and basal cell carcinoma in heart transplant recipients.

BACKGROUND: Cutaneous malignancies are frequent in organ transplant recipients. We retrospectively reviewed a large series of heart transplant recipients and report on the prevalence and risk factors for development of cutaneous squamous and basal cell carcinoma. METHODS: Between Dec. 4, 1985, and Dec. 27, 1996, 299 heart transplantations were performed at the Oregon Health Sciences University. Heart transplant recipients with more than 6 months survival or follow-up were investigated for squamous and basal cell carcinoma (n = 248). RESULTS: Forty-one patients (17%) were found to have 192 squamous or basal cell carcinomas. Squamous cell carcinoma was the predominate skin malignancy, constituting 172 (90%) of the lesions. The mean number of skin malignancies per patient was 4.7 +/- 0.81 (range 125). Patients with development of a skin malignancy were 8 years older on average, with a male-to-female ratio of 19.5:1. The predominant skin type and eye color were fair (59%) and blue (59%), respectively. Cumulative risk, based on actuarial survival analysis for development of a squamous or basal cell carcinoma at 1 year, was 3% and increased to 21% and 35% at 5 and 10 years, respectively. In addition, cumulative risk increased in patients who received treatment with OKT3. CONCLUSION: Cumulative risk of development of a skin malignancy increased with time and use of OKT3. Additional patient risk factors included older age, male sex, fair skin, and blue eyes.

Actuarial Analysis↗
PubMed1997

Cardiac risk stratification in renal transplantation using a form of artificial intelligence.

The purpose of this study was to determine if an expert network, a form of artificial intelligence, could effectively stratify cardiac risk in candidates for renal transplant. Input into the expert network consisted of clinical risk factors and thallium-201 stress test data. Clinical risk factor screening alone identified 95 of 189 patients as high risk. These 95 patients underwent thallium-201 stress testing, and 53 had either reversible or fixed defects. The other 42 patients were classified as low risk. This algorithm made up the "expert system," and during the 4-year follow-up period had a sensitivity of 82%, specificity of 77%, and accuracy of 78%. An artificial neural network was added to the expert system, creating an expert network. Input into the neural network consisted of both clinical variables and thallium-201 stress test data. There were 5 hidden nodes and the output (end point) was cardiac death. The expert network increased the specificity of the expert system alone from 77% to 90% (p < 0.001), the accuracy from 78% to 89% (p < 0.005), and maintained the overall sensitivity at 88%. An expert network based on clinical risk factor screening and thallium-201 stress testing had an accuracy of 89% in predicting the 4-year cardiac mortality among 189 renal transplant candidates.

Adult↗
PubMed1997

Interleukin-12 p40 m-RNA expression in human kidney allograft biopsies.

Interleukin-12 (IL-12) is a heterodimeric cytokine implicated in the early differentiation of naive T-lymphocytes into the Th1 subset. IL-12 is important for induction of the cellular immune response against viruses, intracellular parasites and neoplasms. Its role in alloresponsiveness has not been fully elucidated. Preliminary data in the literature point toward the prevalence of Th1 lymphocytes in processes of allograft rejection. In attempt to further investigate the expression of this cytokine during episodes of cellular rejection of renal allografts, we searched for IL-12 message in human kidney allograft biopsies using the reverse transcriptase-polymerase chain reaction technique. Twenty-three allograft core biopsies from 19 patients were obtained percutaneously for clinical indications in 18 cases, and as part of an investigational protocol in five cases. A portion of the tissue was used for RNA extraction using the guanidium-thiocyanide phenol-chloroform method. Histology was performed on the remaining core material. Ten mg of total RNA were used for reverse transcription. PCR of the c-DNAs was done for 40 cycles using primers for the p40 subunit of IL-12 and GAPDH which was used as a control. PCR products were photographed after electrophoresis, transferred to a nylon membrane and hybridized with a radiolabelled cloned human IL-12 p40 1 kb c-DNA fragment. Autoradiographies were developed after 20-min exposure. All samples were run in triplicate. IL-12 p40 m-RNA was expressed in all 17 biopsies showing acute cellular rejection as well as in all three biopsies showing focal interstitial fibrosis. No message was found in the presence of normal allograft histology. This is the first in vivo report of IL-12 p40 subunit m-RNA expression during renal allograft rejection in humans. The role of this Th1 cytokine in the alloresponse deserves further investigation.

Adult↗
PubMed1997

Allocation of livers for liver transplantation: ethics and politics.

The supply of livers for transplantation is not adequate for the number of patients waiting for liver transplantation. The allocation and distribution of the limited supply of livers is hotly debated at the United Network for Organ Sharing. The principles of medical utility and justice must be balanced in an equitable distribution scheme. Excellent local liver transplant centers should be available to all patients.

Humans↗
PubMed1996

Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism.

The gene apparently responsible for a heritable form of murine pituitary-dependent dwarfism (Ames dwarf, df) has been positionally cloned, identifying a novel, tissue-specific, paired-like homeodomain transcription factor, termed Prophet of Pit-1 (Prop-1). The df phenotype results from an apparent failure of initial determination of the Pit-1 lineage required for production of growth hormone, prolactin or thyroid-stimulating hormone, resulting in dysmorphogenesis and failure to activate Pit-1 gene expression. These results imply that a cascade of tissue-specific regulators is responsible for the determination and differentiation of specific cell lineages in pituitary organogenesis.

Alleles↗
PubMed1996

Identification of high- and low-risk second kidney grafts.

The purpose of this study was to identify recipients who are at low or high risk of early cadaveric regraft failure by segregating results of the flow cytometric crossmatch (FCXM) test with previous graft survival time (PGST). Early immunologic kidney regraft failure was analyzed in 103 multicenter recipients by cross-stratifying FCXM negative/positive status with < or =3- and >3-month PGST. T cell and B cell cytotoxicity crossmatches were negative. All were tested retrospectively in the T cell FCXM and 60 of the 103 were also tested in the B cell FCXM. A positive T and B cell FCXM was defined as a mean channel shift of > or = 9 (256 channel log scale) or > or = 40 (1024 channel log scale) for pretransplant crossmatch serum above negative control serum. Recipients received triple immunosuppression therapy and limited-use antilymphocyte induction therapy. Early cadaveric regraft losses were biopsied. Comparably good rates of second kidney graft survival at 3 years were found among three ow risk subsets: 78% for 18 FCXM-positive patients with PGST >3 months, 78% for 49 FCXM-negative patients with PGST >3 months, and 84% for 19 FCXM-negative patients with PGST < or =3 months. in contrast, 53% 3-month and 44% 3-year regraft survival rates occurred in 17 high-risk FCXM-positive recipients with a PGST < or =3 months. The odds ratio for increased relative risk of early second graft loss was 4.5 (confidence interval: 1.32-1.67) for the high-risk versus low-risk subsets (P = 0.009). Within the high-risk subset, 56% (5 of 9) of those who were FCXM T negative B positive experienced early regraft loss. A positive B cell FCXM has an adverse clinical impact only for high-risk regraft recipients. Pretransplant panel reactive antibody levels, pregnancy, number of blood transfusions between grafts, repeat donor HLA mismatches, and regraft recipient HLA mismatches did not correlate with early regraft loss. We conclude that kidney regraft survival rates in low-risk recipients (PGST >3 months/FCXM negative or positive [T and/or B cell] and PGST < or = 3 months/FCXM negative) approach primary graft survival rates and justify retransplantation, but the rate in high-risk regraft candidates (PGST < or =3 months/FCXM positive T and/or B cell) suggests that retransplantation should be performed only with a negative FCXM.

Female↗