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Connie L Davis

Publications and source records attributed to Connie L Davis.

At least 19 recordsLinked to original sources
PubMed2006

Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro.

Previous investigations of solid organ transplant patients treated with tacrolimus showed that individuals carrying a CYP3A5*1 allele have lower dose-adjusted trough blood concentrations compared with homozygous CYP3A5*3 individuals. The objective of this investigation was to quantify the contribution of CYP3A5 to the hepatic and renal metabolic clearance of tacrolimus. Four primary tacrolimus metabolites, 13-O-desmethyl tacrolimus (13-DMT) (major), 15-O-desmethyl tacrolimus, 31-O-desmethyl tacrolimus (31-DMT), and 12-hydroxy tacrolimus (12-HT), were generated by human liver microsomes and heterologously expressed CYP3A4 and CYP3A5. The unbound tacrolimus concentration was low (4-15%) under all incubation conditions. For CYP3A4 and CYP3A5, V(max) was 8.0 and 17.0 nmol/min/nmol enzyme and K(m,u) was 0.21 and 0.21 muM, respectively. The intrinsic clearance of CYP3A5 was twice that of CYP3A4. The formation rates of 13-DMT, 31-DMT, and 12-HT were >or=1.7-fold higher, on average, in human liver microsomes with a CYP3A5*1/*3 genotype compared with those with a homozygous CYP3A5*3/*3 genotype. Tacrolimus disappearance clearances were 15.9 +/- 9.8 ml/min/mg protein and 6.1 +/- 3.6 ml/min/mg protein, respectively, for the two genotypes. In vitro to in vivo scaling using both liver microsomes and recombinant enzymes yielded higher predicted in vivo tacrolimus clearances for patients with a CYP3A5*1/*3 genotype compared with those with a CYP3A5*3/*3 genotype. In addition, formation of 13-DMT was 13.5-fold higher in human kidney microsomes with a CYP3A5*1/*3 genotype compared with those with a CYP3A5*3/*3 genotype. These data suggest that CYP3A5 contributes significantly to the metabolic clearance of tacrolimus in the liver and kidney.

Algorithms↗
PubMed2006

Risk of lymphoma after renal transplantation varies with time: an analysis of the United States Renal Data System.

BACKGROUND: Characterization of the incidence of posttransplant lymphoma over time may help guide the timing and intensity of posttransplant monitoring. We analyzed the United States Renal Data System to describe the occurrence of lymphoma following renal transplantation. METHODS: All end-stage renal disease patients placed on the transplant waiting list between January 1, 1990 and December 31, 1999 were considered. Survival analysis was used to estimate lymphoma risk in renal transplant patients. RESULTS: Of 89,260 eligible patients, a total of 556 lymphoma cases were identified with 357 in transplant patients. The overall rate of posttransplant lymphoma was 33.3/10,000 person-years in transplant patients. There was variation in the duration and magnitude of increased lymphoma risk by age. The highest rates of lymphoma were among transplanted patients in the first 12 months, after which the rate of lymphoma decreased. Among Caucasian transplant recipients less than 25 years of age, the adjusted relative risk of lymphoma ranged from 13.82 [95% CI: (3.96, 48.15)] within 6 months posttransplant to 3.46 [95% CI: (0.69, 17.44)] within months 30-36 posttransplant. Only patients under 25 years had a notably increased risk beyond the first 2 posttransplant years. The risk of lymphoma differed by race, with Caucasian patients at nearly double the risk of African-Americans. Gender was not associated with lymphoma incidence. CONCLUSIONS: We found and quantified a time-varying relationship between renal transplant and lymphoma risk. This information can be used in combination with knowledge of established risk factors to guide the schedule of posttransplant monitoring.

Adult↗
PubMed2006

Reproduction and pregnancy in transplant recipients: current practices.

Many transplant physicians are faced with questions from their patients about the safety and long-term consequences of pregnancy following transplantation. To better understand how pregnancies are managed and to clarify the outcome of pregnancy after transplantation, a survey questionnaire was developed and mailed to all medical and surgical directors of transplant centers throughout the United States; responses were obtained from 59.1% of the transplant centers. Although many opinions were collected, most respondents conceded that their opinions were based on personal experience rather than evidence-based. The underutilization of existing information was revealing and highlighted a need for an evidence-based approach to care of the pregnant transplant recipient and her offspring. The survey results, reported in this article, led to formation of a consensus conference to determine the optimal approach to pregnant transplant recipients and to define what is currently known and unknown about reproduction and transplantation.

Contraceptives, Oral↗
PubMed2005

Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1alpha,25-dihydroxyvitamin D(3): implications for drug-induced osteomalacia.

The decline in bone mineral density that occurs after long-term treatment with some antiepileptic drugs is thought to be mediated by increased vitamin D(3) metabolism. In this study, we show that the inducible enzyme CYP3A4 is a major source of oxidative metabolism of 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] in human liver and small intestine and could contribute to this adverse effect. Heterologously-expressed CYP3A4 catalyzed the 23- and 24-hydroxylation of 1,25(OH)(2)D(3). No human microsomal cytochrome P450 enzyme tested, other than CYP3A5, supported these reactions. CYP3A4 exhibited opposite product stereochemical preference compared with that of CYP24A1, a known 1,25(OH)(2)D(3) hydroxylase. The three major metabolites generated by CYP3A4 were 1,23R,25(OH)(3)D(3), 1,24S,25(OH)(3)D(3), and 1,23S,25(OH)(3)D(3). Although the metabolic clearance of CYP3A4 was less than that of CYP24A1, comparison of metabolite profiles and experiments using CYP3A-specific inhibitors indicated that CYP3A4 was the dominant source of 1,25(OH)(2)D(3) 23- and 24-hydroxylase activity in both human small intestine and liver. Consistent with this observation, analysis of mRNA isolated from human intestine and liver (including samples from donors treated with phenytoin) revealed a general absence of CYP24A1 mRNA. In addition, expression of CYP3A4 mRNA in a panel of duodenal samples was significantly correlated with the mRNA level of a known vitamin D receptor gene target, calbindin-D9K. These and other data suggest that induction of CYP3A4-dependent 1,25(OH)(2)D(3) metabolism by antiepileptic drugs and other PXR ligands may diminish intestinal effects of the hormone and contribute to osteomalacia.

Base Sequence↗
PubMed2005

Living-donor kidney transplantation: a review of the current practices for the live donor.

The first successful living-donor kidney transplant was performed 50 yr ago. Since then, in a relatively brief period of medical history, living kidney transplantation has become the preferred treatment for those with ESRD. Organ replacement from either a live or a deceased donor is preferable to dialysis therapy because transplantation provides a better quality of life and improved survival. The advantages of live versus deceased donor transplantation now are readily apparent as it affords earlier transplantation and the best long-term survival. Live kidney donation has also been fostered by the technical advance of laparoscopic nephrectomy and immunologic maneuvers that can overcome biologic obstacles such as HLA disparity and ABO or cross-match incompatibility. Congressional legislation has provided an important model to remove financial disincentives to being a live donor. Federal employees now are afforded paid leave and coverage for travel expenses. Candidates for renal transplantation are aware of these developments, and they have become less hesitant to ask family members, spouses, or friends to become live kidney donors. Living donation as practiced for the past 50 yr has been safe with minimal immediate and long-term risk for the donor. However, the future experience may not be the same as our society is becoming increasingly obese and developing associated health problems. In this environment, predicting medical futures is less precise than in the past. Even so, isolated abnormalities such as obesity and in some instances hypertension are no longer considered absolute contraindications to donation. These and other medical risks bring additional responsibility in such circumstances to track the unknown consequences of a live-donor nephrectomy.

Humans↗
PubMed2005

Impact of pretransplant renal failure: when is listing for kidney-liver indicated?

Renal and hepatic function are often intertwined both through the existence of associated primary organ diseases and hemodynamic interrelationships. This connection occasionally results in the chronic failure of both organs, necessitating the need for combined kidney-liver transplantation. Since 1990, over 1,790 patients in the United States have received such transplants with a patient survival somewhat less than that for patients receiving either organ alone. Patients with renal failure due to acute injury or to the hepatorenal syndrome have classically not been included as candidates for combined transplantation due to the reversibility of the renal dysfunction following liver transplantation. However, the rate and duration of renal failure prior to liver transplantation continues to be prolonged even with the new allocation scheme prioritizing liver transplants to those with renal failure. Thus the issue of when kidney transplantation should be offered and what evaluation is necessary prior to the decision continues to confront the transplant community.

Humans↗
PubMed2005

IgA nephropathy with crescents in kidney transplant recipients.

BACKGROUND: Crescentic glomerulonephritis is an uncommon finding in renal allografts. Recurrence or de novo mesangial deposition of immunoglobulin A (IgA) in renal allografts most often is clinically benign, but some case reports have shown that IgA nephropathy in renal allografts can present as crescentic glomerulonephritis and may lead to rapid deterioration of graft function and/or graft loss. METHODS: We reviewed diagnoses of all allograft biopsies at University of Washington Medical Center (Seattle, WA) from 1989 to 2003 and found 33 cases of glomerulonephritis with crescents. Eight of these cases were the result of recurrent or de novo IgA nephropathy. Clinical and pathological features of these patients were reviewed. RESULTS: Six of 8 cases with crescents were the result of recurrent IgA nephropathy, and 2 cases were presumptive de novo IgA nephropathy. Of the 8 patients with IgA nephropathy with crescents, 6 patients presented clinically with increasing serum creatinine levels; 4 patients, with proteinuria; and 4 patients, with hematuria. In 6 patients, there was 10% to 30% involvement of glomeruli, with crescents partially or completely filling urinary spaces. The other patients showed lesser (approximately 7% of sampled glomeruli) involvement. Four patients with IgA nephropathy with crescents developed renal failure and returned to hemodialysis therapy. Three patients had a benign clinical course, with stabilization of renal function. One patient was lost to follow-up. CONCLUSION: We identified a cohort of patients with glomerulonephritis with crescents in renal allografts with IgA nephropathy as the cause. In half the affected patients, this led to early progressive renal insufficiency and return to hemodialysis therapy.

Adult↗
PubMed2005

Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation.

It has been almost 50 years since the first child was born to a female transplant recipient. Since that time pregnancy has become common after transplantation, but physicians have been left to rely on case reports, small series and data from voluntary registries to guide the care of their patients. Many uncertainties exist including the risks that pregnancy presents to the graft, the patient herself, and the long-term risks to the fetus. It is also unclear how to best modify immunosuppressive agents or treat rejection during pregnancy, especially in light of newer agents available where pregnancy safety has not been established. To begin to address uncertainties and define clinical practice guidelines for the transplant physician and obstetrical caregivers, a consensus conference was held in Bethesda, Md. The conferees summarized both what is known and important gaps in our knowledge. They also identified key areas of agreement, and posed a number of critical questions, the resolution of which is necessary in order to establish evidence-based guidelines. The manuscript summarizes the deliberations and conclusions of the conference as well as specific recommendations based on current knowledge in the field.

Female↗
PubMed2004

In vitro metabolism of cyclosporine A by human kidney CYP3A5.

The objectives of this study were to characterize and compare the metabolic profile of cyclosporine A (CsA) catalyzed by CYP3A4, CYP3A5 and human kidney and liver microsomes, and to evaluate the impact of the CYP3A5 polymorphism on product formation from parent drug and its primary metabolites. Three primary CsA metabolites (AM1, AM9 and AM4N) were produced by heterologously expressed CYP3A4. In contrast, only AM9 was formed by CYP3A5. Substrate inhibition was observed for the formation of AM1 and AM9 by CYP3A4, and for the formation of AM9 by CYP3A5. Microsomes isolated from human kidney produced only AM9 and the rate of product formation (2 and 20 microM CsA) was positively associated with the detection of CYP3A5 protein and presence of the CYP3A5*1 allele in 4 of the 20 kidneys tested. A kinetic experiment with the most active CYP3A5*1-positive renal microsomal preparation yielded an apparent Km (15.5 microM) similar to that of CYP3A5 (11.3 microM). Ketoconazole (200 nM) inhibited renal AM9 formation by 22-55% over a CsA concentration range of 2-45 microM. Using liver microsomes paired with similar CYP3A4 content and different CYP3A5 genotypes, the formation of AM9 was two-fold higher in CYP3A5*1/*3 livers, compared to CYP3A5*3/*3 livers. AM19 and AM1c9, two of the major secondary metabolites of CsA, were produced by CsA, AM1 and AM1c when incubated with CYP3A4, CYP3A5, kidney microsomes from CYP3A5*1/*3 donors and all liver microsomes. Also, the formation of AM19 and AM1c9 was higher from incubations with liver and kidney microsomes with a CYP3A5*1/*3 genotype, compared to those with a CYP3A5*3/*3 genotype. Together, the data demonstrate that CYP3A5 may contribute to the formation of primary and secondary metabolites of CsA, particularly in kidneys carrying the wild-type CYP3A5*1 allele.

Biotransformation↗
PubMed2004

Evaluation of the living kidney donor: current perspectives.

Living kidney donation is increasing because of prolonged waiting times on the transplant list, as well as improved outcomes for recipients. In 2001, the number of living donors surpassed the number of deceased donors; this trend likely will continue with ever-increasing margins. Because of this increase, as well as changes in our society's health, it is time to re-review the guidelines for selecting living kidney donors established by Kasiske et al in 1995. A conference will be held this year to review updated literature on medical conditions that impact on renal health. From this, new guidelines for the medical evaluation of living renal donors will be constructed. This review discusses information known to date on the outcomes of individuals undergoing unilateral nephrectomy, the impact of lifestyle on renal function in the setting of nephrectomy, and advancements in the detection of genetically transmitted renal diseases that impact on today's decisions on living donation.

Adult↗
PubMed2004

Polyomavirus nephropathy in pediatric kidney transplant recipients.

Given the limited information regarding BK virus-associated nephropathy (BKVN) in pediatric kidney transplant recipients, we assessed the incidence, risk factors, clinical and virologic features of BKVN in pediatric renal transplant recipients at a single transplant center by means of a retrospective cohort study. Histologically confirmed BKVN developed in 6 of 173 (3.5%) kidney transplant recipients at a median of 15 months post-transplant (range: 4-47 months). At a median follow-up of 28 months (range: 5-32), all patients had functioning grafts with mean creatinine and GFR of 1.9 mg/dL and 58 mL/min/1.73 m2, respectively. At the time of diagnosis, all cases had viruria (median 6.1 x 10(6) copies/mL, range: 10(5) to 3.9 x 10(8) copies/mL) and viremia (median 21,000 copies/mL, range: 10,000-40,000 copies/mL). Recipient seronegativity for BKV was significantly associated with the development of BKVN (p = 0.01). BKVN is an important cause of late allograft dysfunction and is strongly associated with recipient seronegativity in pediatric kidney transplant recipients. Further studies to confirm this finding and to define the clinical utility of routine pre-transplant BKV serologic testing are warranted.

Adolescent↗
PubMed2004

Transplantation in the diabetic patient with advanced chronic kidney disease: a task force report.

On May 7 to 8, 2003, more than 60 physicians, surgeons, nurses, and allied health professionals met in Chicago, IL, to discuss state-of-the-art approaches to transplantation in the clinical management of patients with diabetes and advanced chronic kidney disease. Four work groups addressed pretransplantation evaluation and management, therapeutic alternatives for treatment of patients with chronic kidney disease, posttransplantation diabetes mellitus, and improving long-term kidney transplant outcomes in patients with diabetes. This report summarizes the deliberations and recommendations of the task force.

Coronary Disease↗
PubMed2003

Postbiopsy bleeding in a porcine model: reduction with radio-frequency ablation--preliminary results.

PURPOSE: To test a biopsy needle modified for use of radio-frequency (RF) energy to produce hemostasis after core biopsy of liver or kidney. MATERIALS AND METHODS: RF energy was applied to a partially insulated 17-gauge needle, and tip temperature was monitored with a thermocouple. Domestic Yorkshire pigs (n = 4; mean weight, 23.4 kg) were anesthetized, and their livers and kidneys were exposed. Needles were inserted 2 cm into hepatic and renal parenchyma and retracted, either with or without tract ablation to 65 degrees C, in normal tissue, animals treated with anticoagulants, and an animal with acute inferior vena caval occlusion to produce portal hypertension. Blood loss was assessed by weighing surgical sponges with blood from the puncture sites. Significant differences in blood loss between control and ablated biopsy specimens in each scenario were tested by using a Wilcoxon matched-pairs signed rank test. RESULTS: Mean blood loss for each group was as follows: In the liver, control biopsy specimens (n = 18) lost 0.30 g while ablated biopsy specimens lost 0.00044 g (P <.01), and control biopsy specimens treated with heparin (n = 26) lost 0.45 g while biopsy specimens treated with heparin and ablation lost 0.27 g (P =.03). For inferior vena caval occlusion, control biopsy specimens lost 1.23 g, while ablated biopsy specimens lost 0.00 g. In the kidney, control biopsy specimens (n = 28) lost 0.82 g, while ablated biopsy specimens lost 0.24 g (P =.01), and control biopsy specimens treated with heparin (n = 14) lost 1.04 g, while biopsy specimens treated with heparin and ablation lost 0.19 g (P =.02). CONCLUSION: Tract ablation with thermocouple-monitored RF energy decreased postprocedural hemorrhage after hepatic and renal biopsy.

Animals↗
PubMed2003

Implementing practical interventions to support chronic illness self-management.

BACKGROUND: Self-management support (SMS) is the area of disease management least often implemented and most challenging to integrate into usual care. This article outlines a model of SMS applicable across different chronic illnesses and health care systems, presents recommendations for assisting health care professionals and practice teams to make changes, and provides tips and lessons learned. Strategies can be applied across a wide range of conditions and settings by health educators, care managers, quality improvement specialists, researchers, program evaluators, and clinician leaders. Successful SMS programs involve changes at multiple levels: patient-clinician interactions; office environment changes; and health system, policy, and environmental supports. PATIENT-CLINICIAN INTERACTION LEVEL: Self-management by patients is not optional but inevitable because clinicians are present for only a fraction of the patient's life, and nearly all outcomes are mediated through patient behavior. Clinicians who believe they are in control or responsible for a patient's well-being are less able to adopt an approach that acknowledges the central role of the patient in his or her care. SUMMARY AND CONCLUSIONS: Self-management should be an integral part of primary care, an ongoing iterative process, and patient centered; use collaborative goal setting and decision making; and include problem solving, outreach, and systematic follow-up.

Chronic Disease↗
PubMed2003

Predictors of ARF after cardiac surgical procedures.

BACKGROUND: In a pilot study, a low preoperative serum ferritin level predicted increased risk for acute renal failure (ARF) after cardiopulmonary bypass. It was hypothesized that this may reflect a decreased ability to bind free iron and defend against oxidative stress. However, the pilot study was performed in a small number of patients (n = 30) operated on by a single surgeon. The purpose of this study was to validate whether the serum ferritin level predicts ARF in a larger sample. METHODS: The present study evaluated 120 patients who underwent procedures performed by eight surgeons at another tertiary referral center. Data were collected prospectively and included patient characteristics, laboratory studies, procedure types, and postoperative course. ARF was defined as a 25% or greater increase in creatinine level 48 hours after surgery. RESULTS: The frequency of ARF was 42%, but no patient required dialysis therapy. Preoperative serum ferritin levels did not differ in the groups with and without ARF (158 +/- 119 and 163 +/- 125 ng/mL, respectively), and rates of ARF did not differ when examined by ferritin quartiles. ARF was more frequent in those who underwent valve surgery (54% versus 35% in patients who did not undergo valve procedures; P = 0.044). The odds ratio for ARF after valve surgery was 2.58 (95% confidence interval, 1.06 to 6.29; P = 0.037), adjusted for longer times of surgery and aortic cross-clamp. Most excess ARF occurred in those who underwent aortic valve replacement (AVR; 62%; P = 0.014 versus nonvalve procedures). CONCLUSION: Low preoperative serum ferritin level was not confirmed to predict ARF after cardiac surgery. Valve procedures, particularly AVR, increased the risk for ARF.

Acute Kidney Injury↗