A programme to improve quality of care for patients with chronic diseases, Kazakhstan.

OBJECTIVE: To evaluate the effect of a disease management programme in Kazakhstan on quality indicators for patients with hypertension, diabetes and chronic heart failure. METHODS: A supportive, interdisciplinary, quality improvement programme was implemented between November 2014 and November 2015 at seven polyclinics in Pavlodar and Petropavlovsk. Quality improvement teams were established at each clinic and quality improvement tools were introduced, including patient flowsheets, decision support tools, patient registries, a patient recall process, support for patient self-management and patient follow-up with intensity adjusted for level of disease control. Clinic teams met for four 3-day interactive learning sessions within 1 year, with additional coaching visits. Implementation was managed by five local coordinators and consultants trained by international consultants. National and regional steering committees monitored progress. FINDINGS: Between July and October 2015, the proportion of hypertensive patients with the recommended blood pressure increased from 24% (101/424) to 56% (228/409). Among patients with diabetes, the proportion who recently underwent eye examinations increased from 26% (101/391) to 71% (308/433); the proportion who had their low-density lipoprotein cholesterol measured increased from 57% (221/391) to 85% (369/433); and the proportion who had their albumin : creatinine ratio measured increased from 11% (44/391) to 49% (212/433). The proportion of chronic heart failure patients who underwent echocardiography rose from 91% (128/140) to 99% (157/158). All patients set themselves self-management goals. CONCLUSION: This intensive, supportive, multifaceted programme was associated with significant improvements in quality of care for patients with chronic disease. Further investment in coaching capacity is needed to extend the programme nationally.

Promoting the use of self-management in patients with spine pain managed by chiropractors and chiropractic interns: barriers and design of a theory-based knowledge translation intervention.

Background: The literature supports the effectiveness of self-management support (SMS) to improve health outcomes of patients with chronic spine pain. However, patient engagement in SMS programs is suboptimal. The objectives of this study were to: 1) assess participation in self-care (i.e. activation) among patients with spine pain, 2) identify patients' barriers and enablers to using SMS, and 3) map behaviour change techniques (BCTs) to key barriers to inform the design of a knowledge translation (KT) intervention aimed to increase the use of SMS. Methods: In summer 2016, we invited 250 patients with spine pain seeking care at the Canadian Memorial Chiropractic College in Ontario, Canada to complete the Patient Activation Measure (PAM) survey to assess the level of participation in self-care. We subsequently conducted individual interviews, in summer 2017, based on the Theoretical Domains Framework (TDF) in a subset of patients to identify potential challenges to using SMS. The interview guide included 20 open-ended questions and accompanying probes. Findings were deductively analysed guided by the TDF. A panel of 7 experts mapped key barriers to BCTs, designed a KT intervention, and selected the modes of delivery. Results: Two hundred and twenty-three patients completed the PAM. Approximately 24% of respondents were not actively involved in their care. Interview findings from 13 spine pain patients suggested that the potential barriers to using SMS corresponded to four TDF domains: Environmental Context and Resources; Emotion; Memory, Attention & Decision-Making; and Behavioural Regulation. The proposed theory-based KT intervention includes paper-based educational materials, webinars and videos, summarising and demonstrating the therapeutic recommendations including exercises and other lifestyle changes. In addition, the KT intervention includes Brief Action Planning, a SMS strategy based on motivational interviewing, along with a SMART plan and reminders. Conclusions: Almost one quarter of study participants were not actively engaged in their spine care. Key barriers likely to influence uptake of SMS among patients were identified and used to inform the design of a theory-based KT intervention to increase their participation level. The proposed multi-component KT intervention may be an effective strategy to optimize the quality of spine pain care and improve patients' health-outcomes.

Promoting the use of self-management in novice chiropractors treating individuals with spine pain: the design of a theory-based knowledge translation intervention.

BACKGROUND: Clinical practice guidelines generally recommend clinicians use self-management support (SMS) when managing patients with spine pain. However, even within the educational setting, the implementation of SMS remains suboptimal. The objectives of this study were to 1) estimate the organizational readiness for change toward using SMS at the Canadian Memorial Chiropractic College (CMCC), Toronto, Ontario from the perspective of directors and deans, 2) estimate the attitudes and self-reported behaviours towards using evidence-based practice (EBP), and beliefs about pain management among supervisory clinicians and chiropractic interns, 3) identify potential barriers and enablers to using SMS, and 4) design a theory-based tailored Knowledge Translation (KT) intervention to increase the use of SMS. METHODS: Mixed method design. We administered three self-administered questionnaires to assess clinicians' and interns' attitudes and behaviours toward EBP, beliefs about pain management, and practice style. In addition, we conducted 3 focus groups with clinicians and interns based on the Theoretical Domain Framework (TDF) to explore their beliefs about using SMS for patients with spine pain. Data were analysed using deductive thematic analysis by 2 independent assessors. A panel of 7 experts mapped behaviour change techniques to key barriers identified informing the design of a KT intervention. RESULTS: Participants showed high level of EBP knowledge, positive attitude of EBP, and moderate frequency of EBP use. A number of barrier factors were identified from clinicians (N = 6) and interns (N = 16) corresponding to 7 TDF domains: Knowledge; Skills; Environmental context and resources; Emotion; Beliefs about Capabilities; Memory, attention & decision making; and Social Influence. To address these barriers, the expert panel proposed a multifaceted KT intervention composed of a webinar and online educational module on a SMS guided by the Brief Action Planning, clinical vignettes, training workshop, and opinion leader support. CONCLUSION: SMS strategies can help maximizing the health care services for patients with spine pain. This may in turn optimize patients' health. The proposed theory-based KT intervention may facilitate the implementation of SMS among clinicians and interns.

Kidney Biopsies May Help Predict Renal Function After Liver Transplantation.

BACKGROUND: Renal biopsy has been proposed to determine the cause or reversibility of renal failure for patients with end-stage liver disease and may be useful in the kidney allocation. Nevertheless, little data exist to validate the usefulness of kidney biopsies in this patient population. METHODS: We evaluated the utility of renal biopsies in a cohort of 59 consecutive liver transplant candidates with renal impairment of unclear etiology referred to determine the need for simultaneous liver kidney transplantation (SLK) versus liver alone transplantation (LAT). Pathological diagnoses, patient outcomes and the usefulness of biopsy results in predicting renal recovery were analyzed. RESULTS: Our biopsy complication rate was relatively low with only 2.9% and 4.2% serious complications occurring with transjugular and percutaneous renal biopsies, respectively. The most common pathological diagnoses on renal biopsies were membranoproliferative glomerulonephritis (23%) followed by IgA nephropathy (19%) and acute tubular injury (19%). Simultaneous liver kidney transplantation was recommended for patients with greater than 40% global glomerular sclerosis, or with interstitial fibrosis greater than 30% or for patients on hemodialysis for 2 months or longer. The best histological predictor for posttransplant glomerular filtration rate in the LAT group was the extent of global glomerulosclerosis (P = 0.0001). Based on biopsy criteria, we were able to avoid kidney allocation to 70% of our patients with renal dysfunction. Over the first year posttransplant, SLK and LAT patients had comparable estimated glomerular filtration rates. Kaplan-Meier survival analysis did not demonstrate a difference in patient survival between patients who underwent LAT versus SLK. CONCLUSIONS: Renal biopsy can be relatively safe in this population, may help elucidate the etiology of renal failure, may predict post-LAT kidney function, and may be helpful in kidney allocation for liver transplant candidates.

Testing the feasibility of training peers with a spinal cord injury to learn and implement brief action planning to promote physical activity to people with spinal cord injury.

OBJECTIVE: The present study tested the feasibility of training peers with spinal cord injury (SCI) to learn brief action planning (BAP), an application of motivational interviewing principles, to promote physical activity to mentees with SCI. METHOD: Thirteen peers with SCI attended a half-day BAP workshop. Using a one-arm, pre-, post-test design, feasibility to learn BAP was assessed in terms of peers' (1) BAP and motivational interviewing spirit competence; (2) training satisfaction; and (3) motivations to use BAP as assessed by measures of the theory of planned behavior constructs. Measures were taken at baseline, immediately post-training, and 1 month follow up. RESULTS: Following the training, participants' BAP and motivational interviewing competence significantly increased (P's < 0.05, d's > 2.27). Training satisfaction was very positive with all means falling above the scale midpoint. Participants' perceived behavioral control to use BAP increased from baseline to post (P < 0.05, d = 0.91) but was not maintained at follow up (P > 0.05). CONCLUSION: Training peers with a SCI to learn to use BAP is feasible. PRACTICAL IMPLICATIONS: BAP is a tool that can be feasibly learned by peers to promote physical activity to their mentees.

Understanding how self-management interventions work for disadvantaged populations living with chronic conditions: protocol for a realist synthesis.

INTRODUCTION: Self-management programmes are complex interventions aimed at improving the way individuals self-manage chronic conditions, but there are questions about the overall impact of these programmes on disadvantaged populations, in terms of their capacity to engage with and receive the benefits from these initiatives. Given the increased resources being directed towards self-management initiatives, clinicians and policy makers need knowledge on how self-management interventions work for these populations. Most systematic reviews of self-management interventions do not consider the complex interactions between implementation contexts, intervention strategies, and mechanisms that influence how self-management interventions work in real life for disadvantaged groups. METHODS: To address the need for better understanding of these mechanisms and to create context-relevant knowledge, we are conducting a realist synthesis of evidence on self-management interventions for disadvantaged populations living with chronic conditions. The primary research question is: What are the key mechanisms operating in chronic condition self-management interventions among disadvantaged populations? In this protocol, we outline the steps we will take to identify the programme theory for self-management interventions and candidate middle-range theories; to search for evidence in academic and grey literature; to appraise and extract the collected evidence; to synthesise and interpret the findings to generate key context-mechanism-outcome configurations and to disseminate results to relevant stakeholder and to peer-review publications. DISSEMINATION: Understandings of how chronic conditions self-management interventions work among disadvantaged populations is essential knowledge for clinicians and other decision makers who need to know which programmes they should implement for which groups. Results will also benefit medical researchers who want to direct effort towards current gaps in knowledge in order to advance the self-management field. In addition, the study will make a contribution to the evolving body of knowledge on the realist synthesis method and, in particular, to its application to behaviour change interventions for disadvantaged populations.

Risk of squamous cell skin cancer after organ transplant associated with antibodies to cutaneous papillomaviruses, polyomaviruses, and TMC6/8 (EVER1/2) variants.

Squamous cell skin cancer (SCSC) disproportionately affects organ transplant recipients, and may be related to increased viral replication in the setting of immune suppression. We conducted a nested case-control study among transplant recipients to determine whether SCSC is associated with antibodies to cutaneous human papillomaviruses (HPV), to genes associated with a rare genetic susceptibility to HPV (TMC6/TMC8), or to human polyomaviruses (HPyV). Cases (n = 149) had histologically confirmed SCSC, and controls (n = 290) were individually matched to cases on time since transplant, type of transplant, gender, and race. All subjects had serum drawn immediately prior to transplant surgery. Antibodies to 25 cutaneous HPVs and six HPyVs were assayed by detection of binding to virus-like particles, and 11 TMC6/8 variants were genotyped. After correction for multiple comparisons, only antibodies to HPV37 were associated with SCSC (OR 2.0, 95% CI 1.2-3.4). Common genetic variants of TMC6/8 were not associated with SCSC, but three variants in TMC8 (rs12452890, rs412611, and rs7208422) were associated with greater seropositivity for species 2 betapapillomaviruses among controls. This study suggests that some betaHPVs, but not polyomaviruses, may play a role in the excess risk of SCSC among transplant recipients.

Outcomes of simultaneous liver and kidney transplantation in relation to a high level of preformed donor-specific antibodies.

BACKGROUND: The protective effect of the liver allograft when simultaneously transplanted with a kidney in the setting of allosensitization is unclear. METHODS: We analyzed the significance of sensitization, defined based on positive cytotoxicity crossmatches, positive flow cytometry crossmatches, and/or the presence of high levels of donor-specific antibodies, on the outcomes of simultaneous liver and kidney (SLK) transplantation. We reviewed 56 SLK performed at our center through December 31, 2011 and identified 13 patients who met high sensitization criteria. RESULTS: Median patient survival was not significantly different: 86 months (95% confidence interval [CI], 47-135) for nonsensitized patients versus 151 months (95% CI, 4 to ∞) for sensitized patients (P=0.5). The 5-year survival was 67% (95% CI, 0.5-0.8) in the nonsensitized group and 64% (95% CI, 0.3-0.9) in the sensitized group. There were six renal allograft failures in the nonsensitized group but none in the sensitized group. The adjusted hazard ratios associated with the risk of death or the combined risk of death or renal allograft failure were 0.7 (95% CI, 0.1-3.8) and 0.4 (95% CI, 0.1-2.2) for sensitized versus nonsensitized patients. There were significantly more renal allograft rejections in the sensitized group (5 vs. 1; P=0.002) in the first year after transplantation, only one showing C4d positivity. Creatinine levels at 1 year after transplantation were similar: 1.5 mg/dL in the nonsensitized group versus 1.36 mg/dL in the sensitized group (P=0.6). CONCLUSION: Sensitization does not appear to have a significant negative impact on the survival of SLK patients.

Inhibition of CYP2C19 and CYP3A4 by omeprazole metabolites and their contribution to drug-drug interactions.

The aim of this study was to evaluate the contribution of metabolites to drug-drug interactions (DDI) using the inhibition of CYP2C19 and CYP3A4 by omeprazole and its metabolites as a model. Of the metabolites identified in vivo, 5-hydroxyomeprazole, 5'-O-desmethylomeprazole, omeprazole sulfone, and carboxyomeprazole had a metabolite to parent area under the plasma concentration-time curve (AUC(m)/AUC(p)) ratio ≥ 0.25 when either total or unbound concentrations were measured after a single 20-mg dose of omeprazole in a cocktail. All of the metabolites inhibited CYP2C19 and CYP3A4 reversibly. In addition omeprazole, omeprazole sulfone, and 5'-O-desmethylomeprazole were time dependent inhibitors (TDI) of CYP2C19, whereas omeprazole and 5'-O-desmethylomeprazole were found to be TDIs of CYP3A4. The in vitro inhibition constants and in vivo plasma concentrations were used to evaluate whether characterization of the metabolites affected DDI risk assessment. Identifying omeprazole as a TDI of both CYP2C19 and CYP3A4 was the most important factor in DDI risk assessment. Consideration of reversible inhibition by omeprazole and its metabolites would not identify DDI risk with CYP3A4, and with CYP2C19, reversible inhibition values would only identify DDI risk if the metabolites were included in the assessment. On the basis of inactivation data, CYP2C19 and CYP3A4 inhibition by omeprazole would be sufficient to identify risk, but metabolites were predicted to contribute 30-63% to the in vivo hepatic interactions. Therefore, consideration of metabolites may be important in quantitative predictions of in vivo DDIs. The results of this study show that, although metabolites contribute to in vivo DDIs, their relative abundance in circulation or logP values do not predict their contribution to in vivo DDI risk.

Tacrolimus placental transfer at delivery and neonatal exposure through breast milk.

AIM(S): The current investigation aims to provide new insights into fetal exposure to tacrolimus in utero by evaluating maternal and umbilical cord blood (venous and arterial), plasma and unbound concentrations at delivery. This study also presents a case report of tacrolimus excretion via breast milk. METHODS: Maternal and umbilical cord (venous and arterial) samples were obtained at delivery from eight solid organ allograft recipients to measure tacrolimus and metabolite bound and unbound concentrations in blood and plasma. Tacrolimus pharmacokinetics in breast milk were assessed in one subject. RESULTS: Mean (±SD) tacrolimus concentrations at the time of delivery in umbilical cord venous blood (6.6 ± 1.8 ng ml(-1)) were 71 ± 18% (range 45-99%) of maternal concentrations (9.0 ± 3.4 ng ml(-1)). The mean umbilical cord venous plasma (0.09 ± 0.04 ng ml(-1)) and unbound drug concentrations (0.003 ± 0.001 ng ml(-1)) were approximately one fifth of the respective maternal concentrations. Arterial umbilical cord blood concentrations of tacrolimus were 100 ± 12% of umbilical venous concentrations. In addition, infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight-adjusted dose. CONCLUSIONS: Differences between maternal and umbilical cord tacrolimus concentrations may be explained in part by placental P-gp function, greater red blood cell partitioning and higher haematocrit levels in venous cord blood. The neonatal drug exposure to tacrolimus via breast milk is very low and likely does not represent a health risk to the breastfeeding infant.

Kidney transplant chains amplify benefit of nondirected donors.

IMPORTANCE: Despite the potential for altruistic nondirected donors (NDDs) to trigger multiple transplants through nonsimultaneous transplant chains, concerns exist that these chains siphon NDDs from the deceased donor wait list and that donors within chains might not donate after their partner receives a transplant. OBJECTIVE: To determine the number of transplantations NDDs trigger through chains. DESIGN: Retrospective review of large, multicenter living donor-recipient database. SETTING: Fifty-seven US transplant centers contributing donor-recipient pairs to the database. PARTICIPANTS: The NDDs initiating chain transplantation. MAIN OUTCOMES MEASURE: Number of transplants per NDD. RESULTS: Seventy-seven NDDs enabled 373 transplantations during 46 months starting February 2008. Mean chain length initiated by NDDs was 4.8 transplants (median, 3; range, 1-30). The 40 blood type O NDDs triggered a mean chain length of 6.0 (median, 4; range, 2-30). During the interval, 66 of 77 chains were closed to the wait list, 4 of 77 were ongoing, and 7 of 77 were broken because bridge donors became unavailable. No chains were broken in the last 15 months, and every recipient whose incompatible donor donated received a kidney. One hundred thirty-three blood type O recipients were transplanted. CONCLUSION AND RELEVANCE: This large series demonstrates that NDDs trigger almost 5 transplants on average, more if the NDD is blood type O. There were more blood type O recipients than blood type O NDDs participating. The benefits of transplanting 373 patients and enabling others without living donors to advance outweigh the risk of broken chains that is decreasing with experience. Even 66 patients on the wait list without living donors underwent transplantation with living-donor grafts at the end of these chains.

Living-donor follow-up attitudes and practices in U.S. kidney and liver donor programs.

BACKGROUND: Although U.S. transplantation programs must submit living-donor follow-up data through 2 years after donation, the submissions have high rates of incomplete or missing data. It is important to understand barriers programs face in collecting follow-up information. METHODS: Two hundred thirty-one programs performing living kidney donor (LKD) and/or living liver donor (LLD) transplantation were contacted to complete a survey about program attitudes concerning donor follow-up, follow-up practices, and barriers to success. RESULTS: Respondents representing 147 programs (111 with only LKD and 36 with both LKD and LLD) participated. Sixty-eight percent of LKD and 83% of LLD respondents said that achieving follow-up was a high priority. The majority agreed that donors should be followed at least 2 years (61% LKD programs and 73% LLD programs), and sizeable percentages (31% LKD and 37% LLD) endorsed 5 years of follow-up. However, approximately 40% of programs lost contact with more than 75% of their donors by 2 years after donation. Follow-up barriers included donors not wanting to return to the program (87%), out-of-date contact information (73%), and lack of program (54%) or donor (49%) reimbursement for follow-up costs. Whereas 92% of LKD and 96% of LLD programs inform potential donors about follow-up requirements, fewer (67% LKD and 78% LLD) develop plans with donors to achieve follow-up. CONCLUSIONS: Most respondents agree that donor follow-up is important, but they report difficulty achieving it. Improvements may occur if programs work with donors to develop plans to achieve follow-up, programmatic standards are set for completeness in follow-up data reporting, and sufficient staff resources are available to ensure ongoing post-donation contact.

Interpreting tacrolimus concentrations during pregnancy and postpartum.

Pregnancy after solid organ transplantation, although considered high risk for maternal, fetal, and neonatal complications, has been quite successful. Tacrolimus pharmacokinetic changes during pregnancy make interpretation of whole blood trough concentrations particularly challenging. There are multiple factors that can increase the fraction of unbound tacrolimus, including but not limited to low albumin concentration and low red blood cell count. The clinical titration of dosage to maintain whole blood tacrolimus trough concentrations in the usual therapeutic range can lead to elevated unbound concentrations and possibly toxicity in pregnant women with anemia and hypoalbuminemia. Measurement of plasma or unbound tacrolimus concentrations for pregnant women might better reflect the active form of the drug, although these are technically challenging and often unavailable in usual clinical practice. Tacrolimus crosses the placenta with in utero exposure being approximately 71% of maternal blood concentrations. The lower fetal blood concentrations are likely due to active efflux transport of tacrolimus from the fetus toward the mother by placental P-glycoprotein. To date, tacrolimus has not been linked to congenital malformations but can cause reversible nephrotoxicity and hyperkalemia in the newborn. In contrast, very small amounts of tacrolimus are excreted in the breast milk and are unlikely to elicit adverse effects in the nursing infant.

Urine IL-18, NGAL, IL-8 and serum IL-8 are biomarkers of acute kidney injury following liver transplantation.

BACKGROUND: AKI is common following liver transplantation and is associated with significant morbidity and mortality. Biomarkers of AKI have not been well established in this setting but are needed to help guide patient care and facilitate development of novel therapeutics. METHODS: Serum creatinine, cystatin C, IL-6, and IL-8 and urine IL-18, NGAL, IL-6, and IL-8 were measured before and within 24 hours after liver transplantation in 40 patients. AKI was defined as a ≥50% sustained increase in creatinine above pre-operative values occurring within 24 hours of transplantation and persisting for at least 24 hours. RESULTS: Seven patients met criteria for AKI (17.5%), with mean creatinines of 0.81 mg/dL pre-operatively and 1.75 mg/dL post-operatively. While pre-operative biomarker levels in patients with AKI were similar to those in patients without AKI, differences were seen between the groups with regard to median post-operative serum IL-8 (pg/mL) (242.48 vs. 82.37, p = 0.0463) and urine NGAL (ng/mL) (386.86 vs. 24.31, p = 0.0039), IL-6 (pg/mL) (52 vs. 7.29, p=0.0532), IL-8 (pg/mL) (14.3 vs. 0, p = 0.0224), and IL-18 (pg/mL) (883.09 vs. 0, p = 0.0449). The areas under receiver operating characteristic (ROC) curves were 0.749 for urine IL-18, 0.833 for urine NGAL, 0.745 for urine IL-6, 0.682 for serum IL-6, 0.773 for urine IL-8, and 0.742 for serum IL-8. Post-operative cystatin C was not significantly different between AKI and no AKI groups. CONCLUSION: Serum IL-8 and urine IL-18, NGAL, IL-6, and IL-8 are elevated in AKI within the first 24 hours following liver transplantation.

CYP3A5 gene variation influences cyclosporine A metabolite formation and renal cyclosporine disposition.

BACKGROUND: Higher concentrations of AM19 and AM1c9, secondary metabolites of cyclosporine A (CsA), have been associated with nephrotoxicity in organ transplant patients. The risk of renal toxicity may depend on the accumulation of CsA and its metabolites in the renal tissue. We evaluated the hypothesis that CYP3A5 genotype, and inferred enzyme expression, affects systemic CsA metabolite exposure and intrarenal CsA accumulation. METHODS: An oral dose of CsA was administered to 24 healthy volunteers who were selected based on their CYP3A5 genotype. CsA and its six main metabolites in whole blood and urine were measured by liquid chromatography-mass spectometry. In vitro incubations of CsA, AM1, AM9, and AM1c with recombinant CYP3A4 and CYP3A5 were performed to evaluate the formation pathways of AM19 and AM1c9. RESULTS: The mean CsA oral clearance was similar between CYP3A5 expressors and nonexpressors. However, compared with CYP3A5 nonexpressors, the average blood area under the concentration-time curve (AUC) for AM19 and AM1c9 was 47.4% and 51.3% higher in CYP3A5 expressors (P=0.040 and 0.011, respectively), corresponding to 30% higher AUCmetabolite/AUCCsA ratios for AM19 and AM1c9 in CYP3A5 expressors. The mean apparent urinary CsA clearance based on a 48-hr collection was 20.4% lower in CYP3A5 expressors compared with CYP3A5 nonexpressors (4.2±1.0 and 5.3±1.3 mL/min, respectively; P=0.037), which is suggestive of CYP3A5-dependent intrarenal CsA metabolism. CONCLUSIONS: At steady state, intrarenal accumulation of CsA and its secondary metabolites should depend on the CYP3A5 genotype of the liver and kidneys. This may contribute to interpatient variability in the risk of CsA-induced nephrotoxicity.

Cohort profile: the skin cancer after organ transplant study.

The Skin Cancer after Organ Transplant (SCOT) study was designed to investigate the link between genus beta human papillomavirus (HPV) and squamous cell skin cancer (SCSC). We focused on a population receiving immunosuppressive therapy for extended periods, transplant patients, as they are at extremely high risk for developing SCSC. Two complementary projects were conducted in the Seattle area: (i) a retrospective cohort with interview data from 2004 recipients of renal or cardiac transplants between 1995 and 2010 and (ii) a prospective cohort with interview data from 328 people on the transplant waiting lists between 2009 and 2011. Within the retrospective cohort, we developed a nested case-control study (172 cases and 337 control subjects) to assess risk of SCSC associated with markers of HPV in SCSC tumour tissue and eyebrow hair bulb DNA (HPV genotypes) and blood (HPV antibodies). In the prospective cohort, 135 participants had a 1-year post-transplant visit and 71 completed a 2-year post-transplant visit. In both arms of the cohort, we collected samples to assess markers of HPV infection such as acquisition of new types, proportion positive for each type, persistence of types at consecutive visits and number of HPV types detected. In the prospective cohort, we will also examine these HPV markers in relation to levels of cell-mediated immunity. The goal of the SCOT study is to use the data we collected to gain a more complete understanding of the role of immune suppression in HPV kinetics and of genus beta HPV types in SCSC. For more information, please contact the principal investigator through the study website: http://www.fhcrc.org/science/phs/cerc/The_SCOT_Study.html.

Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3 through CYP3A4 induction in vitro and in vivo: implications for drug-induced osteomalacia.

Long-term therapy with certain drugs, especially cytochrome P450 (P450; CYP)-inducing agents, confers an increased risk of osteomalacia that is attributed to vitamin D deficiency. Human CYP24A1, CYP3A4, and CYP27B1 catalyze the inactivation and activation of vitamin D and have been implicated in the adverse drug response. In this study, the inducibility of these enzymes and monohydroxylation of 25-hydroxyvitamin D3 (25OHD3) were evaluated after exposure to P450-inducing drugs. With human hepatocytes, treatment with phenobarbital, hyperforin, carbamazepine, and rifampin significantly increased the levels of CYP3A4, but not CYP24A1 or CYP27B1 mRNA. In addition, rifampin pretreatment resulted in an 8-fold increase in formation of the major metabolite of 25OHD3, 4ß,25(OH)2D3. This inductive effect was blocked by the addition of 6',7'-dihydroxybergamottin, a selective CYP3A4 inhibitor. With human renal proximal tubular HK-2 cells, treatment with the same inducers did not alter CYP3A4, CYP24A1, or CYP27B1 expression. 24R,25(OH)2 D3 was the predominant monohydroxy metabolite produced from 25OHD3, but its formation was unaffected by the inducers. With healthy volunteers, the mean plasma concentration of 4ß,25(OH)2D3 was increased 60% (p < 0.01) after short-term rifampin administration. This was accompanied by a statistically significant reduction in plasma 1α,25(OH)2D3 (-10%; p = 0.03), and a nonsignificant change in 24R,25(OH)2D3 (-8%; p = 0.09) levels. Further analysis revealed a negative correlation between the increase in 4ß,25(OH)2D3 and decrease in 1α,25(OH)2D3 levels. Examination of the plasma monohydroxy metabolite/25OHD3 ratios indicated selective induction of the CYP3A4-dependent 4ß-hydroxylation pathway of 25OHD3 elimination. These results suggest that induction of hepatic CYP3A4 may be important in the etiology of drug-induced osteomalacia.

Pharmacokinetics of tacrolimus during pregnancy.

BACKGROUND: Information on the pharmacokinetics of tacrolimus during pregnancy is limited to case reports despite the increasing number of pregnant women being prescribed tacrolimus for immunosuppression. METHODS: Blood, plasma, and urine samples were collected over 1 steady-state dosing interval from women treated with oral tacrolimus during early to late pregnancy (n = 10) and postpartum (n = 5). Total and unbound tacrolimus as well as metabolite concentrations in blood and plasma were assayed by a validated liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) method. A mixed-effect linear model was used for comparison across gestational age and using postpartum as the reference group. RESULTS: The mean oral clearance (CL/F) based on whole-blood tacrolimus concentration was 39% higher during mid-pregnancy and late pregnancy compared with postpartum (47.4 ± 12.6 vs. 34.2 ± 14.8 L/h, P < 0.03). Tacrolimus-free fraction increased by 91% in plasma (f(P)) and by 100% in blood (f(B)) during pregnancy (P = 0.0007 and 0.002, respectively). Increased fP was inversely associated with serum albumin concentration (r = -0.7, P = 0.003), which decreased by 27% during pregnancy. Pregnancy-related changes in f(P) and f(B) contributed significantly to the observed gestational increase in tacrolimus whole-blood CL/F (r² = 0.36 and 0.47, respectively, P < 0.01). In addition, tacrolimus whole-blood CL/F was inversely correlated with both hematocrit and red blood cell counts, suggesting that binding of tacrolimus to erythrocytes restricts its availability for metabolism. Treating physicians increased tacrolimus dosages in study participants during pregnancy by an average of 45% to maintain tacrolimus whole-blood trough concentrations in the therapeutic range. This led to striking increases in unbound tacrolimus trough concentrations and unbound area under the concentration-time curve, by 112% and 173%, respectively, during pregnancy (P = 0.02 and 0.03, respectively). CONCLUSIONS: Tacrolimus pharmacokinetics are altered during pregnancy. Dose adjustment to maintain whole-blood tacrolimus concentration in the usual therapeutic range during pregnancy increases circulating free drug concentrations, which may impact clinical outcomes.