Depression, Quantified Medication Adherence, and Quality of Life in Renal Transplant Candidates and Recipients.

Like patients with many chronic illnesses, ESRD patients experience psychological challenges with greater incidence of depression and reduced quality of life (QoL). A series of 139 transplant candidates' depression and QoL, and a subset of 82 candidates' medication adherence were monitored, revealing heterogenous patterns of depression and adherence and reduced QoL. Twenty-eight patients who received kidney transplants were re-evaluated 6 months post-transplant revealing mixed patterns. Mean depression and quantitated adherence decreased and QoL increased. Some patients improved whereas others declined in depression and adherence. Pre-transplant depression was negatively correlated with post-transplant adherence but positively correlated with post-transplant depression. Nevertheless, the ability to predict individuals' post-transplant adherence and depression, principal objectives of pre-transplant psychological evaluations, is limited. Consequently, it is important to provide periodic screening of ESRD patients for depression and adherence pre- and post-transplant as they reflect changing states, rather than static traits, with variable patterns across patients.

Medication adherence is associated with an increased risk of cancer in kidney transplant recipients: a cohort study.

Background: Nonadherence to posttransplant immunosuppressive medication is associated with increased rates of rejection and graft loss, yet it is unknown to what degree ideal adherence is associated with the sequelae of overimmunosuppression. Specifically, we questioned whether excellent adherence increased the posttransplant cancer risk. Methods: Between August 1998 and August 2006, 195 consenting kidney transplant recipients had electronic monitoring of theirimmunosuppressive medication adherence. Results: Based on their average quantitative adherence to a single immunosuppressant drug over the first 6 months posttransplant, recipients were grouped into adherence tertiles (highest, >97.9% adherence; middle, 91-97.8%; lowest, <91%). The cumulative incidence of cancer was calculated for patients in each tertile, treating death as a competing risk. The association between adherence and cancer rate was calculated after adjusting for recipient risk factors, using a competing risk proportional hazards model. The median duration of follow-up was 10.1 years. The 10-year estimated cumulative cancer incidence was 59.4% in the most adherent, 36.1% in the middle group and 38.1% in the least adherent group (P = 0.006). Excluding nonmelanocytic skin cancers, cancer incidence remained significantly higher in the highest adherence group (P = 0.002). Conclusions: These data provide additional support for the need to individualize immunosuppression to minimize both rejection and immunosuppressive drug-related complications including cancer.

Improved Outcomes of Kidney Transplantation in Infants (Age < 2 years): A Single-Center Experience.

BACKGROUND: Infants (age, < 2 years) with end-stage renal disease (ESRD) have increased morbidity and mortality. We evaluated our long-term outcomes of kidney transplants (KTx) in infants. METHODS: Between 1984 and 2014, 136 infants underwent KTx. We examined trends in survival rates and complications by era (1984-1993 [era 1], 1994-2003 [era 2], 2004-2014 [era 3]). RESULTS: Patients were 92.6% white and 70.6% males. Posttransplant (Tx) initial length of hospital stay declined 37% over the 30-year period (P <0.01). Ten-year death-censored graft survival improved from 60% (era 1) to 80% (era 2) (P = 0.04). The incidence of acute rejection, graft thrombosis, cytomegalovirus, and urine leaks did not significantly change across eras. Frequency of Epstein-Barr virus diagnosis (era 2 vs era 3, P < 0.01) increased. Post-Tx lymphoproliferative disorder incidence was increased in era 2 compared with eras 1 and 3 (P = 0.03). CONCLUSIONS: Infants deserve earlier consideration for KTx. Length of initial hospital stay and patient and graft survival rates after KTx have improved in infants since 1984.

Class II Eplet Mismatch Modulates Tacrolimus Trough Levels Required to Prevent Donor-Specific Antibody Development.

Despite more than two decades of use, the optimal maintenance dose of tacrolimus for kidney transplant recipients is unknown. We hypothesized that HLA class II de novo donor-specific antibody (dnDSA) development correlates with tacrolimus trough levels and the recipient's individualized alloimmune risk determined by HLA-DR/DQ epitope mismatch. A cohort of 596 renal transplant recipients with 50,011 serial tacrolimus trough levels had HLA-DR/DQ eplet mismatch determined using HLAMatchmaker software. We analyzed the frequency of tacrolimus trough levels below a series of thresholds <6 ng/ml and the mean tacrolimus levels before dnDSA development in the context of HLA-DR/DQ eplet mismatch. HLA-DR/DQ eplet mismatch was a significant multivariate predictor of dnDSA development. Recipients treated with a cyclosporin regimen had a 2.7-fold higher incidence of dnDSA development than recipients on a tacrolimus regimen. Recipients treated with tacrolimus who developed HLA-DR/DQ dnDSA had a higher proportion of tacrolimus trough levels <5 ng/ml, which continued to be significant after adjustment for HLA-DR/DQ eplet mismatch. Mean tacrolimus trough levels in the 6 months before dnDSA development were significantly lower than the levels >6 months before dnDSA development in the same patients. Recipients with a high-risk HLA eplet mismatch score were less likely to tolerate low tacrolimus levels without developing dnDSA. We conclude that HLA-DR/DQ eplet mismatch and tacrolimus trough levels are independent predictors of dnDSA development. Recipients with high HLA alloimmune risk should not target tacrolimus levels <5 ng/ml unless essential, and monitoring for dnDSA may be advisable in this setting.

Understanding Medication Nonadherence after Kidney Transplant.

Alloimmunity remains a barrier to long-term graft survival that necessitates lifelong immunosuppressive therapy after renal transplant. Medication nonadherence has been increasingly recognized as a major impediment to achieving effective immunosuppression. Electronic medication monitoring further reveals that nonadherence manifests early after transplant, although the effect is delayed. The etiology of nonadherence is multifactorial, with the strongest risk factors including past nonadherence and being an adolescent or young adult. Other risk factors with smaller but consistently important effects include minority race/ethnicity, poor social supports, and poor perceived health. In children, risk factors related to parental and child psychologic and behavioral functioning and parental distress and burden are also important. Qualitative systematic reviews highlight the need to tailor interventions to each transplant recipient's unique needs, motivations, and barriers rather than offer a one size fits all approach. To date, relatively few interventions have been studied, and most studies conducted were underpowered to allow definitive conclusions. If the kidney transplant community's goal of "one transplant for life" is to become a reality, then solutions for medication nonadherence must be found and implemented.

Desirability and feasibility of wireless electronic monitoring of medications in clinical trials.

Medication nonadherence is a vexing problem in health care necessitating patients and health professionals' efforts to prevent, minimize, or reverse it. Research participants' inconsistent medication taking obscures treatment efficacy and adds costs to biomedical research. Electronic monitoring devices (EMDs), like the Medication Event Monitoring System (MEMS), have grown in sophistication, providing precise, timely insights into individuals' medication-taking patterns across clinical populations. This article reports on the desirability and feasibility study of using a wireless EMD in clinical research to promote adherence to clinical regimens and research protocols. Nonadherence in transplant patients has been linked to late acute rejection and graft loss. High levels of adherence (97.7 %) were documented for six renal transplant recipients for a mean of 6 months (M = 196.1 ± 71.2 days) who indicated acceptance of the technology. MEMS data confirmed the feasibility of using wireless EMDs to monitor medication use. Monitoring provides greater assurance that research studies reflect the biological impact of medications and provide a basis for targeting adherence enhancement efforts within research investigations.

Predictive patterns of early medication adherence in renal transplantation.

BACKGROUND: Patients' adherence with posttransplant immunosuppression is known to affect renal transplant outcomes. METHODS: Prospectively, individual medication adherence patterns in 195 kidney transplant recipients were quantified with electronic medication monitors. Monitored drugs were mycophenolate mofetil, sirolimus, or azathioprine. Monitoring began at hospital discharge and continued an average of 15±8 months. Patient follow-up for clinical outcomes averaged 8±3 years. Each month's adherence percentage was calculated as the sum of daily adherence percents, divided by the number of evaluable days. RESULTS: During the first 3 months after transplantation, patients (n=44) with declining medication adherence, defined as dropping by 7% or higher (equal to missing 2 days) between months 1 and 2, later experienced lower mean medication adherence for months 6 to 12, 73% versus 92% respectively (P<0.0001). Compared to patients with stable adherence, they also had more frequent (P=0.034) and earlier (P=0.065) acute rejection episodes. This was additionally associated with more frequent (P=0.017) and earlier (P=0.046) death-censored graft loss.In addition, daily medication adherence, expressed as the percentage of doses taken, decreased as the number of prescribed daily doses increased. During the first 3 months after transplantation, adherence with four doses per day averaged 84%, compared to 91% for patients on twice-daily dosing (P=0.024) and 93.5% for patients on once-daily dosing (P=0.008). CONCLUSIONS: Early declining medication nonadherence is associated with adverse clinical outcomes. This pattern is detectable during the first 2 months after transplantation. Early detection of nonadherence provides opportunities to target interventions toward patients at the highest risk for adverse behaviors and events.

The pharmacokinetics of valganciclovir prophylaxis in pediatric solid organ transplant patients at risk for Epstein-Barr virus disease.

Antiviral prophylaxis with valganciclovir is used frequently in pediatric solid organ transplant patients to prevent Epstein-Barr virus (EBV)-induced infections and tissue-invasive disease including post-transplant lymphoproliferative disorder (PTLD). This approach is untested in clinical trials and valganciclovir dosing strategies in children are highly variable. Our objective was to characterize the pharmacokinetics of ganciclovir in the plasma of pediatric kidney and liver transplant patients taking valganciclovir for EBV prophylaxis. Virologic response was also evaluated. Ganciclovir was measured by liquid chromatography/ultraviolet detection. EBV DNA was quantified by TaqMan(®) polymerase chain reaction. NONMEM(®) VI was used for data analysis. Ganciclovir plasma profiles were consistent with a one-compartment model. Final model estimates of apparent oral clearance (L/h), apparent volume of distribution (L), and absorption rate constant were 7.33, 35.1, and 0.85, respectively. There was evidence of lower bioavailability in children younger than three years. All eight subjects achieved ganciclovir plasma concentrations above reported in vitro concentrations needed to inhibit EBV replication by 50%. However, four subjects had detectable EBV DNA with a median (range) of 18,300 (4,400 to 54,900) copies/mL of whole blood. These findings support the need for further studies of the clinical pharmacology and efficacy of valganciclovir for EBV prophylaxis.

Outcomes of infants <28 days old treated with peritoneal dialysis for end-stage renal disease.

This study evaluates the long-term outcomes of infants with end stage renal disease (ESRD) who required initiation of chronic peritoneal dialysis (PD) prior to 28 days of age. Infants with ESRD present both ethical and technical challenges for pediatric nephrologists and neonatologists. Recent advances in the medical management of ESRD in infants combined with improved infant transplantation outcomes make it more likely that such infants can survive to successful kidney transplantation. We reviewed all infants initiating PD for ESRD before 28 days of age at the University of Minnesota Amplatz Children's Hospital from 1995 to 2004 (n = 23). Overall 1 - and 5-year patient survival was 52 and 48%, respectively. Twelve children received kidney transplants at a median age and weight of 1.12 years and 9.5 kg, respectively, with a 5-year graft survival rate of 83%. In summary, a majority of infants requiring renal replacement therapy with PD in the first month of life achieve long-term survival with a successful kidney transplant.

Quantitative patterns of azathioprine adherence after renal transplantation.

BACKGROUND: Renal transplant recipients regularly fail to take their prescribed immunosuppressive medications, frequently leading to adverse outcomes. METHODS: Medication vials incorporating electronic monitor circuits in their caps compiled prospective data files on the azathioprine dosing patterns of 180 adult renal transplant recipients monitored up to 4 years. These patients were followed for a mean of 8.7 years posttransplantation. RESULTS: Patients were divided into three groups by the medication doses missed during the first 6 months posttransplant. These initial dosing patterns remained remarkably consistent up to 4 years. Patients (n=47) missing the most doses (>or=5%) experienced earlier and more frequent acute rejection episodes (P=0.025). This group also demonstrated significantly longer interdose intervals (P=0.005), with more frequent (P<0.001) and longer (P<0.001) "drug holidays." A patient subgroup with early declining medication adherence (n=23) experienced dramatically poorer outcomes, with significantly increased acute rejection (P<0.001), chronic rejection (P=0.034), graft loss before death (P<0.001), and death (P=0.04). In all tertiles there was a trend toward missing more medication over time. CONCLUSIONS: Excellent posttransplant medication adherence is critical to improved outcomes. Individual dosing patterns are established early after hospital discharge and remain remarkably consistent, despite gradual erosion in adherence over time. The later consequences of medication nonadherence, especially early declines in adherence, include increased frequencies of rejection, graft loss, and death.

Hematuria in children due to schistosomiasis in a nonendemic setting.

Infection with Schistosoma hematobium is common in immigrants from tropical Africa and commonly presents with painless hematuria. Since chronic, heavy infection can lead to significant morbidity, it is imperative for clinicians who serve the immigrant and refugee population to become familiar with this traditionally exotic disease. Increased awareness will allow earlier diagnosis and treatment of infection, avoiding complications and minimizing expensive and invasive diagnostic procedures.

"Why do they do that?" The compliance conundrum.

The problem of compliance or adherence with medical advice is complex in every aspect. Frequently compliance definitions vary, measurements are not well quantified, interventions are uncontrolled or not fully elaborated. Nevertheless the importance of facilitating and maximizing compliance is undeniable. As the medications available become more potent and effective, the challenge of achieving optimal medication compliance comes into sharper focus and becomes a concern for everyone involved in health care. Here some of the recent clinical research on compliance is presented together with strategies intended to improve medication compliance by pediatric patients.

Medication noncompliance: another iceberg's tip.

After renal transplantation, immunosuppressive medications must be taken long-term to avoid acute rejection and the cascade of events leading to "chronic allograft dysfunction" and loss. In the past, when posttransplant immunosuppression was limited to azathioprine and prednisone, acute rejection episodes were common, and it was difficult to identify the impact of medication noncompliance. However, with more potent and effective drugs, acute rejection is uncommon, and medication noncompliance emerges as an increasingly important factor in the outcome of solid-organ transplantation. Recent studies have clearly demonstrated that medication noncompliance leads to an increased incidence of acute rejection, chronic rejection, and graft loss. Today, although a number of questions remain unanswered, new methodologies, such as electronic monitors, provide opportunities to study medication noncompliance and its risk factors, and the potential for earlier intervention to improve clinical outcomes.

Non-compliance and its management in teenagers.

Renal transplantation restores a patient's endogenous renal function. The benefits of this restoration are especially dramatic in children. However, transplantation is a complex and expensive therapy which, when successful, requires consistent adherence to a complex regimen of drug therapy and clinical follow-up. Transplant medications need to be taken for a lifetime. Whilst very effective, immunosuppressant medications can also cause a number of side-effects and require daily multi-dose schedules. Teenagers, in particular, have problems adhering to these regimens and weighing the consequences of non-compliance. Approaches to improving teenagers' compliance must address both the special circumstances of adolescence and the broad, general problem of post-transplant non-compliance.