Background Early in the history of kidney transplantation, short-term graft survival was low. Yet some have had excellent long-term survival. Herein, we describe characteristics of pediatric recipients with > 40 years of graft survival currently alive with a functioning first graft.Methods We reviewed all pediatric (age < 18 years) kidney transplants performed at the University of Minnesota between January 1, 1970, and December 31, 1979 (n = 148), to identify all recipients currently alive with a functioning first graft. Data are presented as medians with interquartile ranges (IQR) and proportions.Results We identified 10 recipients with > 40-year graft survival (median follow-up: 45.0 years (IQR: 43.1, 48.1)). The median age at transplant was 13.8 years (IQR: 5.1, 16.3). All recipients were white; half were male. Of the 10, 4 had glomerulonephritis, 2 had congenital anomalies of the kidney and the urinary tract, 2 had congenital nephrotic syndrome, 1 had Alport syndrome, and 1 had cystic kidney disease as kidney failure cause. Nine patients received a living-related donor transplant, and 1 patient received a deceased-donor transplant. The median estimated glomerular filtration rate at 20 years post-transplant was 79.9 (IQR: 72.3, 98.4); at 30 years, 67.7 (IQR: 63.2, 91.8); and at 40 years, 80.3 ml/min/1.73 m(2) (IQR: 73.7, 86.0). None developed rejection, 5 developed hypertension, 2 developed dyslipidemia, 1 developed diabetes, and 7 patients developed malignancy (4 skin cancer, 2 breast cancer, and 1 post-transplant lymphoproliferative disease).Conclusion Pediatric kidney transplant recipients may achieve > 4 decades of graft survival. Cancer is a common complication warranting vigilant screening.

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.

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.

BackgroundNonadherence 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.MethodsBetween August 1998 and August 2006, 195 consenting kidney transplant recipients had electronic monitoring of theirimmunosuppressive medication adherence.ResultsBased 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).ConclusionsThese data provide additional support for the need to individualize immunosuppression to minimize both rejection and immunosuppressive drug-related complications including cancer.

In adults on chronic hemodialysis, achieving a hemoglobin concentration of 12g/dl and above with erythropoiesis stimulating agents leads to increased cardiovascular events and mortality, but this may not be true in children. Therefore, we conducted a retrospective cohort study of pediatric patients (under 18) from the Centers for Medicare and Medicaid Services End Stage Renal Disease (ESRD) Clinical Performance Measures (CPM) project (2000 to 2008) merged with the United States Renal Data System. Hemoglobin was determined from the Clinical Performance Measures data, and beginning annually on January 1st of the next year, patients were followed for up to 1 year. We determined the outcomes (mortality, hospitalization, and cardiovascular events) during follow-up by hemoglobin group at baseline. Models were adjusted for demographic and clinical characteristics of 1569 children studied. The hemoglobin 12 g/dl and above group was older, had fewer years of ESRD, and was more often transplanted. Inpatient and outpatient visits for congestive heart failure, cardiomyopathy, and valvular heart disease were most common in the hemoglobin under 10g/dl group and the frequency of these diagnoses decreased with increasing hemoglobin. The hazard ratio of all-cause mortality (0.33, 95% confidence interval 0.14-0.81) and the adjusted relative rate of all-cause hospitalizations (0.81, 0.74-0.89) were significantly lower in the hemoglobin 12 g/dl and above group. Cardiovascular hospitalizations were significantly higher in the hemoglobin under 10g/dl group (1.31, 1.05-1.64). Thus, in children on hemodialysis, hemoglobin 12g/dl and above is not associated with increased cardiovascular visits, mortality, or all-cause and cardiovascular-related hospitalizations.

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.

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.

BACKGROUND: Advances in immunosuppression, surgical techniques, and management of infections in children receiving kidney transplants have affected outcomes.STUDY DESIGN: We analyzed a prospectively maintained database of pediatric kidney transplantations.RESULTS: From June 1963 through October 2016, we performed 1,056 pediatric kidney transplantations. Of these, 129 were in children less than 2 years old. The most common indications for transplant were congenital anomalies (dysplastic kidneys), obstructive uropathy, and congenital nephrotic syndrome. Living donors constituted 721 (68%) of all donors. The graft and patient survival rates remarkably improved for both deceased and living donor recipients (p = 0.001). Currently, graft survival rates for deceased donor recipients are 92% at 1 year, 76% at 5 years, and 57% at 10 years post-transplant; for living donor recipients, 96% at 1 year, 85% at 5 years, and 78% at 10 years. The graft half-life was 19 years in deceased donor recipients, compared with 25 years in living donor recipients (p <= 0.001). Acute rejection was the most common cause of graft loss in the first year post-transplant. The following risk factors were associated with an increased risk of graft loss: deceased donor grafts (p = 0.0001), retransplant (p = 0.02), ages 11 to 18 years (p = 0.001) and pre-transplant urologic issues (p 0.04). Living donor grafts (p <= 0.0001) and pre-emptive transplants (p = 0.02) were associated with decreased risks of graft loss.CONCLUSIONS: The success rates of pediatric kidney transplants have significantly improved. Pre-emptive kidney transplantation with a living donor graft continues to be superior and should be the choice in children with end-stage renal disease. (C) 2017 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved.

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.

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.

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.

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 r polymerase chain reaction. NONMEM r 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.

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 (≥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.

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.

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.

BACKGROUND Successful renal transplantation requires long-term adherence to complex medical regimens, yet knowledge of post-transplant medication compliance is still inadequate. METHODS The natural history of medication compliance was quantitatively documented using electronic medicine bottle monitors. Azathioprine use was recorded with medication monitors beginning at hospital discharge in a prospective cohort of 180 renal transplant recipients. These patients and 87 other eligible patients, declining study participation, were followed up to five years. Compliance rates were associated with discrete clinical outcomes: acute rejection, allograft loss, and death. RESULTS During the first six months, only 8% of all azathioprine doses were missed. However, individual compliance rates varied widely, ranging from 16 to 100%, and each month, on average, 18% of patients skipped medication for four or more days. Outcome events were not different between study participants and those refusing study. However, lower compliance rates during the first six months were associated in a "dose-response" fashion with acute rejection (P = 0.006) and allograft loss (P = 0.002). Declining compliance during the first 90 days was a strong risk factor both for later acute rejection (odds ratio = 13.9, 95% CI, 2.9 to 68, P = 0.001), and allograft loss (odds ratio = 4.3, 95% CI, 1.1 to 16, P = 0.032). CONCLUSIONS Electronic monitoring provides a temporal description and quantitation of medication compliance. Reduced azathioprine compliance was highly associated with acute rejection and allograft loss. Trends in early compliance behavior predict later outcomes, thus providing unique opportunities for intervention.

Infants are thought to be more immunoreactive and at a greater risk for developing irreversible rejection compared with older children. We investigated this by analyzing patient and graft survival rates, incidence of acute rejection, reversibility of acute rejection, development of a subsequent acute rejection, and incidence of graft loss due to rejection in 154 children (<18 years of age) after primary renal transplantation. Most patients (n = 139) were treated with quadruple immunosuppression (antibody, azathioprine, prednisone, cyclosporine). Treatment of the first acute rejection episode (ARE) consisted of antibody and increased prednisone (68%) or increased prednisone alone (30%), and was not significantly different between the age groups. Transplants were from living donors (LRD) in 80% of cases. Patients were followed for at least 1 year (mean 58±30 months); 68% (105/154) of recipients experienced 1 or more ARE. The incidence of ARE was significantly lower in patients <2 years of age (45%) compared with patients 2 – 5 (76%, P = 0.01), 6 – 12 (78%, P = 0.005), and 13 – 17 (76%, P = 0.009) years of age. There was no significant difference in the 1-, 2- and 5-year patient or graft survival rates, the development of a subsequent acute rejection, or the incidence of graft loss due to acute rejection when analyzed by age group. These data suggest that the impact of an ARE is similar for younger and older children in our population receiving predominantly LRD transplants and quadruple immunosuppression.

Recent evidence suggests that treatment with recombinant human growth hormone (rhGH) after a successful kidney transplant improves the growth rate of children with short stature. We prospectively investigated eight children (6 boys, 2 girls), focusing on acute rejection episodes and changes in serum creatinine levels during rhGH treatment. The children (mean age 11.6 +/- 3.4 years) received rhGH daily (0.04-0.05 mg/kg subcutaneously). Seven patients completed at least 12 months (20 +/- 8 months) of rhGH treatment. Their mean serum creatinine level was 1.3 +/- 0.7 mg/dl 12 months before, and increased to 3.4 +/- 4.2 mg/dl after 12 months of rhGH treatment, but did not achieve statistical significance (P = 0.06). Their mean calculated glomerular filtration rate was 58 +/- 20 ml/min per 1.73 m2 12 months before, and decreased to 38 +/- 21 ml/min per 1.73 m2 after 12 months of rhGH treatment, but did not achieve statistical significance (P = 0.08). Of the seven patients, two developed acute rejection after 5 and 6 rejection-free years; three lost their grafts and returned to dialysis. These preliminary observations describe untoward renal events in children receiving rhGH treatment after a kidney transplant.