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Background: Pre-emptive kidney transplantation for end-stage kidney disease in children has many advantages and may lead to the consideration of marginal parent donors., Methods: Using the example of the transplant of a kidney with medullary sponge disease from a parent to the child, we review the ethical framework for working up such donors., Results: The four principles of health ethics include autonomy (the right of the patient to retain control over his/her own body); beneficence (healthcare providers must do all they can do to benefit the patient in each situation); non-maleficence ("first do no harm"-providers must consider whether other people or society could be harmed by a decision made, even if it is made for the benefit of an individual patient) and justice (there should be an element of fairness in all medical decisions). Highly motivated donors may derive significant psychological benefit from their donation and may thus be willing to incur more risk. The transplantation team and, ideally, an independent donor advocate team must make a judgment about the acceptability of the risk-benefit ratio for particular potential donors, who must also make their own assessment. The transplantation team and donor advocate team must be comfortable with the risk-benefit ratio before proceeding., Conclusions: An independent donor advocacy team that focuses on the donor needs is needed with sufficient multidisciplinary ethical, social, and psychological expertise. The decision to accept or reject the donor should be within the authority of the independent donor advocacy team and not the providers or the donor., (© 2021 Wiley Periodicals LLC.)

Background: Aortic dilatation is a cardiovascular complication in pediatric renal transplant recipients and may have an increased risk of aortic dissection, aortic rupture, and death. Studies failed to show an association between blood pressure and aortic dilatation; however, 24-hours ambulatory blood pressure monitoring (ABPM) was not performed. There was also no comparison between preemptive transplantation and dialysis., Methods: After ethics approval, a retrospective cross-sectional study was performed on all prevalent pediatric renal transplant recipients from a single tertiary care center. The presence of aortic dilatation was determined using standard echocardiographic measurements, and those with other risk factors for aortic dilatation were excluded. Associations between 24-hours ABPM, renal function, dialysis history, and aortic dimensions were determined., Results: We enrolled 37 participants with the following characteristics: 46% female, mean age 14.5 ± 3.7 years, 16% preemptive transplantation, and median end-stage renal disease (ESRD) combined vintage (time from ESRD onset to echocardiogram) 597 days (range 289-1290 days). We found 16/37 patients (43%) with aortic dilatation at any level, mostly mild. There was no association between 24-hours ABPM measurements and aortic dilatation. None of the preemptively transplanted children had aortic dilatation., Conclusion: This study confirms a high prevalence of aortic dilatation among pediatric renal transplant recipients, which appears to be independent of hypertension on 24-hour ABPM. Patients with preemptive renal transplantation did not have aortic dilatation, suggesting that the effects of dialysis may contribute to the high prevalence of this complication. Pediatric cardiologists need to carefully assess aortic dimensions in these at-risk patients., (© 2020 Wiley Periodicals LLC.)

Depression is common in pediatric chronic kidney disease (CKD) patients. Depression is associated with inferior long-term outcomes. There is a paucity of studies that evaluate depression and possible associated factors in children and adolescents requiring renal replacement therapy (RRT). Cross-sectional study using Children`s Depression Inventory in a cohort from a large urban center. Forty-seven pediatric RRT patients (26 female, 12 peritoneal dialysis (PD), 17 hemodialysis (HD), 18 after successful kidney transplantation (KTX)) with a mean age at the time of assessment of 13.9 ± 2.3 years. Symptoms of depression were found in 30 (64%, 11KTX, 11HD, 8PD) patients. We found no association with age, sex, renal function, dialysis adequacy markers, anemia, electrolytes, socioeconomical status, IQ, educational status of the child including school attendance and distance from the house to the hospital among HD patients. Significant differences only applied for age at diagnosis of CKD, RRT vintage and deceased donor for KTX. The group with depression had a higher age at diagnosis of CKD and less time on RRT than the group without depression. There was also a high rate of depression in KTX patients. In this cohort, depression was a common comorbidity of RRT in children and adolescents with RRT and also for KTX patients, even though biomarkers of kidney function and time for RRT are much improved., (© 2019 Wiley Periodicals, Inc.)

Objectives: MMA is associated with chronic tubulointerstitial nephritis and a progressive decline in GFR. Optimal management of these children is uncertain. Our objectives were to document the pre-, peri-, and post-transplant course of all children with MMA who underwent liver or combined liver-kidney transplant in our centers., Design and Methods: Retrospective chart review of all cases of MMA who underwent organ transplantation over the last 10 years., Results: Five children with MMA underwent liver transplant (4/5) and combined liver-kidney transplant (1/5). Three were Mut 0 and two had a cobalamin B disorder. Four of five were transplanted between ages 3 and 5 years. Renal dysfunction prior to transplant was seen in 2/5 patients. Post-transplant (one liver transplant and one combined transplant) renal function improved slightly when using creatinine-based GFR formula. We noticed in 2 patients a big discrepancy between creatinine- and cystatin C-based GFR calculations. One patient with no renal disease developed renal failure post-liver transplantation. Serum MMA levels have decreased in all to <300 μmol/L. Four patients remain on low protein diet, carnitine, coenzyme Q, and vitamin E post-transplant., Conclusions: MMA is a complex metabolic disorder. Renal disease can continue to progress post-liver transplant and close follow-up is warranted. More research is needed to clarify best screening GFR method in patients with MMA. Whether liver transplant alone, continued protein restriction, or the addition of antioxidants post-transplant can halt the progression of renal disease remains unclear., (© 2019 Wiley Periodicals, Inc.)

Cardiovascular disease is a frequent cause of morbidity and mortality in pediatric patients following solid organ transplant. CKD is also common in pediatric patients after a solid organ transplant, and the link between CKD and cardiovascular morbidity is strong. In this review, we examine potential etiologies to explain the risk of cardiovascular morbidity and mortality in pediatric solid organ recipients and identify targets for improving outcomes., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The management of non-renal pediatric solid organ transplant recipients has become complex over the last decade with innovations in immunosuppression and surgical techniques. Post-transplantation follow-up is essential to ensure that children have functioning allografts for as long as possible. CKD is highly prevalent in these patients, often under recognized, and has a profound impact on patient survival. These practice recommendations focus on the early detection and management of hypertension, proteinuria, and renal dysfunction in non-renal pediatric solid organ transplant recipients. We present seven practice recommendations. Renal function should be monitored regularly in organ transplant recipients, utilizing assessment of serum creatinine and cystatin C. GFR should be calculated using the new Schwartz formula. Transplant physicians should also monitor blood pressure using automated oscillometric devices and confirm repeated abnormal measures with manual blood pressure readings and ambulatory 24-h blood pressure monitoring. Proteinuria and microalbuminuria should also be assessed regularly. Referrals to a pediatric nephrologist should be made for non-renal organ transplant recipients with repeated blood pressures >95th percentile using the Fourth Task Force reference intervals, microalbumin/creatinine ratio >32.5 mg/g (3.7 mg/mmol) creatinine on repeated testing and/or GFR <90 mL/min/1.73 m(2) ., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Although de novo DSA are associated with inferior graft survival, there are no effective strategies to prevent their formation. Underexposure to MPA (prodrug: MMF) also contributes to rejection rates early after transplantation, but the effect of this phenomenon on the formation of DSA long-term post-transplantation is unknown. Data are expressed as mean (standard deviation). All available data from 32 renal transplant recipients (age at transplantation 7.5 [4.5] yr) on tacrolimus and MPA immunosuppression with an average follow-up of 9.4 (s.d. 4.6) yr were analyzed. DSA were measured using the Luminex assay (>500 MFI was considered DSA-positive). Tacrolimus and MPA levels were measured with the Abbot Tacro II and EMIT assay, respectively. Among 1964 MPA and 3462 tacrolimus trough levels, the average MPA trough level was 3.2 (1.5) mg/L and the average tacrolimus level was 6.7 (2.8) ng/mL. At last follow-up, only 5/32 patients had undetectable DSA, with 5/32 having no class I antibodies and 6/32 having no class II antibodies. DSA formation was associated with a lower minimum MPA trough level (0.27 [0.23] vs. 0.47 [0.18] mg) and cystatin C eGFR (48 [21] vs. 70 [23] mL/min/1.73 m(2)) for class I DSA formers. The average eGFR of patients without class I DSA was 70 (23) mL/min/1.73 m(2), whereas the average eGFR of patients with class I DSA was 48 (21) mL/min/1.73 m(2) (p = 0.0071). MPA trough levels <1.3 mg/L long-term post-transplantation are associated with the formation of DSA. The association between the formation of DSA and minimum MPA exposure may support a strategy for preventing the formation of DSA., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

TDM of MPA, the active compound of MMF, is rarely used despite its substantial intra- and interpatient variability. Little is known about the utility of long-term MPA TDM. Data are expressed as mean (one standard deviation). All available data from 27 renal transplant recipients (mean age at transplantation: 7.7 [5.0] yr) with an average follow-up of 9.3 (4.6) yr were analyzed. MPA levels were measured using the EMIT. GFR was measured using cystatin C and eGFR was calculated using the Filler formula. Intrapatient CV of the trough level was calculated as the ratio of the mean divided by one standard deviation. Mean cystatin C eGFR was 56.9 (24.4) mL/min/1.73 m(2) . There was a weak but significant correlation between the MPA trough level and the AUC (Spearman r = 0.6592, p < 0.0001). A total of 1964 MPA trough levels (73 [45]/patient) were measured, as compared to 3462 Tac trough levels (144 [71]/patient). The average MPA trough level was 3.01 (1.26) mg/L and the average trough Tac level was 7.3 (1.8) ng/mL. Intrapatient CV was statistically higher (p = 0.00093) for MPA at 0.68 (0.29) when compared to Tac with a CV of 0.46 (0.12). CV did not correlate with eGFR. Intrapatient MPA trough level CV is significantly higher than for Tac, while CV for both MPA and Tac was high. MPA trough level monitoring may be a feasible monitoring option to improve patient exposure and possibly outcomes., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Management of late humoral rejection remains challenging, and DSA may persist. A case report illustrates how individual DSA titers using solid-phase-based assays may help to assess for accommodation. A male cystinosis patient received a cadaveric renal transplant at the age of 12 yr with a daclizumab, tacrolimus, MMF, and steroids-based immunosuppression. After three acute rejection episodes over the first eight months, interstitial fibrosis/tubular atrophy (IF/TA) was diagnosed on biopsy, while the immunosuppression was left unchanged with a high target exposure for both tacrolimus and MPA. One yr later, AMR type III (C4d and DSA positive) was treated with daily plasmapheresis, IVIG 100 mg/kg and pulse steroids 5 mg/kg. DSA (DR 53, DQ4, and DQ 2) were not responding until the plasma volume was increased to 2.5 plasma volumes. A second rise of creatinine confirmed worse humoral rejection; daily plasma exchange was resumed, and two doses of rituximab (375 mg/m(2)) were given. Subsequently, all DSA dropped, but only DR53 DSA remained unchanged, whereas the DQ antibodies rebounded to very strong titers. With a follow-up of over 120 days after recovery of the CD19 count, off all additional treatment and on identical immunosuppression with tacrolimus and MMF and prednisone, the patient's creatinine remained stable between 45 and 50 um while DQ DSA remain strong to very strong. We conclude that the patient is in a state of accommodation. DSA titers should be monitored when managing late humoral rejection., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Life expectancy after pediatric renal transplantation remains lower than that of the normal population largely due to cardiovascular morbidity and mortality. Hyperlipidemia is a potentially modifiable risk factor for cardiovascular morbidity. Retrospective chart review of all available pediatric renal transplant patients (26) in a single center with assessment of anthropometry, renal function, steroid, calcineurin or mTOR inhibitor exposure and Ω3 FA supplementation. Eighteen transplant recipients without Ω3 FA supplementation served as control. Nutrition and supplement surveys were conducted with standardized questionnaires. Fasting cholesterol values were compared using the latest value prior to start of Ω3 FA and at last follow-up. Eight patients (five receiving mTOR inhibitor) started Ω3 FA supplementation at a mean dose of 29.2 ± 12 mg of EPA/kg and 16.1 ± 7.4 mg DHA/kg body weight. Median duration of treatment was 2.5 yr (range 0.8-5.9 yr) and their total fasting cholesterol at last follow-up dropped significantly from 5.08 ± 0.97 (control group 3.77 ± 0.81, p = 0.0084) to 4.17 ± 0.54 mm (p = 0.0158). High-density lipoprotein cholesterol increased not significantly from 1.74 ± 0.49 to 2.02 ± 0.93 mm. No patient had increased bleeding. Supplementation of omega-3 FAs may reduce hyperlipidaemia after pediatric renal transplantation., (© 2012 John Wiley & Sons A/S.)

To compare the pattern of serum FGF23 levels in pediatric renal transplant recipients and GFR-matched controls. We performed a cross-sectional matched pair study in 19 stable pediatric renal transplant recipients and 19 GFR-matched controls with native CKD. After assessment for normal distribution, demographic and bone metabolism parameters were compared with Student's t-test, Wilcoxon's matched pairs (for non-normal distribution) test, and correlation analysis. The groups were comparable for anthropometric parameters, cystatin C eGFR (71.10 ± 37.28 vs. 76.11 ± 26.80 mL/min/1.73 m(2) ), cystatin C, urea, creatinine, intact PTH, pH, CRP, alkaline phosphatase, phosphate, calcium, ionized calcium, FGF-23 (63.44 [IQR 38.42, 76.29], 49.92 [IQR 42.48, 76.97]), albumin, and urinary calcium/creatinine ratio. The renal transplant patients had significantly lower 25-(OH) vitamin D levels (66.63 ± 17.54 vs. 91.42 ± 29.16 ng/mL), and higher 1,25-(OH)(2) vitamin D levels (95.78 ± 34.54 vs. 67.11 ± 35.90 pm). FGF-23 levels correlated negatively with cystatin C eGFR (r = -0.3571, p = 0.02770) and positively with PTH (r = 0.5063, p = 0.0026), but not with serum phosphate (r = 0.2651, p = 0.1077). We conclude that the increase in FGF23 levels with GFR decline in pediatric renal transplant patients remains similar to that in the patients with CKD. The relationship between FGF23 and serum vitamin D needs further evaluation., (© 2011 John Wiley & Sons A/S.)

Barriers to successful outcomes following pediatric transplantation have shifted from ischemic reperfusion injury and rejection to more long-term complications. Of particular concern is the high prevalence of CKD owing to preexisting damage and nephrotoxicity, as well as other CV complications such as hypertension and cardiomyopathy. All of these contribute to graft loss and shortened life expectancy, thereby limiting the success story of solid-organ transplantation. Managing CKD and related CV morbidity should be integral to the care of pediatric transplant patients, and timely detection of any irregularities would increase the chances of restoring lost kidney function. GFR is still the widely accepted indicator of renal function, and nuclear medicine techniques are the gold standard measurement methods. These methods are limited by costs, radiation exposure and substrate injection, and current practice still uses the Schwartz estimate, despite its well-documented limitations. Newer endogenous markers of GFR, such as cystatin C clearance, give a more accurate measure of true GFR but have not been embraced in the management of pediatric transplant recipients. Furthermore, indirect markers (e.g., microalbuminuria and hypertension) could also aid early detection of renal damage. The effects of mainstay immunosuppressants on kidney and heart function are varied, with available data indicating favorable outcomes with tacrolimus compared with ciclosporin. There is a need for appropriately designed and powered randomized controlled trials to validate innovative concepts for tailored immunosuppression in the pediatric population. To date, very few studies have generated long-term data in pediatric renal transplant patients - results of 1-4-yr study favored tacrolimus over ciclosporin, but other immunosuppressive agents also need to be evaluated., (© 2010 John Wiley & Sons A/S.)

SRL has been increasingly used in renal transplantation, but limited sampling approaches for estimation of AUC remain elusive. A post-hoc analysis of 94 PK profiles in 75 patients from four previous studies was performed to generate limited sampling approaches for approximation of AUC based on two to four time points for both BID and OD SRL dosing. AUC was calculated using the trapezoid rule. Stepwise linear regression was performed to generate an abbreviated AUC from the limited sampling approaches. For BID dosing, complete AUC had a strong correlation with the trough levels (r(2) = 0.882, p < 0.0001) and with C2 level (r(2) = 0.9025, p < 0.0001). A three-point and a four-point limited sampling approach showed improved agreement with complete AUC compared with single-point sampling. A convenient and accurate (r(2) = 0.992) four-point limited sampling approach reads: AUC = 10;(1.085 + 0.117 x log C0 + 0.164 x log C1-0.131 x log C2 + 0.823 x log C4). Similarly, complete AUC had a statistically significant correlation with the trough levels (r(2) = 0.549, p < 0.0001) and with C2 level (r(2) = 0.716, p < 0.0001) for OD dosing. The estimation of AUC for OD dosing was improved over single-point sampling (r(2) = 0.951) using the formula: AUC = 10;(1.100 + 0.115 x log C0 + 0.803 x log C4). This study represented the first limited sampling approach for SRL. Further studies are required to determine the optimal SRL target AUC.

Potential age-dependent changes of sirolimus metabolite patterns in pediatric renal transplant recipients remain elusive. Thirteen pediatric solid organ transplant recipients (10 kidney, one combined liver-kidney, two liver, mean age 8.0 +/- 5.0 yr) underwent a sirolimus pharmacokinetic profile in steady-state with 10 samples drawn over 12 h post-intake to calculate the AUC(0-12 h). Concentrations of sirolimus and metabolite were quantified using a validated LC-MS/MS assay and metabolite structures were identified directly in blood extracts using LC-MS/iontrap. Average sirolimus AUC(0-12 h) was 64.9 +/- 29.7 ng h/mL. Median (range) AUC(0-12 h) for each metabolite (ng h/mL) was: 12-hydroxy-sirolimus 7.6 (0.2-18.8), 46-hydroxy sirolimus 3.1 (0.0-12.4), 24-hydroxy sirolimus 4.3 (0.0-12.6), piperidine-hydroxy sirolimus 3.5 (0.0-8.3), 39-O-desmethyl sirolimus 3.6 (0.0-11.3), 16-O-desmethyl sirolimus 5.0 (0.1-9.9), and di-hydroxy sirolimus 4.3 (0.0-32.5). The metabolites reached a median total AUC(0-12 h) of 60% of that of sirolimus. The range was 2.6-136%, indicating significant variability. In all, 77.5% of the metabolites were hydroxylated, while 39-O-desmethyl sirolimus accounted for only 8.4% of the AUC(0-12 h). This is clinically relevant as 39-O-desmethyl sirolimus shows 86-127% cross-reactivity with the antibody of the widely used Abbott sirolimus immunoassay. The metabolism of sirolimus in the children included in our study differed from that reported in adults, which should be considered when monitoring sirolimus exposure immunologically.

BKVN has emerged as an important cause of pediatric renal allograft nephropathy, with significant graft dysfunction in majority of the cases. Reduced immunosuppression and cidofovir therapy are the most commonly used therapeutic options for the treatment of BKVN in these patients. Recently, a preliminary study in adult renal allograft recipients with BKVN showed a therapeutic response to a combined approach of immunosuppression reduction and IVIg administration. A therapeutic benefit of IVIg without another concomitant treatment intervention has not been evaluated. We report stabilization of renal functions, histological resolution of BKVN and significant reduction in BK viremia in pediatric renal transplant with the use of IVIg, after an inadequate response to immunosuppression reduction and cidofovir therapy. In addition, we review the current literature on the use of cidofovir in pediatric renal transplant patients with BKVN and the potential of IVIg use in this condition.

The aim is to review the tools for early detection of renal dysfunction after pediatric solid organ transplantation. Currently, the most widely used marker for detection of renal dysfunction involves measurement of GFR. Inulin clearance forms the "gold standard" method for measuring GFR; however, nuclear medicine methods ((51)Cr EDTA and (99)Tc DTPA isotope clearance studies) have replaced inulin clearance. The measurement of serum creatinine has a low sensitivity for the early detection of renal damage. The Schwartz formula using patient height and serum creatinine requires center-specific constants and has limitations associated with creatinine determination. These limitations may be overcome using a cystatin C-based GFR estimation. In diabetic nephropathy, and more recently in hemolytic uremic syndrome, microalbuminuria has been established as a useful screening tool for renal damage, while its predictive value in the transplantation setting needs to be established. All transplant recipients should be screened for hypertension. Early referral for ambulatory 24-h blood pressure monitoring and involvement of pediatric nephrologists should be considered. All pediatric solid organ transplant recipients receiving CNI should be screened regularly for high blood pressure and early evidence of renal damage using either GFR scans or cystatin C-based GFR estimations.

Similar to adults, CKD may persist after pediatric RTx. Clinical and laboratory parameters were analyzed retrospectively in 23 RTx recipients (13 males, age 11.9 +/- 5.2 yr), initially treated with prednisone, calcineurin inhibitor (TAC = 18, cyclosporine neoral = 5), and MMF at four months post-RTx (T1) and at 3.4 +/- 2.8 yr post-RTx (T2). Mean (+/-s.d.) cystatin C GFR (mL/min/1.73 m(2)) was 72 +/- 19 at T1 and 70 +/- 22 at T2 (NS). At T2, CKD stage I was present in five patients (22%), stage II in eight patients (35%), and stage III in 10 patients (43%). At T2, calcineurin inhibitors were utilized in 19, MMF in 13, and SIR in 13 patients. The prevalence of hypertension was 69% at T1 and 87% at T2 (p = NS). Anemia was diagnosed in 61% at T1 and 69% at T2 with average therapeutic MMF (2.78 +/- 1.3 mg/mL) and SIR (7.62 +/- 2.3 mg/mL) trough levels. Hypercholesterolemia was detected in 44.0% at T1 and 47% at T2. Bone disease was diagnosed in 26.0% at T1 and 21.7% at T2. Mean height Z-scores were -1.0 +/- 1.2 (T1) and -1.0 +/- 1.59 (T2, NS), with 21% at T1 and 30% at T2 below two SDS. We observed suboptimal growth, hypertension, hypercholesterolemia, bone disease, and anemia in a significant proportion of transplanted children.

An eight-yr-old combined liver and kidney transplant recipient for hyperoxaluria type I developed significant proteinuria and hypertension after conversion of a Tacrolimus, MMF, and corticosteroids-based immunosuppression to Sirolimus, low-dose Tacrolimus, and corticosteroids six and a half yr after the transplant for chronic allograft nephropathy. There was only one class I HLA match and the recipient had multiple blood exposures prior to transplantation. The patient was treated with combined hemodialysis and peritoneal dialysis while awaiting transplantation to reduce the oxalate load. A renal biopsy revealed a de novo transplant glomerulopathy that was associated with specific HLA antibodies unrelated to the donor (HLA DR 17 and 18). After reintroduction of MMF, these antibodies became undetectable and the proteinuria completely resolved. We hypothesize that HLA antibodies may cause transplant glomerulopathy even if they are not donor-specific. Their production appears more susceptible to MMF therapy. A thorough work-up of new-onset proteinuria after conversion to Sirolimus should be performed, including an immunological work-up and a renal biopsy.

Few studies report Ganciclovir or Valganciclovir levels in children. Single-center, retrospective study of all available Ganciclovir levels in transplanted children. Ganciclovir monitoring was performed as previously described [G. Filler (1998); Pediatric Nephrology, 12, 6]. For the normalization of dosing to GFR and target trough levels, we assumed first-order kinetics. We analyzed 57 Ganciclovir levels in 20 children (mean age 8.6 +/- 5.5 yr) treated with intravenous or oral Ganciclovir or oral Valganciclovir. Ganciclovir levels were drawn after IV therapy (n = 9), during oral Ganciclovir (n = 5), or during oral Valganciclovir (n = 15). Oral bioavailability of Valganciclovir was 42.0 +/- 21.8%. The dose-normalized intrapatient Valganciclovir variability was 83%. Mean GFR was 92 +/- 22 mL/min/1.73 m(2). Mean Ganciclovir concentration at last available measurement was 0.60 +/- 0.09 mg/L. While target trough Ganciclovir levels have not been established, possibly subtherapeutic Ganciclovir levels <0.5 mg/L on recommended IV doses were found in eight patients. This subset of patients was significantly younger (4.5 +/- 3.1 vs. 11.4 +/- 5.0 yr). Levels <0.5 mg/L were found in 24/57 instances and 10 patients subsequently had their dose increased. The last Valganciclovir dose adjusted to a GFR of 100 mL/min/1.73 m(2) was 842 +/- 323 mg/m(2)/day. A high proportion of patients had low Ganciclovir levels both on intravenous and oral therapy. The oral bioavailability of Valganciclovir was 42%. Our data suggest substantial inter- and intrapatient variability of Ganciclovir levels after pediatric renal transplantation and may support the need for pharmacokinetic monitoring of Ganciclovir and Valganciclovir therapy for the prevention and treatment of CMV disease after pediatric transplantation. It is currently unclear what target trough level would be most suitable.

Not infrequently, physicians elect to divide CyA-ME from b.i.d. to t.i.d. dosing in an effort to minimize toxicity. Equivalent exposure is assumed. Few studies have compared 24-h PK profiles on both dosing regimes in the same patient. We retrospectively studied a heterogeneous population of seven pediatric patients (one heart transplant, five renal transplants and one FSGS patient) on both dosing regimes who had complete 24-h PK profiles on CyA-ME. Four patients were converted from b.i.d. to t.i.d. and three patients from t.i.d. to b.i.d. dosing. There was no difference in the dose/kg (5.66 +/- 2.52 mg/kg on b.i.d. dosing and 5.75 +/- 1.81 mg/kg on t.i.d. dosing, p = 0.8578, two-sided t-test). When comparing the dose-normalized AUCs over 24 h, every single patient demonstrated lower CyA-ME exposure on t.i.d. than on b.i.d. dosing with an average relative bioavailability that was 37.9% lower on t.i.d. than on b.i.d. dosing. The median dose-normalized AUC(0-->24h) dropped from 1620 ng x h x kg/mL x mg (range: 1253-4319) on b.i.d. to 1016 ng x h x kg/mL x mg (range: 712-1485, p = 0.02, Wilcoxon's matched pairs test) on t.i.d. dosing. Our results indicate t.i.d. dosing of CyA-ME results in significantly lower exposure when the same total dose is administered in two divided doses. This reduced exposure may potentially increase the risk for rejection.

Sensitization, as measured by panel reactive antibodies (PRAs), occurs as a result of previous organ transplantation, blood transfusions, or pregnancy. The high-PRA levels increase the risk of complications during transplantation and may result in long time duration for future transplants. Mycophenolate mofetil (MMF) has been shown to decrease lymphocyte proliferation and antibody formation. We report the use of prophylactic MMF in preventing the formation of PRAs in a pediatric renal transplant recipient with multiple donor exposures. A four-yr-old girl received an unsuccessful living-related renal transplant in February 2003 and was subject to multiple blood transfusions in the perioperative period. MMF, 500 mg/m2/day in two divided doses, achieved suppression of PRAs to less than 20% and allowed successful renal transplantation within nine months. No side effects occurred. This approach may reduce the risk of sensitization in future potential organ donor recipients in similar situations.

Viral infections post-renal transplant (Tx) impact on outcome. Increased rejection rates and decreased renal function secondary to acute CMV, EBV and HHV-6 infections are well described. However, the clinical significance of a mere presence of these viruses on kidney tissue biopsy remains questionable. Thirty-six kidney biopsies obtained from 17 renal transplants (five females) and two combined liver-kidney recipients (one female) were retrospectively evaluated. Age at Tx ranged from 1.7 to 17.2 yr (median = 7.4). Biopsies were performed as protocol biopsies or when renal function deteriorated, between 6 weeks and 11 yr post-Tx (median = 1.2 yr). Immunosuppression included steroids and combination of tacrolimus/cyclosporin, mycophenolate mofetil/azathioprin and induction therapy. Fourteen patients received antiviral prophylaxis (ganciclovir/valganciclovir/acyclovir). Renal tissue was classified according to Banff '97 criteria. Tissue CMV, EBV, HHV-6 and HHV-7 was analyzed by PCR. We used an estimation of GFR from average plasma Cystatin C (CysC) and slopes of 1/CysC to assess renal function. The 16/36 biopsies were positive for one virus; 5/36 biopsies were positive for two viruses. In the infected group, Banff '97 scores for interstitial fibrosis (ci) and tubular degeneration/atrophy (ct) were significantly higher (p < 0.03 vs. the non-infected group for both). The slope of 1/CysC, or the proportion of patients on antiviral prophylaxis, did not differ significantly between both groups. In conclusion, a significant number of kidney biopsies showed PCR positivity for CMV, EBV, HHV-6 and HHV-7. This was associated with a significantly higher Banff score for ci and ct; while renal function was not affected. Further controlled studies are required.

Gastrostomy tube (G-tube) removal has been suggested at 3 months following successful renal transplantation (Tx). We noticed a delay in the removal of G-tubes in our pediatric patients following Tx and therefore conducted a cross-sectional single center survey on all renal transplant recipients to assess the causes of delayed G-tube removal. In total, 17 of 23 patients completed the survey, including all patients with G-tubes (n = 10) and seven patients without G-tubes. Median age at Tx of gastrostomy patients was significantly lower than that of patients without a G-tube (median 3.0 yr, range 1.2-4.7 yr vs. median 14 yr, range 6-17 yr, p < 0.0001) and significantly younger than in previous studies on gastrostomies. At the time of the survey, only three of 10 patients had their G-tube removed at 22, 41 and 61 months after Tx at the ages of 3, 5.5 and 9 yr, respectively. The median age at recent follow up of the remaining seven patients was 4.7 yr (range 2.6-8.75 yr). The most important reason for continued use was fluid intake and medication. Results of our survey showed appropriate concern regarding the risk of prolonged use of the gastrostomy. Caregivers felt that benefits of the gastrostomy in the post-transplant period outweighed the risks. Caregivers felt pressured towards removal by the physicians. Our findings support the decision to remove gastrostomies based on individual patient needs and total fluid intake rather than a fixed time following successful Tx.

This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with cyclosporin microemulsion (CyA) in pediatric renal recipients. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 yr) were randomly assigned (1:1) to receive either Tac (n = 103) or CyA (n = 93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection (intent-to-treat). Baseline characteristics were comparable between treatment groups. Excluding deceased patients (n = 9) and patients lost to follow-up (n = 31, mostly transferred to adult care), 95% of 2-yr data (159 of 167 possible patients), 87% of 3-yr data (142 of 163) and 73% of 4-yr data (114 of 156) were retrieved. At 1 yr Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA (59.1%, p = 0.003). The incidence of corticosteroid-resistant rejection was also significantly lower with Tac (7.8% vs. 25.8%, p = 0.001). At 4 yr, patient survival was similar (94% vs. 92%, p = 0.86) but graft survival significantly favored Tac (86% vs. 69%; p = 0.025, log-rank test), respectively. At 1 yr, the mean glomerular filtration rate (GFR) (Schwartz formula, ml/min/1.73 m(2)) was 64.9 +/- 20.7 (n = 84) vs. 57.8 +/- 21.9 (n = 77, p = 0.0355), at 2 yr 64.9 +/- 19.8 (n = 71) vs. 51.7 +/- 20.3 (n = 66, p = 0.0002), at 3 yr 66.7 +/- 26.4 (n = 81) vs. 53.0 +/- 23.3 (n = 55, p = 0.0022), and at 4 yr 71.5 +/- 22.9 (n = 51) vs. 53.0 +/- 21.6 (n = 44, p = 0.0001) for Tac vs. CyA, respectively. Cholesterol remained significantly higher with CyA throughout follow-up. Three patients in each arm developed post-transplant lymphoproliferative disease. Incidence of insulin-dependent diabetes mellitus was not different. Tac was significantly more effective than CyA in preventing acute rejection in pediatric renal recipients. Renal function and graft survival were also superior with Tac. Glomerular filtration rate appears to be an useful surrogate marker for long-term outcome.

There is controversy about the feasibility of cystatin C (CysC) as a marker of glomerular filtration rate (GFR) post-transplant (Tx). We studied intra-patient variability of CysC in comparison with serum creatinine (SCr) in 20 children (11 males, mean age 11.5 +/- 6.4 yr) with solid organ transplants (14 kidney, four liver, and two combined liver + kidney transplants). The mean age at Tx was 7.0 +/- 5.6 yr. A total of 178 simultaneous SCr and CysC measurements (median 8 per patient) were analyzed. In addition, GFR was calculated using the Schwartz and a novel CysC-based formula. Intra-individual coefficient of variations (CV) was calculated as ratio of standard deviation over mean. The mean CV was significantly lower for SCr (7.71 +/- 4.16%) when compared with CysC (10.27 +/- 4.87, p = 0.04), but was no longer significantly different when excluding patients with a bladder augment. The CV of the GFR estimated by Schwartz formula (7.44 +/- 3.77) was significantly lower than GFR calculated from CysC (12.52 +/- 7.37), p = 0.001. The mean ratio between the Schwartz GFR and the GFR calculated from CysC was 102.6 +/- 12.8%, not significantly different from 100% (p = 0.3796). The only potential confounding factors to explain increased CV after Tx were gender and bladder augmentation, whereas calcineurin inhibitors or steroids did not influence CV. With the limitation of a small number of subjects, our data suggest that the CysC and the CysC-calculated GFR is equivalent but not better than SCr and Schwartz formula. We therefore conclude that measurement of CysC can be used for longitudinal intra-individual follow-up of renal function post-Tx.

Only with prospective randomized controlled trials is it possible to evaluate the several immunosuppressive regimens available to renal allograft recipients. Commonly used surrogate markers of clinical outcome, such as patient and graft survival, are constantly improving. Current immunosuppressive protocols have improved 1-yr graft survival to over 90%. The small differences in graft survival among the various immunosuppressive regimes require large patient cohorts in order to establish statistical significance. Such studies are often difficult to conduct in a timely manner, particularly in children. This necessitates the search for better surrogate markers sensitive enough to detect differences in smaller cohorts and in a shorter period of time. While the degree of fibrosis in transplant biopsies might well predict long-term graft survival, protocol biopsies are expensive, invasive, and unpopular among clinicians. In native kidneys, glomerular filtration rate (GFR) closely correlates with disease progression and interstitial fibrosis and appears to be well positioned as a less invasive surrogate marker for long-term outcome. Nonetheless, the ideal marker for GFR remains obscure. Serum creatinine has several major drawbacks, making it a poor predictor of GFR. This review discusses the several methods used to estimate or measure GFR with emphasis on 125I-iothalamate clearance and serum cystatin C (cys-C). Of all the serum markers, cys-C is the most reliable and the most promising. However, cys-C and other endogenous markers cannot replace the diagnostic sensitivity and reliability of radiolabeled markers of GFR such as 125I-iothalamate in renal transplant clinical trials. Unfortunately, clearance of most radiolabeled markers of GFR including 125I-iothalamate remain costly and time consuming.