Tacrolimus dose requirements in paediatric renal allograft recipients are characterized by a biphasic course determined by age and bone maturation.

AIMS: Despite longstanding recognition of significant age-dependent differences in drug disposition during childhood, the exact course and the underlying mechanisms are not known. Our aim was to determine the course and determinants of individual relative dose requirements, during long-term follow-up in children on tacrolimus. METHODS: This was a cohort study in a tertiary hospital with standardized annual pharmacokinetic (PK) follow-up (AUC0-12hr ) in recipients of a renal allograft (≤19 years), between 1998 and 2015. In addition, the presence of relevant pharmacogenetic variants was determined. The evolution of dose-corrected exposure was evaluated using mixed models. RESULTS: A total of 184 PK visits by 43 children were included in the study (median age: 14.6). AUC0-12h corrected for dose per kg demonstrated a biphasic course: annual increase 4.4% (CI: 0.3-8.7%) until ±14 years of age, followed by 13.4% increase (CI 8.7-18.3%). Moreover, exposure corrected for dose per m2 proved stable until 14 years (+0.8% annually; CI: -3.0 to +4.8%), followed by a steep increase ≥14 years (+11%; CI: 7.0-16.0%). Analysis according to bone maturation instead of age demonstrated a similar course with a distinct divergence at TW2: 800 (P = 0.01). Genetic variation in CYP3A4, CYP3A5, and CYP3A7 was associated with altered dose requirements, independent of age. CONCLUSIONS: Children exhibit a biphasic course in tacrolimus disposition characterized by a high and stable drug clearance until a specific phase in pubertal development (TW2: 800 at age: ±14 years), followed by an important decline in relative dose requirements thereafter. Pharmacogenetic variation demonstrated an age/puberty independent effect. We suggest a critical reappraisal of current paediatric dosing algorithms for tacrolimus and drugs with a similar disposition.

Single-Nucleotide Polymorphism of CYP3A5 Impacts the Exposure to Tacrolimus in Pediatric Renal Transplant Recipients: A Pharmacogenetic Substudy of the TWIST Trial.

BACKGROUND: The pharmacokinetics of tacrolimus (TAC) and mycophenolic acid (MPA) are highly variable. An impact of single-nucleotide polymorphisms (SNPs) of the genes coding for enzymes and transporters involved in the pharmacokinetics of TAC and/or MPA is intuitively conceivable. Accordingly, we sought to analyze the influence of different SNPs on TAC and MPA exposure in pediatric renal transplant recipients. METHODS: A subpopulation of 37 patients (median age: 12.8 years, range 2.2-18.3 years) participating in the TWIST study was included in the analysis of SNPs of CYP3A5, ABCB1 (MDR1), ABCG2, SLCO1B3 (coding for OATP2), ABCC2 (coding for cMOAT), and UGT1/2. TAC trough concentrations and abbreviated area under the concentration-time curves (AUC) of MPA were measured on days 7, 28, 91, and 183 after transplant. Both of these were adjusted to the respective dose the patient received. RESULTS: The allele frequencies of analyzed SNP's were comparable to those reported previously for white populations. Dose-adjusted trough concentrations of TAC were approximately 60% lower in patients with the CYP3A5*1/*3 allele as compared with the CYP3A5*3/*3 allele (P = 0.004). Steroid-free patients in CYP3A5*3/*3 and CYP3A5*1/*3 carrier subgroups had comparable dose-adjusted TAC concentrations to the subgroup on steroids (P = 0.13). Patients younger than 10 years had a significantly lower median dose-adjusted TAC C0 concentration than patients older than 10 years; this age effect was comparable in heterozygous and homozygous CYP3A5 carriers as well as in patients on and off steroid medication. As for MPA, the genetic variability of transporters or enzymes had no impact on dose-adjusted MPA-AUC due to the low allele frequencies. Patients off steroids had a higher dose-adjusted MPA-AUC (0.18 mg·h/L per mg/m, 0.012-0.27) compared with patients on steroids (0.12 mg·h·L·mg, 0.09-0.19; P = 0.04). CONCLUSIONS: Genetic variability of CYP3A5 has an impact on TAC metabolism in pediatric renal transplant recipients, contributing partly to the variability of TAC exposure. Therefore, adjusting initial TAC dosing to the genotype of CYP3A5 might be of clinical benefit.

Rethinking peritubular capillary basement membrane multilayering in renal transplant pathology: a case report.

BACKGROUND: Severe multilayering (ML) of the peritubular capillary basement membranes in kidney allografts is considered to be an ultrastructural hallmark of chronic antibody-mediated rejection (CAMR). We describe here the unexpected findings in a young male adolescent with underlying focal segmental glomerulosclerosis who underwent a living-related donor transplant procedure, a case which brought into question the specificity of ML. METHODS: The patient received a kidney from his mother, whose donor screening was unremarkable. He developed nephrotic-range proteinuria shortly after the procedure. Biopsies performed within the first 6 months after transplantation demonstrated ML (5-6 layers). RESULTS: Since there were no other criteria for CAMR, electron microscopic analysis of the baseline biopsy was performed, which in retrospect also demonstrated ML. The donor is still asymptomatic after 7 years of follow-up, with normal renal function and no proteinuria. CONCLUSIONS: We discuss the phenomenon of ML in renal disease and together with the findings in our case would like to draw attention to the fact that ML in the setting of renal transplantation is not specific to CAMR, as it can exist in several kidney diseases and even in asymptomatic donors.

Important differences in management policies for children with end-stage renal disease in the Netherlands and Belgium--report from the RICH-Q study.

BACKGROUND: The low prevalence of childhood end-stage renal disease and the small centre sizes have been a barrier for clinical studies and the development of evidence-based guidelines for chronic renal replacement therapy (cRRT) in children. Few data exist on the quality of care for these patients and the applicability of existing guidelines. The aim of this study is to quantify variation in treatment policies and actually delivered care in nine centres that deliver cRRT for children. METHODS: We surveyed treatment policies in all nine centres in the Netherlands and Belgium and compared them with the actually provided therapies and with recommendations from available guidelines. Data on treatment policies were gathered by questionnaires; actually provided care and outcomes were registered prospectively from 2007 to 2010. RESULTS: Data on policies and actual patient care were obtained from all nine centres. We found relevant differences between centres in treatment policies on various topics, e.g. estimated glomerular filtration rate threshold as an indication for initiation of cRRT, preferred initial mode of cRRT, peritoneal dialysis catheter care, haemodialysis frequency and vascular access. Discrepancies were seen between stated treatment policies and actual performed therapies. For the majority of policies, no evidence-based guidelines are available. CONCLUSIONS: Health care disparities exist due to large and unwanted variation in treatment policies between hospitals providing cRRT for children. Delivered care does not live up to stated policies, for which clear and internationally accepted guidelines are lacking.

Fewer pre-emptive renal transplantations and more rejections in immigrant children compared to native Dutch and Belgian children.

BACKGROUND: In the Netherlands and Belgium, an increasing number of children who have end-stage renal disease (ESRD) are of non-Western origin. We analysed renal transplantation practices and outcome for immigrant ESRD children as compared to native children in both countries. METHODS: All Dutch and Belgian children aged <19 years who received their first renal transplantation between 1 September 2007 and 1 January 2011 were included. Therapy characteristics and outcomes were registered prospectively on a 3-monthly basis. Immigrants were defined as children of whom one or both parents had been born outside Western European countries. Multivariable Cox regression analysis was used to quantify the hazard ratio for acute rejection. RESULTS: One hundred and nineteen first renal transplant recipients were included, of which 41 (34%) were immigrants. Median [range] follow-up time of transplantation was 18 [2-28] months. Compared to native children, immigrants had pre-emptive transplantations (15 versus 32%, P = 0.040) and transplantations with a kidney from a living donor less often (24 versus 59%, P < 0.001). Survival analysis in 96 children with at least 3 months of follow-up showed an increased risk for acute rejection in immigrants adjusted for donor source, duration of dialysis and number of HLA mismatches on the DR locus [hazard ratio (95% confidence interval) 2.5 (1.1-5.9)]. CONCLUSIONS: Immigrant children receive fewer pre-emptive and living donor transplantations compared to native children. After transplantation, immigrant children are at higher risk for acute rejection irrespective of the mode of transplantation.

Budd-Chiari syndrome as presenting symptom of hepatic sarcoidosis in a child, with recurrence after liver transplantation.

A seven-yr-old boy presented with a severe Budd-Chiari syndrome, complicated by recurrent thrombosis of several successive TIPSs. Because of liver failure secondary to venous outflow tract obstruction and deterioration of his general condition, an emergency liver transplantation was performed. Steroids were discontinued three months after transplantation, and maintenance immunosuppressive therapy consisted of tacrolimus and azathioprine. Seven years later, this patient presented symptoms of recurrence of venous outflow obstruction in the transplant liver, comparable to the initial event. Histopathology of the liver revealed diffuse granulomatous inflammation with confluent non-caseating granulomas compressing the centrolobular veins. Extensive investigations excluded infections, immune deficiency, and systemic vasculitides. After treatment with a high dose of corticosteroids, the granulomas in the allograft disappeared completely. We report the first case of hepatic sarcoidosis, presenting with venous outflow obstruction and recurring after liver transplantation, in a child.

Disparities in dialysis treatment and outcomes for Dutch and Belgian children with immigrant parents.

BACKGROUND: In Belgium and the Netherlands, up to 40% of the children on dialysis are children with immigrant parents of non-Western European origin (non-Western). Concerns exist regarding whether these non-Western patients receive the same quality of care as children with parents of Western European origin (Western). We compared initial dialysis, post-initial treatment, and outcomes between non-Western and Western patients on dialysis. METHODS: All children <19 years old on chronic dialysis in the Netherlands and Belgium between September 2007 and May 2011 were included in the study. Non-Western patients were defined as children of whom one or both parents were born in non-Western countries. RESULTS: Seventy-nine of the 179 included patients (44%) were non-Western children. Compared to Western patients, non-Western patients more often were treated with hemodialysis (HD) instead of peritoneal dialysis (PD) as first dialysis mode (52 vs. 37%, p = 0.046). Before renal transplantation, non-Western patients were on dialysis for a median (range) of 30 (5-99) months, vs. 15 (0-66) months in Western patients (p = 0.007). Renal osteodystrophy was diagnosed in 34% of non-Western vs. 18% of Western patients (p = 0.028). The incidence rate ratio [95% confidence interval] for acute peritonitis was 2.44 [1.43-4.17] (p = 0.032) for non-Western compared to Western patients. CONCLUSIONS: There are important disparities between children on chronic dialysis with parents from Western European origin and those from non-Western European origin in the choice of modality, duration, and outcomes of dialysis therapy.

Cerebrocostomandibular-like syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1.

We describe two patients with a cerebrocostomandibular-like syndrome and a novel mutation in conserved oligomeric Golgi (COG) subunit 1, one of the subunits of the conserved oligomeric Golgi complex. This hetero-octameric protein complex is involved in retrograde vesicular trafficking and glycosylation. We identified in both patients an intronic mutation, c.1070+5G>A, that disrupts a splice donor site and leads to skipping of exon 6, a frameshift and a premature stopcodon in exon 7. Real-time reverse transcriptase polymerase chain reaction showed in the first patient only 3% of normal transcript when compared with control. A delay in retrograde trafficking could be demonstrated by Brefeldin A treatment of this patient's fibroblasts. The costovertebral dysplasia of the two patients has been described in cerebrocostomandibular syndrome (CCMS), but also in cerebrofaciothoracic dysplasia and spondylocostal dysostosis. CCMS itself is heterogeneous because both autosomal dominant and autosomal recessive inheritance has been described. We anticipate further genetic heterogeneity because no mutations in COG1 were found in two additional patients with a CCMS.

Determinants of eGFR at start of renal replacement therapy in paediatric patients.

BACKGROUND: Few studies have investigated the determinants of glomerular filtration rate (GFR) in paediatric patients starting on dialysis or with a transplant. METHODS: Data were collected as part of the European Society of Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association registry from 14 European countries and referred to incident paediatric patients starting on renal replacement therapy (RRT) between 2002 and 2007 under the age of 18 years. Estimated glomerular filtration rate (eGFR) was calculated using the Schwartz formula. Data were adjusted for age, gender, treatment modality at start, primary cause of renal failure (PRD) and regions in Europe (eGFR(adj)). RESULTS: Median eGFR in the 938 patients starting RRT was 10.4 mL/min/1.73 m(2) (5th and 95th percentile: 4.0-26.9). Twenty-six patients (2.8%), mainly infants with Finnish-type nephropathy, started with eGFR levels >50 mL/min/1.73 m(2). Younger age, female gender, starting on dialysis and having a short time between the first visit to a paediatric nephrologist (PN) and start of RRT were associated with lower eGFR at start of RRT. Gender differences were only present during adolescent age and disappeared when using the same K value for both genders. The various PRDs showed large differences in the rate of decline in eGFR between the first visit to a PN and start of RRT; however, this did not result in differences in eGFR(adj) at start of RRT. CONCLUSIONS: The main determinants of eGFR at start of RRT were age, gender, treatment modality at start, and the time between the first visit to a PN and start of RRT. Research is needed to determine the consequences of these differences.

Health-related quality of life, treatment adherence, symptom experience and depression in adolescent renal transplant patients.

Few studies comprehensively assessed psychological and behavioral functioning in adolescent kidney transplant patients. The purpose of this cross-sectional study was to evaluate depression, QOL, treatment adherence and presence of side effects from the perspective of the patient and his parents, and to compare scores with norm data. All patients (age 10-18 yr) and their parents completed the following instruments: KIDSCREEN-27 (QOL), a treatment adherence interview, the MTSOSD-59R (side effects) and the Beck Depression Inventory (depression). Twenty-three of 26 patients and 22 parents agreed to participate (70% male; median age 15 yr). Adolescents rated their QOL as satisfactory, but parents reported significant problems on several QOL dimensions. Depressive symptoms occurred in 17.4%, and 75% were non-adherent with their immunosuppressive drugs (confirmed by their parents) and show other problematic health behavior, including smoking, illicit drug use, dietary non-adherence, and suboptimal exercise levels. The most frequently occurring side effects were increased appetite, fatigue and headache; the most distressing ones were hair loss or thinning of hair, warts on hands or feet, and sores in the mouth or on the lips. Our results underscore the need for regular screening and adequate treatment of the above-mentioned aspects.

Pharmacokinetics of tacrolimus in stable paediatric renal transplant recipients.

Because tacrolimus (Tac) has a narrow therapeutic index and highly inter- and intra-individual variable pharmacokinetic (PK) characteristics, monitoring of drug exposure is recommended, but limited data are available on the kinetics of Tac in paediatric renal transplant recipients, especially of limited sampling strategies. To investigate the correlation between Tac trough level (TL) and the 0-12 h area under the curve (AUC), and the value of abbreviated AUC monitoring, we evaluated 12 h PK profiles in 27 children at least 1 year after transplantation. There was a significant discrepancy between Tac TLs and 0-12 h AUC (r = 0.60). Every time point, different from C(0), gave a better prediction for the drug exposure, with C(4) and C(6) as best predictors (r = 0.93 and r = 0.92, respectively). The 0-12 h AUC was estimated with great precision by the use of a two- or three-point sampling strategy, and the latter is more time-point independent. In paediatric renal transplant recipients on Tac maintenance therapy, whose condition is stable, Tac TL is not a reliable tool for the estimation of drug exposure. Abbreviated monitoring, especially at three points in time, give reliable predictions of the complete 0-12 h AUC. We suggest a 0-12 h AUC of around 150 ng x h/ml for stable paediatric renal transplant recipients 1 year after transplantation and around 100 ng x h/ml in the following years. Target AUC values should be further established for paediatric transplant recipients according to the time after transplantation.

Clinical characteristics and outcomes of children with stage 3-5 chronic kidney disease.

The aim of this study was to report on the clinical characteristics and outcomes of Belgian children with chronic kidney disease (CKD). Between 2001 and 2005, we followed 143 new successive patients younger than 20 years of age with a glomerular filtration rate of <60 ml/min/1.73 m(2) prospectively in a Belgian department of pediatric nephrology. The incidence of diagnosed CKD was 11.9 per million child population (pmcp), and the incidence of renal replacement therapy was 6.2 pmcp. There were 67% patients in CKD stage 3, 19% in CKD stage 4 and 14% in CKD stage 5. Patients with congenital anomalies of the kidney and urinary tract (CAKUTs), hereditary diseases and glomerular diseases were diagnosed at a median age of 1, 2 and 10 years, respectively. CAKUTs were the main causes of CKD, accounting for 59% of all cases. After 3, 4 and 5 years of follow-up, 27, 31 and 38% of patients treated conservatively, respectively, reached end-stage renal failure (ESRF). The progression rate to ESRF was eightfold higher in patients with CKD stage 4 than in those with CKD stage 3. Among our patient group, hereditary diseases progressed more rapidly to ESRF than CAKUTs. Transplantation was performed preemptively in 22% of these children. Infections and cardiovascular diseases were the main causes of death.

Long-term outcome of idiopathic steroid-resistant nephrotic syndrome: a multicenter study.

Long-term outcome of idiopathic steroid-resistant nephrotic syndrome was retrospectively studied in 78 children in eight centers for the past 20 years. Median age at onset was 4.4 years (1.1-15.0 years) and the gender ratio was 1.4. Median follow-up period was 7.7 years (1.0-19.7 years). The disease in 45 patients (58%) was initially not steroid-responsive and in 33 (42%) it was later non-responsive. The main therapeutic strategies included administration of ciclosporine (CsA) alone (n = 29; 37%) and CsA + mycophenolate mofetil (n = 18; 23%). Actuarial patient survival rate after 15 years was 97%. Renal survival rate after 5 years, 10 years and 15 years was 75%, 58% and 53%, respectively. An age at onset of nephrotic syndrome (NS) > 10 years was the only independent predictor of end-stage renal disease (ESRD) in a multivariate analysis using a Cox regression model (P < 0.001). Twenty patients (26%) received transplants; ten showed recurrence of the NS: seven within 2 days, one within 2 weeks, and two within 3-5 months. Seven patients lost their grafts, four from recurrence. Owing to better management, kidney survival in idiopathic steroid-resistant nephrotic syndrome (SRNS) has improved during the past 20 years. Further prospective controlled trials will delineate the potential benefit of new immunosuppressive treatment.

Peripheral bile duct paucity and cholestasis in the liver of a patient with Alagille syndrome: further evidence supporting a lack of postnatal bile duct branching and elongation.

Alagille syndrome (AGS) is a developmental, multiorgan disease caused by mutations of the Jagged1 gene. The liver is one of the major organs affected in AGS, and the hallmark of liver pathology in AGS is an age-related increase in the proportion of portal tracts that have no bile duct, but without evidence of prominent bile duct damage. The pathogenesis of this bile duct paucity is currently not well understood. (Immuno)histochemical and molecular analyses were performed on several liver biopsies that were taken during macroscopic examination of the explant liver of a 17-year-old AGS patient. The liver periphery was macroscopically pale and was microscopically characterized by complete absence of bile ducts and presence of severe cholestasis, but there was no ductular reaction. Conversely, the central, hilar portion contained normally developed bile ducts showing no or minimal damage and cholestasis. A missense mutation in the Jagged1 gene was present in both parts of the liver, indicating that mosaicism did not cause this peculiar picture. There was also a hypertrophy of the hepatic arterial branches in the liver periphery. Together with previous indirect findings, the current study of the explant liver of an AGS patient strongly suggests that a lack of branching and elongation of bile ducts during postnatal liver growth is the mechanism by which peripheral bile duct paucity and cholestasis develops in AGS. Our findings also suggest that anomalies of the intrahepatic arterial branches may be part of AGS in some patients.

Capillary deposition of complement C4d and C3d in pediatric renal allograft biopsies.

BACKGROUND: Peritubular capillary deposition of C4d (C4d(PTC)) is a marker of antibody-mediated alloresponse and is associated with poor graft survival in adults. C3d(PTC) has received less attention; its significance is unclear. To date no information has been gained in children. METHODS: The prevalence of C4d(PTC) and C3d(PTC) in pediatric renal allograft biopsies (n=77, 31 cadaveric kidneys) was analyzed retrospectively. Associations with histology, donor-specific antibodies (DSAs), and outcome were investigated. RESULTS: The overall prevalence of C4d(PTC) and C3d(PTC) was 52% and 48%, respectively. C3d(PTC) was associated with C4d(PTC) (P<0.0001). Thirty-six percent of acute rejections were cellular, 28% were humoral, and 36% were combined cellular and humoral. C3d(PTC) was found in 57% of acute rejection biopsies. C4d(PTC), but not C3d(PTC), was associated with accumulation of polymorphonuclear cells in peritubular capillaries (P=0.02). Fifty-one percent of late biopsies (>6 months posttransplantation) had features of chronic allograft nephropathy: 50% were C4d(PTC_ positive, and 50% were C3d(PTC) positive. C4d(PTC) positive chronic allograft nephropathy biopsies had more transplant glomerulopathy (P=0.020) and mesangial matrix increase (P=0.026). C3d(PTC) tended to be associated with transplant glomerulopathy (P=0.06), but not with mesangial matrix increase. C4d(PTC) was correlated with DSA (P=0.011). Excluding early nonrejection graft losses, more grafts were lost in the C4d(PTC) positive group (P=0.019). C3d(PTC) was not associated with DSA or graft outcome. CONCLUSIONS: Our results support C4d(PTC) being a hallmark of humoral rejection in pediatric renal transplantation; its presence was associated with DSA and poorer immunologic graft outcome. In contrast, C3d(PTC), although highly associated with C4d(PTC), did not correlate with DSA or outcome.

Corticosteroid-free Kidney Transplantation Improves Growth: 2-Year Follow-up of the TWIST Randomized Controlled Trial.

BACKGROUND: Corticosteroid withdrawal (CW) after pediatric kidney transplantation potentially improves growth while avoiding metabolic and other adverse events. We have recently reported the results of a 196 subject randomized controlled trial comparing early CW (tacrolimus, mycophenolate mofetil (MMF), daclizumab, and corticosteroids until day 4) with tacrolimus, MMF, and corticosteroid continuation (CC). At 6 months, CW subjects showed better growth with no adverse impact on acute rejection or graft survival (Am J Transplant 2010; 10: 828-836). This 2-year investigator-driven follow-up study aimed to determine whether improved growth persisted in the longer term. METHODS: Data regarding growth, graft outcomes and adverse events were collected at 1 year (113 patients) and 2 years (106 patients) after transplantation. The primary endpoint, longitudinal growth calculated as delta height standard deviation score, was analyzed using a mixed model repeated measures model. RESULTS: Corticosteroid withdrawal subjects grew better at 1 year (difference in adjusted mean change, 0.25; 95% confidence interval, 0.10, 0.40; P = 0.001). At 2 years, growth remained numerically better in CW subjects (0.20 (-0.01, 0.41); P = 0.06), and significantly better in prepubertal subjects (0.50 (0.16, 0.84); P = 0.004). Bacterial and viral infection was significantly more common in CW subjects at 1 year only. Corticosteroid withdrawal and CC subjects received similar exposure to both tacrolimus and MMF at 1 and 2 years. No significant difference in patient or graft survival, rejection, estimated glomerular filtration rate, or other adverse events was detected. CONCLUSION: Early CW effectively and safely improves growth up to 2 years after transplantation, particularly in prepubertal children.

Cobalamin disorder Cbl-C presenting with late-onset thrombotic microangiopathy.

Two siblings, a boy age 12 and his sister age 4 years, presented with proteinuria and hematuria, hypertension, and chronic hemolytic anemia. At age 13 years, the boy developed an episode of severe hypertensive encephalopathy and transient renal failure. Both children are attending normal school, have no neurologic symptoms, and only minimal pigmentary retinal abnormalities. Renal biopsy showed a chronic thrombotic microangiopathic nephropathy. Both patients had hyperhomocysteinemia and mild methylmalonic aciduria. Fibroblasts showed decreased cobalamin uptake, reduced methyl- and adenosyl-cobalamin formation, and deficient incorporation of formate and propionate, compatible with the Cbl-C complementation group, but milder than that found in cells from most patients. Both patients and their father carry a balanced reciprocal translocation. Parenteral hydroxycobalamin treatment reduced the homocysteine levels, and methylmalonic acid disappeared. Increasing the dosage of hydroxycobalamin from 1 to 2.5, then 5 mg daily together with betaine, further reduced homocysteine levels (boy from 118 to 23 microM and girl from 59 to 14 microM). With this treatment, hemolysis has stopped, hematuria has disappeared, proteinuria has almost normalized, and creatinine clearance has been stable. Investigations for chronic thrombotic microangiopathy should include testing for this unusual but treatable disorder, regardless of age of presentation.

Successful treatment with rituximab of lymphoproliferative disorder in a child after cardiac transplantation.

Post-transplantation lymphoproliferative disorders (PTLDs) are life-threatening complications. We report the case of a 7-year-old girl in whom a lymphoproliferative disorder developed more than 2 years after cardiac transplantation. The patient was taking ganciclovir for Epstein-Barr virus hepatitis at the time the PTLD occurred. Rituximab, an anti-CD20 monoclonal antibody, given in the presence of reduced immunosuppression therapy, resulted in a complete response of the PTLD. The Epstein-Barr viral load in the peripheral blood, which was extremely high at diagnosis, dropped promptly and remained below the detection threshold 11 months after completion of therapy. We observed complete depletion of B lymphocytes until 7 months after rituximab therapy, which was associated with an important decrease in immunoglobulin levels.

An unusual presentation of Denys-Drash syndrome due to bigenic disease.

We report a case of Denys-Drash syndrome (DDS) in a 3-month-old girl presenting with bilateral renal cortical cysts mimicking polycystic kidney disease. Genetic analysis revealed a de novo heterozygous missense mutation c.1186G>A (p.Asp396Asn) in the WT1 gene, confirming the diagnosis of DDS. Because multiple renal cysts have never been reported in DDS, we explored several genes responsible for these renal manifestations, such as HNF-1ß, PAX2, PKD1, and PKD2. Remarkably, we identified a heterozygous missense variant c.12439A>G (p.Lys4147Glu) in the PKD1 gene. The same variant was found in the patient's mother, who had no renal cysts, and in the grandfather, who had several renal cysts. Mutation prediction programs classified the c.12439A>G variant as being "likely pathogenic." We hypothesize that the severe cystic phenotype in the index patient could be due to the WT1 mutation, enhancing pathogenicity of the "hypomorph" PKD1 allele. A possible role for Wilms tumor suppressor 1 (WT1) in renal cyst development should be considered. From a conceptual point of view, this case shows that an unusual presentation of a known genetic syndrome might point to bigenic inheritance, with unexpected interference of mutated genes causing an uncommon clinical phenotype.