IVIg therapy in the management of BK virus infections in pediatric kidney transplant patients.

BK virus-associated nephropathy (BKPyVAN) induces kidney allograft dysfunction. Although decreasing immunosuppression is the standard for managing BK virus (BKPyV) infection, this strategy is not always effective. The use of polyvalent immunoglobulins (IVIg) may be of interest in this setting. We performed a retrospective single-center evaluation of the management of BKPyV infection in pediatric kidney transplant patients. Among the 171 patients who underwent transplantation between January 2010 and December 2019, 54 patients were excluded (combined transplant n = 15, follow-up in another center n = 35, early postoperative graft loss n= 4). Thus, 117 patients (120 transplants) were included. Overall, 34 (28%) and 15 (13%) transplant recipients displayed positive BKPyV viruria and viremia, respectively. Three had biopsy-confirmed BKPyVAN. The pre-transplant prevalence of CAKUT and HLA antibodies was higher among BKPyV-positive patients compared to non-infected patients. After the detection of BKPyV replication and/or BKPyVAN, the immunosuppressive regimen was modified in 13 (87%) patients: either by decreasing or changing the calcineurin inhibitors (n = 13) and/or switching from mycophenolate mofetil to mTor inhibitors (n = 10). Starting IVIg therapy was based on graft dysfunction or an increase in the viral load despite reduced immunosuppressive regimen. Seven of 15(46%) patients received IVIg. These patients had a higher viral load (5.4 [5.0-6.8]log vs. 3.5 [3.3-3.8]log). In total, 13 of 15 (86%) achieved viral load reduction, five of seven after IVIg therapy. As long as specific antivirals are not available for the management of BKPyV infections in pediatric kidney transplant patients, polyvalent IVIg may be discussed for the management of severe BKPyV viremia, in combination with decreased immunosuppression.

Are plasma proteins a valid alternative for assessing nephrotic syndrome in children from low-income countries?

BACKGROUND: A diagnosis of nephrotic syndrome (NS) in children with edema relies on urinary albumin excretion and usually plasma protein (Pprot) and albumin (Palb) concentrations. METHODS: In order to fit laboratory tests to optimal healthcare in low-resource countries, we established correlations between Pprot and Palb in children with NS (217 measurements in 60 patients) and in children with exudative enteropathy and chronic hepatopathy/liver insufficiency (186 measurements in 21 patients); all patients had repeated measurements at various stages of their disease. RESULTS: There was a good correlation between Pprot and Palb in children with idiopathic NS and genetic NS (ICC=0.8, p < 0.0001, 95% CI: 0.8-0.9 and ICC=0.8, p < 0.0001, 95% CI: 0.7-0.8, respectively), whereas the correlation was average (exudative enteropathy) or absent (chronic hepatopathy) in those without renal protein loss. CONCLUSION: Since Palb measurement is around two times more expensive than Pprot measurement, these results suggest giving priority to total Pprot measurement in the diagnosis and follow-up of children with the NS, mainly in low-resource countries.

RMND1 mutations in two siblings: Severe renal hypoplasia but different levels of extrarenal abnormality severity: The ethics of decision making.

Mutations in the RMND1 gene, causing defects in the mitochondrial respiratory chain, result in a very heterozygous phenotype. Currently there are 36 cases reported in the literature. We report two siblings from a non-consanguineous family who were severely affected by a compound heterozygous RMND1 mutation that had not been described previously and were treated differently for their end-stage renal disease. We summarize all previous published cases and focus on the importance of extrarenal comorbidities in the context of therapeutic decision making (renal replacement therapy) and its ethical relevance.

Pediatric bone evaluation with HR-pQCT: A comparison between standard and height-adjusted positioning protocols in a cohort of teenagers with chronic kidney disease.

BACKGROUND: High-resolution peripheral quantitative computed tomography (HR-pQCT) evaluates different components of bone fragility. The positioning and length of the region of interest (ROI) in growing populations remain to be defined. METHODS: Using HR-pQCT at the ultradistal tibia, we compared a single-center cohort of 28 teenagers with chronic kidney disease (CKD) at a median age of 13.6 (range, 10.2-19.9) years to local age-, gender-, and puberty-matched healthy peers. Because of the potential impact of short stature, bone parameters were assessed on two different leg-length-adjusted ROIs in comparison to the standard analysis, namely the one applied in adults. The results are presented as median (range). RESULTS: After matching, SDS height was -0.9 (-3.3;1.6) and 0.3 (-1.4;2.0) in patients and controls, respectively (P<0.001). In younger children (e.g., prepubertal, n=11), bone texture parameters and bone strength were not different using standard analysis. However, using a height-adjusted ROI enabled better characterization of cortical bone structure. In older patients (e.g., pubertal, n=17), there were no differences for height between patients and controls: with the standard evaluation, cortical bone area and cortical thickness were significantly lower in CKD patients: 85 (50-124) vs. 108 (67-154) mm2 and 0.89 (0.46-1.31) vs 1.09 (0.60-1.62) mm, respectively (both P<0.05). CONCLUSIONS: Adapting the ROI to leg length enables better assessment of bone structure, especially when height discrepancies exist between controls and patients. Larger cohorts are required to prospectively validate this analytic HR-pQCT technique.

[Renal abnormalities in Down syndrome: A review]. / Atteintes rénales de la trisomies 21.

Down syndrome (DS) is often associated with cardiac malformations, so that kidney damage is little known. The objective of this study was to present the diversity of renal abnormalities and their potential progression to chronic renal failure. Among congenital abnormalities of the kidney and urinary tract (CAKUT) abnormalities appear to be frequent: pyelectasis, megaureters, posterior urethra valves, as well as renal malformations such as renal hypoplasia, horseshoe kidney, or renal ectopia. Contributing factors to acute kidney failure have been described in patients with DS: bilateral lesions and minor renal injury, such as glomerular microcysts, tubular dilation, and immature glomeruli. Histological lesions can be found, albeit nonspecific; they occur earlier than in the general population. Two metabolic specificities have also been described: decreased clearance of uric acid and a hypercalciuria by passive hyperabsorption. End-stage renal disease can occur, thus raising the problem of the best choice of management. In conclusion, renal abnormalities in patients in DS should be known so as to preserve a good renal functional prognosis: systematic screening with renal ultrasound can be proposed.

[Type 1 xanthinuria: Report on three cases]. / Xanthinurie héréditaire de type 1 : à propos de trois cas.

Type 1 xanthinuria is a rare cause of urolithiasis due to xanthine dehydrogenase deficiency. Pediatric cases are exceptional. Through the genetic analysis of two cases, we discovered three mutations responsible for a loss of enzyme activity. The first one had a C.3536T>C missense mutation in the XDH gene and the other one was heterozygous for two mutations c.700+1G>T and c.31778_82delTCAT. We review the diagnostic methods, possible complications, and preventive measures for stone formation.

[Relationship between glomerular filtration rate, uric acid, and parathyroid hormone in children]. / Relation entre débit de filtration glomérulaire, parathormone et acide urique chez l'enfant.

INTRODUCTION: Parathyroid hormone (PTH) and uric acid (UA) levels increase early during chronic kidney disease (CKD). The objective of this study was to evaluate the relationship between these two parameters at different stages of pediatric CKD. PATIENTS AND METHODS: One hundred patients (range, 5-18 years) were included in this retrospective study: they had undergone renal exploration with a direct measurement of the glomerular filtration rate (GFR) using the reference standard (i.e., inulin clearance, Cin) and presented with increased circulating levels of PTH and/or UA. RESULTS: GFR was normal in 39% of patients, with UA increased in 44% and PTH in 75% of them. Interestingly, 29% of the children with increased PTH levels had a strictly normal GFR (i.e., above 90 mL/min/1.73 m(2)). An inverse association was found between UA and GFR (r=-0.452, P ≤ 0.0001) as well as between PTH and GFR (r=-0.226, P=0.024). The same negative relationships were found between UA and PTH (r=-0.266, P=0.007), and between UA and the phosphate reabsorption rate (r=-0.415, P<0.001). DISCUSSION: Since hyperuricemia was found at all stages of CKD, an early silent tubular impairment can be discussed to explain these findings. The early increase in PTH levels during CKD has not been described by all authors, with North American studies describing rather late increased PTH levels during CKD. Prospective studies are required to confirm these data and evaluate the role of UA in the pathophysiology of the mineral disorders observed during CKD.

[Pediatric seizures and end-stage renal disease]. / État de mal convulsif révélateur d'une ostéodystrophie rénale.

Neonates and infants with hypocalcemia usually present with seizures, whereas this is less common in older children and teenagers. We report on a case of hypocalcemic seizures in a 16-year-old girl with undiagnosed end-stage renal disease with progressive growth retardation and bone deformations. We highlight the value of checking serum calcium, phosphate, and creatinine in children with growth retardation, seizures, and/or unexplained bone deformations. We also discuss the clinical consequences of pediatric renal osteodystrophy.

Comparison of cystatin C- and creatinine-based glomerular filtration rate formulas with inulin clearance in pediatric renal transplantation.

BACKGROUND: It has been suggested that plasma cystatin C (Cyst-C) concentrations provide better indicators of changes in glomerular filtration rate (GFR) than plasma creatinine concentration (PCr). METHODS: We compared the performance of five equations--2009 Schwartz, Local Schwartz, Larsson, Le Bricon, and Schwartz Combined--in 60 renal transplant children by calculating the mean bias, Pearson correlation coefficient (R) and determination (R2), 10% (P10) and 30% (P30) accuracies, and Bland-Altman plots. GFR was measured by inulin clearance. RESULTS: For the whole population, R2 was slightly lower for formulas based on Cyst-C or PCr, but the mean bias was lower, and P10 and P30 were greater, than using combined Schwartz equation. However, the mean estimated GFR by Schwartz 2009, Local Schwartz, and Schwartz combined equations was not statistically different from the mean inulin clearance measurement. CONCLUSIONS: In our pediatric transplant population, the combined Schwartz formula exhibited better performance to estimate GFR than formulae based on Cyst-C or combined PCr.

Nephrogenic syndrome of inappropriate antidiuresis.

Mutations in the vasopressin V2 receptor gene are responsible for two human tubular disorders: X-linked congenital nephrogenic diabetes insipidus, due to a loss of function of the mutant V2 receptor, and the nephrogenic syndrome of inappropriate antidiuresis, due to a constitutive activation of the mutant V2 receptor. This latter recently described disease may be diagnosed from infancy to adulthood, as some carriers remain asymptomatic for many years. Symptomatic children, however, typically present with clinical and biological features suggesting inappropriate antidiuretic hormone secretion with severe hyponatremia and high urine osmolality, but a low plasma arginine vasopressin level. To date, only two missense mutations in the vasopressin V2 receptor gene have been found in the reported patients. The pathophysiology of the disease requires fuller elucidation as the phenotypic variability observed in patients bearing the same mutations remains unexplained. The treatment is mainly preventive with fluid restriction, but urea may also be proposed.

Cutaneous bacillary angiomatosis in renal transplant recipients: report of three new cases and literature review.

Bacillary angiomatosis (BA) is a rare vasculoproliferative disorder due to Bartonella henselae (BH) or Bartonella quintana. It can involve many organs, including the skin, and has been mainly reported in patients with acquired immunodeficiency syndrome. In organ transplant recipients (OTR), this disorder remains misdiagnosed and therapeutic guidelines are nonexistent. We report 3 cases of BA with skin involvement in OTR and review similar cases from the literature. BA manifests on the skin with violaceous lesions mimicking Kaposi sarcoma, and is associated with fever, lymphadenopathy, and liver, spleen, or lung nodules. Bartonellosis infections in OTR are due to BH, the agent causing cat-scratch disease (CSD), but BA comprises histologically a prominent vascular proliferation, which is usually lacking in CSD. Cultures and serologic tests are poorly reliable for the diagnosis, which relies on demonstration of BH within the lesions. A history of cat exposure exists in most cases and pediatric OTR are at higher risk. Prevention consists of regular use of a flea-control product in cats and prompt cleaning of scratches. Our cases highlight several original features of this rare condition, which could potentially improve the management of BA in OTR.

[Post-diarrheal haemolytic uremic syndrome: when shall we consider it? Which follow-up?]. / Syndrome hémolytique et urémique post-diarrhéique : Quand y penser ? Quel suivi ?

Haemolytic uremic syndrome (HUS) is characterized by thrombotic microangiopathy with acute renal failure, haemolytic anaemia with schizocytes and thrombocytopenia. Typical forms (D(+) HUS) are caused by gastrointestinal infection with Escherichia coli species producing verotoxines (or Shiga toxins, STEC). It is estimated that 5-8 % of infected individuals will develop HUS following STEC infection. E. coli O157:H7 is the most commonly involved serotype and can lead to D(+) HUS in 15 % of young infected children. Vehicles of STEC transmission are contaminated food (ground beef, unpasteurised dairy products, unwashed and uncooked fruit and vegetables), person-to-person transmission and contact with farm animals with STEC. After an average incubation period of 3 to 8 days, patients develop painful bloody diarrhoea followed by systemic toxinemia. This may lead to thrombotic microangiopathy with endothelial damage and activation of local thrombosis. Since 1996, the Institut de Veille Sanitaire (InVS) centralises all notified French cases of D(+) HUS in children less than 15 years of age and investigates cases regrouped by time and place for the presence of STEC risk factors. The average annual incidence ranges between 0.6 and one for 100 000 children younger than 15 years and with a peak at 1 year of age. Fifty-one percent of HUS occur between June and September. Patients with a suspicion of STEC infection or bloody diarrhoea should not receive antibiotics, antimotility agents, narcotics and non-steroidal anti-inflammatory drugs. Maintenance optimal hydration provides nephroprotection. The management of HUS remains supportive. Dialysis was required for 46 % of HUS cases in 2009. For similar indication, peritoneal dialysis has to be a first choice treatment. Neurological injury is the most frequent non-renal complication and the first cause of death. Early initiation of plasmapheresis might improve the prognosis. Overall mortality rate ranges between 1 and 5 %. One third of patients suffer from long-term renal morbidity such as proteinuria, arterial hypertension and decrease of glomerular filtration rate. The longer the duration of anuria, the greater the risk of sequellae. Any patient with a history of HUS needs a long-term renal follow-up.

Development of a Bayesian estimator for the therapeutic drug monitoring of mycophenolate mofetil in children with idiopathic nephrotic syndrome.

The use of mycophenolate mofetil (MMF) in children with idiopathic nephrotic syndrome (INS) is increasing. However, the clinical benefit of its monitoring has been scarcely studied, and little is known about its pharmacokinetics in this context. The objectives of the present study were: (i) to study and model the pharmacokinetics of mycophenolic acid (MPA; the active moiety of MMF) in paediatric patients with INS given MMF, at all stages of the disease; (ii) to develop a Bayesian estimator (MAP-BE) for individual inter-dose area under the concentration-time curve (AUC) prediction in this population, using a limited blood sampling strategy (LSS). Full-pharmacokinetic (PK) profiles of MPA collected in paediatric inpatients with INS already treated with a maintenance immunosuppressive therapy based on MMF (with no calcineurin inhibitors; CNI) were studied. A classical iterative two-stage (ITS) method was applied to model the data and develop MAP-BEs using a one-compartment open model where the absorption is described by a double gamma law allowing the description of a potential enterohepatic recirculation. The performance of the MAP-BE developed for individual exposure assessment was evaluated by the bias and precision of predicted AUCs with respect to measured, trapezoidal AUCs (reference value), and by the proportion of predicted AUCs with absolute error >20%. These PK tools were tested in an independent group of patients. Sixty PK profiles of MPA from children receiving MMF in association to corticosteroids or given alone were included in the study. Forty-five of these PK profiles were used to develop a PK model and a MAP-BE, and 15 for their validation. In the building group, the PK model fitted accurately the PK profiles of MPA: mean residual error of modelled vs. reference AUC was m±SD=-0.015±0.092 (range: -0.153 to 0.204). The MAP-BE which allowed the estimation of MPA AUC on the basis of a 20 min-60 min-180 min LSS was then developed. In the independent group of patients, its mean residual error vs. reference AUCs was m±SD=-0.036±0.145 (range: -0.205 to 0.189). Thus, a PK model and its derived MAP-BE for MMF (without any associated CNI) when given to children with INS have been developed. Clinical trials using these PK tools could test the potential impact of the therapeutic drug monitoring of MMF based on the AUC on the clinical evolution of INS.

[Vitamin D revisited: a cornerstone of health?]. / Vitamine D : un acteur majeur en santé ?

There is a recent renewed interest in vitamin D metabolism and pathophysiology, due to its recent description as a hormone with a positive impact on global health rather than a strictly bone hormone: vitamin D could be a protective factor against infection, autoimmunity, cardiovascular morbidity, and cancer. By contrast, vitamin D deficiency appears to be increasingly frequent worldwide. We propose a review of these new aspects of vitamin D metabolism, with a focus on vitamin D status in a local pediatric cohort. There is an urgent need for revisiting current guidelines on vitamin D supplementation and for closely monitoring serum vitamin D in children with chronic diseases, i.e., at greater risk of cardiovascular impairment, bone morbidity, infectious disease, and acute inflammation.

Mortality in pediatric renal transplantation: a study of the French pediatric kidney database.

OBJECTIVE AND METHODS: To assess patient survival in pediatric renal transplantation, we retrospectively reviewed 573 transplants in 553 patients, registered from 1995 to 2005. RESULTS: Mean age at transplantation was 9.9 years. Patient survival at 1, 5 and 10 years was respectively 99%, 97% and 96%. Death occurred at a median time of 2.6 years after transplantation. Long-term patient survival was significantly lower in recipients younger than 5 years old. Seventeen patients (3.1%) died. Two deaths occurred while under maintenance dialysis. Among the remaining patients, the two main causes of death were infections (33%) and malignancies (27%). Interestingly, initial disease-related complications were a major cause of death (34%). CONCLUSION: A low mortality rate was observed, with the majority of deaths due to malignancies and infections, and with a notable participation of complications related to the initial disease. No impact of cardiovascular disease was noted with the given follow-up period. Improvements in managing immunosuppression may contribute to reducing mortality in pediatric renal transplantation.

Survey of first-year medical students to assess their knowledge and attitudes toward organ transplantation and donation.

BACKGROUND: The important shortage of organ donors is still a fundamental public health problem in France. Improving the knowledge and attitudes of health care professionals could help to promote organ donation. The aim of this survey was to evaluate the level of knowledge of medical students and their gaps about organ donation prior to any medical course. MATERIALS AND METHODS: A survey was conducted among 571 first-year medical students at a medical faculty in Lyon. Their knowledge, attitudes, personal views, and perceptions toward organ donation and transplantation were investigated prior to any medical course. A 31-item anonymous questionnaire including queries about personal views of organ donation, factual knowledge, and awareness of French law was distributed to the students. RESULTS: To "willingness to donate a kidney to a relative," 97.7% of respondents consented, 0.9% objected, and 1.4% did not answer. Their attitudes toward cadaveric organ donation were different: 81.1% agreed, 13.5% refused, and 5.4% did not answer. Regarding their knowledge about which organs could be transplanted, 95% of the respondents were aware of the possibility to transplant a face and 14% thought that xenotransplantation was performed nowadays. CONCLUSIONS: First-year medical students have a good knowledge level regarding the organ donation and transplantation system prior to their medical course. Some gaps remain which could be improved. The results of this study supported a greater emphasis on providing information regarding transplantation in medical schools to improve the knowledge of future health care professionals. A follow-up survey of the participants at the end of their medical course will be interesting to assess the progress of their attitudes.

[Active drug monitoring of adverse drug reactions in pediatric emergency department]. / Recueil systématique et actif des évènements indésirables médicamenteux chez les enfants admis aux urgences pédiatriques.

OBJECTIVES: The aim of this study was to systematically evaluate adverse drug reactions (ADRs) in children consulting at the pediatric emergency unit during a 6-month period. METHOD: The regional pharmacovigilance center (CRPV) and the department of clinical pharmacology prospectively and systematically recorded all potential ADRs among patients younger than 18 years of age in the pediatric emergency unit reported at the daily staff meetings. All cases were then screened and validated by the CRPV. For validated cases, preventability, seriousness, and off-label use were evaluated. RESULTS: During the study period, from 1 March to 1 September 2005, 90 children presented potential adverse drug events. ADRs were confirmed in 43 patients, 19 females and 24 males. Thirty-four patients (79%) were under the age of 5. According to the European definition, 14 patients (33%) had serious ADRs. One anaphylactic shock after amoxicillin injection; antimalarial prophylaxis misuse leading to convulsive status epilepticus, convulsion, and coma after hepatitis B and MMR vaccines were deemed life-threatening. Three ADRs were considered avoidable. Antibiotics and vaccines were the most common possible cause of ADRs (76%). Skin reactions (n=27), fever (n=8), and gastric disorders (n=5) were the most common clinical manifestations. CONCLUSIONS: Because ADRs were reported by clinicians on a voluntary basis, serious ADRs were probably reported more systematically. Compared to a similar period without active monitoring, active drug monitoring of ADRs doubled the number of confirmed cases 43 vs 17, p<0.001. Close collaboration between the pharmacovigilance center, pharmacologists, and clinicians is necessary and seems feasible for improving the monitoring of ADRs in children.

Unusual neurologic manifestations (II): posterior reversible encephalopathy syndrome (PRES) in the context of juvenile systemic lupus erythematosus.

Posterior reversible encepalopathy syndrome (PRES), or reversible posterior leukoencephalopathy, is a neurologic condition characterized by recognizable pattern of altered mental status, headache, visual changes and seizures in association with findings indicating a predominantly posterior leucoencephalopathy on imaging studies. It has rarely been described in children. We report two cases of pediatric systemic lupus erythematosus (SLE) complicated by PRES and review the literature.