Widespread kidney anomalies in children with Down syndrome.

BACKGROUND: Rare autopsy studies have described smaller kidneys as well as urinary tract anomalies in Down syndrome. This observation has never been investigated in vivo and little is known about the possible consequences upon kidney function. Here we wish to confirm whether children with Down syndrome have smaller kidneys and to evaluate their kidney function in vivo. METHODS: This retrospective cohort study enrolled 49 children with Down syndrome, as well as 49 age- and sex-matched controls at the Queen Fabiola Children's University Hospital in Brussels, Belgium. Doppler and kidney ultrasonography, spot urine albumin to creatinine ratio, estimated glomerular filtration rate (eGFR), and anthropometric data were recorded. RESULTS: Kidney size in children with Down syndrome was smaller than age- and sex-matched controls in terms of length (p < 0.001) and volume (p < 0.001). Kidney function based on eGFR was also decreased in Down syndrome compared to historical normal. Twenty-one of the children with Down syndrome (42%) had eGFR < 90 mL/min/1.73 m2, with 5 of these (10%) having an eGFR < 75 mL/min/1.73 m2. In addition, 7 of the children with Down syndrome (14%) had anomalies of the kidney and/or urinary tract that had previously been undiagnosed. CONCLUSIONS: Children with Down syndrome have significantly smaller kidneys than age-matched controls as well as evidence of decreased kidney function. These findings, in addition to well-noted increased kidney and urologic anomalies, highlight the need for universal anatomical and functional assessment of all individuals with Down syndrome. A higher resolution version of the Graphical abstract is available as Supplementary information.

Indications and efficiency of dapsone in IgA vasculitis (Henoch-Schonlein purpura): case series and a review of the literature.

Immunoglobulin A (IgA) vasculitis (Henoch-Schonlein purpura (HSP)) is the most common vasculitis in children. It is characterized by purpuric rash, arthritis, gastrointestinal, and/or renal involvement. Spontaneous resolution is the typical outcome. In chronic cutaneous manifestations of IgA vasculitis, dapsone seems to show a good effectiveness. Multiple case reports and case series about dapsone in chronic IgA vasculitis are available. However, no clear evaluation of its indications, its effectiveness, or its usage guidelines (optimal dosage or duration of treatment) is available. We reviewed the published cases of IgA vasculitis treated by dapsone and compared them with 2 similar cases that we encountered. Seventeen patients (ranging from 22 months old to 16 years old) with severe or persistent clinical signs of IgA vasculitis were included. Dapsone showed good results on the resolution of cutaneous lesions but not on renal manifestations. Complications (methemoglobinemia) were observed on 1 patient. Half of the patients relapsed after treatment discontinuation. The difference between the time lapse before initiation and the duration of the treatment was not significant.Conclusion: We suggest that dapsone can have a positive effect in chronic IgA vasculitis when cutaneous manifestations last more than 6 weeks at the dosage of 1-2 mg/kg once per day during 1 week. What is Known: • IgA vasculitis or Henoch-Schonlein purpura is the most common vasculitis in children and affects mostly small vessels of the skin, kidney, and gastrointestinal tract. It resolves spontaneously in most of the cases. Exceptionally, cutaneous lesions can last several weeks. • Dapsone is a bacteriostatic antibacterial sulfonamide drug found to be effective in the treatment of some inflammatory dermatological diseases like IgA vasculitis. What is New: • Dapsone is effective against chronic purpuric lesion (> 6 weeks) at the minimal dose of 1 mg/kg/day. • Relapse occurs frequently after discontinuation but responds after a second course of treatment. A longer duration of treatment or a delay in treatment by dapsone does not seem to influence the relapse rate.

A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome.

Levamisole has been considered the least toxic and least expensive steroid-sparing drug for preventing relapses of steroid-sensitive idiopathic nephrotic syndrome (SSINS). However, evidence for this is limited as previous randomized clinical trials were found to have methodological limitations. Therefore, we conducted an international multicenter, placebo-controlled, double-blind, randomized clinical trial to reassess its usefulness in prevention of relapses in children with SSINS. The efficacy and safety of one year of levamisole treatment in children with SSINS and frequent relapses were evaluated. The primary analysis cohort consisted of 99 patients from 6 countries. Between 100 days and 12 months after the start of study medication, the time to relapse (primary endpoint) was significantly increased in the levamisole compared to the placebo group (hazard ratio 0.22 [95% confidence interval 0.11-0.43]). Significantly, after 12 months of treatment, six percent of placebo patients versus 26 percent of levamisole patients were still in remission. During this period, the most frequent serious adverse event (four of 50 patients) possibly related to levamisole was asymptomatic moderate neutropenia, which was reversible spontaneously or after treatment discontinuation. Thus, in children with SSINS and frequent relapses, levamisole prolonged the time to relapse and also prevented recurrence during one year of treatment compared to prednisone alone. However, regular blood controls are necessary for safety issues.

Outcomes of kidney transplantations in children weighing 15 kilograms or less: a retrospective cohort study.

Kidney transplantation (KT) is often delayed in small children because of fear of postoperative complications. We report early- and long-term outcomes in children transplanted at ≤15 kg in the two largest Belgian pediatric transplant centers. Outcomes before (period 1) and since the introduction of basiliximab and mycophenolate-mofetil in 2000 (period 2) were compared. Seventy-two KTs were realized between 1978 and 2016: 38 in period 1 and 34 in period 2. Organs came from deceased donors in 48 (67%) cases. Surgical complications occurred in 25 KTs (35%) with no significant difference between the two periods. At least one acute rejection (AR) occurred in 24 (33%) KTs with significantly less patients experiencing AR during period 2: 53% and 12% in period 1 and, period 2 respectively (P < 0.001). Graft survival free of AR improved significantly in period 2 compared with period 1: 97% vs. 50% at 1 year; 87% vs. 50% at 10 years post-KT (P = 0.003). Graft survival tended to increase over time (period 1: 74% and 63% at 1 and 5 years; period 2: 94% and 86% at 1 and 5 years; P = 0.07), as well as patient survival. Kidney transplantation in children ≤15 kg remains a challenging procedure with 35% of surgical complications. However, outcomes improved and are nowadays excellent in terms of prevention of AR, patient and graft survival.

Role of truncating mutations in MME gene in fetomaternal alloimmunisation and antenatal glomerulopathies.

BACKGROUND: Membranous glomerulonephritis is an immune-mediated disease. In a recent case of antenatal membranous glomerulonephritis, we identified neutral endopeptidase (NEP) as the podocyte target antigen of circulating antibodies produced by the mother who failed to express NEP on granulocytes. We aimed to investigate whether the disease could affect other families, to search for mutations in the metallomembrane endopeptidase (MME) gene for NEP, and to analyse the outcome of the antenatal renal insult. METHODS: From three families with a case of neonatal membranous glomerulopathy, we detected mutations by direct sequencing of genomic PCR products. Single nucleotide polymorphism (SNP) analysis was undertaken with five SNPs located in the MME gene. IgG subclasses with anti-NEP activity were determined by western blotting. FINDINGS: In five mothers, we identified two compound heterozygous or homozygous mutations in the MME gene. The first, a 1342C-->T nonsense mutation, was detected in one family. The second, 446delC, was detected in all three families; all chromosomes bearing this mutation had the same alleles for the five SNPs. Severity of neonatal renal disease was determined by the mothers' IgG response to fetal NEP antigens expressed on glomerular podocytes. The oldest affected individual, now aged 20 years, has developed severe chronic renal failure. INTERPRETATION: Truncating mutations in the MME gene are the cause of alloimmunisation during pregnancy. Idiopathic renal failure in early adulthood might be caused by immune-mediated fetal nephron loss. We show that disease caused by fetomaternal alloimmunisation secondary to a genetic defect is not restricted to blood cells. RELEVANCE TO CLINICAL PRACTICE: During pregnancy, the absence of the NEP protein induces an alloimmunisation process against NEP presented by fetal cells, including syncytiotrophoblasts. The fetal podocyte insult and ensuing nephron loss could lead to chronic renal failure in early adulthood. Alloimmunisation against NEP should be considered as a leading cause of membranous glomerulopathy early in life. Concentrations of circulating anti-NEP antibodies should be carefully monitored during subsequent pregnancies, and specific therapeutic approaches developed. This new disease might also account for idiopathic chronic renal failure detected during adolescence, in individuals who can be identified by searching for anti-NEP antibodies in their mother and by MME gene mutation analysis. NEP deficiency should also be considered in patients developing de-novo membranous glomerulopathy after renal transplantation.

A new fast-melting oral formulation of desmopressin: a pharmacodynamic study in children with primary nocturnal enuresis.

OBJECTIVE: To determine the pharmacodynamic properties of a new oral lyophilisate formulation of desmopressin (in single doses of 30, 60, 120, 240, 360 or 480 microg) in children with known primary nocturnal enuresis (PNE) and thus identify those dosages that could provide a duration of action corresponding to a typical length of night-time sleep in children with PNE; additional objectives were to determine the safety and tolerability of desmopressin in this population. PATIENTS AND METHODS: Children with PNE (mean three or more wet nights/week), aged 6-12 years, were randomized into a double-blind, placebo-controlled study. An overhydration technique was used before dosing to suppress endogenous vasopressin production and thereby ensure that any antidiuresis could be attributed to treatment. Dosing with desmopressin or placebo occurred when urinary production was >0.13 mL/min/kg. Urinary volume, osmolality and duration of urinary-concentrating action (above three threshold levels: 125, 200 and 400 mOsm/kg) were determined as endpoints. RESULTS: All 72 participants receiving desmopressin had a pharmacodynamic response to the drug, while there was no change in urinary output in the 12 placebo-treated patients. There was a clear relationship between desmopressin dose and duration of action and osmolality during action, although the three highest-dose groups had similar results. The mean duration of action of desmopressin at the lowest osmolality threshold level was 3.6-10.6 h, according to dose; for the highest threshold, the values were 1.3-8.6 h. CONCLUSION: Desmopressin, as the oral lyophilisate, causes a marked decrease in urinary output in hydrated children with PNE. A small dose range (120-240 microg) is likely to control diuresis for a period corresponding to a night's sleep (7-11 h) in most children with PNE. However, some patients might require a higher dose to obtain antidiuresis for the complete night.