Background
Schistosomiasis affects approximately 230 million people worldwide. There is an increased incidence of schistosomiasis cases in France acquired from outside the country. This increases the ...risk of schistosomiasis outbreaks as observed in Corsica. Clinicians from non-endemic regions are not accustomed to diagnosing and managing this pathology. The objective of this study is to provide a better description of the clinical and paraclinical characteristics and disease evolution of affected children.
Methods
Through the French Pediatric Nephrology Society and the Pediatric Infectious Pathology Group, we contacted all French pediatric centers that may have treated children with urinary schistosomiasis between 2013 and 2019. Age, sex, comorbidities, and clinical, biological, and radiological data (at discovery and follow-up) were collected retrospectively.
Results
A total of 122 patients from 10 different centers were included. The median age was 14 years and the sex ratio M/F was 4:1. Hematuria was present in 82% of the patients while urinary tract abnormality was found in 36% of them. Fourteen patients (11%) displayed complicated forms of urinary schistosomiasis including 10 patients with chronic kidney disease. A total of 110 patients received treatment with praziquantel, which was well-tolerated and led to clinical resolution of symptoms in 98% of cases.
Conclusion
Patients with schistosomiasis present frequent kidney, urinary, or genital involvement. Systematic screening of patients returning from endemic areas is therefore recommended, especially since treatment with antiparasitic drugs is effective and well-tolerated. Enhancing medical knowledge of this pathology among all practitioners is essential to improve care and outcomes.
Graphical abstract
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Supplementary information
Energetic metabolism controls key steps of kidney development, homeostasis, and epithelial repair following acute kidney injury (AKI). Hepatocyte nuclear factor‐1β (HNF‐1β) is a master transcription ...factor that controls mitochondrial function in proximal tubule (PT) cells. Patients with HNF1B pathogenic variant display a wide range of kidney developmental abnormalities and progressive kidney fibrosis. Characterizing the metabolic changes in PT cells with HNF‐1β deficiency may help to identify new targetable molecular hubs involved in HNF1B‐related kidney phenotypes and AKI. Here, we combined 1H‐NMR‐based metabolomic analysis in a murine PT cell line with CrispR/Cas9‐induced Hnf1b invalidation (Hnf1b−/−), clustering analysis, targeted metabolic assays, and datamining of published RNA‐seq and ChIP‐seq dataset to identify the role of HNF‐1β in metabolism. Hnf1b−/− cells grown in normoxic conditions display intracellular ATP depletion, increased cytosolic lactate concentration, increased lipid droplet content, failure to use pyruvate for energetic purposes, increased levels of tricarboxylic acid (TCA) cycle intermediates and oxidized glutathione, and a reduction of TCA cycle byproducts, all features consistent with mitochondrial dysfunction and an irreversible switch toward glycolysis. Unsupervised clustering analysis showed that Hnf1b−/− cells mimic a hypoxic signature and that they cannot furthermore increase glycolysis‐dependent energetic supply during hypoxic challenge. Metabolome analysis also showed alteration of phospholipid biosynthesis in Hnf1b−/− cells leading to the identification of Chka, the gene coding for choline kinase α, as a new putative target of HNF‐1β. HNF‐1β shapes the energetic metabolism of PT cells and HNF1B deficiency in patients could lead to a hypoxia‐like metabolic state precluding further adaptation to ATP depletion following AKI.
Background
Henoch–Schönlein purpura is the most common vasculitis in children. Its long-term prognosis depends on renal involvement. The management of Henoch–Schönlein purpura nephritis (HSPN) ...remains controversial. This study reports the prognosis of children with HSPN presenting with class 2 International Study of Kidney Disease in Children (ISKDC) nephritis.
Methods
All children with HSPN class 2 diagnosed between 1995 and 2015 in four pediatric nephrology centers were included, and clinical and biological data were collected from the medical files. The primary endpoint was proteinuria remission defined as a proteinuria <200 mg/L.
Results
Ninety-two children were included in the study with a median follow-up of 36 (6–120) months; 28% had nephrotic syndrome, 31% proteinuria >3 g/L, 52% proteinuria between 1 and 3 g/L, and 18% proteinuria <1 g/L. Forty-seven percent of patients received orally treatment with steroids alone, 37% received methylprednisolone pulses followed by steroids orally, 18% received no steroids. Although 85% reached remission during follow-up, 12% did not maintain complete remission over time so that only 75% remained in complete remission by the end of the follow-up. Univariate analysis found a higher likelihood of remission in patients with higher proteinuria at disease onset (
p
= 0.009). This trend was not found in the multivariate analysis after adjusting for treatments, as patients with higher proteinuria were most often treated with steroids.
Conclusion
Our study shows that one fourth of patients with HSPN class 2 remain proteinuric and thus carry the risk of developing chronic kidney disease over the long term. This finding, together with the better outcome of patients treated with steroids, is in favor of using high-dose steroids orally or IV in these patients.
Although capillary electrophoresis coupled to mass spectrometry (CE-MS) has potential application in the field of metabolite profiling, very few studies actually used CE-MS to identify clinically ...useful body fluid metabolites. Here we present an optimized CE-MS setup and analysis pipeline to reproducibly explore the metabolite content of urine. We show that the use of a beveled tip capillary improves the sensitivity of detection over a flat tip. We also present a novel normalization procedure based on the use of endogenous stable urinary metabolites identified in the combined metabolome of 75 different urine samples from healthy and diseased individuals. This method allows a highly reproducible comparison of the same sample analyzed nearly 130 times over a range of 4 years. To demonstrate the use of this pipeline in clinical research we compared the urinary metabolome of 34 newborns with ureteropelvic junction (UPJ) obstruction and 15 healthy newborns. We identified 32 features with differential urinary abundance. Combination of the 32 compounds in a SVM classifier predicted with 76% sensitivity and 86% specificity UPJ obstruction in a separate validation cohort of 24 individuals. Thus, this study demonstrates the feasibility to use CE-MS as a tool for the identification of clinically relevant urinary metabolites.
Kidney transplantation (KT) is the optimal treatment for children with end-stage kidney disease. The aim of this study was to evaluate the impact of preemptive kidney transplantation (PKT) and of ...pretransplant dialysis duration on graft survival among French pediatric kidney transplant recipients.
We analyzed all first pediatric kidney-only transplantations performed in France between 1993 and 2012. A Cox multivariable model was used to investigate the association of PKT and pretransplant dialysis time with the hazard of graft failure defined as death, return to dialysis, or retransplant, whichever occurred first.
Patients (n = 1911) were included, of which 380 (19.8%) received a PKT. Median time of follow-up was 7.0 y. PKT was associated with a 55% reduction of the hazard of graft failure at any time after KT compared with patients transplanted after dialysis (hazard ratio, 0.45; 95% confidence interval, 0.33-0.62), after adjustment for recipient sex and age, primary kidney disease, donor age and type (living or deceased donor), number of HLA mismatches, cold ischemia time, and year of transplantation. A reduction of the hazard of graft failure was found in PKT whatever the compared duration of dialysis, even when <6 mo and whatever the dialysis modality. Results were similar in multiple sensitivity analyses.
In France, PKT among pediatric patients is associated with a better graft survival when compared with KT after dialysis, even when <6 mo. Based on these findings, we suggest that PKT should be considered as the treatment of choice for children with end-stage kidney disease.
Socioeconomic status is an important determinant of health. Its impact on kidney transplantation outcome has been studied among adults but data in children are scarce, especially in Europe. Here, we ...investigate the association between the level of social deprivation (determined by the continuous score European Deprivation Index) and graft failure risk in pediatric kidney transplant recipients. All patients listed under 18 years of age who received a first kidney transplant between 2002 and 2014 in France were included. Of 1050 kidney transplant recipients (males 59%, median age at transplantation 13.2 years, preemptive transplantation 23%), 211 graft failures occurred within a median followup of 5.9 years. Thirty-seven percent of these patients belong to the most deprived quintile, suggesting that deprivation is more frequent in pediatric patients with end-stage kidney disease (ESKD) than in the general population. Five- and ten-year graft survival were 85% and 69%, respectively, in the most deprived quintile vs. 90% and 83%, respectively, in the least deprived quintile. At any time after transplantation, patients in the most deprived quintile had almost a two-fold higher hazard of graft failure compared with the least deprived quintile, after adjustment for age at renal replacement therapy, duration of dialysis, primary kidney disease, and rural/urban living environment (hazard ratio 1.99; 95% confidence interval 1.20-3.28). The hazard of graft failure did not differ significantly between girls and boys. Thus, our findings suggest a lower socioeconomic status is independently associated with poor graft outcome in pediatric kidney transplantation.
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Background. Ante/neonatal Bartter syndrome (BS) is a hereditary salt-losing tubulopathy due to mutations in genes encoding proteins involved in NaCl reabsorption in the thick ascending limb of ...Henle's loop. Our aim was to study the frequency, clinical characteristics and outcome of each genetic subtype. Methods. Charts of 42 children with mutations in KCNJ1 (n = 19), SLC12A1 (n = 13) CLCNKB (n = 6) or BSND (n = 4) were retrospectively analysed. The median follow-up was 8.3 0.4–18.0 years. Results. We describe 24 new mutations: 10 in KCNJ1, 11 in SLC12A1 and 3 in CLCNKB. The onset of polyhydramnios, birth term, height and weight were similar for all groups; three patients had no history of polyhydramnios or premature birth and had CLCNKB mutations according to a less severe renal sodium wasting. Contrasting with these data, patients with CLCNKB had the lowest potassium (P = 0.006 versus KCNJ1 and P = 0.034 versus SLC12A1) and chloride plasma concentrations (P = 0.039 versus KCNJ1 and P = 0.024 versus SLC12A1) and the highest bicarbonataemia (P = 0.026 versus KCNJ1 and P = 0.014 versus SLC12A1). Deafness at diagnosis was constant in patients with BSND mutations; transient neonatal hyperkalaemia was present in two-thirds of the children with KCNJ1 mutations. Nephrocalcinosis was constant in KCNJ1 and SLC12A1 but not in BSND and CLCNKB patients. In most cases, water/electrolyte supplementation + indomethacin led to catch-up growth. Three patients developed chronic renal failure: one with KCNJ1 mutations during the second decade of age and two with CLCNKB and BSND mutations and without nephrocalcinosis during the first year of life. Conclusions. We confirmed in a large cohort of ante/ neonatal BS that deafness, transient hyperkalaemia and severe hypokalaemic hypochloraemic alkalosis orientate molecular investigations to BSND, KCNJ1 and CLCNKB genes, respectively. Chronic renal failure is a rare event, associated in this cohort with three genotypes and not always associated with nephrocalcinosis.
Therapeutic drug monitoring of mycophenolic acid can improve clinical outcome in organ transplantation and lupus, but data are scarce in idiopathic nephrotic syndrome. The aim of our study was to ...investigate whether mycophenolic acid pharmacokinetics are associated with disease control in children receiving mycophenolate mofetil for the treatment of steroid-dependent nephrotic syndrome.
This was a retrospective multicenter study including 95 children with steroid-dependent nephrotic syndrome treated with mycophenolate mofetil with or without steroids. Area under the concentration-time curve of mycophenolic acid was determined in all children on the basis of sampling times at 20, 60, and 180 minutes postdose, using Bayesian estimation. The association between a threshold value of the area under the concentration-time curve of mycophenolic acid and the relapse rate was assessed using a negative binomial model.
In total, 140 areas under the concentration-time curve of mycophenolic acid were analyzed. The findings indicate individual dose adaptation in 53 patients (38%) to achieve an area under the concentration-time curve target of 30-60 mg·h/L. In a multivariable negative binomial model including sex, age at disease onset, time to start of mycophenolate mofetil, previous immunomodulatory treatment, and concomitant prednisone dose, a level of area under the concentration-time curve of mycophenolic acid >45 mg·h/L was significantly associated with a lower relapse rate (rate ratio, 0.65; 95% confidence interval, 0.46 to 0.89;
=0.01).
Therapeutic drug monitoring leading to individualized dosing may improve the efficacy of mycophenolate mofetil in steroid-dependent nephrotic syndrome. Additional prospective studies are warranted to determine the optimal target for area under the concentration-time curve of mycophenolic acid in this population.
Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in
...encoding the Na
-Cl
cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of
,
,
, or
may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown.
We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in
and
, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive
Na
transport.
Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (
=7), m.616T>C (
=1), m.643A>G (
=1) (all in
), and m.4291T>C (
=4, in
). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an
variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts.
pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake.
Pathogenic mtDNA variants in
and
can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.
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