Idiopathic infantile hypercalcemia (IIH) is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis. Recently, mutations in the vitamin D ...catabolizing enzyme 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) were described that lead to increased sensitivity to vitamin D due to accumulation of the active metabolite 1,25-(OH)2D3. In a subgroup of patients who presented in early infancy with renal phosphate wasting and symptomatic hypercalcemia, mutations in CYP24A1 were excluded. Four patients from families with parental consanguinity were subjected to homozygosity mapping that identified a second IIH gene locus on chromosome 5q35 with a maximum logarithm of odds (LOD) score of 6.79. The sequence analysis of the most promising candidate gene, SLC34A1 encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four index cases and in 12 patients with sporadic IIH. Functional studies of mutant NaPi-IIa in Xenopus oocytes and opossum kidney (OK) cells demonstrated disturbed trafficking to the plasma membrane and loss of phosphate transport activity. Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice highlighted the effect of phosphate depletion and fibroblast growth factor-23 suppression on the development of the IIH phenotype. The human and mice data together demonstrate that primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25-(OH)2D3 with subsequent symptomatic hypercalcemia. Clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation. Therefore, early differentiation between SLC34A1 (NaPi-IIa) and CYP24A1 (24-hydroxylase) defects appears critical for targeted therapy in patients with IIH.
This study implicates loss-of-function variants in
MAGED2
as a cause of X-linked transient antenatal Bartter's syndrome and polyhydramnios. The authors also showed that MAGE-D2 regulates key ...components of salt reabsorption in the distal renal tubule.
In the second trimester of gestation, fetal kidneys become the predominant source of amniotic fluid, which is primarily removed by the fetus swallowing it.
1
Excessive amniotic fluid (called polyhydramnios) is caused by an imbalance between its production and removal — as observed, for instance, in fetuses with esophageal atresia. Overall, polyhydramnios has a prevalence of 1 to 2% and confers an increased risk of adverse perinatal outcome, especially preterm delivery.
2
The cause of polyhydramnios remains unknown in 30 to 60% of cases.
2
,
3
There are only a few mendelian diseases associated with polyhydramnios, including antenatal Bartter’s syndrome, a rare autosomal . . .
Cystinosis is caused by mutations in the CTNS gene (17p13.2), which encodes for a lysosomal cystine/proton symporter termed cystinosin. It is the most common cause of inherited renal Fanconi syndrome ...in young children. Because of its rarity, the diagnosis and specific treatment of cystinosis are frequently delayed, which has a significant impact on the overall prognosis. In this document, we have summarized expert opinions on several aspects of the disease to improve knowledge and provide guidance for diagnosis and treatment.
Chitotriosidase enzyme (EC: 3.2.1.14) is the major active chitinase in the human body. It is produced mainly by activated macrophages, in which its expression is regulated by multiple intrinsic and ...extrinsic signals. Chitotriosidase was confirmed as essential element in the innate immunity against chitin containing organisms such as fungi and protozoa; however, its immunomodulatory effects extend far beyond innate immunity. In the current review, we will try to explore the expanding spectrum of immunological roles played by chitotriosidase enzyme in human health and disease and will discuss its up-to-date clinical value.
Receptor-mediated endocytosis, involving megalin and cubilin, mediates renal proximal-tubular reabsorption and is decreased in Dent disease because of mutations of the chloride/proton antiporter, ...chloride channel-5 (CLC-5), resulting in low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. To facilitate studies of receptor-mediated endocytosis and the role of CLC-5, we established conditionally immortalized proximal-tubular epithelial cell lines (ciPTECs) from three patients with CLC-5 mutations (30:insH, R637X, and del132-241) and a normal male. Confocal microscopy using the tight junction marker zona occludens-1 (ZO-1) and end-binding protein-1 (EB-1), which is specific for the plus end of microtubules demonstrated that the ciPTECs polarized. Receptor-mediated endocytic uptake of fluorescent albumin and transferrin in 30:insH and R637X ciPTECs was significantly decreased, compared with normal ciPTECs, and could be further reduced by competition with 10-fold excess of unlabeled albumin and transferrin, whereas in the del132-241 ciPTEC, receptor-mediated endocytic uptake was abolished. Investigation of endosomal acidification by live-cell imaging of pHluorin-VAMP2 (vesicle-associated membrane protein-2), a pH-sensitive-GFP construct, revealed that the endosomal pH in normal and 30:insH ciPTECs was similar, whereas in del132-241 and R637X ciPTECs, it was significantly more alkaline, indicating defective acidification in these ciPTECs. The addition of bafilomycin-A1, a V-ATPase inhibitor, raised the pH significantly in all ciPTECs, demonstrating that the differences in acidification were not due to alterations in the V-ATPase, but instead to abnormalities of CLC-5. Thus, our studies, which have established human Dent disease ciPTECs that will facilitate studies of mechanisms in renal reabsorption, demonstrate that Dent disease-causing CLC-5 mutations have differing effects on endosomal acidification and receptor-mediated endocytosis that may not be coupled.
The life expectancy of individuals with sickle cell disease has increased over the years, majorly due to an overall improvement in diagnosis and medical care. Nevertheless, this improved longevity ...has resulted in an increased prevalence of chronic complications such as sickle cell nephropathy (SCN), which poses a challenge to the medical care of the patient, shortening the lifespan of patients by 20–30 years. Clinical presentation of SCN is age-dependent, with kidney dysfunction slowly beginning to develop from childhood, progressing to chronic kidney disease and kidney failure during the third and fourth decades of life. This review explores the epidemiology, pathology, pathophysiology, clinical presentation, and management of SCN by focusing on the pediatric population. It also discusses the factors that can modify SCN susceptibility.
Summary Glomerular hyperfiltration and albuminuria are frequent kidney abnormalities in children with sickle cell anaemia (SCA). However, little is known about their persistence in African SCA ...children. This prospective study included 600 steady‐state SCA children aged 2–18 years from the Democratic Republic of Congo. Participants were genotyped for apolipoprotein L1 ( APOL1 ) risk variants (RVs) and haem oxygenase‐1 ( HMOX1 ) GT‐dinucleotide repeats. Kidney abnormalities were defined as albuminuria, hyperfiltration or decreased estimated creatinine‐based glomerular filtration rate (eGFRcr). At baseline, 247/600 (41.2%) participants presented with kidney abnormalities: 82/592 (13.8%) with albuminuria, 184/587 (31.3%) with hyperfiltration and 15/587 (2.6%) with decreased eGFRcr. After a median follow‐up of 5 months, repeated testing was performed in 180/247 (72.9%) available participants. Persistent hyperfiltration and persistent albuminuria (PA) were present in 29.2% (38/130) and 39.7% (23/58) respectively. eGFR normalized in all participants with a baseline decreased eGFRcr. Haemoglobinuria ( p = 0.017) and male gender ( p = 0.047) were significantly associated with PA and persistent hyperfiltration respectively. APOL1 RVs (G1G1/G2G2/G1G2) were borderline associated with PA ( p = 0.075), while HMOX1 long repeat was not associated with any persistent kidney abnormality. This study reveals that a single screening can overestimate the rate of kidney abnormalities in children with SCA and could lead to overtreatment.
Summary
Clinical and genetic factors have been reported as influencing the development of sickle cell nephropathy (SCN). However, such data remain limited in the paediatric population. In this ...cross‐sectional study, we enrolled 361 sickle cell disease children from the Democratic Republic of Congo. Participants were genotyped for the beta (β)‐globin gene, apolipoprotein L1 (APOL1) risk variants, and haem oxygenase‐1 (HMOX1) GT‐dinucleotide repeats. As markers of kidney damage, albuminuria, hyperfiltration and decreased estimated glomerular filtration with creatinine (eGFRcr) were measured. An association of independent clinical and genetic factors with these markers of kidney damage were assessed via regression analysis. Genetic sequencing confirmed sickle cell anaemia in 326 participants. Albuminuria, hyperfiltration and decreased eGFRcr were present in 65 (20%), 52 (16%) and 18 (5·5%) patients, respectively. Regression analysis revealed frequent blood transfusions, indirect bilirubin and male gender as clinical predictors of SCN. APOL1 high‐risk genotype (G1/G1, G2/G2 and G1/G2) was significantly associated with albuminuria (P = 0·04) and hyperfiltration (P = 0·001). HMOX1 GT‐dinucleotide long repeats were significantly associated with lower eGFRcr. The study revealed a high burden of kidney damage among Congolese children and provided evidence of the possible role of APOL1 and HMOX1 in making children more susceptible to kidney complications.
HIV infection remains one of the leading causes of morbidity and mortality worldwide, especially in children living in resource-limited settings. Although the World Health Organization (WHO) recently ...recommended antiretroviral therapy (ART) initiation upon diagnosis regardless of the number of CD4, ART access remains limited, especially in children living in sub-Saharan Africa (SSA). HIV-infected children who do not receive appropriate ART are at increased risk of developing HIV-associated nephropathy (HIVAN). Although due to genetic susceptibility, SSA is recognized to be the epicenter of HIVAN, limited information is available regarding the burden of HIVAN in children living in Africa. The present review discusses the information available to date on the prevalence, pathogenesis, risk factors, diagnosis, and management of HIVAN in children, focusing on related challenges in a resource-limited setting.
Presented are the main design features and performance results of the cathode strip chambers (CSCs) for the CMS Endcap Muon System. The six-plane structure of these chambers yields a spatial ...resolution of about 80 /spl mu/m, essentially uniform and independent of the strip width (up to 16 mm, which is unusually wide for the cathode-to-anode wire distance of 5 mm). In addition, the net spatial resolution of about one-tenth of the strip width at the hardware trigger level (300ns) is obtained using a simple network of comparators. The time resolution achieved at the trigger level is /spl sim/4ns (RMS) that allows unambiguous tagging of bunch crossing occurring every 25 ns. Aging tests, including those obtained with a recirculating gas system, showed only minor aging effects. The aging studies were performed with large-scale chambers; 700 m of wire were irradiated for a dose up to 0.4 C/cm of the total accumulated charge.