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Background: The severity of X-linked hypophosphataemic rickets (XLH) may be affected by genotype and sex. However, burosumab, a fully humanized monoclonal antibody against fibroblast growth factor 23, has the same pediatric dose recommendation for both sexes (0.8 mg/kg every 2 weeks). Patients and methods: In a retrospective cohort study, we describe the burosumab response differences by sex in children with XLH. Results: We treated 10 children (5 females, mean age at initiation 4.2 ± 3.5 years) with XLH with burosumab. Initial mean serum phosphate was 0.69 ± 0.18 mmol/L in males and 0.86 ± 0.22 mmol/L in females (p = 0.108). The mean ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) was 0.55 ± 0.11 mmol/L in males and 0.76 ± 0.23 mmol/L in females (p = 0.06). The mean starting dose of burosumab was 0.83 ± 0.19 mg/kg subcutaneously every 14 days (males: 0.79 ± 0.19 mg/kg; females: 0.87 ± 0.21 mg/kg, n.s.). Two weeks after starting burosumab, serum phosphate differed significantly between males (0.90 ± 0.21 mmol/L) and females (1.27 ± 0.25 mmol/L) (p = 0.018). All males required a dose increase to try to normalize serum phosphate. On day 140 after starting, the average dose in males increased further to 1.24 ± 0.41 mg/kg to achieve a phosphate of 0.87 ± 0.11 mmol/L while females had a normal phosphate and alkaline phosphatase on the starting dose. After a mean of 458 ± 79 days, the mean burosumab dose/kg in males was 1.68 ± 0.61 mg/kg, mean serum phosphate was 1.08 ± 0.23 mmol/L, mean TmP/GFR was 1.01 ± 0.20, mean alkaline phosphatase had normalized to 303.6 ± 40.7U/L, and mean 1.25(OH)2 vitamin D level was 186.4 ± 16.6 nmol/L. Conclusions: Our findings may suggest a sex difference in response to burosumab in XLH patients. Our data suggest that males may require higher doses. [ABSTRACT FROM AUTHOR]

The article presents answers to a clinical quiz about low molecular weight proteinuria, congenital myopia and hearing loss in a ten-year-old boy.

Background: Wiskott–Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia and eczema and is caused by a mutation in the WAS gene. WAS has heterogeneous clinical manifestations, and its clinically milder form is called X-linked thrombocytopenia (XLT). Patients with WAS/XLT sometimes have kidney complications, the most common of which is immunoglobulin (Ig)A nephropathy associated with aberrant glycosylation of IgA. Case diagnosis/treatment: The patient was a 6-year-old girl who was diagnosed with female XLT at the age of 4 years; she presented with microscopic hematuria and proteinuria at a school urinalysis. Her father had thrombocytopenia and IgA nephropathy while in his 20 s. The patient and her father had the same WAS gene mutations. A kidney biopsy was performed, and no abnormal findings were observed by light microscopy. Immunofluorescence analysis revealed a granular pattern of IgG staining along the capillary wall. Electron microscopy revealed small electron-dense deposits in subepithelial lesions. Consequently, we diagnosed her with membranous nephropathy (MN). Tissue PLA2R and THSD7A were negative, and she was judged unlikely to have secondary MN on the basis of blood test findings and IgG staining. We started the administration of angiotensin-converting enzyme inhibitors, and her proteinuria gradually decreased. Conclusion: To our knowledge, this is the first report of MN in a female WAS/XLT patient. WAS protein expression defects affect all immune system cells; however, the mechanisms underlying the occurrence of autoimmunity are not completely understood. In WAS/XLT patients, MN may develop as a result of increased autoantibody production, similar to other types of immunodeficiency. [ABSTRACT FROM AUTHOR]

Background: The underlying mechanisms of obesity in X-linked hypophosphatemia (XLH) are not known. We aimed to evaluate whether FGF21, an endocrine FGF involved in the regulation of carbohydrate–lipid metabolism, could be involved. Methods: We performed a prospective multicenter cross-sectional study comparing FGF23, Klotho, and FGF21 levels in teenagers with XLH compared to healthy controls (VITADOS cohort) after matching for age, gender, and puberty. Non-parametric tests were performed (results presented as median (min–max)). Results: A total of 40 XLH teenagers (n = 20 Standard Of Care, SOC, n = 20 burosumab) were included. While patients receiving burosumab displayed increased BMI as compared to patients receiving SOC, systolic blood pressure expressed as percentile was progressively and significantly lower when comparing the three groups: 77 (4–99) in SOC, 47 (9–98) in burosumab, and 28 (1–94) in controls (p = 0.007). When compared to patients receiving SOC, patients receiving burosumab displayed significantly increased phosphate and 1,25(OH)2D levels. We found increased Klotho levels in patients receiving burosumab. No differences were found for either carbohydrate–lipid biomarkers or FGF21 between the three groups. A total of 21 XLH patients (53%) had insulin resistance (HOMA > 2.4, N = 10 SOC, N = 11 burosumab). Conclusion: FGF21 does not explain obesity/overweight in XLH. Of note, this study was performed in France in 2018–2019, early after the approval authorizing burosumab only in case of severe XLH despite SOC. As such, the data on systolic blood pressure highlighting a possible impact of burosumab to decrease blood pressure as well as increase Klotho levels deserve further studies given their potential effect on long-term cardiovascular risk. A higher resolution version of the Graphical abstract is available as Supplementary information [ABSTRACT FROM AUTHOR]

Background: X-linked hypophosphatemic rickets (XLH) is the most common cause of inherited rickets. Historically, XLH was treated with oral phosphate and calcitriol (conventional treatment). Burosumab, a fibroblast growth factor 23 (FGF-23) monoclonal antibody, was approved by the United States Food and Drug Administration (FDA) in 2018 for XLH treatment. Nevertheless, conventional treatment of XLH continues to be recommended by some specialists due to lack of published experience with burosumab in the clinical setting. We compared laboratory and radiographic changes observed following transition from conventional therapy to burosumab in pediatric XLH patients as part of routine care. Methods: This retrospective single-center study identified and retroactively studied twelve patients aged 1–18 years old with XLH previously treated with conventional therapy and transitioned to burosumab. Laboratory studies and radiographs were obtained routinely as standard of care during two treatment periods: (1) conventional therapy and (2) burosumab treatment. Laboratory values and radiologic rickets severity scores were compared between periods. Results: All laboratory values demonstrated improvement following 1 month of burosumab treatment, findings which were sustained over the 2-year study period. Rickets severity scores and height z-scores also improved with burosumab. There were no serious adverse events with burosumab, and adverse events overall were very infrequent and mild. One patient developed an asymptomatic mild elevation of serum phosphate while taking burosumab resulting in a temporary pause in therapy. Conclusions: Safety and effectiveness of burosumab in treatment of XLH were demonstrated as burosumab yielded statistically significant improvement in laboratory and radiographic markers of rickets and height compared to conventional therapy. A higher resolution version of the Graphical abstract is available as Supplementary information. [ABSTRACT FROM AUTHOR]

A clinical quiz on a case of a pediatric male patient with gross hematuria, edema, and hypocomplementemia is presented.

A quiz concerning the unexpected fnding in kidney biopsy of a child with nephrotic proteinuria including renal tubular function tests including urine protein electrophoresis.

Specific variants in genes that encode the α3α4α5 chains of type IV collagen cause Alport syndrome (AS), which encompass a clinical spectrum from isolated hematuria to multisystem disease affecting sight, hearing and kidney function. The commonest form is X-linked Alport syndrome (XLAS; COL4A5) with autosomal AS (COL4A3 and COL4A4) comprising a minority of cases. While historic data estimates the frequency of AS at 1:5000–10,000, recent population-based genetic studies suggest the prevalence is considerably higher. Genome-wide association studies (GWAS) have been performed in the Icelandic (deCODE) and UK (UK Biobank) populations, demonstrating an association of type IV collagen gene variants with AS relevant kidney traits. In the Icelandic population, 1 in 600 carries a 2.5-kb COL4A3 coding deletion or a COL4A3 missense variant (rs200287952[A], Gly695Arg), both of which are strongly associated with hematuria and albuminuria (P values = 1.9 × 10−5 to 2.5 × 10−20). In the UK Biobank, COL4A4 rs35138315 (Ser969X; carrier frequency 0.13%) is strongly associated with both hematuria and albuminuria (P = 1.5 × 10−73). Thus, the frequency for autosomal AS is 5–16 times higher than the historic prevalence of all forms of the disorder. Furthermore, COL4A4 rs3518315 (Ser969X) is also a reported founder mutation in families with autosomal dominant focal and segmental glomerulosclerosis and autosomal recessive forms of AS. This supports an additive mode of inheritance for specific variants, wherein a number of copies of a mutation influence disease severity in a cumulative fashion. These studies did not include the X chromosome, excluding analysis of COL4A5, which represents an area for future study. [ABSTRACT FROM AUTHOR]

The article discusses the diagnosis of a 5-year-old boy who was rushed to a pediatric nephrology clinic due to insufficient weight gain, bony deformities, nocturnia, excessive thirst and polyuria. His diagnosis was polyuria. Other topics include the causes of polyuria like Bartter and Gitelman syndromes, and the algorithms for refractory rickets, metabolic alkalosis and polyuria.

Background: Dent disease is associated with low molecular weight proteinuria and hypercalciuria and caused by pathogenic variants in either of two genes: CLCN5 (Dent disease 1) and OCRL (Dent disease 2). It is generally not accompanied by extrarenal manifestations and it is difficult to distinguish Dent disease 1 from Dent disease 2 without gene testing. We retrospectively compared the characteristics of these two diseases using one of the largest cohorts to date. Methods: We performed gene testing for clinically suspected Dent disease, leading to the genetic diagnosis of 85 males: 72 with Dent disease 1 and 13 with Dent disease 2. A retrospective review of the clinical findings and laboratory data obtained from questionnaires submitted in association with the gene testing was conducted for these cases. Results: The following variables had significantly higher levels in Dent disease 2 than in Dent disease 1: height standard deviation score (height SDS), serum creatinine-based estimated GFR (Cr-eGFR) (median: 84 vs. 127 mL/min/1.73 m2, p < 0.01), serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum lactate dehydrogenase (LDH), serum creatine phosphokinase (CK), serum potassium, serum inorganic phosphorus, serum uric acid, urine protein/creatinine ratio (median: 3.5 vs. 1.6 mg/mg, p < 0.01), and urine calcium/creatinine ratio. There were no significant differences in serum sodium, serum calcium, alkaline phosphatase (ALP), urine β2-microglobulin, incidence of nephrocalcinosis, and prevalence of intellectual disability or autism spectrum disorder. Conclusions: The clinical and laboratory features of Dent disease 1 and Dent disease 2 were shown in this study. Notably, patients with Dent disease 2 showed kidney dysfunction at a younger age, which should provide a clue for the differential diagnosis of these diseases. [ABSTRACT FROM AUTHOR]

The article presents questions on the possible diagnosis and treatments of a 10-year-old male who was presented to a pediatric department of nephrology in May 2017 due to kidney impairment and was tested with autoimmune diabetes autoantibodies.

Background: Dent disease type 1 (DD1) is a rare X-linked disorder caused mainly by CLCN5 mutations. Patients may present with nephrotic-range proteinuria leading to erroneous diagnosis of focal segmental glomerulosclerosis (FSGS) and unnecessary immunosuppressive treatments. Methods: The following cohorts were screened for CLCN5 mutations: Chronic Kidney Disease in Children (CKiD; n = 112); Multicenter FSGS-Clinical Trial (FSGS-CT) (n = 96), and Novel Therapies for Resistant FSGS Trial (FONT) (n = 30). Urinary α1-microglobulin (α1M), albumin (A), total protein (TP), and creatinine (Cr) were assessed from CKiD subjects (n = 104); DD1 patients (n = 14); and DD1 carriers (DC; n = 8). TP/Cr, α1M/Cr, α1M/TP, and A/TP from the CKiD cohort were compared with DD1 and DC. Results: No CLCN5 mutations were detected. TP/Cr was lower in DC and CKiD with tubulointerstitial disease than in DD1 and CKiD with glomerular disease (p < 0.002). α1M/Cr was higher in DD1 than in CKiD and DC (p < 0.001). A/TP was lower in DD1, DC, and CKiD with tubulointerstitial disease and higher in CKiD with glomerular disease (p < 0.001). Thresholds for A/TP of ≤ 0.21 and α1M/Cr of ≥ 120 mg/g (> 13.6 mg/mmol) creatinine were good screens for Dent disease. Conclusions: CLCN5 mutations were not seen in screened CKiD/FSGS cohorts. In our study, a cutoff of TP/Cr > 600 mg/g (> 68 mg/mmol) and A/TP of < 0.3 had a high sensitivity and specificity to distinguish DD1 from both CKiD glomerular and tubulointerstitial cohorts. α1M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations. [ABSTRACT FROM AUTHOR]

The diagnosis of Alport syndrome is suspected when an individual has haematuria or renal failure, together with a hearing loss; haematuria or renal failure, and a family history of Alport syndrome; or a pathognomonic Alport feature, such as lenticonus, fleck retinopathy, a lamellated glomerular basement membrane (GBM), or a GBM that lacks the collagen IV α3α4α5 network. The diagnosis of Alport syndrome is optimally confirmed by the demonstration of a mutation in the COL4A5 gene or two mutations in trans in the COL4A3 or COL4A4 genes. In practice, genetic testing for Alport syndrome is not widely available, and even with testing, causative mutations are not demonstrated in 5% of cases. Often, haematuria is only known in some family members, and the other characteristic features are not present or have not been sought. Where Alport syndrome remains likely, it is important to distinguish between X-linked inheritance, which occurs in 85% of families, and autosomal recessive inheritance, in the remaining 15%. This distinction is important because different modes of inheritance mean that different family members are at risk of being affected. Clinicians generally rely on the presence of haematuria to identify affected individuals in families with suspected Alport syndrome and on the information from three-generational family trees to assess the likely mode of inheritance. While often helpful, this strategy can also be misleading. The major sources of error are families with few members or where few members are tested; families comprising mainly women, where the typical Alport features are absent; families where the father is not available for testing for haematuria; and families with a coincidental renal disease. These difficulties emphasise the helpfulness of genetic testing in distinguishing between X-linked and autosomal recessively inherited forms of Alport syndrome. [ABSTRACT FROM AUTHOR]

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD), first described in 2005, is a rare genetic X-linked disease, presenting with hyponatremia, hyposmolarity, euvolemia, inappropriately concentrated urine, increased natriuresis, and undetectable or very low arginine-vasopressine (AVP) circulating levels. It can occur in neonates, infants, or later in life. NSIAD must be early recognized and treated to prevent severe hyponatremia, which can show a dangerous impact on neonatal outcome. In fact, it potentially leads to death or, in case of survival, neurologic sequelae. This review is an update of NSIAD 12 years after the first description, focusing on reported cases of neonatal and infantile onset. The different molecular patterns affecting the AVP receptor 2 (V2R) and determining its gain of function are reported in detail; moreover, we also provide a comparison between the different triggers involved in the development of hyponatremia, the evolution of the symptoms, and modality and efficacy of the different treatments available. [ABSTRACT FROM AUTHOR]

Background: The oculocerebrorenal syndrome of Lowe gene ( OCRL) is located on chromosome Xq25-26 and encodes an inositol polyphosphate-5-phosphatase (OCRL-1). Mutations in this gene cause Lowe syndrome (LS) or type 2 Dent disease, of which low-molecular-weight (LMW) proteinuria is a characteristic feature. Megalin is considered to play an important role in the development of renal tubular proteinuria. Two forms of megalin are excreted into the urine: full-length megalin (C-megalin) and megalin ectodomain (A-megalin). We have explored the role of megalin in the development of LMW proteinuria in patients with OCRL mutations by determining urinary megalin fractions. Methods: We measured A- and C-megalin in spot urine samples from five male patients with OCRL mutations (median age 9 years), using sandwich enzyme-linked immunosorbent assays, and adjusted the obtained values for excreted creatinine. The results were compared with those of 50 control subjects and one patient with type 1 Dent disease (T1D). Results: All patients demonstrated normal levels of urinary C-megalin. However, patients with OCRL mutations or T1D showed abnormally low levels of urinary A-megalin, with the exception of one 5-year-old boy with LS, who was the youngest patient enrolled in the study. Conclusions: Decreased excretion of urinary A-megalin in four out of five patients with OCRL mutations suggests that LMW proteinuria may be caused by impaired megalin recycling within the proximal tubular cells. Homologous enzymes, similar to inositol polyphosphate-5-phosphatase B in mice, may help to compensate for defective OCRL-1 function during early childhood. [ABSTRACT FROM AUTHOR]

Background: Dent disease 1 is a rare cause of chronic kidney disease (CKD) in childhood secondary to mutations in the gene encoding the chloride-proton exchanger, CLC-5, which is found mainly in the proximal tubule. Clinical manifestations are variable and there are no known genotype-phenotype correlations. Case diagnosis/treatment: The proband was identified as having a mutation in CLCN5. The extended family of the proband was invited to participate in a study of Dent disease after several males were noted to have a history of CKD. Urine retinol binding protein, urine calcium, serum creatinine, and DNA samples were collected for analysis. Ten hemizygous males and 6 heterozygous females were identified. Advanced CKD was detected in 3 males (1 child). Renal biopsies in 4 children showed both glomerular and tubulo-interstitial changes. There was no correlation between age and disease severity. Conclusions: This is the first reported family from the southern hemisphere with this condition. A novel CLCN5 mutation is described, c.1618G>C (p.Ala540Pro). The severity of renal disease varies greatly among individuals. [ABSTRACT FROM AUTHOR]

The article provides answers on the possible diagnosis and treatments of a 10-year-old male who was presented to a pediatric department of nephrology in May 2017 due to kidney impairment, with diagnosis of secondary membranous glomerulonephritis (MGN) and treatments like oral prednisolone.

Background: Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder is an autoimmune disease caused by loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor. These mutations affect the normal function of circulating regulatory T cells. IPEX is characterized by profound immune dysregulation leading to dermatitis, enteropathy, multiple endocrinopathies and failure to thrive. Different forms of renal injury have also been noted in these patients but these have been described to a very limited extent. Case-Diagnosis: Three patients with IPEX with characteristic renal findings and mutations in FOXP3, including one novel mutation, are described. Case presentations are followed by a review of the renal manifestations noted in IPEX and the range of therapeutic options for this disorder. Conclusions: We recommend that IPEX be considered in the differential diagnosis of young children who present with signs of immune dysregulation with a concomitant renal biopsy demonstrating immune complex deposition in a membranous-like pattern and/or interstitial nephritis. [ABSTRACT FROM AUTHOR]