Genotype-phenotype correlation of X-linked Alport syndrome observed in both genders: a multicenter study in South Korea.

The genotype-phenotype correlation of the X-linked Alport syndrome (XLAS) has been well elucidated in males, whereas it remains unclear in females. In this multicenter retrospective study, we analyzed the genotype-phenotype correlation in 216 Korean patients (male:female = 130:86) with XLAS between 2000 and 2021. The patients were divided into three groups according to their genotypes: the non-truncating group, the abnormal splicing group, and the truncating group. In male patients, approximately 60% developed kidney failure at the median age of 25.0 years, and kidney survival showed significant differences between the non-truncating and truncating groups (P < 0.001, hazard ratio (HR) 2.8) and splicing and truncating groups (P = 0.002, HR 3.1). Sensorineural hearing loss was detected in 65.1% of male patients, while hearing survival periods showed a highly significant difference between the non-truncating and truncating groups (P < 0.001, HR 5.1). In female patients, approximately 20% developed kidney failure at the median age of 50.2 years. The kidney survival was significantly different between the non-truncating and truncating groups (P = 0.006, HR 5.7). Our findings support the presence of genotype-phenotype correlation not only in male patients but also in female patients with XLAS.

Urine specific gravity, pyuria, and neutrophil gelatinase-associated lipocalin for identifying urinary tract infection in young children.

BACKGROUND: To determine whether urine neutrophil gelatinase-associated lipocalin (uNGAL) might be superior to pyuria for detecting urinary tract infection (UTI) regardless of urine specific gravity (SG) in young children. METHODS: We conducted a retrospective analysis of children aged < 3 years who were evaluated for UTI with urinalysis, urine culture, and uNGAL measurements during a 5-year period. Sensitivity, specificity, likelihood ratios (LRs), predictive values (PVs), area under the curves (AUCs) of uNGAL cut-off levels, and various microscopic pyuria thresholds for detecting UTI were calculated for dilute (SG < 1.015) and concentrated urine (SG ≥ 1.015). RESULTS: Of 456 children included, 218 had UTI. The diagnostic value of urine white blood cell (WBC) concentration to define UTI changed with urine SG. For detecting UTI, uNGAL cut-off of 68.4 ng/mL had higher AUC values than pyuria ≥ 5 WBCs/high power field (HPF) for dilute and concentrated urine samples (both P < 0.05). Positive LR and PV and specificity of uNGAL were all greater than those of pyuria ≥ 5 WBCs/HPF regardless of urine SG, although the sensitivity of pyuria ≥ 5 WBCs/HPF was higher than that of uNGAL cut-off for dilute urine (93.8% vs. 83.5%) (P < 0.05). At uNGAL ≥ 68.4 ng/mL and ≥ 5 WBCs/HPF, posttest probabilities of UTI were 68.8% and 57.5% for dilute urine and 73.4% and 57.3% for concentrated urine, respectively. CONCLUSIONS: Urine SG can affect the diagnostic performance of pyuria for detecting UTI and uNGAL might be helpful for identifying UTI regardless of urine SG in young children. A higher resolution version of the Graphical abstract is available as Supplementary information.

Exposure to airborne particulate matter induces renal tubular cell injury in vitro: the role of vitamin D signaling and renin-angiotensin system.

Background: Exposure to air pollution can interfere with the vitamin D endocrine system. This study investigated the effects of airborne particulate matter (PM) on renal tubular cell injury in vitro and explored the underlying mechanisms. Methods: HK-2 human renal proximal tubule cells were treated with PM with or without 1,25(OH)2D3 analog, 19-Nor-1,25(OH)2D2 (paricalcitol, 10 nM) for 48 h. The dose- and time-dependent cytotoxicity of PM with or without paricalcitol was determined via cell counting kit-8 assay. Cellular oxidative stress was assessed using commercially available enzyme-linked immunosorbent assay kits. The protein expression of vitamin D receptor (VDR), cytochrome P450(CYP)27B1, CYP24A1, renin, angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AT1), nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor-kB (NF-kB), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 was determined. Results: PM exposure decreased HK-2 cell viability in a dose- and time-dependent manner. The activities of superoxide dismutase and malondialdehyde in HK-2 cells increased significantly in the group exposed to PM. PM exposure decreased VDR and Nrf2, while increasing CYP27B1, renin, ACE, AT1, NF-kB, TNF-α, and IL-6. The expression of VDR, CYP27B1, renin, ACE, AT1, and TNF-α was reversed by paricalcitol treatment. Paricalcitol also restored the cell viability of PM-exposed HK-2 cells. Conclusion: Our findings indicate that exposure to PM induces renal proximal tubular cell injury, concomitant with alteration of vitamin D endocrine system and renin angiotensin system. Vitamin D could attenuate renal tubular cell damage following PM exposure by suppressing the renin-angiotensin system and by partially inhibiting the inflammatory response.

Correction: Park et al. Genetic Study in Korean Pediatric Patients with Steroid-Resistant Nephrotic Syndrome or Focal Segmental Glomerulosclerosis. J. Clin. Med. 2020, 9, 2013.

In the original article [...].

Characteristics of pediatric rhabdomyolysis and the associated risk factors for acute kidney injury: a retrospective multicenter study in Korea.

BACKGROUND: The clinical features of pediatric rhabdomyolysis differ from those of the adults with rhabdomyolysis; however, multicenter studies are lacking. This study aimed to investigate the characteristics of pediatric rhabdomyolysis and reveal the risk factors for acute kidney injury (AKI) in such cases. METHODS: This retrospective study analyzed the medical records of children and adolescents diagnosed with rhabdomyolysis at 23 hospitals in South Korea between January 2007 and December 2016. RESULTS: Among 880 patients, those aged 3 to 5 years old composed the largest subgroup (19.4%), and all age subgroups were predominantly male. The incidence of AKI was 11.3%. Neurological disorders (53.6%) and infection (39.0%) were the most common underlying disorder and cause of rhabdomyolysis, respectively. The median age at diagnosis in the AKI subgroup was older than that in the non-AKI subgroup (12.2 years vs. 8.0 years). There were no significant differences in body mass index, myalgia, dark-colored urine, or the number of causal factors between the two AKI-status subgroups. The multivariate logistic regression model indicated that the following factors were independently associated with AKI: multiorgan failure, presence of an underlying disorder, strong positive urine occult blood, increased aspartate aminotransferase and uric acid levels, and reduced calcium levels. CONCLUSIONS: Our study revealed characteristic clinical and laboratory features of rhabdomyolysis in a Korean pediatric population and highlighted the risk factors for AKI in these cases. Our findings will contribute to a greater understanding of pediatric rhabdomyolysis and may enable early intervention against rhabdomyolysis-induced AKI.

Obesity and chronic kidney disease: prevalence, mechanism, and management.

The prevalence of childhood obesity is increasing worldwide at an alarming rate. While obesity is known to increase a variety of cardiovascular and metabolic diseases, it also acts as a risk factor for the development and progression of chronic kidney disease (CKD). During childhood and adolescence, severe obesity is associated with an increased prevalence and incidence of the early stages of kidney disease. Importantly, children born to obese mothers are also at increased risk of developing obesity and CKD later in life. The potential mechanisms underlying the association between obesity and CKD include hemodynamic factors, metabolic effects, and lipid nephrotoxicity. Weight reduction via increased physical activity, caloric restriction, treatment with angiotensin-converting enzyme inhibitors, and judicious bariatric surgery can be used to control obesity and obesity-related kidney disease. Preventive strategies to halt the obesity epidemic in the healthcare community are needed to reduce the widespread deleterious consequences of obesity including CKD development and progression.

Impact of early-life weight status on urinary tract infections in children: a nationwide population-based study in Korea.

OBJECTIVES: We aimed to evaluate the association between early-life weight status and urinary tract infection (UTI) risk in children. METHODS: A nationwide study was conducted using Korean National Health Screening (NHS) data and National Health Insurance Service data. A sample cohort was selected using data from the 2014 and 2015 NHS for infants and children (4-71 months) and followed up until the end of 2017. Participants were divided into 4 groups (underweight, normal weight, overweight, and obese) based on the weight-for-age (< 2 years) or body mass index (≥ 2 years). Hazard ratios (HRs) with 95% confidence intervals (CIs) for developing UTIs, cystitis, and acute pyelonephritis (APN) were calculated using a Cox proportional hazard model. RESULTS: Of 1,653,106 enrolled children, 120,142 (7.3%) developed UTIs, cystitis, and APN during follow-up. The underweight, overweight, and obese groups had higher risks of UTIs than the reference group after adjusting for age, sex, birth weight, and preterm birth. Between 2 years and 6 years of age, boys with underweight had a high risk of UTI and APN, while girls with overweight and obesity revealed elevated risks of UTIs, cystitis, and APN. The HRs for APN in boys with underweight and in girls with obesity were 1.46 (95% CI, 1.03 to 2.07) and 1.41 (95% CI, 1.13 to 1.75), respectively, after adjusting for age, sex, birth weight, and preterm birth. The incidence of APN did not decrease with age in underweight and obese children aged 2-6 years. CONCLUSIONS: Children with underweight, overweight, and obesity may be at high risk for UTIs.

Lower albumin level and longer disease duration are risk factors of acute kidney injury in hospitalized children with nephrotic syndrome.

BACKGROUND: Children with nephrotic syndrome (NS) are at an increased risk of acute kidney injury (AKI) and the incidence of AKI in this population is reportedly increasing. This study aimed to investigate the incidence, clinical profiles, and risk factors of AKI in hospitalized children with NS through a nationwide study. METHODS: This retrospective multicenter study included 14 pediatric nephrology centers in Korea. From 2013 to 2017, a total of 814 patients with idiopathic NS were cared for at participating centers. Among them, 363 patients were hospitalized for NS and investigated in this study. RESULTS: A total of 363 children with NS were hospitalized 574 times. AKI occurred in 93 admissions (16.2%) of 89 patients: 30 (32.3%) stage 1; 24 (25.8%) stage 2; and 39 (41.9%) stage 3. Multivariate logistic regression analysis showed that longer disease duration, lower albumin level, and methylprednisolone pulse treatment were significantly associated with AKI development in hospitalized children with NS. AKI was associated with a longer hospital stay than non-AKI (median 10 vs. 7 days, P = 0.001). Among 93 admissions, 85 (91.4%) episodes recovered from AKI without complication, whereas 6 (6.5%) progressed to advanced chronic kidney disease (CKD). CONCLUSIONS: AKI is not uncommon in hospitalized children with NS, and its incidence in this nationwide study was 16.2%. Risk factors for AKI in hospitalized children with NS include longer disease duration, lower albumin level, and methylprednisolone pulse therapy. Pediatric NS patients with these characteristics should be under more strict scrutiny for the occurrence of AKI. Graphical abstract.

Urinary neutrophil gelatinase-associated lipocalin: a marker of urinary tract infection among febrile children.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a valuable biomarker of urinary tract infection (UTI) in children. PURPOSE: This study aimed to compare the diagnostic accuracy of urinary NGAL (uNGAL) with those of serum C-reactive protein (CRP) and white blood cell (WBC) count for predicting UTI and acute pyelonephritis (APN) in febrile children. METHODS: The medical charts of children undergoing uNGAL measurements between November 2017 and August 2019 were retrospectively reviewed. Patients with a suspected or diagnosed UTIs were included. The diagnostic accuracies of uNGAL, serum CRP, and WBC count for detecting UTI and APN were investigated. Independent predictors of UTI and APN were investigated using multivariable logistic regression analyses. RESULTS: A total of 321 children were enrolled in this study. The uNGAL levels were higher in the UTI group (n=157) than in the non-UTI group (n=164) (P<0.05). Among children with a UTI, uNGAL levels were higher in the APN group (n=70) than, the non-APN group (n=87) (P<0.05). In the multivariate analysis, uNGAL was independently associated with UTI and APN (both P<0.05). Serum CRP and WBC count were not correlated with the presence of UTI and APN. Receiver operating curve analyses showed that the uNGAL level had the highest area under the curve (AUC) for predicting UTI and APN, respectively (AUC, uNGAL vs. CRP vs. WBC count, 0.860 vs. 0.608 vs. 0.669 for UTI; 0.780 vs. 0.680 vs. 0.639 for APN, all P<0.05, respectively). The predictive values and likelihood ratios of uNGAL were superior to those of serum CRP and WBC count for detecting UTI and APN at each cutoff level. CONCLUSION: UNGAL may be more useful than serum CRP and WBC count for identifying and assessing UTI in febrile children.

Angiotensin inhibition and cellular senescence in the developing rat kidney.

Cellular senescence is important for the maintenance of tissue homeostasis during normal development. In this study, we aimed to investigate the effect of renin angiotensin system (RAS) blockade on renal cell senescence in the developing rat kidney. Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle for seven days after birth. We investigated the intrarenal expressions of cell cycle regulators p21 and p16 with immunoblots and immunohistochemistry at postnatal day 8. For the determination of renal cellular senescence, immunostaining for senescence-associated ß-galactosidase (SA-ß-gal) and telomerase reverse transcriptase (TERT) was also performed. Enalapril treatment showed significant alterations in cellular senescence in neonatal rat kidneys. In the enalapril-treated group, intrarenal p16 and p21 protein expressions decreased compared to controls. The expressions of both p21 and p16 were reduced throughout the renal cortex and medulla of enalapril-treated rats. The immunoreactivity of TERT in enalapril-treated kidneys was also weaker than that in control kidneys. Control kidneys revealed a clear positive SA-ß-gal signal in the cortical tubules; however, SA-ß-gal activity was noticeably lower in the enalapril-treated kidneys than in control kidneys. Interruption of the RAS during postnatal nephrogenesis may disrupt physiologic renal cellular senescence in the developing rat kidney.

Remission of Proteinuria May Protect against Progression to Chronic Kidney Disease in Pediatric-Onset IgA Nephropathy.

Immunoglobulin A nephropathy (IgAN) is one of the most common primary glomerulopathies diagnosed in children and adolescents. This study aimed to evaluate the clinical features in and outcomes of pediatric IgAN over the last 30 years. Patients who were diagnosed before age of 18 at 20 centers in Korea were evaluated retrospectively. Of the 1154 patients (768 males, 386 females) with a median follow-up of 5 years, 5.6% (n = 65) progressed to stage 3-5 chronic kidney disease (CKD). The 10- and 20-year CKD-free survival rates were 91.2% and 75.6%, respectively. Outcomes did not differ when comparing those in Korea who were diagnosed prior to versus after the year 2000. On multivariate analysis, combined asymptomatic hematuria and proteinuria as presenting symptoms and decreased renal function at the time of biopsy were associated with progression to CKD, while remission of proteinuria was negatively associated with this outcome. Patients who presented with gross hematuria or nephrotic syndrome tended toward positive outcomes, especially if they ultimately achieved remission. While remission of proteinuria might imply that the disease is inherently less aggressive, it also can be achieved by management. Therefore, more aggressive management might be required for pediatric-onset IgAN.

Genetic Study in Korean Pediatric Patients with Steroid-Resistant Nephrotic Syndrome or Focal Segmental Glomerulosclerosis.

Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage renal disease (ESRD) in childhood and is mostly associated with focal segmental glomerulosclerosis (FSGS). More than 50 monogenic causes of SRNS or FSGS have been identified. Recently, the mutation detection rate in pediatric patients with SRNS has been reported to be approximately 30%. In this study, genotype-phenotype correlations in a cohort of 291 Korean pediatric patients with SRNS/FSGS were analyzed. The overall mutation detection rate was 43.6% (127 of 291 patients). WT1 was the most common causative gene (23.6%), followed by COQ6 (9.4%), NPHS1 (8.7%), NUP107 (7.1%), and COQ8B (6.3%). Mutations in COQ6, NUP107, and COQ8B were more frequently detected, and mutations in NPHS2 were less commonly detected in this cohort than in study cohorts from Western countries. The mutation detection rate was higher in patients with congenital onset, those who presented with proteinuria or chronic kidney disease/ESRD, and those who did not receive steroid treatment. Genetic diagnosis in patients with SRNS provides not only definitive diagnosis but also valuable information for decisions on treatment policy and prediction of prognosis. Therefore, further genotype-phenotype correlation studies are required.

Associations of Plasma Neutrophil Gelatinase-associated Lipocalin, Anemia, and Renal Scarring in Children with Febrile Urinary Tract Infections.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL), a bacteriostatic agent, is known to inhibit erythropoiesis leading to anemia. We aimed to investigate the associations of NGAL, anemia, and renal scarring in children with febrile urinary tract infections (UTIs). METHODS: We retrospectively reviewed the medical records of 261 children with febrile UTIs. The relationship between the presence of anemia and plasma NGAL levels was investigated. NGAL performance in comparison with serum C-reactive protein (CRP) at admission and after 72 hours of treatment was also evaluated for the prediction of renal scarring as well as acute pyelonephritis (APN) and vesicoureteral reflux (VUR). RESULTS: Plasma NGAL levels were elevated in patients with anemia compared with those without anemia. Multiple linear regression analysis showed an inverse relationship between NGAL levels and erythrocyte counts (standard ß = -0.397, P < 0.001). Increased NGAL, but not CRP, was independently associated with the presence of anemia (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.07-5.27; P < 0.05). Receiver operating curve analyses showed good diagnostic profiles of pre- and post-treatment NGAL for identifying APN, VUR, and renal scarring (all P < 0.05). For detecting renal scars, the area under the curve of post-treatment NGAL (0.730; 95% CI, 0.591-0.843) was higher than that of post-treatment CRP (0.520; 95% CI, 0.395-0.643; P < 0.05). The presence of anemia and elevated NGAL at admission (> 150 ng/mL) were independent risk factors for renal scarring in children with febrile UTIs. With anemia, NGAL levels increased consecutively in children with febrile UTI without renal involvement, with APN without scar, and with APN with renal scarring. CONCLUSION: Increased plasma NGAL levels may be associated with the presence of anemia and renal scarring in children with febrile UTIs.

A Novel VPS33B Variant Identified by Exome Sequencing in a Patient with Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome.

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare autosomal recessive multisystemic disease that is associated with the liver, kidney, skin, and central nervous and musculoskeletal systems. ARC occurs as a result of mutations in the VPS33B (Vacuolar protein sorting 33 homolog B) or VIPAR (VPS33B interacting protein, apical-basolateral polarity regulator) genes. A female infant presented with neonatal cholestasis with a severe clinical outcome. She was diagnosed with ARC syndrome using targeted exome sequencing (TES). Exome sequencing revealed compound heterozygous mutations, c.707A>T and c.239+5G>A, in VPS33B, where c.707A>T was a novel variant; the resultant functional protein defects were predicted via in silico analysis. c.239+5G>A, a pathogenic mutation that affects splicing, is found in less than 0.1% of the general population. Invasive techniques, such as liver biopsies, did not contribute to a differential diagnosis of ARC syndrome; thus, early TES together with clinical presentations constituted an apparently accurate diagnostic procedure.

Angiotensin inhibition in the developing kidney; tubulointerstitial effect.

BACKGROUND: Renin-angiotensin system (RAS) blockade during nephrogenesis causes a broad range of renal mal-development. Here, we hypothesized that disruption of renal lymphangiogenesis may contribute to tubulointerstitial alterations after RAS blockade during kidney maturation. METHODS: Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle for 7 days after birth. Lymphangiogenesis was assessed via immunostaining and/or immunoblots for vascular endothelial growth factor (VEGF)-C, VEGF receptor (VEGFR)-3, Podoplanin, and Ki-67. The intrarenal expression of fibroblast growth factor (FGF)-1, FGF-2, FGF receptor (R)-1, α-smooth muscle actin (α-SMA), and fibroblast-specific protein (FSP)-1 was also determined. Sirius Red staining was performed to evaluate interstitial collagen deposition. RESULTS: On postnatal day 8, renal lymphangiogenesis was disrupted by neonatal enalapril treatment. The expression of podoplanin and Ki-67 decreased in enalapril-treated kidneys. While the expression of VEGF-C was decreased, the levels of VEGFR-3 receptor increased following enalapril treatment. Enalapril treatment also reduced the renal expression of FGF-1, FGF-2, and FGFR-1. Enalapril-treated kidneys exhibited profibrogenic properties with increased expression of α-SMA and FSP-1 and enhanced deposition of interstitial collagen. CONCLUSION: Enalapril treatment during postnatal renal maturation can disrupt renal lymphangiogenesis along with tubulointerstitial changes, which may result in a pro-fibrotic environment in the developing rat kidney.

Capillary rarefaction and altered renal development: the imbalance between pro- and anti-angiogenic factors in response to angiotensin II inhibition in the developing rat kidney.

Proper and timely assembly of the kidney vasculature with their respective nephrons is crucial during normal kidney development. In this study, we investigated the effects of enalapril (angiotensin-converting enzyme inhibitor) on angiogenesis-related gene expression and microvascular endothelium related to glomeular and tubular changes in the neonatal rat kidney. Enalapril-treated rats had higher tubular injury scores and lower glomerular maturity grades than those of untreated rats. In the enalapril-treated group, intrarenal angiopoietin-2, Tie-2, and thrombospondin-1 protein expression increased, whereas intrarenal angiopoietin-1 protein expression decreased. JG12-positive glomerular and peritubular capillary staining was reduced in the enalapril-treated rat kidney. The number of JG12-positive capillary endothelial cells was directly correlated with glomerular maturation grade and was inversely related with the tubular injury. Our findings suggest the imbalance between pro- and anti-angiogenic factors may be implicated in the loss of capillaries in associated with impaired nephrogenesis after angiotensin II blockade in the developing rat kidney.

Genetic Contributions to Childhood Obesity: Association of Candidate Gene Polymorphisms and Overweight/Obesity in Korean Preschool Children.

This study was aimed to investigate the association of candidate gene polymorphisms and obesity or overweight in young Korean children. A total of 190 Korean preschool children (96 control, 48 overweight, and 46 obese children) were genotyped for the angiotensin converting enzyme (ACE) insertion (I)/deletion (D), angiotensin II type 2 receptor (AT2) C3123A, transforming growth factor (TGF)-ß1 T869C, vascular endothelial growth factor (VEGF) T460C, and tumor necrosis factor (TNF)-α G308A polymorphisms. No differences were found among the groups with respect to age, sex, birth weight, blood pressure levels, and serum concentrations of glucose and total cholesterol. Obese children showed a higher incidence of ACE DD genotype and D allelic frequency compared to the controls (odds ratio [OR], 2.7, 95% confidence interval [CI], 1.01-7.21; OR, 2.5, 95% CI, 1.49-4.19; all P < 0.05). The frequency of TC genotype and C allele in the TGF-ß1 T869C polymorphism (OR, 2.08, 95% CI, 1.01-4.27; OR, 1.93, 95% CI, 1.15-3.21) and that in the VEGF T460C polymorphism (OR, 2.5, 95% CI, 1.19-5.28; OR, 2.15, 95% CI, 1.26-3.68) was also higher in obese children than in control subjects (all P < 0.05). Overweight children exhibited a higher frequency of the A allele in the AT2 C3123A polymorphism compared to the controls (OR, 1.72, 95% CI, 1.03-2.88, P < 0.05). There were no differences in the TNF-α G308A polymorphism among the groups. The ACE I/D, AT2 C3123A, TGF-ß1 T869C, and VEGF T460C polymorphisms can affect susceptibility to obesity or overweight in Korean children.

Clinical Manifestation and Molecular Analysis of Three Korean Patients with the Renal Form of Pseudohypoaldosteronism Type 1.

Pseudohypoaldosteronism (PHA) type 1 is a rare, heterogeneous disease characterized by hyponatremia and hyperkalemia due to mineralocorticoid resistance. The clinical features of PHA are usually failure to thrive, vomiting, and dehydration in the neonatal period. Heterozygous mutations in the Nuclear receptor subfamily 3, group C, member 2 (NR3C2) gene result in the dominant renal form of PHA type 1. Mutations in the epithelial sodium channel gene result in the more severe, recessive, systemic form of PHA type 1. Here, we describe the clinical and biochemical characteristics of three sporadic cases from two Korean families diagnosed with the renal form of PHA type 1. Mutation analysis of the NR3C2 gene revealed one novel mutation in twin patients and two functional polymorphisms in one patient with unusual clinical symptoms. Our data contribute to a better understanding of the distinct mutations and clinical manifestations of the renal form of PHA type 1.

COQ6 Mutations in Children With Steroid-Resistant Focal Segmental Glomerulosclerosis and Sensorineural Hearing Loss.

The phenotypic combination of steroid-resistant focal segmental glomerulosclerosis (SR-FSGS) and sensorineural hearing loss has been mainly reported in patients with mitochondrial cytopathies, including primary coenzyme Q10 (CoQ10) deficiency. In this report of 10 children with SR-FSGS and sensorineural hearing loss, we found 6 patients with biallelic COQ6 mutations. Median age at the onset of nephrotic syndrome was 29 (range, 15-47) months. All patients progressed to end-stage renal disease within a median of 13 (range, 1-27) months after the onset. Kidney biopsy revealed abnormal mitochondrial proliferation in podocytes in all 6 patients. None of the 5 patients who underwent kidney transplantation developed recurrence of FSGS. Primary CoQ10 deficiency due to COQ6 mutations should be considered in children presenting with both SR-FSGS and sensorineural hearing loss. An early diagnosis of COQ6 mutations is essential because the condition is treatable when CoQ10 supplementation is started at the early stage. We recommend early kidney biopsy because detection of abnormal mitochondrial proliferation in podocytes might provide an earlier diagnostic clue.