Genotype-phenotype correlations in children with Gitelman syndrome.

BACKGROUND: This study aimed to analyze genotype-phenotype correlations in children with Gitelman syndrome (GS). METHODS: This multicenter retrospective study included 50 Korean children diagnosed with SLC12A3 variants in one or both alleles and the typical laboratory findings of GS. Genetic testing was performed using the Sanger sequencing except for one patient. RESULTS: The median age at the diagnosis was 10.5 years (interquartile range, 6.8;14.1), and 41 patients were followed up for a median duration of 5.4 years (interquartile range, 4.1;9.6). A total of 30 different SLC12A3 variants were identified. Of the patients, 34 (68%) had biallelic variants, and 16 (32%) had monoallelic variants on examination. Among the patients with biallelic variants, those (n = 12) with the truncating variants in one or both alleles had lower serum chloride levels (92.2 ± 3.2 vs. 96.5 ± 3.8 mMol/L, P = 0.002) at onset, as well as lower serum potassium levels (3.0 ± 0.4 vs. 3.4 ± 0.3 mMol/L, P = 0.016), and lower serum chloride levels (96.1 ± 1.9 vs. 98.3 ± 3.0 mMol/L, P = 0.049) during follow-up than those without truncating variants (n = 22). Patients with monoallelic variants on examination showed similar phenotypes and treatment responsiveness to those with biallelic variants. CONCLUSIONS: Patients with GS who had truncating variants in one or both alleles had more severe electrolyte abnormalities than those without truncating variants. Patients with GS who had monoallelic SLC12A3 variants on examination had almost the same phenotypes, response to treatment, and long-term prognosis as those with biallelic variants.

Increasing trend in hypertension prevalence among Korean adolescents from 2007 to 2020.

BACKGROUND: The purpose of this study was to examine the prevalence of hypertension in Korean adolescents, its long-term trends, and factors associated with the development of hypertension. METHODS: Data of the Korea National Health and Nutrition Examination Survey (KNHANES) from 2007 to 2020 were combined into three time periods (2007-2011, 2012-2016, and 2017-2020). A total of 11,146 Korean adolescents aged 10-18 were included in the analysis. The definition of hypertension was based on the 2017 American Academy of Pediatrics guidelines for hypertension. RESULTS: The age-adjusted prevalence of hypertension was 5.47%, 7.85%, and 9.92% in 2007-2011, 2012-2016, and 2017-2020, respectively. Long-term trend analysis using Joinpoint analysis over the observation period showed a significantly increasing trend in hypertension prevalence with a mean annual percentage change of 6.4%. Boys, those aged 13-15, those aged 16-18, overweight/obese, and those living in urban areas were more likely to develop hypertension (OR 1.980, 1.492, 3.180, 2.943, and 1.330, respectively). CONCLUSION: The prevalence of hypertension in Korean adolescents was higher than the global prevalence of hypertension and showed an increase over a 13-year period. Targeted strategies for prevention and early detection of hypertension are needed in this population.

Effects of urinary tract infection during the first years of life in subsequent growth: a nationwide comparative matched cohort study.

Background: Although various childhood illnesses are known to influence growth status, the impact of urinary tract infections (UTI) on subsequent childhood growth remains unclear. This study was conducted to examine the association between UTI during infancy and growth status at 30-36 months. Methods: Nationwide population-based matched cohort study was done using data from the Korean National Health Insurance System (NHIS) and the Korean National Health Screening Program for Infants and Children (NHSPIC) between January 2018 and December 2020. Height and weight standard deviation scores (SDSs) at the fourth Korean NHSPIC conducted at 30-36 months were compared between children who experienced UTI during infancy and age- and sex-matched controls. We used weighted multiple linear regression analysis with inverse probability of treatment weighting (IPTW) and identified differences between the two groups using ß coefficient with corresponding 95% confidence intervals (CIs). Results: We analyzed 84,519 children diagnosed with UTI during infancy and 84,519 age- and sex-matched controls. The height SDS between children who experienced UTI and the control group was not statistically different (ß coefficient for height SDS, -0.0034; 95% CI: -0.0121 to 0.0054). However, the body mass index (BMI) SDS was significantly higher in children who had experienced UTI (ß coefficient for BMI SDS, 00426; 95% CI: 0.0304 to 0.0547). Subgroup and sensitivity analysis showed consistent results. Conclusions: Our findings suggest that a history of UTI during infancy is associated with high BMI measured at 30-36 months.

Baseline characteristics of participants enrolled in the KoreaN cohort study for Outcomes in patients With Pediatric Chronic Kidney Disease (KNOW-Ped CKD).

BACKGROUND: We developed the KoreaN cohort study for Outcomes in patients With Pediatric Chronic Kidney Disease (KNOW-Ped CKD) as a subcohort of KNOW-CKD to investigate the different characteristics of pediatric CKD between countries and races. METHODS: Children aged younger than 18 years with stage 1 ~ 5 CKD were recruited at seven major pediatric nephrology centers in Korea. Blood and urine samples, as well as demographic and clinical data, were collected. From 2011 to 2016, 458 children were enrolled, and the baseline profiles of 437 children were analyzed. RESULTS: The median age of the cohort was 10.9 years old, and 68.0% were males. The median estimated glomerular filtration rate was 53.1 mL/min/1.73 m2. The most common etiology of CKD was congenital anomalies of the kidney and urinary tract (42.6%), followed by glomerulopathies (25.6%). CONCLUSION: We report a cross-sectional analysis of the overall baseline characteristics such as age, CKD stage, and underlying kidney disease of the KNOW-Ped CKD. The cohort will be longitudinally followed for ten years. "A higher resolution version of the Graphical abstract is available as Supplementary information."

Genotype and Phenotype Analysis in X-Linked Hypophosphatemia.

Background: X-linked hypophosphatemia (XLH) is the most frequent form of hypophosphatemic rickets and is caused by mutations in the PHEX gene. We analyzed genotype-phenotype correlations in XLH patients with proven PHEX mutations. Methods: PHEX mutations were detected in 55 out of 81 patients who clinically presented with hypophosphatemic rickets. The patients were grouped into nontruncating (n = 9) and truncating (n = 46) mutation groups; their initial presentation as well as long-term clinical findings were evaluated according to these groups. Results: Initial findings, including presenting symptoms, onset age, height standard deviation scores (SDS), and laboratory tests, including serum phosphate level and tubular resorption of phosphate, were not significantly different between the two groups (onset age: nontruncating mutation group, 2.0 years, truncating mutation group, 2.2 years; height SDS: nontruncating mutation group, -1.9, truncating mutation group, -1.7; serum phosphate: nontruncating mutation group, 2.5 mg/dL, truncating mutation group, 2.6 mg/dL). However, at their last follow-up, the serum phosphate level was significantly lower in patients with truncating mutations (nontruncating mutation group: 3.2 mg/dl, truncating mutation group: 2.3 mg/dl; P = 0.006). Additionally, 62.5% of patients with truncating mutations developed nephrocalcinosis at their last follow-up, while none of the patients with nontruncating mutations developed nephrocalcinosis (P = 0.015). Orthopedic surgery due to bony deformations was performed significantly more often in patients with truncating mutations (52.3 vs. 10.0%, P = 0.019). Conclusion: Although considerable inconsistency exists regarding the correlation of truncating mutations and their disease phenotype in several other studies, we cautiously suggest that there would be genotype-phenotype correlation in some aspects of disease manifestation after long-term follow-up. This information can be used when consulting patients with confirmed XLH regarding their disease prognosis.

Clinical Relevance of Fluid Volume Status Assessment by Bioimpedance Spectroscopy in Children Receiving Maintenance Hemodialysis or Peritoneal Dialysis.

Bioimpedance spectroscopy (BIS) is a noninvasive method used to evaluate body fluid volume status in dialysis patients, but reports on its effectiveness in pediatrics are scarce. We investigated the correlation between BIS and clinical characteristics and identified the changes in patients whose dialysis prescription was modified based on BIS. The medical records of children on maintenance dialysis who had undergone BIS between 2017 and 2019 were reviewed. Of the 49 patients, 14 were overhydrated, based on the >15% proportion of overhydration relative to extracellular water (OH/ECW) measured by BIS. Intake of ≥two antihypertensive medications was noted in the majority (85.7%) of children with fluid overload and only in 48.6% of those without fluid overload (p = 0.017). Elevated blood pressure despite medication use was significantly more common in patients with fluid overload than in those without fluid overload (78.6% vs. 45.7%, p = 0.037). Of the 14 overhydrated children, 13 (92.9%) had significant changes in body weight, OH/ECW, the number of antihypertensive drugs, left ventricular end-diastolic diameter, and cardiothoracic ratio after the change in dialysis prescription. BIS is a useful and noninvasive method to assess fluid status in dialysis children. Long-term follow-up and correlation with a more objective clinical indicator of fluid overload is necessary to verify the clinical effectiveness of BIS.

Out-of-Hospital Cohort Treatment of Coronavirus Disease 2019 Patients with Mild Symptoms in Korea: an Experience from a Single Community Treatment Center.

The outbreak of Coronavirus Disease 2019 (COVID-19) caused a worldwide pandemic. Less than 6 weeks after the first confirmed cases in Korea, the patient number exceeded 5,000, which overcrowded limited hospital resources and forced confirmed patients to stay at home. To allocate medical resources efficiently, Korea implemented a novel institution for the purpose of treating patients with cohort isolation out of hospital, namely the Community Treatment Center (CTC). Herein, we report results of the initial management of patients at one of the largest CTC in Korea. A total of 309 patients were admitted to our CTC. During the first two weeks, 7 patients were transferred to the hospital because of symptom aggravation and 107 patients were discharged without any complication. Although it is a novel concept and may have some limitations, CTC may be a very cost-effective and resource-saving strategy in managing massive cases of COVID-19 or other emerging infectious diseases.

Acute kidney injury predicts all-cause mortality in patients with cancer.

BACKGROUND: Acute kidney injury (AKI) is a critical issue in cancer patients because it is not only a morbid complication but also able to interrupt timely diagnostic evaluation or planned optimal treatment. However, the impact of AKI on overall mortality in cancer patients remains unclear. METHODS: We conducted a retrospective cohort study of 67 986 cancer patients, from 2004 to 2013 to evaluate the relationship between AKI and all-cause mortality. We used KDIGO AKI definition and grading system. RESULTS: During 3.9 ± 3.1 years of follow-up, 33.8% of the patients experienced AKI at least once. Among AKI events, stage 1, 2, and 3 was 71.0%, 13.8%, and 15.1%, respectively. AKI incidence was highest in hematologic malignancies, followed by urinary tract cancer, and hepatocellular carcinoma. Male sex, older age, underlying diabetes and hypertension, lower serum albumin and plasma hemoglobin, more frequent radio-contrast exposure, entrance of clinical trials, and receiving chemotherapy were associated with AKI occurrence. AKI development was an independent risk factor for elevated mortality in cancer patients with dose-responsive manner (Stage 1, hazard ratio [HR] 1.183, 95% confidence interval [CI] 1.145-1.221, P < 0.001; Stage 2, HR 1.710, 95% CI 1.629-1.796; Stage 3, HR 2.000, 95% CI 1.910-2.095; No AKI, reference group) even after adjustment. This tendency was reproduced in various cancer types except thyroid cancer and in various treatment modalities, however, not shown in patients with baseline renal dysfunction. CONCLUSION: AKI was an independent risk factor for all-cause mortality in overall cancer patients with dose-responsive manner.

Acute Kidney Injury in Pediatric Cancer Patients.

OBJECTIVE: To analyze the incidence of acute kidney injury (AKI) in the first year after cancer diagnosis in children and to evaluate the short-term and long-term effects on renal function and proteinuria. STUDY DESIGN: Retrospective review of medical records was done on children who were diagnosed and treated for cancer at Seoul National University Hospital between 2004 and 2013. AKI was defined according to the Kidney Disease: Improving Global Outcomes criteria. Impaired renal function of estimated glomerular filtration rate less than 90 mL/minute/1.73 m2 and development of proteinuria of cancer survivors were also assessed. RESULTS: This study included 1868 patients who were diagnosed with cancer at a median age of 7.9 years. During the course of treatment, 983 patients (52.6%) developed 1864 episodes of AKI, and the cumulative incidence at 2 weeks, 3 months, and 1 year after diagnosis was 28.9%, 39.6%, and 53.6%, respectively. The 1-year cumulative incidence was the highest in patients with acute myeloid leukemias (88.4%). In all, 6.1% of patients had more than 4 episodes of AKI and 11.8% of patients had stage 3 AKI. Among the 1096 childhood cancer survivors, 22.6% were found to have impaired renal function. A greater number of AKI episodes (≥4 times) and nephrectomy were independent risk factors of impaired renal function. Also, 8.2% of the survivors developed proteinuria among 742 childhood cancer survivors. CONCLUSIONS: A large percentage of children with cancer experience AKI during the course of treatment, and AKI is associated with impaired long-term renal function.

Cutaneous Skeletal Hypophosphatemia Syndrome in Association with a Mosaic HRAS Mutation.

Recent molecular genetic studies have revealed that Schimmelpenning-Feuerstein-Mims syndrome (SFMS), which presents as sebaceous nevi, is a mosaic RASopathy caused by postzygotic somatic activating mutations in HRAS, NRAS, or KRAS Some patients with SFMS also have hypophosphatemic rickets, called cutaneous skeletal hypophosphatemia syndrome (CSHS). We here report a pediatric case of biopsy-proven CSHS with mosaic mutation in the HRAS gene. A girl who showed extensive nevus sebaceous since birth had suffered progressive lower extremity deformity since the age of 5 years. We found hypophosphatemic rickets in laboratory and radiological studies. From the molecular study with skin tissue with nevus sebaceous, we identified a heterozygous mutation, c.182A>G (p.Gln61Arg), in exon 3 of HRAS by Sanger sequencing. However, we did not find this mutation in the peripheral blood and unaffected tissue, which demonstrated mosaic distribution of the mutation throughout the body. Given the rarity of the previous genetically proven CSHS cases, accumulation of more cases is needed to establish the role of Ras activation in skeletal manifestations in CSHS, which is likely due to excessive production of fibroblast growth factor 23.

Three cases of multicentric carpotarsal osteolysis syndrome: a case series.

BACKGROUND: Multicentric carpotarsal osteolysis syndrome (MCTO) is characterized by progressive destruction and disappearance of the carpal and tarsal bones associated with nephropathy. MCTO is caused by loss-of-function mutations in the MAF bZIP transcription factor B (MAFB) gene. CASE PRESENTATION: This report describes three unrelated patients with MAFB mutations, including two male and one female patient. Osteolytic lesions in the carpal and tarsal bones were detected at 2 years, 12 years, and 14 months of age, respectively. Associated proteinuria was noted at 4 years, 12 years, and 3 months of age, respectively. Kidney biopsy was performed in two of them and revealed focal segmental glomerulosclerosis (FSGS). One patient showed progression to end-stage renal disease, that is by 1 year after the detection of proteinuria. The second patient had persistent proteinuria but maintained normal renal function. In the third patient, who did not undergo a kidney biopsy, the proteinuria disappeared spontaneously. The bony lesions worsened progressively in all three patients. Mutational study of MAFB revealed three different mutations, two novel mutations [c.183C > A (p.Ser61Arg) and c.211C > G (p.Pro71Ala)] and one known mutation [c.212C > T (p.Pro71Leu)]. CONCLUSION: We report three cases with MCTO and two novel MAFB mutations. The renal phenotypes were different among the three patients, whereas progressive worsening of the bony lesions was common in all patients. We also confirmed FSGS to be an early renal pathologic finding in two cases. A diagnosis of MCTO should be considered in patients with progressive bone loss concentrated primarily in the carpal and tarsal bones and kidney involvement, such as proteinuria.