Asymptomatic hematuria in children: Korean Society of Pediatric Nephrology recommendations for diagnosis and management.

Hematuria is a relatively common condition among school-aged children. Because international guidelines for asymptomatic hematuria in children are unavailable, developing practical guidelines for the diagnosis and management of asymptomatic hematuria based on scientific evidence while considering real-world practice settings, values, and patient and physician preferences is essential. The Korean Society of Pediatric Nephrology developed clinical guidelines to address key questions regarding the diagnosis and management of asymptomatic hematuria in children.

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.

Longitudinal progression trajectory of estimated glomerular filtration rate in children with chronic kidney disease: results from the KNOW-Ped CKD (KoreaN cohort study for Outcomes in patients With Pediatric Chronic Kidney Disease).

Background: The natural course of chronic kidney disease (CKD) progression in children varies according to their underlying conditions. This study aims to identify different patterns of subsequent decline in kidney function and investigate factors associated with different patterns of estimated glomerular filtration rate (eGFR) trajectories. Methods: We analyzed data from the KNOW-Ped CKD (KoreaN cohort study for Outcomes in patients With Pediatric Chronic Kidney Disease), which is a longitudinal, prospective cohort study. A latent class linear mixed model was applied to identify the trajectory groups. Results: In a total of 287 patients, the median baseline eGFR (mL/min/1.73 m2) was 63.3, and the median age was 11.5 years. The eGFR decline rate was -1.54 during a 6.0-year follow-up. The eGFR trajectory over time was classified into four groups. Classes 1 (n = 103) and 2 (n = 11) had a slightly reduced eGFR at enrollment with a stable trend (ΔeGFR, 0.2/year) and a rapid decline eGFR over time (ΔeGFR, -10.5/year), respectively. Class 3 had a normal eGFR (n = 16), and class 4 had a moderately reduced eGFR (n = 157); both these chasses showed a linear decline in eGFR over time (ΔeGFR, -4.1 and -2.4/year). In comparison with classes 1 and 2, after adjusting for age, causes of primary renal disease, and baseline eGFR, nephrotic-range proteinuria was associated with a rapid decline in eGFR (odds ratio, 8.13). Conclusion: We identified four clinically relevant subgroups of kidney function trajectories in children with CKD. Most children showed a linear decline in eGFR; however, there are different patterns of eGFR trajectories.

X-linked hypophosphatemic rickets: from diagnosis to management.

X-linked hypophosphatemia (XLH), the most common cause of hypophosphatemic rickets, affects one in every 20,000 people. Although conventional therapy for XLH was introduced approximately 4 decades ago, the temporary replacement of oral phosphate salts and activated vitamin D cannot completely control chronic hypophosphatemia, leaving patients with incomplete healing and residual skeletal deformity as well as at risk of endocrine abnormalities and adverse drug reactions. However, understanding the pathophysiology has led to the development of a targeted therapy, burosumab, a fibroblast growth factor-23 inhibitor that was recently approved in Korea for the treatment of XLH. This review provides insight into the diagnosis, evaluation, treatment, and recommended follow-up for a typical case of XLH and reviews its pathophysiology.

Long-term outcomes and associated prognostic risk factors of childhood-onset lupus nephritis.

Background: This study investigated the clinical characteristics and kidney outcomes of childhood-onset lupus nephritis (LN), and risk factors associated with prognosis. Methods: We enrolled 216 patients with histologically diagnosed LN during childhood. The Korean Society of Pediatric Nephrology organized a retrospective cohort study of childhood-onset LN in 13 major pediatric nephrology centers in South Korea. Results: The mean age at kidney biopsy was 13.2 ± 3.22 years. The main forms of presentation were nephrotic syndrome and/or hematuria in 152 patients (70.4%), and the most common histological finding was World Health Organization (WHO) class IV in 138 patients (63.9%), followed by WHO class III in 34 patients (15.7%). In the outcome analysis, the mean follow-up period of the patients was 7.8 ± 5.11 years. At last follow-up, 32 patients (14.8%) developed advanced chronic kidney disease (CKD). Male sex and failure to achieve remission at 12 months of treatment were significant risk factors for developing advanced CKD (hazard ratio of 2.57 and 2.29, respectively). Conclusion: Our study demonstrated the clinical characteristics and long-term outcomes of patients with childhood-onset LN. Male sex and failure to achieve remission in the first year of treatment were predictive of advanced CKD. Therefore, prompt awareness and close monitoring of these high-risk patients are needed, which may further improve the prognosis of children with LN.

Baseline characteristics of the Korean genetic cohort of inherited cystic kidney disease.

BACKGROUND: Identifying genetic mutations in individuals with inherited cystic kidney disease is necessary for precise treatment. We aimed to elucidate the genetic characteristics of cystic kidney disease in the Korean population. METHODS: We conducted a 3-year prospective, multicenter cohort study at eight hospitals from May 2019 to May 2022. Patients with more than three renal cysts were enrolled and classified into two categories, typical autosomal dominant polycystic kidney disease (ADPKD) and atypical PKD. We identified the clinical characteristics and performed a genetic analysis using a targeted gene panel. RESULTS: A total of 725 adult patients were included in the study, of which 560 (77.2%) were diagnosed with typical ADPKD and 165 (22.8%) had atypical PKD. Among the typical ADPKD cases, the Mayo imaging classification was as follows: 1A (55, 9.9%), 1B (149, 26.6%), 1C (198, 35.8%), 1D (90, 16.3%), and 1E (61, 11.0%). The atypical PKD cases were classified as bilateral cystic with bilateral atrophic (31, 37.3%), lopsided (27, 32.5%), unilateral (nine, 10.8%), segmental (eight, 9.6%), bilateral cystic with unilateral atrophic (seven, 8.4%), and asymmetric (one, 1.2%). Pathogenic variants were found in 64.3% of the patients using the ciliopathy-related targeted gene panel. The typical ADPKD group demonstrated a higher discovery rate (62.3%) than the atypical PKD group (41.8%). CONCLUSION: We present a nationwide genetic cohort's baseline clinical and genetic characteristics for Korean cystic kidney disease.

Corrigendum: Mineral bone disorder in children with chronic kidney disease: data from the KNOW-Ped CKD (Korean cohort study for outcome in patients with pediatric chronic kidney disease) study.

[This corrects the article DOI: 10.3389/fped.2023.994979.].

Association between serum total cholesterol and chronic kidney disease progression in children: results from the KNOW-PedCKD.

BACKGROUND: Dyslipidemia can cause cardiovascular disease and increase the fatality rate among children with chronic kidney disease (CKD); this makes early screening and treatment of dyslipidemia crucial. This study aimed to assess the association between the changes in serum total cholesterol levels over time and the degree of CKD progression in children. METHODS: From April 2011 to August 2021, 379 of the 432 participants enrolled in the KoreaN cohort study for Outcomes in patients With Pediatric CKD (KNOW-PedCKD) were included and divided into 4 categories based on total cholesterol levels (< 170 mg/dL, acceptable; 170-199, borderline; 200-239, high; and ≥ 240, very high). Survival analysis using conventional and time-dependent Cox proportional hazards model were performed for a composite event of CKD progression (≥ 50% decrease in estimated glomerular filtration rate from baseline, a twofold increase in creatinine, or the occurrence of dialysis or kidney transplantation). RESULT: The incidence of composite event of CKD progression was 96.3, 90.4, 87.3, and 270.6 cases per 1000 person-years in the acceptable, borderline, high, and very high categories, respectively. On using the time-dependent Cox proportional hazards model, the hazard ratio of the very high category was significantly higher than that of the acceptable category by 3.13 times as per univariate analysis and 2.37 times as per multivariate analysis. CONCLUSIONS: Very high serum total cholesterol is a significant risk factor for CKD progression in children. Lowering total cholesterol levels below the very high category in children with CKD may delay the progression of CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Mineral bone disorder in children with chronic kidney disease: Data from the KNOW-Ped CKD (Korean cohort study for outcome in patients with pediatric chronic kidney disease) study.

Background: Children with chronic kidney disease (CKD) are at high risk of mineral bone disorder (MBD), which leads to fractures, growth retardation, and cardiovascular disease. We aimed to comprehensively understand the relationship between renal function and factors related to MBD and evaluate the prevalence and distribution characteristics of MBD, specifically among Korean patients from the KNOW-PedCKD cohort. Methods: From the baseline data of the KNOW-PedCKD cohort, we examined the prevalence and distribution of MBD in 431 Korean pediatric CKD patients, including the level of corrected total calcium, serum phosphate, serum alkaline phosphatase, serum intact parathyroid hormone (iPTH), fibroblast growth factor 23 (FGF-23), serum vitamin D, fractional excretion of phosphate (FEP), and bone densitometry Z-scores. Results: The median serum calcium level remained relatively normal regardless of the CKD stage. The levels of 1,25-dihydroxy vitamin D, urine calcium-to-creatinine ratio, and bone densitometry Z-score significantly decreased with advancing CKD stage, while those of serum phosphate, FGF-23, and FEP significantly increased with CKD stage. The prevalence of hyperphosphatemia (17.4%, 23.7%, and 41.2% from CKD stages 3b, 4, and 5, respectively) and hyperparathyroidism (37.3%, 57.4%, 55.3%, and 52.9% from CKD stages 3a, 3b, 4, and 5, respectively) significantly increased with the CKD stage. Prescriptions of medications, such as calcium supplements (39.1%, 42.1%, 82.4%), phosphate binders (39.1%, 43.4%, 82.4%), and active vitamin D (21.7%, 44.7%, and 64.7%) significantly increased with CKD stage 3b, 4, and 5, respectively. Conclusions: The results demonstrated the prevalence and relationship of abnormal mineral metabolism and bone growth according to CKD stage in Korean pediatric CKD patients for the first time.

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 [...].

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."

Intellectual Functioning of Pediatric Patients with Chronic Kidney Disease: Results from the KNOW-Ped CKD.

BACKGROUND: Chronic kidney disease (CKD) has a negative impact on growth and development in children and is a risk factor for neurocognitive impairment; however, there is limited research on the cognitive function of children and adolescents with CKD. This study therefore aimed to investigate the mean intelligence and risk factors for low intelligence in children and adolescents with CKD. METHODS: Eighty-one patients with CKD under 18 years old were included in the KoreaN cohort study for Outcomes in patients With Pediatric Chronic Kidney Disease (KNOW-Ped CKD). Participants completed either the Wechsler Intelligence Scale for Children (6-16 years), or Wechsler Adult Intelligence Scale (> 16 years). RESULTS: The mean full-scale intelligence quotient (IQ) was 91 ± 19; 24.7% of participants scored a full-scale IQ below 80. Participants with a short stature (height Z scores < -1.88), failure to thrive (weight Z scores < -1.65), more severe CKD stage (≥ IIIb), longer duration of CKD (≥ 5 years), and those who were Medicare or Medicaid beneficiaries, had significantly lower mean full-scale IQs. CONCLUSION: On linear regression analysis, the association between the full-scale IQ, and longer duration of CKD and growth failure, remained significant after controlling for demographic and clinical variables. It is therefore necessary to investigate cognitive impairment in pediatric patients with CKD who exhibit growth failure or for a longer postmorbid period. It is believed that early interventions, such as kidney transplantation, will have a positive effect on IQ in children with CKD, as the disease negatively affects IQ due to poor glomerular filtration rate over time. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02165878.

Incidence of and risk factors for short stature in children with chronic kidney disease: results from the KNOW-Ped CKD.

BACKGROUND: Preserving optimal growth has long been a significant concern for children with chronic kidney disease (CKD). We aimed to examine the incidence of and risk factors for short stature in Asian pediatric patients with CKD. METHODS: We analyzed growth status by height, weight, and body mass index (BMI) standard deviation scores (SDSs) for 432 participants in the KoreaN cohort study for Outcome in patients With Pediatric Chronic Kidney Disease. RESULTS: The median height, weight, and BMI SDSs were - 0.94 (interquartile range (IQR) - 1.95 to 0.05), - 0.58 (IQR - 1.46 to 0.48), and - 0.26 (IQR - 1.13 to 0.61), respectively. A high prevalence of short stature (101 of 432 patients, 23.4%) and underweight (61 of 432 patients, 14.1%) was observed. In multivariable logistic regression analysis, CKD stages 4 and 5 (adjusted odds ratio (aOR) 2.700, p = 0.001), onset before age 2 (aOR 2.928, p < 0.0001), underweight (aOR 2.353, p = 0.013), premature birth (aOR 3.484, p < 0.0001), LBW (aOR 3.496, p = 0.001), and low household income (aOR 1.935, p = 0.030) were independent risk factors associated with short stature in children with CKD. CONCLUSIONS: Children with CKD in Korea were shorter and had lower body weight and BMI than the general population. Short stature in children with CKD was most independently associated with low birth weight, followed by premature birth, onset before age 2, CKD stages 4 and 5, underweight, and low household income. Among these, underweight is the only modifiable factor. Therefore, we suggest children with CKD should be carefully monitored for weight, nutritional status, and body composition to achieve optimal growth.

Genetic identification of inherited cystic kidney diseases for implementing precision medicine: a study protocol for a 3-year prospective multicenter cohort study.

BACKGROUND: Inherited cystic kidney disease is a spectrum of disorders in which clusters of renal cysts develop as the result of genetic mutation. The exact methods and pipelines for defining genetic mutations of inherited cystic kidney disease are not clear at this point. This 3-year, prospective, multicenter, cohort study was designed to set up a cohort of Korean patients with inherited cystic kidney disease, establish a customized genetic analysis pipeline for each disease subtype, and identify modifying genes associated with the severity of the disease phenotype. METHODS/DESIGN: From May 2020 to May 2022, we aim to recruit 800 patients and their family members to identify pathogenic mutations. Patients with more than 3 renal cysts in both kidneys are eligible to be enrolled. Cases of simple renal cysts and acquired cystic kidney disease that involve cyst formation as the result of renal failure will be excluded from this study. Demographic, laboratory, and imaging data as well as family pedigree will be collected at baseline. Renal function and changes in total kidney volume will be monitored during the follow-up period. Genetic identification of each case of inherited cystic kidney disease will be performed using a targeted gene panel of cystogenesis-related genes, whole exome sequencing (WES) and/or family segregation studies. Genotype-phenotype correlation analysis will be performed to elucidate the genetic effect on the severity of the disease phenotype. DISCUSSION: This is the first nationwide cohort study on patients with inherited cystic kidney disease in Korea. We will build a multicenter cohort to describe the clinical characteristics of Korean patients with inherited cystic kidney disease, elucidate the genotype of each disease, and demonstrate the genetic effects on the severity of the disease phenotype. TRIAL REGISTRATION: This cohort study was retrospectively registered at the Clinical Research Information Service ( KCT0005580 ) operated by the Korean Center for Disease Control and Prevention on November 5th, 2020.

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.

Dyslipidemia in pediatric CKD patients: results from KNOW-PedCKD (KoreaN cohort study for Outcomes in patients With Pediatric CKD).

BACKGROUND: Pediatric as well as adult patients with chronic kidney disease (CKD) are susceptible to cardiovascular disease (CVD) events, which increase their mortality. Dyslipidemia is thought to be one of the most important contributing risk factors for developing CVD. This study aimed to evaluate the prevalence of dyslipidemia and assess clinical and laboratory risk factors associated with dyslipidemia in East Asian pediatric patients with CKD. METHODS: From April 2011 to April 2016, 469 patients with CKD aged < 20 years were enrolled in KNOW-PedCKD (the KoreaN cohort study for Outcomes in patients With Pediatric Chronic Kidney Disease); 356 patients were included in the final analysis. Using the baseline data of the cohort cross-sectionally, a multivariable logistic regression analysis was performed to assess the risk factors for dyslipidemia; a subanalysis for each lipid abnormality was also done. RESULTS: The prevalence of dyslipidemia was 61.5% (n = 219). For dyslipidemia, nephrotic range proteinuria and 25-hydroxyvitamin D deficiency significantly increased the adjusted odds ratio. In the subanalysis, glomerulonephropathy as the origin of CKD and nephrotic range proteinuria significantly increased the risks for high total cholesterol and high low-density lipoprotein cholesterol. Overweight or obese body mass index z-score, elevated proteinuria, hypocalcemia, and 1,25-dihydroxyvitamin D deficiency were significantly associated with low high-density lipoprotein cholesterol. Glomerular filtration rate stage 3b or higher and hyperphosphatemia significantly increased the risk for high triglycerides. CONCLUSIONS: Long-term data accumulation and prospective analysis are needed to clarify the relationship between CKD progression and dyslipidemia and to find additional risk factors for dyslipidemia.

Targeted Exome Sequencing Provided Comprehensive Genetic Diagnosis of Congenital Anomalies of the Kidney and Urinary Tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. The search for genetic causes of CAKUT has led to genetic diagnosis in approximately 5-20 % of CAKUT patients from Western countries. In this study, genetic causes of CAKUT in Korean children were sought using targeted exome sequencing (TES) of 60 genes reported to cause CAKUT in human or murine models. We identified genetic causes in 13.8% of the 94 recruited patients. Pathogenic single nucleotide variants of five known disease-causing genes, HNF1B, PAX2, EYA1, UPK3A, and FRAS1 were found in 7 cases. Pathogenic copy number variations of 6 patients were found in HNF1B, EYA1, and CHD1L. Genetic abnormality types did not significantly differ according to CAKUT phenotypes. Patients with pathogenic variants of targeted genes had syndromic features more frequently than those without (p < 0.001). This is the first genetic analysis study of Korean patients with CAKUT. Only one-seventh of patients were found to have pathogenic mutations in known CAKUT-related genes, indicating that there are more CAKUT-causing genes or environmental factors to discover.

Erratum: Post-Transplant Lymphoproliferative Diseases in Pediatric Kidney Allograft Recipients with Epstein-Barr Virus Viremia.

This corrects the article on e203 in vol. 34, PMID: 31373185.

Post-Transplant Lymphoproliferative Diseases in Pediatric Kidney Allograft Recipients with Epstein-Barr Virus Viremia.

BACKGROUND: Post-transplant lymphoproliferative disease (PTLD) is one of the major complications of organ transplantation, especially in children with Epstein-Barr virus (EBV) viremia (EV). We performed a retrospective study to evaluate risk factors for PTLD in children with EV. METHODS: Among 199 pediatric kidney transplantation (KT) recipients at our center from January 2001 to October 2015, records of those with EBV viral loads of > 1,000 copies/mL and/or PTLD were reviewed. RESULTS: Diagnosis of PTLD was made in seven patients (PTLD group), and 39 patients had EV only (EV only group). The median time from KT to EV and PTLD diagnosis was 6.7 (range 0.4-47.8) months and 8.2 (range, 2.8-98.9) months, respectively. There were no significant differences between the groups in terms of sex, age at transplantation, donor type, EBV viral load, or EV-free duration after KT. Higher tacrolimus level before EV (hazard ratio, 44.5; P = 0.003) was an independent risk factor for PTLD in multivariate Cox regression analysis. Six patients with a high EBV load (median 171,639 copies/mL) were treated with preemptive rituximab (RTX) therapy, resulting in transient reduction of EBV load. None of these patients developed PTLD (median follow-up 51.5 months); however, two had neutropenia and two developed infection requiring hospital admission. CONCLUSION: In pediatric KT recipients, higher tacrolimus levels were associated with a higher incidence of PTLD. Conversely, those who received preemptive RTX for EV did not develop PTLD.