Hye Sun Hyun

PREVALENCE OF 25(OH) VITAMIN D INSUFFICIENCY AND DEFICIENCY IN PEDIATRIC PATIENTS ON CHRONIC DIALYSIS

♦ Background: 25(OH) Vitamin D [25(OH)D] is the major circulating form of vitamin D and the parameter used to reflect vitamin D status. Patients with chronic kidney disease (CKD) are likely to have low levels of 25(OH)D, and recent observations have linked suboptimal vitamin D status with adverse cardiovascular outcomes, inflammation, insulin resistance, and the rate of progression of renal insufficiency. Little is known about the magnitude of vitamin D deficiency in pediatric patients with stage 5 CKD on chronic dialysis. ♦ Objectives: The aim of the present cross-sectional study was to assess the prevalence of abnormal vitamin D status in children on chronic dialysis. ♦ Methods: Serum 25(OH)D, 1,25(OH)2 vitamin D [1,25(OH)2D], calcium, phosphorus, and parathyroid hormone (PTH) were evaluated in 59 pediatric patients on chronic dialysis. Weekly renal Kt/V and creatinine clearance (CCr) were evaluated as parameters reflecting residual renal function. In these patients, serum 25(OH)D concentrations less than 10 ng/mL were considered deficiency and concentrations of 10 - 30 ng/mL were considered insufficiency. ♦ Results: Of the 59 pediatric patients (mean age: 14.4 ± 5.1 years), 51 (86.4%) were on peritoneal dialysis (PD), and 8 (13.6%) were on hemodialysis. Vitamin D deficiency was found in 32.2% of the patients (n = 19), and vitamin D insufficiency, in 50.8% (n = 30). Patients with serum 25(OH)D concentrations less than 30 ng/mL were older than those with normal 25(OH)D concentrations (15.4 ± 4.5 years vs 9.2 ± 5.1 years, p = 0.000). Patients with 25(OH) D concentrations less than 30 ng/mL had higher PTH levels than did those with normal 25(OH)D concentrations (349.5 ± 318.3 pg/mL vs 142.5 ± 116.9 pg/mL, p = 0.001). In the univariate analysis, there was no correlation between serum 25(OH)D and serum 1,25(OH)2D (r = 0.242, p = 0.064), calcium (r = 0.108, p = 0.415), phosphorus (r = -0.050, p = 0.706), or body mass index (r = -0.046, p = 0.729). In PD patients, serum 25(OH)D was positively correlated with weekly renal Kt/V (r = 0.385, p = 0.005) and CCr (r = 0.443, p = 0.001). In addition, serum 25(OH)D and serum albumin were positively correlated (r = 0.297, p = 0.035) in the PD patients. ♦ Conclusions: The present study found a high prevalence of 25(OH)D deficiency and insufficiency in children on chronic dialysis. Serum 25(OH)D was associated with residual renal function in children on PD. Further studies to evaluate the consequences of vitamin D deficiency and the impact of therapeutic interventions are needed in pediatric CKD patients.

Long-term repeated rituximab treatment for childhood steroid-dependent nephrotic syndrome

Background Rituximab (RTX) can be used as a rescue therapy for steroid-dependent nephrotic syndrome (SDNS). However, the efficacy and safety of long-term, repeated use of RTX are not established. This study was conducted to assess the efficacy and safety of long-term, repeated RTX treatment in children. Methods Eighteen consecutive child patients with SDNS who were treated with three or more cycles of RTX for one year or longer were recruited, and their medical records were retrospectively reviewed. Results The patients were followed for 4.7 ± 1.9 years and received 5.2 ± 2.3 cycles of RTX over 2.8 ± 1.1 years. Approximately 70% of the additional RTX cycles were administered due to recovery of B-cells without relapse. The relapse rate decreased from 3.4 ± 2.0 per year initially to 0.4 ± 0.8 per year at the third year after RTX treatment. Approximately 10% of the RTX infusions were accompanied by mild infusion reactions. Eight patients showed sustained remission without any oral medication after the last cycle of RTX, while 10 patients had one or more episodes of relapse after the last cycle of RTX. The relapse rate in the latter group decreased from 2.8 ± 1.5 per year before RTX treatment to 1.3 ± 0.8 per year after cessation of RTX treatment. No significant differences in clinical parameters were found between the two groups. Conclusion This retrospective study showed that pre-emptive and long-term, repeated RTX treatment is relatively effective and safe in children with SDNS. However, well-designed prospective studies are needed to confirm these findings.

Three cases of Gordon syndrome with dominant KLHL3 mutations

Abstract Background: Gordon syndrome (GS) is a rare form of monogenic hypertension characterized by low renin hypertension, hyperkalemia, hyperchloremic metabolic acidosis, and normal glomerular filtration rate. To date, four genes causing GS have been identified as: WNK1, WNK4, CUL3, and KLHL3. Case presentation: We report three cases of GS in two families. All patients presented with typical clinical features of GS and had a known dominant KLHL3 mutation. Oral thiazide treatment with low salt diet resulted in normalization of blood pressure and serum electrolytes in all three cases. Conclusions: GS should be considered in patients with low renin hypertension and hyperkalemia. Although it is a rare disease, the correct diagnosis of GS is clinically important, as it can easily be treated with a low sodium diet or thiazides. In addition, family studies can identify individuals with undiagnosed GS as all mutations causing this disease, except for some recessive KLHL3 mutations, are dominant mutations.

Genotype–Phenotype Analysis in Pediatric Patients with Distal Renal Tubular Acidosis

Background/Aims: Primary distal renal tubular acidosis (dRTA) in children is a rare genetic disorder, and three causative mutated genes have been identified: SLC4A1, ATP6V1B1, and ATP6V0A4. We analyzed the prevalence and phenotypic differences of genetic mutations in children with dRTA. Methods: A total of 17 children with dRTA were enrolled in the study. All patients underwent genetic testing for all three candidate genes. Results: Pathogenic mutations, including six novel mutations, were detected in 15 (88.2%) patients: dominant SLC4A1 mutations in ten (58.8%) patients, recessive ATP6V0A4 mutations in three (17.6%) patients, and recessive ATP6V1B1 mutations in two (11.8%) patients. Compared to other patients, patients with SLC4A1 mutations showed an older age of onset (3.7 ± 2.6 years) and less severe metabolic acidosis at initial presentation. All patients developed nephrocalcinosis, and sensorineural hearing loss was observed in two patients with ATP6V1B1 mutations. Three (17.6%) patients had decreased renal function (chronic kidney disease stage 2), and five (29.4%) patients had persistent growth retardation at the last follow-up. Long-term prognosis showed no genotype–phenotype correlation. Conclusions: SLC4A1 is the most common defective gene in Korean children with dRTA. Patients with SLC4A1 mutations show later onset and milder disease severity. Long-term follow-up of hearing ability, renal function, and growth is necessary for patients with dRTA.

A 7-year-old girl presenting with a Bartter-like phenotype: Answers

The patient presented multiorgan-involving symptoms and signs sequentially: lower extremity muscle weakness at 3 years and 5 months, sensorineural hearing loss at 6 years, and Bartter-like renal tubulopathy and hypoparathyroidism at 7 years. The initial clinical diagnosis made at the age of 7 years was that of Bartter syndrome with an uncertain genotype. The presence of Gitelman syndrome-like features, i.e., normal or low urinary calcium excretion level and hypomagnesemia, suggested Bartter syndrome type III due to mutat ions in CLCNKB [1]. Meanwhile, sensorineural hearing loss and hypoparathyroidsim are typical findings of Bartter syndrome type IV due to mutations in BSND and Bartter syndrome type V due to gain-of-function mutations in CASR, respectively [1]. Initially, we thought that the muscle weakness was related to chronic hypokalemia and/or hypocalcemia. However, mutational studies of all five genes (SLC12A1, KCNJ1, CLCNKB, BSND, and CASR) implicated in Bartter syndrome revealed no pathogenic mutation. Notably, the patient also presented other proximal tubular dysfunctions, including low-molecular-weight proteinuria and hypouricemia, which are not detected in patients with the classic forms of Bartter syndrome. Therefore, at the age of 8 years, a biopsy of the left thigh muscle was performed to enable a correct diagnosis, with the biopsy revealing findings typical of mitochondrial myopathy (Fig. 1). Genetic analysis using a peripheral blood sample then revealed a homoplasmic 8932-bp deletion (m.6130_15061del) in the mitochondrial DNA (mtDNA) (Fig. 2). In addition, an electrocardiogram taken before the muscle biopsy revealed left axis deviation, left bundle branch block, and borderline degree of left ventricular hypertrophy and QT interval prolongation. One month after the muscle biopsy, a decrease in visual acuity with bilateral ptosis was noted in the school physical examination, and the results of an ophthalmologic examination revealed pigmentary retinopathy. With these additional cardiac and ocular findings, the diagnostic criteria for Kearns–Sayre syndrome (KSS) were fulfilled. This refers to the article that can be found at doi:10.1007/s00467-0163473-7.

A 7-year-old girl presenting with a Bartter-like phenotype: Questions.

A 7-year-old girl was transferred to Seoul National University Children’s Hospital, Seoul, Korea due to failure to thrive. She was born at term with a birth weight of 3.03 kg and without perinatal problems. At the age of 3 years and 4 months, she was examined at a hospital for poor weight gain and difficulty in running and climbing stairs. At that time, her height was 92.4 cm (5th–10th percentile) and weight was 11.8 kg (<3rd percentile). Neurologic development and cognitive and social language skills were found to be normal. The laboratory tests, including those for serum electrolyte levels and thyroid function, revealed no abnormality. At the age of 6 years, she was diagnosed with bilateral sensorineural hearing loss and she started wearing a hearing aid. At the first visit to our hospital (age 7 years), her height was 104 cm (<3rd percentile) and weight was 13.45 kg (<3rd percentile). Her blood pressure was 99/53 mmHg. She did not eat well and had a mildly poor motor function, especially in climbing upstairs, while her intelligence was normal. Laboratory tests revealed Bartter-like electrolyte imbalance: serum sodium, potassium, chloride, and bicarbonate levels were 133, 2.7, 93, and 31.4 mEq/L, respectively, and the arterial blood pH was 7.504. Serum creatinine level was 0.34 mg/dL and creatinine clearance was 79.7 mL/min/ 1.73 m. The serum albumin (4.9 g/dL) level was normal. Serum calcium, phosphorus, and magnesium levels were 9.5 mg/dL, 3.9 mg/dL, and 1.1 mEq/L, respectively. Serum uric acid level was 1.4 mg/dL. Plasma renin activity was 70.64 (normal 1–2.5) ng/mL/h and serum aldosterone level was 125.7 (normal 3–16.0) ng/dL. Urinalysis revealed 1+ albumin and 1+ glucose. In the spot urine test, the protein/creatinine ratio was 1.72 mg/mg, the calcium/creatinine ratio was 0.06 mg/mg, the β2-microglobulin level was 28.0 (normal The answers to these questions can be found at doi: 10.1007/s00467-0163480-8.

Genotype and Phenotype Analysis in Pediatric Patients with Cystinuria

Cystinuria is an inherited disorder characterized by defective renal reabsorption of cystine and dibasic amino acids leading to nephrolithiasis. This study was conducted to analyze the genotypes and phenotypes of pediatric patients with cystinuria. Eight children from Seoul National University Hospital and Asan Medical Center presenting with cystinuria from January 2003 to June 2016 were retrospectively analyzed. Mutational studies were performed by direct sequencing. Two of the 8 were male and 6 were female. The median ages at onset and diagnosis were 1.5 (range, 0.3–13.6) and 2.6 (range, 0.7–16.7) years, respectively. The median followed up was 7.7 (range, 3.4–14.0) years. Mutational analyses were performed in 7 patients and revealed biallelic SLC3A1 mutations (AA genotype) in 4 patients, a single heterozygous SLC3A1 mutation (A- genotype) in 1 patient, biallelic SLC7A9 mutations (BB genotype) in 1 patient, and a single heterozygous SLC7A9 mutation (B- genotype) in 1 patient. Two of the mutations were novel. No genotype-phenotype correlations were observed, except for earlier onset age in patients with non-AA genotypes than in patients with the AA genotype. All patients suffered from recurrent attacks of symptomatic nephrolithiasis, which lead to urologic interventions. At the last follow-up, 3 patients had a mild-to-moderate degree of renal dysfunction. This is the first study of genotypic and phenotypic analyses of patients with cystinuria in Korea.