Prognostic Factors in Children with Acute Kidney Injury Requiring Continuous Renal Replacement Therapy.

INTRODUCTION: This study aimed to evaluate prognostic factors and outcomes in a single-center PICU cohort that received continuous renal replacement therapy (CRRT). METHODS: This retrospective study analyzed clinical characteristics, laboratory data, and outcomes. Ninety-day mortality and advanced chronic kidney disease (CKD) (eGFR <60 mL/min/1.73 m2) were defined as primary and secondary outcomes, respectively. RESULTS: Seventy-five patients were enrolled, all of whom received CRRT for indications including acute kidney injury with complicated refractory metabolic acidosis, electrolyte derangement, and existed or impending fluid overload. The 90-day mortality and advanced CKD were 53% and 29%, respectively. Multivariate Cox regression analysis demonstrated that only underlying bone marrow transplantation (BMT) (HR 4.58; 95% CI: 2.04-10.27) and a high pSOFA score (HR 1.12; 95% CI: 1.01-1.23) were independent risk factors for 90-day mortality. Among survivors, ten developed advanced CKD on the 90th day, and this group had a higher serum fibrinogen level (OR 1.01; 95% CI: 1.01-1.03) at the start of CRRT. CONCLUSION: In critically ill children with AKI requiring CRRT, post-BMT and high pSOFA scores are independent risk factors for 90-day mortality. Additionally, a high serum fibrinogen level at the initiation of CRRT is associated with the development of advanced CKD.

Phenotype, genotype, and clinical outcome of Taiwanese with congenital nephrotic syndrome.

BACKGROUND/PURPOSE: Congenital nephrotic syndrome (CNS) is one of the important causes of end-stage kidney disease in children. Studies on the genotype, phenotype, and clinical outcome in infants with CNS caused by genetic mutations are scarce. METHODS: We analyzed the genetic background, clinical manifestations, treatment response, and prognosis of pediatric patients with CNS in Taiwan. RESULTS: Fifteen infants with CNS were enrolled, and 11 patients of median age 21 (interquartile range 3∼44) days caused by genetic mutations from 10 unrelated families were included in the study. Of the eleven patients, 9 had extra-renal manifestations including microcephaly, facial dysmorphism, and skeletal anomalies. More than two-thirds of the patients had disease onset before 1 month of age. Diffuse meningeal sclerosis was the most common histological characteristic. Whole exome sequencing followed by direct Sanger sequence revealed mutations in OSGEP (R247Q), WT1 (R366H and R467Q), LAMB2 (Q1209∗ and c. 5432-5451 19 bp deletion), NUP93 (D302V), and LAGE3 (c.188+1G > A). Three of the variants were novel. Corticosteroids and/or immunosuppressants were administered in 2 patients, but both were refractory to treatment. During the mean 3.5 years of follow-up, all but two died of uremia and sepsis. The two survivors reached end-stage kidney disease and required peritoneal dialysis, and one of them underwent uneventful renal transplantation. CONCLUSIONS: The majority of patients with CNS in Taiwan were caused by OSGEP followed by WT1 mutation. R247Q is the hotspot mutation of OSGEP in Taiwan. CNS patients in Taiwan suffer from significant morbidity and mortality.

Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure.

CNNM2 is primarily expressed in the brain and distal convoluted tubule (DCT) of the kidney. Mutations in CNNM2 have been reported to cause hypomagnesemia, seizure, and intellectual disability (HSMR) syndrome. However, the clinical and functional effect of CNNM2 mutations remains incompletely understood. We report our clinical encounter with a 1-year-old infant with HSMR features. Mutation screening for this trio family was performed using next-generation sequencing (NGS)-based whole exome sequencing (WES) with the identified mutation verified by Sanger sequencing. We identified a de novo heterozygous mutation c.G1439T (R480L) in the essential cystathionine ß-synthase (CBS) domain of CNNM2 encoding CNNM2 (cyclin M2) without any other gene mutations related to hypomagnesemia. The amino acid involved in this missense mutation was conserved in different species. It was also found to be pathogenic based on the different software prediction models and ACGME criteria. In vitro studies revealed a higher expression of the CNNM2-R480L mutant protein compared to that of the wild-type CNNM2. Like the CNNM2-wild type, proper localization of CNNM2-R480L was shown on immunocytochemistry images. The Mg2+ efflux assay in murine DCT (mDCT) cells revealed a significant increase in intracellular Mg2+ green in CNNM2-R480L compared to that in CNNM2-WT. By using a simulation model, we illustrate that the R480L mutation impaired the interaction between CNNM2 and ATP-Mg2+. We propose that this novel R480L mutation in the CNNM2 gene led to impaired binding between Mg2+-ATP and CNNM2 and diminished Mg2+ efflux, manifesting clinically as refractory hypomagnesemia.

Clinical and genetic approach to renal hypomagnesemia.

Magnesium (Mg2+) is an important intracellular cation and essential to maintain cell function including cell proliferation, immunity, cellular energy metabolism, protein and nucleic acid synthesis, and regulation of ion channels. Consequences of hypomagnesemia affecting multiple organs can be in overt or subtle presentations. Besides detailed history and complete physical examination, the assessment of urinary Mg2+ excretion is help to differentiate renal from extra-renal (gastrointestinal, tissue sequestration, and shifting) causes of hypomagnesemia. Renal hypomagnesemia can be caused by an increased glomerular filtration and impaired reabsorption in proximal tubular cells, thick ascending limb of the loop of Henle or distal convoluted tubules. A combination of renal Mg2+ wasting, familial history, age of onset, associated features, and exclusion of acquired etiologies point to inherited forms of renal hypomagnesemia. Based on clinical phenotypes, its definite genetic diagnosis can be simply grouped into specific, uncertain, and unknown gene mutations with a priority of genetic approach methods. An unequivocal molecular diagnosis could allow for prediction of clinical outcome, providing genetic counseling, avoiding unnecessary studies or interventions, and possibly uncovering the pathogenic mechanism. Given numerous identified genes responsible for Mg2+ transport in renal hypomagnesemia over the past two decades, several potential and specific molecular and cellular therapeutic strategies to correct hypomagnesemia are promising.

Refractory hyponatremia in neuromyelitis optica in a pediatric patient: A case report.

RATIONALE: Neuromyelitis optica spectrum disorders (NMOSD) is a rare autoimmune disease predominantly involving optic nerves and spinal cord, and possible comorbidities including syndrome of inappropriate antidiuretic hormone secretion or urinary complication. We reported a young girl diagnosed with NMOSD presented with refractory hyponatremia, acute urine retention, and general weakness. Clinical symptoms improved gradually after receiving intravenous immunoglobulin, high-dose methylprednisolone, and plasmapheresis. NMOSD should be kept in mind in adolescence with acute urine retention, intermittent fever, and hyponatremia. PATIENT CONCERNS: A 15-year-old girl admitted to our hospital due to no urination for 2 days. DIAGNOSIS: Aquaporin-4 antibodies were detected showing positive both in serum and cerebrospinal fluid. Long transverse myelitis in cervical and thoracic spinal cord and optic neuritis was revealed in magnetic resonance imaging. INTERVENTIONS: Intravenous immunoglobulin 2 g/kg was infused totally in 4 days, and methylprednisolone pulse therapy was subsequently followed in 5 days; followed by 5 courses of plasmapheresis a week later. OUTCOMES: Her muscle power, syndrome of inappropriate antidiuretic hormone secretion condition, and urinary function were all improved after immune-modulated treatment course; NMOSD relapsed twice within the first year after diagnosis, however no relapse of NMOSD in the subsequent 1 year. LESSONS: To the best of our knowledge, this was the first childhood case of NMO accompanied by refractory hyponatremia in the reported literature. In childhood cases presenting with refractory hyponatremia and limb weakness, NMO or NMOSD should be considered possible diagnoses despite their rarity in pediatric cases.

Case Report: Acute Renal Infarction in a Child With Coarctation of Aorta.

Renal arterial infarction can present with hematuria, proteinuria, and hypertension, features often linked to glomerular disease. An aortic aneurysm is an extraordinarily rare complication of coarctation of the aorta. Acute renal infarction caused by emboli from the aortic aneurysm is a possible complication that has not been reported. We herein report a 10-year-old boy who presented with hematuria, proteinuria, hypertension, and skin rashes on both lower extremities mimicking acute glomerulonephritis but actually resulting from acute renal infarction caused by a coarcted aneurysm-associated thrombus. He was successfully treated with surgical excision of the coarcted aorta and aneurysm followed by subcutaneous low molecular weight heparin without recurrence.

Effect of Hydrocortisone on Angiotensinogen (AGT) Mutation-Causing Autosomal Recessive Renal Tubular Dysgenesis.

We has identified a founder homozygous E3_E4 del: 2870 bp deletion + 9 bp insertion in AGT gene encoding angiotensinogen responsible for autosomal recessive renal tubular dysgenesis (ARRTD) with nearly-fatal outcome. High-dose hydrocortisone therapy successfully rescued one patient with an increased serum Angiotensinogen (AGT), Ang I, and Ang II levels. The pathogenesis of ARRTD caused by this AGT mutation and the potential therapeutic effect of hydrocortisone were examined by in vitro functional studies. The expression of this truncated AGT protein was relatively low with a dose-dependent manner. This truncated mutation diminished the interaction between mutant AGT and renin. The truncated AGT also altered the glucocorticoid receptor (GR)-dependent transactivation, indicating that AGT may affect the development of proximal convoluted tubule by alteration of glucocorticoid-dependent transactivation. In hepatocytes, hydrocortisone increased the AGT level by accentuating the stability of mutant AGT and increasing its binding with renin. Therefore, hydrocortisone may exert the therapeutic effect through the enhanced stability and interaction with renin of truncated AGT in patients carrying this AGT mutation.

Autosomal Recessive Renal Tubular Dysgenesis Caused by a Founder Mutation of Angiotensinogen.

INTRODUCTION: Autosomal recessive renal tubular dysgenesis (ARRTD) caused by inactivation mutations in AGT, REN, ACE, and AGTR is a very rare but fatal disorder with an unknown prevalence. METHODS: We report 6 Taiwanese individuals with ARRTD from 6 unrelated families diagnosed by renal histology. Clinical features, outcome, and prevalence of carrier heterozygosity were examined. RESULTS: All patients exhibited antenatal oligohydramnios, postnatal anuria, pulmonary hypoplasia, and profound hypotension refractory to interventions. Angiotensinogen (AGT) protein levels were diminished in the liver, along with reduced serum AGT, angiotensin I (Ang I) and angiotensin II (Ang II) levels. Neonatal demise occurred in all but 1 case. All individuals carried the same homozygous E3_E4 del:2870bp deletion+9bp insertion in AGT, which led to a truncated protein (1-292 amino acid). The allelic frequency of this heterozygous AGT mutation was approximately 1.2% (6/500), suggesting that ARRTD may not be exceedingly rare in Taiwan. This mutation results in skipping of exons encoding the serpin domain of AGT, which is important for renin interaction and the generation of truncated protein. In silico modeling revealed a diminished interaction between mutant AGT and renin. One patient survived after responding to high-dose hydrocortisone therapy, with resolution of profound hypotension, accompanied by an increase in serum AGT, Ang I, and Ang II levels. CONCLUSION: This AGT mutation may lead to the diminished interaction with renin and decreased Ang I and Ang II generation. Hydrocortisone may potentially rescue cases of ARRTD caused by this truncated AGT.

Complement Factor I Mutation May Contribute to Development of Thrombotic Microangiopathy in Lupus Nephritis.

Objective: Renal thrombotic microangiopathy (TMA) is associated with complement overactivation and poor outcome in patients with lupus nephritis (LN). The role of genetic makeup of complement system in these patients remains to be elucidated. Methods: The clinical and laboratory characteristics of 100 patients with LN during 2010-2017 were retrospectively analyzed. LN patients with renal TMA and condition-matched LN patients without renal TMA were studied. Twenty normal subjects were also enrolled for comparison. Whole exome sequence followed by Sanger sequence was used in our study cohort. Results: Eight patients with renal TMA and eight condition-matched patients were enrolled from 100 LN patients with mean age 11.2 ± 2.0 years. Compared with condition-matched LN patients without renal TMA, LN patients with renal TMA exhibited statistically higher serum urea. Although most patients with renal TMA responded to plasma exchange, they had significantly higher relapse rate of nephritis, lower remission rate, and higher risk of end-stage renal disease and mortality. Compared with patients without renal TMA and normal subjects, those with renal TMA had significantly lower serum complement factor H (CFH) and plasma ADAMTS13 activity. Molecular analysis of all 100 patients with LN uncovered that three patients with renal TMA harbored mutations, two missense and non-sense, on CFI and CFHR2. The non-sense mutation, E302X, on CFI may impair its interaction C3b/CFH complex by loss of the heavy chain of complement factor I on simulation model. Conclusion: In addition to low serum CFH level and plasma ADAMTS13 activity, defects in genes responsible for complement regulatory proteins may contribute to the development of renal TMA in patients with LN.

Clinical features, genetic background, and outcome in infants with urinary tract infection and type IV renal tubular acidosis.

BACKGROUND: Type IV renal tubular acidosis (RTA) is a severe complication of urinary tract infection (UTI) in infants. A detailed clinical and molecular analysis is still lacking. METHODS: Infants with UTI who exhibited features of type IV RTA were prospectively enrolled. Clinical, laboratory, and image characteristics and sequencing of genes responsible for phenotype were determined with follow-up. RESULTS: The study cohort included 12 infants (9 males, age 1-8 months). All exhibited typical type IV RTA such as hyperkalemia with low transtubular potassium gradient, hyperchloremic metabolic acidosis with positive urine anion gap, hypovolemic hyponatremia with renal salt wasting, and high plasma renin and aldosterone levels. Seven had hyperkalemia-related arrhythmia and two of them developed life-threatening ventricular tachycardia. With prompt therapy, all clinical and biochemical abnormalities resolved within 1 week. Five had normal urinary tract anatomy, and three of them carried genetic variants on NR3C2. Three variants, c.1645T>G (S549A), c.538G>A (V180I), and c.1-2C>G, on NR3C2 were identified in four patients. During follow-up, none of them had recurrent type IV RTA, but four developed renal scaring. CONCLUSIONS: Genetic mutation on NR3C2 may contribute to the development of type IV RTA as a complication of UTI in infants without identifiable risk factors, such as urinary tract anomalies.

Risk factors for complications of percutaneous ultrasound-guided renal biopsy in children.

BACKGROUND: Percutaneous ultrasound-guided renal biopsy (PURB) is an invasive but essential procedure in establishing the histologic diagnosis of pediatric renal diseases. Large studies which describe PURB complications and its contributory risk factors are scarce in the pediatric literature. METHODS: Patients who underwent real-time PURB from September 2011 to August 2017 were retrospectively reviewed. Data pertaining to clinical characteristics, histologic diagnosis and biopsy-related complications were collected. In addition, the risk factors for complications were also analyzed. RESULTS: Overall, 183 patients (109 females) were enrolled and 201 biopsies were obtained. The mean age was 14.4 ± 13.7 years. Over 98% of the biopsies were considered adequate in quality. The major complications were perirenal hematoma requiring blood transfusion (4 cases, 2.0%), followed by perirenal abscess (1 case, 0.5%) and arteriovenous fistula (1 case, 0.5%). All patients recovered without sequelae after treatment. Hypertension, low estimated glomerular filtration rate (eGFR) and anemia were more common in patients with complication than in those without. Further logistic regression model analysis demonstrated that eGFR <30 ml/1.73m2/min was an independent risk factor for major complications. CONCLUSIONS: Perirenal hematoma needing blood transfusion is the most common major complication for children undergoing renal biopsy. Low eGFR is an independent risk factor for major complications. Early recognition and timely treatment should be delivered to children with renal function impairment accordingly.

Unilateral renal artery stenosis presented with hyponatremic-hypertensive syndrome - case report and literature review.

BACKGROUND: Renal artery stenosis is one of the secondary causes of pediatric hypertension. Cases with critical unilateral renal artery stenosis manifesting with the hyponatremic hypertensive syndrome are rare and a comprehensive description of this disorder in the pediatric population is lacking in the literature. CASE PRESENTATION: We describe a 4-year-old boy who presented with severe hypertension, profound hyponatremia, hypokalemia, nephrotic range proteinuria, and polyuria. Distinctly, the diagnosis of hyponatremic hypertensive syndrome secondary to unilateral renal artery stenosis was confirmed in light of laboratory and radiographic findings of severe natriuresis, elevated renin, and unilateral small kidney. Two weeks following nephrectomy, there was resolution of hyponatremia, hypokalemia, nephrotic range proteinuria and hypertension. CONCLUSIONS: Findings of hyponatremia, hypokalemia, hypertension, polyuria, and unilateral renal hypoplasia can be attributed to a unifying pathology of unilateral renal artery stenosis.