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.

Atypical hemolytic uremic syndrome: Consensus of diagnosis and treatment in Taiwan.

Atypical hemolytic uremic syndrome (aHUS), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, is a rare but life-threatening systemic disorder caused by the dysregulation of the complement pathway. Current advances in molecular analysis and pathogenesis have facilitated the establishment of diagnosis and development of effective complement blockade. Based on this recent consensus, we provide suggestions regarding the diagnosis and management of aHUS in Taiwan. The diagnosis of aHUS is made by the presence of TMA with normal ADAMTS13 activity without known secondary causes. Although only 60% of patients with aHUS have mutations in genes involving the compliment and coagulation systems, molecular analysis is suggestive for helping establish diagnosis, clarifying the underlying pathophysiology, guiding the treatment decision-making, predicting the prognosis, and deciding renal transplantation. Complement blockade, anti-C5 monoclonal antibody, is the first-line therapy for patients with aHUS. Plasma therapy should be considered for removing autoantibody in patients with atypical HUS caused by anti-CFH or complement inhibitor is unavailable.

Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain.

The Kelch-like 3 ( KLHL3) mutations contributed to the most common causative genes in patients with pseudohypoaldosteronism type II (PHAII); however, the molecular mechanisms of PHAII-causing mutations in BTB domain of KLHL3 in vivo have not been investigated. We generated and analyzed Klhl3 knock-in (KI) mice carrying a missense M131V mutation in the BTB domain (corresponding to human KLHL3 M78V mutation). Klhl3M131V/+ KI mice exhibited typical PHAII phenotype with an exaggerated diuretic response to hydrochlorothiazide. Their kidney tissues showed an unchanged KLHL3, decreased cullin 3 (Cul3), and increased with-no-lysine kinases (WNKs) WNK1 and WNK4 along with an enhanced downstream ste20-related proline/alanine-rich kinase/oxidative stress response kinase 1-N(K)CC phosphorylation. Their Cul3 protein in the cytosol of distal convoluted tubule cells was also significantly attenuated on immunogold-labeling electron microscopy. In microdissected renal tubules, Klhl3M131V/+ KI mice expressed high levels of Wnk4 mRNA in the distal nephron. In vitro coimmunoprecipitation showed the KLHL3 BTB domain mutation retained intact interaction with WNKs but reduced binding to Cul3, thus leading to the increased abundance of total WNKs. In summary, Klhl3M131V/+ KI mice feature typical PHAII with a simultaneous increase of WNK1 and WNK4 through the impaired KLHL3 BTB domain binding to Cul3.-Lin, C.-M., Cheng, C.-J., Yang, S.-S., Tseng, M.-H., Yen, M.-T., Sung, C.-C., Lin, S.-H. Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain.

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.

Urinary clusterin-a novel urinary biomarker associated with pediatric lupus renal histopathologic features and renal survival.

BACKGROUND: Lupus nephritis (LN) is a major risk factor for systemic lupus erythematous (SLE)-related morbidity and mortality. With the aim of bypassing renal biopsy, we analyzed urinary biomarkers for their ability to predict renal histopathologic features and end-stage kidney disease (ESKD). METHODS: Urinary albumin, ß2-microglobulin (B2M), cystatin C, kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), clusterin, calbindin, interleukin-18 (IL-18), neutrophil gelatinase-associated lipocalin (NGAL), trefoil factor 3 (TFF3), osteopontin, and glutathione S-transferase π (GST-π) levels were measured at time of renal biopsy. Renal histopathologies were carefully reviewed. RESULTS: Urine from 60 pediatric SLE cases with LN, 29 without and 22 healthy controls were collected. Median age at SLE diagnosis was 12.92 years (range = 4.27-17.30 years) and 10 cases progressed to ESKD during a period of 4.12 ± 2.17 years. Urinary albumin and clusterin were significantly elevated (p = 0.035 and 0.048, respectively) in patients with tubulointerstitial renal lesions. Urinary clusterin among all urinary markers, performed best at predicting ESKD with cutoff of 0.61 × 10-4 (AUC = 0.804; p = 0.002). Interestingly, elevation of urinary clusterin likely resulted from local over-expression in tubulointerstitial tissue since the level of serum clusterin was not concomitantly higher (p = 0.424). CONCLUSION: Urinary biomarkers are emerging as non-invasive indicators for lupus-related renal histopathology and renal outcome prediction in pediatric SLE patients. Urinary clusterin, a newly identified biomarker, is an indicator that shows an association with tubulointerstitial renal lesions and demonstrates the best ability to predict ESKD.

Hyponatremia is a surrogate marker of poor outcome in peritoneal dialysis-related peritonitis.

BACKGROUND: Hyponatremia is known to be a marker of poor prognosis in many clinical conditions. The association between hyponatremia and clinical outcomes in peritoneal dialysis-related peritonitis (PDRP) has not been studied. We evaluated the association between hyponatremia and clinical parameters of patients with PDRP. METHODS: We conducted a retrospective analysis of medical records of patients with PDRP admitted to a medical center in the period 2004-2011. Patients with serum Na+ <130 mEq/L and ≥ 130 mEq/L at admission were divided into hyponatremic and normonatremic groups, respectively. The demographic and laboratory characteristics, pathogens of peritonitis, length of hospital stay and mortality rate were analyzed. RESULTS: Hyponatremia occurred in 27% (27/99) patients with PDRP. Gram-negative bacilli were the major pathogen responsible for 78% (21/27) PDRP in hyponatremic group while gram-positive cocci were found in 75% (41/55) PDRP in normonatremic groups. There was no significant difference in age, duration of dialysis, PD catheter removal rate and technique failure between two groups. Hyponatremic group had significantly higher serum CRP (p <0.001), lower serum albumin (p < 0.001) and phosphate (p < 0.05). Of note, serum Na+ level was positively correlated with serum albumin (p < 0.001), phosphate (p < 0.04) levels, and subjective global assessment (SGA) score (p < 0.001). Moreover, the length of hospital stay was longer and in-hospital mortality rate was higher in hyponatremic group (p < 0.001). Using a multivariable logistic regression, we showed that hyponatremia at admission is an independent predictor of in-hospital mortality (OR 76.89 95% CI 3.39-1741.67, p < 0.05) and long hospital stay (OR 5.37, 95% CI 1.58- 18.19, p < 0.05). CONCLUSIONS: In uremic patients with PDRP, hyponatremia at admission associated with a high frequency of gram negative bacilli infection, low serum albumin and phosphate levels, low SGA score, and poor prognosis with long hospital stay and high mortality rate.

Phosphorylation regulates NCC stability and transporter activity in vivo.

A T60M mutation in the thiazide-sensitive sodium chloride cotransporter (NCC) is common in patients with Gitelman's syndrome (GS). This mutation prevents Ste20-related proline and alanine-rich kinase (SPAK)/oxidative stress responsive kinase-1 (OSR1)-mediated phosphorylation of NCC and alters NCC transporter activity in vitro. Here, we examined the physiologic effects of NCC phosphorylation in vivo using a novel Ncc T58M (human T60M) knock-in mouse model. Ncc(T58M/T58M) mice exhibited typical features of GS with a blunted response to thiazide diuretics. Despite expressing normal levels of Ncc mRNA, these mice had lower levels of total Ncc and p-Ncc protein that did not change with a low-salt diet that increased p-Spak. In contrast to wild-type Ncc, which localized to the apical membrane of distal convoluted tubule cells, T58M Ncc localized primarily to the cytosolic region and caused an increase in late distal convoluted tubule volume. In MDCK cells, exogenous expression of phosphorylation-defective NCC mutants reduced total protein expression levels and membrane stability. Furthermore, our analysis found diminished total urine NCC excretion in a cohort of GS patients with homozygous NCC T60M mutations. When Wnk4(D561A/+) mice, a model of pseudohypoaldosteronism type II expressing an activated Spak/Osr1-Ncc, were crossed with Ncc(T58M/T58M) mice, total Ncc and p-Ncc protein levels decreased and the GS phenotype persisted over the hypertensive phenotype. Overall, these data suggest that SPAK-mediated phosphorylation of NCC at T60 regulates NCC stability and function, and defective phosphorylation at this residue corrects the phenotype of pseudohypoaldosteronism type II.

Kidney Cysts in Children With Alport Syndrome: A Report of 3 Cases.

Alport syndrome (AS) is a progressive hereditary kidney disease characterized by hematuria, proteinuria, and progressive kidney dysfunction accompanied by sensorineural hearing loss and ocular abnormalities. Pathogenic COL4A3-5 variants can result in different AS spectra. Further, kidney cysts have been reported in adults with AS. However, the relationship between kidney cysts and AS remains unclear. Here, we report 3 cases of AS in children that occurred with kidney cysts. The patient in case 1 was initially diagnosed with IgA nephropathy at the age of 8 years but later developed bilateral multiple kidney cysts at the age of 17 years, suggesting autosomal-dominant polycystic kidney disease. Whole-exome sequencing identified a pathogenic COL4A5 variant and confirmed the AS diagnosis. The patients in cases 2 and 3 had already been diagnosed with X-linked AS using kidney biopsy and genetic analysis. Initial kidney ultrasonography showed nephromegaly; however, kidney cyst formation was observed during their annual follow-up. Our study supports the association between AS and kidney cysts. Kidney cysts in adolescents with suspected AS should not discourage clinicians from testing for pathogenic COL4A3-COL4A5 variants. Early detection of kidney cysts is critical because it may indicate kidney disease progression.

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.

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.

Characteristics and genetic analysis of patients suspected with early-onset systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is rarely diagnosed before 5-years-old. Those with disease onset at a very young age are predicted by a higher genetic risk and a more severe phenotype. We performed whole-exome sequencing to survey the genetic etiologies and clinical manifestations in patients fulfilling 2012 SLICC SLE classification criteria before the age of 5. CASE PRESENTATION: Among the 184 childhood-onset SLE patients regularly followed in a tertiary medical center in Taiwan, 7 cases (3.8%) of which onset ≦ 5 years of age were identified for characteristic review and genetic analysis. Compared to those onset at elder age, cases onset before the age of 5 are more likely to suffer from proliferative glomerulonephritis, renal thrombotic microangiopathy, neuropsychiatric disorder and failure to thrive. Causative genetic etiologies were identified in 3. In addition to the abundance of autoantibodies, patient with homozygous TREX1 (c.292_293 ins A) mutation presented with chilblain-like skin lesions, peripheral spasticity, endocrinopathy and experienced multiple invasive infections. Patient with SLC7A7 (c.625 + 1 G > A) mutation suffered from profound glomerulonephritis with full-house glomerular deposits as well as hyperammonemia, metabolic acidosis and episodic conscious disturbance. Two other cases harbored variants in lupus associating genes C1s, C2, DNASE1 and DNASE1L3 and another with CFHR4. Despite fulfilling the classification criteria for lupus, many of the patients required treatments beyond conventional therapy. CONCLUSIONS: Genetic etiologies and lupus mimickers were found among a substantial proportion of patients suspected with early-onset SLE. Detail clinical evaluation and genetic testing are important for tailored care and personalized treatment.