Are children with IgA nephropathy different from adult patients?

BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.

Acyl-Coenzyme A: Cholesterol Acyltransferase-1 is Related to Hyperlipidemia in Children with Nephrotic Syndrome.

BACKGROUND: Hyperlipidemia is one of the characteristics of nephrotic syndrome, and cellular lipid accumulation in the kidney can accelerate kidney disease. ACAT1 plays important roles in cellular cholesterol homeostasis. The purpose of this study was to investigate the effect of ACAT1 on lipid metabolism in nephrotic syndrome, and its role in clinical diagnosis and efficacy evaluation. METHODS: In this case control study, 30 patients with nephrotic syndrome and 30 healthy controls were enrolled. ACAT1 mRNA was detected by qPCR, and methylation of ACAT1 promoter was assayed by sodium bisulfite sequencing. RESULTS: The expression of ACAT1 mRNA in NS group, remission group, and controls was 0.14 ± 0.06, 0.08 ± 0.03, and 0.08 ± 0.04, respectively. The methylation of ACAT1 promoter in NS group, remission group, and controls was 2.27 ± 2.71, 4.00 ± 3.15, and 4.93 ± 3.59, respectively. The AUC value of ACAT1 mRNA was 0.856 (95% CI: 0.760 - 0.951), while the AUC value of ACAT1 methylation was 0.653 (95% CI: 0.514 - 0.792). The results of Pearson's correlation suggested that the high expression of ACAT1 mRNA and the hypomethylation of ACAT1 were related to hyperlipidemia and hypoalbuminemia in nephrotic syndrome. CONCLUSIONS: This study shows that ACAT1 is related to hyperlipidemia and hypoproteinemia in nephrotic syndrome and can be a useful biomarker for the efficacy evaluation of nephrotic syndrome.

Semiquantitative analysis of power doppler ultrasonography versus Tc-99m DMSA scintigraphy in diagnostic and severity assessment of acute childhood pyelonephritis.

BACKGROUND: This study aimed to compare the diagnostic and predictive value of power Doppler ultrasonography (PDU) with Tc-99m dimercaptosuccinic acid (DMSA) renal scintigraphy in pediatric acute pyelonephritis (APN) using a semiquantitative analysis system. METHODS: A total of 92 children and infants (184 kidneys) were hospitalized with possible APN. All children were examined by PDU and DMSA scintigraphy within 72 hours of admission. An empiric 9-point semiquantitative analysis system was used to sort kidneys into four grades (grade 0-III). Patients with several episodes of APN and congenital structural anomalies were excluded. RESULTS: Of 184 kidneys, we found 68 abnormal (grade I-III) and 116 normal (Grade 0) with DMSA scintigraphy, and 84 abnormal and 100 normal with PDU. In all, 23 kidneys were shown to be diseased by PDU but normal on DMSA scintigraphy while 7 kidneys showed the opposite trend. The sensitivity and specificity of PDU for diagnosing APN was 89.7% and 80.2%, respectively (P<0.05). In children older than 6 months, the sensitivity was higher (92%, P<0.05) than that in children younger than 6 months (87%, P<0.05). A moderate agreement (41%, P<0.05) on grade was found between the two methods. CONCLUSIONS: With the help of a semiquantitative analysis system, PDU can obviate the use of DMSA scintigraphy in children older than 6 months for APN diagnosis.

Direct effect of protein kinase A on four putative phosphorylation sites of aquaporin 2 in vitro.

The water channel aquaporin 2 (AQP2) has four phosphorylation sites at Ser256, Ser261, Ser264, and Ser269 in the C-terminus and these sites are important for AQP2 bioactivity. However, the exact role of each phosphorylation site still remains unclear. In this study, we generated unique AQP2 mutants in which we eliminated three phosphorylation sites but maintained only one site at the C-terminal end. The AQP2 phosphorylation of each single site by protein kinase A (PKA) was examined by in vitro translation and 32P incorporation. The ability of AQP2 trafficking to the cell membrane was evaluated by cell surface biotinylation. Among the four phosphorylation sites, AQP2 mutant with only S256 preserved the most ability of AQP2 to cell membrane expression. The AQP2 water permeability was measured in oocyte. Ser256 is the most important site for AQP2 function. Interestingly, Ser261 and Ser264 significantly inhibit AQP2 activity. Ser269 slightly but not statistically reduced AQP2 activity. Our data suggest that the four phosphorylation sites execute differential roles in concert in AQP2 functional regulation. AQP2 activity regulated by phosphorylation at Ser256 can be counterbalanced by phosphorylation at Ser261 and Ser264.

Atypical hemolytic uremic syndrome induced by CblC subtype of methylmalonic academia: A case report and literature review.

RATIONALE: Methylmalonic acidemia (MMA) is a common organic acidemia, mainly due to methylmalonyl-CoA mutase (MCM) or its coenzyme cobalamin (VitB12) metabolic disorders. Cobalamin C (CblC) type is the most frequent inborn error of cobalamin metabolism; it can develop symptoms in childhood and often combine multisystem damage, which leads to methylmalonic acid, propionic acid, methyl citrate, and other metabolites abnormal accumulation, causing nerve, liver, kidney, bone marrow, and other organ damage. PATIENT CONCERNS: A 4-year-old girl presented with paleness, fatigue, severe normochromic anemia, and acute kidney injury. DIAGNOSIS: Based on severe normochromic anemia and acute kidney injury, renal biopsy showed membranous proliferative glomerular lesions and thrombotic microvascular disease, supporting the diagnosis of aHUS. Although the serum vitamin B12 was normal, further investigation found the concentration of urinary methylmalonic acid and serum homocysteine increased obviously, genetic analysis revealed a heterozygous MMACHC mutation (exonl: c. 80A >G, c. 609G >A). The final diagnosis was aHUS induced by inherited methylmalonic acidemia (MMACHC heterozygous mutation exonl: c. 80A >G, c. 609G >A). INTERVENTIONS: The patient was treated with a 1mg vitamin B12 intramuscular injection daily for 4 days after which the dose was then adjusted to a 1mg intramuscular injection twice a week. At the same time, the girl was given levocarnitine, betaine, folic acid, along with supportive treatment. OUTCOMES: After treated by vitamin B12 for 10 days, the patient condition significantly improved, Follow-up results showed complete recovery of hemoglobin and renal function. LESSONS: Although the majority of MMA onset from neurological damage, our case illustrates that partial CblC-type MMA can onset with severe metabolic aHUS. On the basis of chronic thrombotic microangiopathy (TMA)-induced renal damage, it can be complicated by acute hemolytic lesions. MMA should be considered in those patients with unclear microangiopathic hemolytic anemia accompany significant megaloblastic degeneration in bone marrow. We should pay attention to the causes and adopt a reasonable treatment strategy.

Elevation of plasma-soluble HLA-G in childhood nephrotic syndrome is associated with IgE.

Background Nephrotic syndrome is related to immune system dysfunction. Soluble human leukocyte antigen-G has been suggested to have an immunomodulatory role. Additionally, human leukocyte antigen-G expression may be influenced by the 14-base pair insertion/deletion polymorphism. However, this molecule has not been investigated in nephrotic syndrome. Methods Fifty-five children with nephrotic syndrome were enrolled: 24 primary nephrotic syndrome patients and 31 recurrent nephrotic syndrome patients. A group of 120 healthy subjects were included as reference controls. Additionally, 22 patients in nephrotic syndrome remission after treatments were also included. Both nephrotic syndrome patients and healthy subjects were genotyped for the 14-base pair insertion/deletion polymorphism. Plasma soluble human leukocyte antigen-G concentrations and serum immunoglobulin concentrations were determined. Results Nephrotic syndrome patients showed significantly higher levels of both soluble human leukocyte antigen-G and immunoglobulin E compared to normal controls. Nephrotic syndrome patients presented a higher frequency of the -14-base pair allele than did normal controls. Soluble human leukocyte antigen-G concentrations in remission patients were dramatically lower compared to in nephrotic syndrome patients. Moreover, soluble human leukocyte antigen-G and immunoglobulin E were moderately correlated in nephrotic syndrome patients. Conclusions The present study demonstrated that plasma soluble human leukocyte antigen-G concentrations were significantly elevated and that a relationship between serum total immunoglobulin E in nephrotic syndrome patients and the human leukocyte antigen-G -14-base pair allele may be a risk factor for nephrotic syndrome. These findings suggest that soluble human leukocyte antigen-G may be used as a monitoring marker for nephrotic syndrome patients' condition.

Low serum 25-hydroxyvitamin D level and risk of urinary tract infection in infants.

The aim of the study is to determine whether serum 25-hydroxyvitamin D (25(OH)D) deficiency in infants increased odds of urinary tract infection (UTI). A total of 238 infants including 132 patients experiencing a first episode of UTI and 106 controls, aged from 1 to 12 months, were enrolled. Serum 25(OH)D levels were tested through blood sampling. The serum 25(OH)D levels were significantly lower in cases with UTI than controls. The mean serum 25(OH)D levels were 29.09 ±â€Š9.56 ng/mL in UTIs and 38.59 ±â€Š12.41 ng/mL in controls (P < 0.001). Infants with acute pyelonephritis (APN) had lower serum 25(OH)D than those with lower UTI. The multivariate logistic regression analyses showed that serum 25(OH)D < 20 ng/mL (OR 5.619, 95% CI 1.469-21.484, P = 0.012) was positively related to an increased odds of UTI. Vitamin D supplementation (OR 0.298, 95% CI 0.150-0.591; P = 0.001) was associated with a decreased likelihood of UTI. Vitamin D deficiency in infants was associated with an increased odds of UTI. Interventional studies evaluating the role of vitamin D supplementation to reduce the burden of UTI are warranted.

Dexamethasone increases aquaporin-2 protein expression in ex vivo inner medullary collecting duct suspensions.

Aquaporin-2 (AQP2) is the vasopressin-regulated water channel that controls renal water reabsorption and plays an important role in the maintenance of body water homeostasis. Excessive glucocorticoid as often seen in Cushing's syndrome causes water retention. However, whether and how glucocorticoid regulates AQP2 remains unclear. In this study, we examined the direct effect of dexamethasone on AQP2 protein expression and activity. Dexamethasone increased AQP2 protein abundance in rat inner medullary collecting duct (IMCD) suspensions. This was confirmed in HEK293 cells transfected with AQP2 cDNA. Cell surface protein biotinylation showed an increase of dexamethasone-induced cell membrane AQP2 expression and this effect was blocked by glucocorticoid receptor antagonist RU486. Functionally, dexamethasone treatment of oocytes injected with an AQP2 cRNA increased water transport activity as judged by cell rupture time in a hypo-osmotic solution (66 ± 13 s in dexamethasone vs. 101 ± 11 s in control, n = 15). We further found that dexamethasone treatment reduced AQP2 protein degradation, which could result in an increase of AQP2 protein. Interestingly, dexamethasone promoted cell membrane AQP2 moving to less buoyant lipid raft submicrodomains. Taken together, our data demonstrate that dexamethasone promotes AQP2 protein expression and increases water permeability mainly via inhibition of AQP2 protein degradation. The increase in AQP2 activity promotes water reabsorption, which may contribute to glucocorticoid-induced water retention and hypertension.

Activation of protein kinase C-α and Src kinase increases urea transporter A1 α-2, 6 sialylation.

The urea transporter A1 (UT-A1) is a glycosylated protein with two glycoforms: 117 and 97 kD. In diabetes, the increased abundance of the heavily glycosylated 117-kD UT-A1 corresponds to an increase of kidney tubule urea permeability. We previously reported that diabetes not only causes an increase of UT-A1 protein abundance but also, results in UT-A1 glycan changes, including an increase of sialic acid content. Because activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway is elevated in diabetes and PKC-α regulates UT-A1 urea transport activity, we explored the role of PKC in UT-A1 glycan sialylation. We found that activation of PKC specifically promotes UT-A1 glycan sialylation in both UT-A1-MDCK cells and rat kidney inner medullary collecting duct suspensions, and inhibition of PKC activity blocks high glucose-induced UT-A1 sialylation. Overexpression of PKC-α promoted UT-A1 sialylation and membrane surface expression. Conversely, PKC-α-deficient mice had significantly less sialylated UT-A1 compared with wild-type mice. Furthermore, the effect of PKC-α-induced UT-A1 sialylation was mainly mediated by Src kinase but not Raf-1 kinase. Functionally, increased UT-A1 sialylation corresponded with enhanced urea transport activity. Thus, our results reveal a novel mechanism by which PKC regulates UT-A1 function by increasing glycan sialylation through Src kinase pathways, which may have an important role in preventing the osmotic diuresis caused by glucosuria under diabetic conditions.

Activation of the cAMP/PKA pathway induces UT-A1 urea transporter monoubiquitination and targets it for lysosomal degradation.

Regulation of urea transporter UT-A1 in the kidney is important for the urinary concentrating mechanism. We previously reported that activation of the cAMP/PKA pathway by forskolin (FSK) leads to UT-A1 ubiquitination, endocytosis, and degradation. In this study, we discovered that FSK-induced UT-A1 ubiquitination is monoubiquitination as judged by immunoblotting with specific ubiquitin antibodies to the different linkages of the ubiquitin chain. UT-A1 monoubiquitination induced by FSK was processed mainly on the cell plasma membrane. Monoubiquitination facilitates UT-A1 endocytosis, and internalized UT-A1 is accumulated in the early endosome. Inhibition of ubiquitination by E1 ubiquitin-activating enzyme inhibitor PYR-41 significantly reduced FSK-induced UT-A1 endocytosis and degradation. Interestingly, FSK-stimulated UT-A1 degradation occurs through a lysosomal protein degradation system. We further found that the PKA phosphorylation sites of UT-A1 at Ser486 and Ser499 are required for FSK-induced UT-A1 monoubiquitination. The physiological significance was confirmed using rat kidney inner medullary collecting duct suspensions, which showed that vasopressin treatment promotes UT-A1 ubiquitination. We conclude that unlike under basal conditions in which UT-A1 is subject to polyubiquitination and proteasome-mediated protein degradation, activation of UT-A1 by FSK induces UT-A1 monoubiquitination and protein lysosomal degradation.

[Renal expression of macrophage migration inhibitory factor in children with Henoch-Sch-nlein purpura nephritis].

OBJECTIVE: To examine the expression of macrophage migration inhibitory factor (MIF) in renal tissues obtained from children with Henoch-Sch-nlein purpura nephritis (HSPN). METHODS: The renal tissue samples were obtained from 11 children with different pathological grades of HSPN and 8 children with thin glomerular basement membrane disease (controls). The MIF expression was measured by immunohistochemistry. The correlation between MIF expression and 24 hrs urinary protein excretions was evaluated using a linear correlation analysis. RESULTS: MIF expression was seldom found in renal tissues obtained from controls. However, a significantly increased MIF expression was found and was concordant with the increased severity of renal pathology in renal tissues obtained from children with HSPN. The MIF expression in renal tissues of grade III-IV of renal pathology was significantly higher than that in grade I-II in children with HSPN (p<0.01). In children with HSPN, there was an increased MIF expression in renal tissues with crescent formation and inflammatory cell infiltration. Renal MIF expression was significantly positively correlated with 24 hrs urinary protein excretions in children with HSPN (p<0.01). CONCLUSIONS: MIF may play an important role in renal injury of HSPN. Up-regulation of MIF expression may reflect the degree of renal lesions in HSPN.