Primary Nephrotic Syndrome Group Research Articles

Investigation of brain diffusion changes in children with primary nephrotic syndrome

AimPrimary nephrotic syndrome, which occurs with the deterioration of kidney functions, can subsequently affect the brain with systemic immune activation, vasculopathy and ischemia. The main aim of this study was to investigate the effectiveness of Apparent Diffusion Coefficient (ADC) and Diffusion Weighted Imaging (DWI) in identifying and detecting brain changes in pediatric patients with primary nephrotic syndrome (PNS). Materials and MethodsThe study included 24 pediatric patients with PNS and 60 healthy children as a control group. The Apparent Diffusion Coefficient values of caudate nucleus, frontal cortex, thalamus, lentiform nucleus, anterior crus and posterior crus of the internal capsule, frontal and occipital white matter were measured quantitatively. ResultsThe ADC values of thalamus, occipital white matter, caudate nucleus and frontal cortex in the PNS group were significantly lower than in the control group (p<0.05 for all). No statistically significant difference was detected between the groups in respect of other brain locations. ConclusionsSystemic effects and possible complications of primary nephrotic syndrome may lead to diffusion changes in brain tissue. The decrease in ADC values in patients with PNS may be explained by decreased cerebral perfusion due to cerebral vasoconstriction and vasculopathy.

Significance of changes in FGF23 levels in childhood primary nephrotic syndrome and children who progress to end‑stage renal disease.

Fibroblast growth factor 23 (FGF23) is an important phosphaturic hormone, yet few studies have focused on FGF23 in children with primary nephrotic syndrome (PNS) and children who progressed to end-stage renal disease (ESRD). This cross-sectional study investigated the significance of changes in FGF23 levels in childhood PNS and children who progressed to ESRD. Of the 41 children included in the study, 17 had PNS with proteinuria and normal renal function (PNS group), 4 had ESRD (ESRD group), and 20 were healthy (control group). Following corticosteroid treatment, patients with PNS and proteinuria entered the remission phase. Serum levels of FGF23, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OH-D), and calcium were measured. It was found that FGF23 levels in the PNS and ESRD groups were higher than those in the control group, while serum 25-OH-D levels were lower. Serum PTH levels increased significantly in the ESRD group. In the control group, FGF23 levels were negatively correlated with serum PTH and positively correlated with serum 25-OH-D. FGF23 levels were positively correlated with serum calcium and corrected calcium levels in children with PNS during the remission phase. Increased FGF23 levels in children with PNS, particularly in children who progressed to ESRD. It was also confirmed that serum FGF23 levels begin to rise in children with PNS prior to Stage 1 chronic kidney disease. These findings indicated that increased FGF23 levels may be associated with the progression and severity of nephrosis in children, and that serum FGF23 levels were useful for early detection of abnormal mineral metabolism in children with PNS.

Left ventricular global longitudinal strain can detect subclinical left ventricular systolic dysfunction in adult patients with primary nephrotic syndrome.

It has been shown that there is an increased risk of cardiovascular events such as heart failure and death in nephrotic syndrome. Left ventricle global longitudinal strain (LVGLS) is a more sensitive measure of assessing myocardial dysfunction and is more reproducible than left ventricle ejection fraction (LVEF%). LVGLS can detectsubclinical deterioration in the left ventricle early. In this study, we aimed to investigate LVGLS in Primary Nephrotic Syndrome (PNS) patients with normal LVEF%. Patients with histopathologically confirmed PNS were evaluated for this prospective single-center study. Patients with similar age and gender characteristics without nephrotic syndrome were included as the control group. LVGLS measurements were performed by 2D speckle tracking echocardiography. A total of 171 patients, 57 with PNS and 114 in the control group, were included in the study. The mean age was 38±12 years in the study population, and 95(56%) of the patients were women. LVEF% was 60.2±4.2 in the PNS group and 61.1±3.2 in the control group, and there was no significant difference between the two groups (p=0.111). LVGLS was found to be significantly lower in the PNS group (-19.3±2.3% vs.-20.8±1.5 %, p<0.001). A significant relationship was observed between PNS and LVGLS in the multivariable linear regression analysis (β= 4.428, CI 95% =0.57?1.48, p<0.001). A significant relationship was observed between PNS and LVGLS, and LVGLS was found to be lower in PNS patients. In patients with PNS, subclinical left ventricular systolic dysfunction may be detected in the early period by measuring LVGLS.

Quantitative vessel density analysis of macular and peripapillary areas by optical coherence tomography angiography in adults with primary nephrotic syndrome.

To compare the microvascular parameters of macular and peripapillary areas in adults with primary nephrotic syndrome (PNS) and healthy controls (HCs). In this cross-sectional study, optical coherence tomography angiography (OCTA) was used to evaluate the changes in retinal microvascular in 37 adult patients with PNS and 30 HCs in this study. All subjects underwent OCTA for measuring vascular density (VD), perfusion density (PD), and foveal avascular zone (FAZ) in the superficial capillary plexus (SCP) and optical coherence tomography (OCT) for measuring central macular thickness (CMT) and retinal nerve fiber layer (RNFL) thickness. The following clinical data of the PNS group were collected: hemoglobin, platelet, total protein, albumin, prealbumin, creatinine, urea nitrogen, glomerular filtration rate, blood lipid, urinary protein, urine microalbumin, urine microalbumin/creatinine, 24-h urine volume, and 24-h urine protein quantification. The OCTA data were compared between patients with PNS and HCs, and the correlation between the OCTA data and clinical data was analyzed in the PNS group. VD and PD in the macular area of the PNS group were significantly lower than those in the HC group (VD: 17.025±2.229 vs. 18.290±0.721, P=0.001; PD: 0.417±0.058 vs. 0.450±0.019, P=0.003). No significant differences in the FAZ area and perioptic disc microvascular parameters were observed between the two groups, and patients in the PNS group showed consistent changes in the left and right eyes. VD and PD in the central macular area were positively correlated with plasma prealbumin level (VD: ρ=0.541, P=0.001; PD: ρ=0.562, P<0.001) and negatively correlated with urinary protein level (VD: ρ=-0.579, P<0.001; PD: ρ=-0.596, P<0.001). In adult patients with PNS, the decrease in VD and PD was mainly occurred in the macular area. Partly vascular density of the macular area was positively correlated with plasma prealbumin level and negatively correlated with urinary protein level. OCTA provides a convenient, non-invasive and effective method for evaluating and monitoring retinal microcirculation damage in patients with PNS.

ANGPTL3 impacts proteinuria and hyperlipidemia in primary nephrotic syndrome

BackgroundIt is unclear why primary nephrotic syndrome (PNS) patients often have dyslipidemia. Recent studies have shown that angiopoietin-like protein 3 (ANGPTL3) is an important regulator of lipid metabolism. In this study, we explored how ANGPTL3 impacts dyslipidemia during PNS development.MethodsWe measured the serum levels of ANGPTL3 in PNS patients (n=196). Furthermore, the degree of proteinuria and lipid metabolism were examined in angptl3-overexpressing transgenic (angptl3-tg) mice at different ages. Moreover, in this study, we used the clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) system to create angptl3-knockout (angptl3-/-) mice to investigate lipopolysaccharide (LPS)-induced nephrosis.ResultsCompared with that in the healthy group, the serum level of ANGPTL3 in the PNS group was significantly increased (32 (26.35-39.66) ng/ml vs. 70.44 (63.95-76.51) ng/ml, Z =-4.81, P < 0.001). There were significant correlations between the serum level of ANGPTL3 and the levels of cholesterol (r=0.34, P < 0.001), triglycerides (r= 0.25, P = 0.001) and low-density lipoprotein (r= 0.50, P < 0.001) in PNS patients. With increasing age, angptl3-tg mice exhibited increasingly severe hypertriglyceridemia and proteinuria. The pathological features of angptl3-tg mice included rich lipid droplet deposition in hepatocytes and diffuse podocyte effacement. Compared to wild-type mice, angptl3-/- mice showed significantly lower degrees of lipid dysfunction and proteinuria after stimulation with LPS. The effects of ANGPTL3 on nephrotic dyslipidemia were confirmed in cultured hepatocytes subjected to angptl3 knockdown or overexpression. Finally, significant alterations in lipoprotein lipase (LPL) levels were observed in liver tissues from Angptl3-/- and wild-type mice stimulated with LPS.ConclusionsANGPTL3 could be involved in the development of dyslipidemia, as well as proteinuria, during PNS pathogenesis. Inhibition of LPL expression may the mechanism by which ANGPTL3 induces hyperlipidemia in PNS.

Ox-low density lipoprotein (ox-LDL) increased the susceptibility of primary nephrotic syndrome (PNS) by regulating the Treg/Th17 ratio via the MEG3 signaling

IntroductionPatients with primary nephrotic syndrome (PNS) were reported to exhibit the evident imbalance between the number of Th17 and Treg cells in their peripheral blood monocytes (PBMCs), which might be the immunological basis of the disease.Material and methods40 PNS patients and 42 healthy individuals were recruited in this study. FCM assay was used to observe the levels of Treg and Th17 cells.ResultsThe Treg/Th17 ratio was evidently decreased in PNS patients. The levels of MEG3 and RORγt were increased in the PNS group, while the levels of miR-17, miR-125a and FOXP3 mRNA were reduced in the PNS group. Moreover, the levels of IL-6 and IL-1β were highly increased in PNS patients. Ox-low density lipoprotein (ox-LDL) treatment significantly increased the levels of MEG3 and RORγt mRNA/protein while decreasing the levels of miR-17, miR-125a, and FOXP3 mRNA/protein in THP-1 cells, and the transfection of MEG3 siRNA partly alleviated the dysregulation in the expression of MEG3, relevant miRNAs and relevant mRNAs induced by ox-LDL. Also, the expression of miR-17 and miR-125a was evidently decreased upon the successful transfection of MEG3, but the RORγt mRNA/protein levels were promoted while the FOXP3 mRNA/protein levels were inhibited.ConclusionsOur results demonstrated that ox-LDL could promote the inflammatory response of PNS by decreasing the Treg/Th17 ratio via activating the MEG3 signaling. The activation of MEG3/miR-125a/FOXP3 axis and MEG3/miR-17/RORγt axis respectively lead to the Treg/Th17 imbalance, which resulted in up-regulated IL-6 and IL-1β levels, thus increasing the susceptibility of PNS.

Relationship between TIM-3 gene polymorphisms and steroid-resistant primary nephrotic syndrome in children

Nephrotic syndrome, also known as nephrosis, is a collection of symptoms in medicine and urology caused by damage to the basement membrane of the kidney glomeruli and the kidneys excrete a large amount of protein. This experiment was carried out to investigate the association of three single nucleotide polymorphisms (SNPs) of T-cell immunoglobulin and mucin-domain-containing-3 (Tim-3) with childhood primary nephrotic syndrome (PNS) steroid response in Han Chinese. For this purpose, a total of 218 children with steroid-resistant PNS and 189 children with steroid-responsive PNS were enrolled in this case-control study. Three single nucleotide polymorphisms (SNPs) of the TIM-3 gene promoter region (rs4704853, rs1051746, and rs10053538) were analyzed by polymerase chain reaction (PCR) and restriction enzyme digestion. Results showed that there were 124 males and 94 females in the steroid-resistant PNS group and 114 males and 75 females in the steroid-responsive PNS group. The mean ages of the two groups were 7.9 years and 7.7 years, respectively. The distribution of alleles of Rs1051746 and Rs10053538 were significantly different between the steroid-resistant PNS group and the steroid-responsive PNS group (P-value = 0.047 and 0.012, respectively). The distribution of their genotypes was also significantly different between the steroid-resistant PNS group and the steroid-responsive PNS group (P-value = 0.044 and 0.010, respectively). Haplotype G-C-G was less frequent among steroid-resistant PNS children than the steroid-responsive PNS children (P = 0.015). There was no significant difference between the three SNPs of TIM-3 and the clinical features of these PNS children (P&gt;0.05). It concluded that this study provided evidence showing that the polymorphisms of Rs1051746 and Rs10053538 at the TIM-3 gene were related to childhood PNS steroid response. This result provided fundamental support for future studies on the role of TIM-3 in pathogenesis and therapy of childhood PNS.

Augmentation index, a predictor of cardiovascular events, is increased in children and adolescents with primary nephrotic syndrome.

Arterial stiffness is associated with an increased risk of cardiovascular diseases. Augmentation index (AIx@75), a measure of arterial stiffness and wave reflection, has not been evaluated in patients with primary nephrotic syndrome (PNS). We investigated whether central and peripheral vascular profiles, hemodynamic parameters, and biochemical tests are associated with AIx@75 in PNS patients. This observational study involved 38 children and adolescents with PNS (12.14 ± 3.65years) and 37 healthy controls (13.28 ± 2.80years). Arterial stiffness and vascular and hemodynamic parameters were measured noninvasively using the Mobil-O-Graph® (IEM, Stolberg, Germany). In the PNS group, biochemical tests and corticosteroid dosage/treatment time were analyzed. Peripheral and central systolic blood pressure (SBPp, SBPc) Z-scores were significantly higher in the PNS patients. AIx@75 was significantly higher in the PNS patients (25.14 ± 9.93%) than in controls (20.84 ± 7.18%). In the control group, AIx@75 negatively correlated with weight (r = - 0.369; p = 0.025), height (r = - 0.370; p = 0.024), and systolic volume/body surface (r = - 0.448; p = 0.006). In the PNS group, a univariate linear correlation showed that AIx@75 negatively correlated with weight (r = - 0.360; p = 0.027), height (r = 0.381; p = 0.18), and systolic volume/body surface (r = - 0.447; p < 0.002) and positively with the Z-score of SBPp (r = 0.407; p = 0.011), peripheral diastolic blood pressure (DBPp, r = 0.452; p = 0.004), SBPc (r = 0.416; p = 0.009), DBPc (r = 0.407; p = 0.011), triglycerides (r = 0.525; p = 0.001), and cholesterol [total (r = 0.539; p < 0.001), LDLc (r = 0.420; p = 0.010), and non-HDLc (r = 0.511; p = 0.001)]. Early abnormalities of AIx@75 and vascular parameters suggest that patients with PNS, even in stable condition, present subclinical indicators for the development of cardiovascular disease.

Correlation of soluble thrombomodulin and high sensitive C reactive protein with hypercoagulability in children with primary nephrotic syndrome

Objective To explore the correlations of soluble thrombomodulin(sTM) and high sensitive C reactive protein(hs-CRP) levels with the hypercoagulable state and indicators of predicting thrombosis in children with primary nephrotic syndrome(PNS). Methods Sixty-four PNS patients who had primary clinical diagnosis or recurrence after hormone withdrawal for 6 months or more hospitalized in Department of Urology, the Second Children′s Hospital of Tianjin from January 2010 to January 2014 were selected as PNS group.Thirty patients with inguinal hernia undergoing elective surgery hospitalized in Department of Surgery, the Second Children′s Hospital of Tianjin from January 2010 to January 2014 were selected as control group.All the selected patients were extracted for venous blood samples, and the double-antibody sandwich enzyme-linked immunosorbent assay was used to detect plasma sTM levels, while immunoturbidimetric assay was used to detect plasma hs-CRP levels; the indicators of predicting thrombosis as blood lipid and fibrinogen(Fb)etc.were simultaneously detected.Inspection results were compared and the correlation was analyzed by using statistical methods. Results The level of plasma sTM in children with PNS was significantly higher than that in the control group[(1.63±0.68) μg/L vs.(0.30±0.24) μg/L], and the difference was statistically significant between the 2 groups(t=12.545, P<0.05). The level of plasma sTM in PNS group with urine protein negative was significantly lower than that before hormone treatment[(1.05±0.56) μg/L vs.(1.63±0.68) μg/L], and there was a statistically significant difference(t=6.298, P<0.05). The level of plasma sTM in children with PNS had positive correlation with 24 h urinary protein, low density lipoprotein, apolipoprotein B, lipoprotein a and Fb(r=0.379, 0.203, 0.184, 0.177, 0.224, all P<0.05). The level of plasma hs-CRP in children with PNS was significantly higher than that in the control group[(1.9±1.7) mg/L vs.(0.7±0.6) mg/L], and the difference was statistically significant between the 2 groups(t=3.487, P<0.05). In PNS group, the level of plasma hs-CRP with urine protein negative was significantly lower than that before hormone treatment[(0.4±0.3) mg/L vs.(1.9±1.7) mg/L], and there was a statistically significant difference(t=5.473, P<0.05). The level of plasma hs-CRP in children with PNS was negatively correlated with plasma albumin(r=-0.194, P<0.05), but positively correlated with Fb(r=0.257, P<0.01). Plasma sTM and hs-CRP levels in children with PNS were positively correlated(r=0.395, P<0.05). Conclusions sTM involves in the formation process of PNS hypercoagulable state possibly through dual influencing by blood coagulation process and blood lipids.sTM may be used as one of the reference indicators for PNS activity and prediction of thrombosis.Plasma hs-CRP reflects the micro-inflammatory state in children with PNS, and involves in the formation of hypercoagulability by effecting blood coagulation process, and should be used as indicators for monitoring the hypercoagulability of active PNS. Key words: Nephrotic syndrome, primary; Thrombomodulin; High sensitivity C reactive protein; Child

Clinical significance of serum and urinary soluble urokinase receptor (suPAR) in primary nephrotic syndrome and MPO-ANCA-associated glomerulonephritis in Japanese.

The soluble urokinase receptor (suPAR) has been implicated as a cause of primary focal segmental glomerulosclerosis (FSGS). However, the clinical significance of suPAR in glomerular diseases currently remains unclear. In this retrospective single-center cohort study, we investigated serum (s-) and urinary (u-) suPAR in patients with primary nephrotic syndrome (NS) (serum/urine: 37/32 cases) and MPO-ANCA-associated glomerulonephritis (ANCA-GN) (serum/urine: 13/11 cases). In pretreatment s- and u-suPAR, no significant differences were observed between the primary NS and ANCA-GN groups or among the pathological types of primary NS. An inverse correlation was noted between pretreatment s-suPAR and eGFR in the primary NS and ANCA-GN groups. A positive correlation was noted between pretreatment u-suPAR and proteinuria in the primary NS group. Furthermore, time-course changes in s- and u-suPAR over 2 months after therapy were associated with the therapeutic responsiveness of primary NS, particularly the differentiation of MCNS from FSGS (s-suPAR: AUC-ROC = 0.905, p = 0.007; u-suPAR: AUC-ROC = 0.816, p = 0.048). In the ANCA-GN group, a positive correlation was found between pretreatment s-suPAR and clinical severity or crescent formation, whereas u-suPAR was not correlated with these parameters. S- and u-suPAR after therapy may serve as clinical markers to judge the treatment response of untreated NS and differentiate MCNS from FSGS, but not in pretreatment patients. S-, but not u-suPAR may predict the severity of and crescent formation in ANCA-GN.

Insulin resistance in children with primary nephrotic syndrome and normal renal function

Insulin resistance (IR) is an independent risk factor for atherosclerosis or cardiovascular events and renal function impairment. The aim of this study was to investigate IR in children with primary nephrotic syndrome (NS). One-hundred and nineteen primary NS patients with normal renal function and 125 normal controls were studied. Fasting blood glucose, fasting serum insulin, and fasting serum C-peptide were measured. The Homa index of insulin resistance (HOMA-IR), Islet B cell function, and insulin sensitivity index were calculated. Correlations were assessed between HOMA-IR, fasting serum C-peptide, blood pressure, blood lipids, renal function, coagulation, clinical disease type, pathology and the early therapeutic effectiveness of high-dose glucocorticoids. There was no evidence of IR in the primary NS group. Although levels of fasting blood glucose, fasting serum insulin and fasting serum C-peptide were all within the normal ranges, fasting serum C-peptide was significantly higher compared to the controls. There was no disorder of carbohydrate metabolism in different hormone therapy efficacy and pathological diagnosis. Although IR was not detected, a significant increase in blood pressure, uric acid, blood lipids and coagulability was observed in the primary NS group. A correlation observed between HOMA-IR, age, blood pressure, serum creatinine (Cr) and triglyceride may suggest that insulin sensitivity will emerge as renal disease progresses. Fasting serum C-peptide levels were increased in the primary NS group, suggesting that fasting serum C-peptide may be a protective factor.

Sympathetic nervous system level and ambulatory blood pressure in children with primary nephrotic syndrome

To explore the change in ambulatory blood pressure monitoring (ABPM) value and the sympathetic nervous system (SNS) level in children with primary nephrotic syndrome(PNS) and their relationship. ABPM and casual blood pressure(CBP) were tested in 114 children with PNS and 12 normal children as a control group. The 24-h urine noradrenaline(NA), adrenaline(A) and dopamine(DA) content were detected through high-performance liquid chromatography with electrochemical luminescence and the correlation with ABP was analyzed. Among 114 children with PNS, 101 had elevated blood pressure (88.6%), 45 showed high incidence of masked hypertension (39.5%), and 80 non-dipper blood pressure (70.2%). Systolic blood pressure level and blood pressure load were greater than diastolic blood pressure. NA, A, and DA levels of the PNS group were significantly higher than those of the control group, while those of the elevated blood pressure group were significantly higher than those of the normal blood pressure group in PNS children. SNS levels were positively correlated with blood pressure levels and blood pressure load, and negatively correlated with night BP decreasing rates. Children with PNS have high incidence of hypertension with large proportion of masked hypertension and non-dipper blood pressure. Severe masked hypertension classification should be set up. In PNS children, SNS activity is elevated that might evaluate the blood pressure level and decrease blood pressure circadian rhythm.