The risk of thromboembolic events in patients with nephrotic syndrome and relatively high albumin levels: a study over 10 years.

BACKGROUND: Low albumin level is a risk factor for thromboembolic events in patients with NS (nephrotic syndrome). However, little is known about the proportion and characteristics of patients with NS who experience thromboembolic events with relatively high albumin levels (≥ 25 g/L). Therefore, we explored the features of this specific group of patients. METHODS: This study included all hospitalized patients in our center for the past 10 years who had diagnoses of NS and relevant thromboembolic events. We divided them into 2 groups based on their serum albumin level when the thromboembolic event occurred. The clinical data were analyzed with SPSS software. RESULTS: There were 312 patients enrolled in our study. Eighty-four (26.9%) of them had relatively high albumin levels (≥ 25 g/L). Patients with NS with high albumin levels had significantly lower levels of 24-h proteinuria (P < 0.01) and a higher rate of autoimmune disease (P = 0.03) than the low-albumin group. Membranous nephropathy (MN) was the most frequent pathological type of NS in patients with thromboembolic events, regardless of their albumin level. There were significantly fewer patients with anti-PLA2R (M-type phospholipase A2 receptor)-positive MN in the high-albumin group than in the low-albumin group (P < 0.01). CONCLUSIONS: Our study found that there was still a high risk for patients with NS and relatively high albumin levels to develop thromboembolic events.

Serum tumour necrosis factor-alpha as a marker of disease activity in children with nephrotic syndrome.

Idiopathic nephrotic syndrome (NS) is a common glomerular disease in children throughout the world; however, the exact pathogenesis of the disease remains unknown. Several studies have shown that tumour necrosis factor-alpha (TNF-α), a proinflammatory cytokine, plays a significant role in the pathogenesis of NS. The literature lacks sufficient data to establish the relationship between TNF-α and NS. This prospective study was conducted on children aged 1-14 years diagnosed with idiopathic NS. All enrolled individuals were followed up from disease onset or relapse of NS until remission or at least 42 days with steroid therapy if remission was not achieved. Serum TNF-α levels were measured at presentation and remission or after 42 days of steroid therapy if remission was not achieved. The role of TNF-α levels in response to steroid therapy in NS was also assessed. One hundred and twelve children (68% boys) with idiopathic NS were enrolled. The median age (interquartile range) at enrolment was 58.5 (37-84.7) months, while the median age at symptom onset was 47.5 (24-60.7) months. The median TNF-α level at presentation was 7.5 (3.5-12.1) pg/ml, and that at remission was 5.25 (1.62-8.8) pg/ml. The median TNF-α levels among first-episode NS at presentation were 3.98 pg/ml and 1.88 pg/ml (P = .04) at remission, whereas in steroid-resistant NS, it was 6.59 pg/ml at presentation and 9.02 pg/ml at 42 days (P = .45). There was a significant negative correlation between the duration of steroid therapy and TNF-α levels, with a correlation factor of -0.021 and R2 of 0.154 (P≤.001). Serum TNF-α levels decrease with steroid therapy in children with steroid-sensitive NS, which correlates clinically with the achievement of remission.

[Comparison of thrombodynamic methods and routine hemostasis tests in the evaluation of hypercoagulable syndrome in chronic glomerulonephritis].

BACKGROUND: Nephrotic syndrome (NS) is associated with a high risk of thrombotic complications. In this group of patients, routine local tests for assessing hemostasis do not accurately reflect hypercoagulable state. Global functional tests for assessing hemostasis, including thrombodynamics (TD), are considered promising for assessing disorders in the blood coagulation system of these patients. AIM: To compare the rate of hypercoagulability according to routine hemostatic tests and TD and to evaluate the factors associated with increased risk of thrombotic complications in patients with chronic glomerulonephritis (CGN). MATERIALS AND METHODS: The study included 94 patients with active CGN who were not receiving anticoagulant therapy; 63 (80.3%) patients had NS, and 31 (19.7%) had active CGN without NS. Hemostasis parameters were assessed using local coagulation tests and TD test. Using logistic regression analysis, factors associated with the risk of thrombosis were assessed. RESULTS: Of the 94 patients with active CGN in 63 without preventive anticoagulant therapy, hypercoagulability according to routine tests was detected in 6 (9.5%) patients with NS and in 3 (9.7%) patients without NS (p<0.05). Hypercoagulability according to the TD test was detected in 24 (53.9%) patients with NS and in 5 (32.2%) without NS (p<0.05). The formation of spontaneous clots was observed in 29 (30.9%) of patients with CGN, most of them 24 (83%) with NS. 10.6% of patients in our cohort experienced thromboembolic events. The risk of thromboembolic events according to the univariate regression analysis was associated with older age, higher lipid levels, use of glucocorticosteroids and detection of spontaneous clots by the TD test. No association of thromboembolic events with abnormalities in routine hemostasis tests was obtained. CONCLUSION: In patients with CGN with nephrotic syndrome, hypercoagulability is detected in 9.5% of cases with routine coagulation tests and in 53.9% of cases with TD test. Detection of spontaneous clots by TD test is associated with a risk of thromboembolic events.

Fibrinogen-albumin ratio predicts treatment response in phospholipase A2 receptor-associated membranous nephropathy with nephrotic syndrome.

BACKGROUND: The M-type phospholipase A2 receptor (PLA2R)-associated primary membranous nephropathy (PMN) is an immune-related disease in adults with increasing morbidity and variable treatment response, in which inflammation may contribute to the multifactorial immunopathogenesis. The relationship between fibrinogen-albumin ratio (FAR), serving as a novel inflammatory biomarker, and PMN is still unclear. Therefore, this study aims to clarify the association between FAR and disease activity and therapy response of PMN. METHODS: 110 biopsy-proven phospholipase A2 receptor (PLA2R) -associated PMN participants with nephrotic syndrome from January 2017 to December 2021 were recruited in the First Affiliated Hospital of Nanjing Medical University. The independent risk factors of non-remission (NR) and the predictive ability of FAR were explored by Cox regression and receiver-operating characteristic (ROC) curve analysis. According to the optimal cutoff value, study patients were categorized into the low-FAR group (≤the cutoff value) and the high-FAR group (>the cutoff value). Spearman's correlations were used to examine the associations between FAR and baseline clinicopathological characteristics. Kaplan-Meier method was used to assess the effects of FAR on remission. RESULTS: In the entire study cohort, 78 (70.9%) patients reached complete or partial remission (CR or PR). The optimal cutoff value of FAR for predicting the remission outcome (CR + PR) was 0.233. The Kaplan-Meier survival analysis demonstrated that the high-FAR group (>0.233) had a significantly lower probability to achieve CR or PR compared to the low-FAR group (≤0.233) (Log Rank test, p = 0.021). Higher levels of FAR were identified as an independent risk factor for NR, and the high-FAR group was associated with a 2.27 times higher likelihood of NR than the low-FAR group (HR 2.27, 95% CI 1.01, 5.13, p = 0.048). These relationships remained robust with further analysis among calcineurin inhibitors (CNIs)-receivers. In the multivariate Cox regression model, the incidence of NR was 4.00 times higher in the high-FAR group than in the low-FAR group (HR 4.00, 95% CI 1.41, 11.31, p = 0.009). Moreover, ROC analysis revealed the predictive value of FAR for CR or PR with a 0.738 area under curve (AUC), and the AUC of anti-PLA2R Ab was 0.675. When combining FAR and anti-PLA2R Ab, the AUC was boosted to 0.766. CONCLUSIONS: FAR was significantly correlated with proteinuria and anti-PLA2R Ab in PMN. As an independent risk factor for NR, FAR might serve as a potential inflammation-based prognostic tool for identifying cases with poor treatment response, and the best predictive cutoff value for outcomes was 0.233.

Proteomic Analysis of Idiopathic Nephrotic Syndrome Triggered by Primary Podocytopathies in Adults: Regulatory Mechanisms and Diagnostic Implications.

Idiopathic nephrotic syndrome (NS) is a heterogeneous group of glomerular disorders which includes two major phenotypes: minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). MCD and FSGS are classic types of primary podocytopathies. We aimed to explore the molecular mechanisms in NS triggered by primary podocytopathies and evaluate diagnostic value of the selected proteomic signatures by analyzing blood proteome profiling. Totally, we recruited 90 participants in two cohorts. The first cohort was analyzed using label-free quantitative (LFQ) proteomics to discover differential expressed proteins and identify enriched biological process in NS which were further studied in relation to clinical markers of kidney injury. The second cohort was analyzed using parallel reaction monitoring-based quantitative proteomics to verify the data of LFQ proteomics and assess the diagnostic performance of the selected proteins using receiver-operating characteristic curve analysis. Several biological processes (such as immune response, cell adhesion, and response to hypoxia) were found to be associated with kidney injury during MCD and FSGS. Moreover, three proteins (CSF1, APOC3, and LDLR) had over 90% sensitivity and specificity in detecting adult NS triggered by primary podocytopathies. The identified biological processes may play a crucial role in MCD and FSGS pathogenesis. The three blood protein markers are promising for diagnosing adult NS triggered by primary podocytopathies.

Differences of clinicopathological characteristics and outcomes of IgA nephropathy patients with and without nephrotic syndrome.

PURPOSE: To evaluate the differences in clinicopathological features and outcomes of IgA nephropathy (IgAN) patients with and without nephrotic syndrome. METHODS: In this retrospective cohort study, IgAN patients from January 2006 to December 2011 in the First Affiliated Hospital of Sun Yat-sen University were enrolled and followed up to Dec 31, 2013. Logistic and Cox regression were conducted to evaluate the associated factors of nephrotic syndrome (NS) and its relation with outcomes of creatinine doubling and progression to end-stage kidney disease (ESKD). RESULTS: A total of 1413 patients with IgAN were enrolled in this study, 57 (4.0%) of whom exhibited NS. Meanwhile, 13 (22.8%) of NS IgAN patients had minimal change disease (MCD). Logistic regression showed that more presence of hypertension, less glomerular sclerosis, less tubular atrophy/interstitial fibrosis, and lower density of IgA deposition in mesangial region were significantly associated with NS IgAN that were independent of age and gender. In addition, a total of 921 patients (890 with non-NS IgAN and 31 with NS IgAN) were followed up to Dec 31, 2013. After adjusting for age, sex, baseline estimated glomerular rate, hypertension and hemoglobin, no significant difference was observed in outcomes of serum creatinine doubling and ESKD between patients with or without NS IgAN. CONCLUSIONS: Prevalence of NS IgAN patients was 4.0%, and 22.8% of them had MCD. Patients with NS IgAN had more severe clinical but less severe pathological features. However, outcomes of serum creatinine doubling and ESKD were not significantly different between patients with or without NS IgAN.

Antineutrophil cytoplasmic antibody in children with nephrotic syndrome treated with levamisole: a cross-sectional cohort study.

BACKGROUND: Levamisole is a commonly used steroid-sparing agent (SSA), but the reported incidence of antineutrophil cytoplasmic antibody (ANCA) positivity has been concerning. METHODS: Observational cross-sectional study wherein children aged 2 to 18 years with frequently relapsing/steroid dependent nephrotic syndrome (FRNS/SDNS) on levamisole for ≥ 12 months were tested for ANCA. RESULTS: A total of 210 children (33% female), median age of 7.3 (IQR: 5.6-9.6) years, and a median duration of levamisole exposure of 21 (IQR: 15-30) months were tested. ANCA was positive in 18% (n = 37): 89% (n = 33) perinuclear ANCA (pANCA), 3% (n = 1) cytoplasmic ANCA (cANCA), and 8% (n = 3) both. Of ANCA-positive children, none had reduced eGFR or abnormal urinalysis. The majority of these children were asymptomatic (81%, n = 30). Rash was more common among ANCA-positive children [6/37 (16%) vs. 3/173 (2%), p = 0.0001]. On multivariate analysis, higher age (OR = 1.02, [95th CI: 1.01 to 1.03], p = 0.007) and longer duration of levamisole exposure (OR = 1.05, [95th CI: 1.02 to 1.08], p = 0.0007) were associated with ANCA positivity. Levamisole was stopped in ANCA-positive children with the resolution of any clinical manifestations if present. Repeat ANCA testing was performed in 54% (20/37), and all were ANCA negative by 18 months. CONCLUSIONS: Children with FRNS/SDNS on longer duration of levamisole were associated with increasing prevalence of ANCA positivity, but most of these children were clinically asymptomatic. Prospective studies are required to determine the chronology of ANCA positivity and its clinical implication.

Longitudinal analysis of blood pressure and lipids in childhood nephrotic syndrome.

BACKGROUND: In the current study, longitudinal BP and lipid measurements were examined in a NEPTUNE cohort of children with newly diagnosed nephrotic syndrome (cNEPTUNE). We hypothesized that hypertensive BP and dyslipidemia would persist in children with nephrotic syndrome, regardless of steroid treatment response. METHODS: A multi-center longitudinal observational analysis of data obtained from children < 19 years of age with new onset nephrotic syndrome enrolled in the Nephrotic Syndrome Study Network (cNEPTUNE) was conducted. BP and lipid data were examined over time stratified by disease activity and steroid exposure. Generalized estimating equation regressions were used to find determinants of hypertensive BP and dyslipidemia. RESULTS: Among 122 children, the prevalence of hypertensive BP at any visit ranged from 17.4% to 57.4%, while dyslipidemia prevalence ranged from 40.0% to 96.2% over a median of 30 months of follow-up. Hypertensive BP was found in 46.2% (116/251) of study visits during active disease compared with 31.0% (84/271) of visits while in remission. Dyslipidemia was present in 88.2% (120/136) of study visits during active disease and in 66.0% (101/153) while in remission. Neither dyslipidemia nor hypertensive BP were significantly different with/without medication exposure (steroids and/or CNI). In regression analysis, male sex and urine protein:creatinine ratio (UPC) were significant determinants of hypertensive BP over time, while eGFR was found to be a determinant of dyslipidemia over time. CONCLUSIONS: Results demonstrate persistent hypertensive BPs and unfavorable lipid profiles in the cNEPTUNE cohort regardless of remission status or concurrent steroid or calcineurin inhibitor treatment.

Rationale and design of the Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study.

INTRODUCTION: Disease subtyping and monitoring are essential for the management of nephrotic syndrome (NS). Although various biomarkers for NS have been reported, their clinical efficacy has not been comprehensively validated in adult Japanese patients. METHODS: The Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study is a nationwide, multicenter, and prospective cohort study in Japan, enrolling adult (≥18 years) patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), and lupus nephritis (LN). Baseline clinical information and plasma and urine samples will be collected at the time of immunosuppressive therapy initiation or biopsy. Follow-up data and plasma and urine samples will be collected longitudinally based on the designated protocols. Candidate biomarkers will be measured: CD80, cytotoxic T-lymphocyte antigen 4, and soluble urokinase plasminogen activator receptor for MCD and FSGS; anti-phospholipase A2 receptor and thrombospondin type-1 domain-containing protein 7A antibodies for MN; fragment Ba, C3a, factor I, and properdin for MPGN/C3G; and CD11b, CD16b, and CD163 for LN. Outcomes include complete and partial remission, relapse of proteinuria, a 30% reduction in estimated glomerular filtration rate (eGFR), eGFR decline, and initiation of renal replacement therapy. The diagnostic accuracy and predictive ability for clinical outcomes will be assessed for each biomarker. RESULTS: From April 2019 to April 2023, 365 patients were enrolled: 145, 21, 138, 10, and 51 cases of MCD, FSGS, MN, MPGN/C3G, and LN, respectively. CONCLUSION: This study will provide valuable insights into biomarkers for NS and serve as a biorepository for future studies.

The Sensitivity and Specificity of Serum Phospholipase A2 Receptor Antibodies in Diagnosing Primary Membranous Nephropathy in Patients with Adult Nephrotic Syndrome and its Correlation with Serum Phospholipase A2 Receptor Staining in Kidney Biopsies.

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome (NS) in nondiabetic adults, with about 70%-80% of cases of MN being primary MN (pMN). Many studies have shown that serum phospholipase A2 receptor (PLA2R) antibodies are a diagnostic and prognostic biomarker for pMN, with a pooled diagnostic sensitivity and specificity of 54%-82% and 89%-100%, respectively, resulting in PLA2R staining and serum PLA2R antibodies being incorporated in the management algorithms of MN. We studied the sensitivity and specificity of serum PLA2R antibodies for diagnosing pMN and its correlation with PLA2R staining in kidney biopsies in a prospective observational study of 58 adult NS subjects undergoing a kidney biopsy. Serum PLA2R antibodies were determined by indirect immunofluorescence (IF) before the biopsy. Kidney biopsies were sent for light microscopy and IF examinations. Biopsy samples with MN histology were stained for PLA2R antigens. Out of the 58 adult NS subjects, 28 were diagnosed with pMN and one with secondary MN. Serum PLA2R antibodies were positive in 12 subjects with pMN, and one had focal segmental glomerulosclerosis not otherwise specified, giving a sensitivity of 42.8% and specificity of 96.7% for diagnosing pMN. There was a significant association between glomerular staining for PLA2R (24 of 28 subjects) and a diagnosis of pMN by kidney biopsy, with a sensitivity of 82.8%. Cohen's kappa agreement between glomerular staining for PLA2R and a diagnosis of MN was 0.83 (0.57-1.08).

Treatment of rituximab in patients with idiopathic membranous nephropathy: a case series and literature review.

BACKGROUND/AIMS: Membranous nephropathy (MN) is a major cause of nephrotic syndrome in adults. This study aimed to evaluate the effect of rituximab (RTX) in patients with idiopathic MN (iMN) who have a high risk of progression. METHODS: We retrospectively analyzed data of 13 patients with iMN, who received RTX treatments from January 2014 to July 2020. RTX was indicated in patients with iMN with severe proteinuria and decreasing estimated glomerular filtration rate (eGFR) in the previous 6 months despite other immunosuppressive therapies. RESULTS: The patients were predominantly males (n = 11) and with a mean age of 55.3 years; median eGFR, 37.0 mL/min/1.73 m2 (interquartile range [IQR], 26.3 to 66.5); serum albumin level, 2.6 g/dL (IQR, 1.9 to 3.1); and spot urine protein-to-creatinine ratio at baseline, 6.6 g/g (IQR, 5.7 to 12.9). In a median follow-up of 22 months, eight patients (61.5%) achieved complete or partial remission. In responder group (n = 8), median eGFR increased from 31.5 to 61.5 mL/min/1.73 m2 (p = 0.049) and serum albumin level increased from 2.3 to 4.2 g/dL (p = 0.017) from RTX initiation to last follow-up. Antiphospholipase A2 receptor antibody (anti-PLA2R-Ab) was positive in six among seven tested patients, which markedly decreased in the responder group. There were no adverse events after RTX. CONCLUSION: This study suggests that RTX is a safe and effective treatment option for patients with iMN who have a high risk of progression. Individualized therapy based on anti-PLA2R-Ab titer would be needed for better outcomes.

The Curative Effect of Shuangshen Decoction Combined with Immunological Preparations in the Treatment of Pediatric Nephrotic Syndrome and Its Influence on the Rate of Complicated Infection and Recurrence.

BACKGROUND: To explore the curative effect of Shuangshen Decoction combined with immunological preparations in the treatment of pediatric nephrotic syndrome and its influence on concurrent infection and recurrence rate. METHODS: Ninety children with nephrotic syndrome were divided into the routine group and the combined group. The routine group received conventional treatment and immune agents, and the combined group was treated with Shuangshen Decoction on the basis of the routine group. The clinical indexes of the two groups were analyzed and followed up. The infection rate and recurrence rate were calculated. RESULTS: The TCM syndrome scores in the combined group were significantly lower than those in the routine group. The total effective rate of the combined group was significantly higher than that of the routine group. The recurrence rate and infection rate of the combined group were significantly lower than those of the routine group. The incidence of adverse reactions in the combined group was significantly lower than that in the routine group. CONCLUSION: Shuangshen Decoction combined with immune preparations is effective in treating pediatric nephrotic syndrome and can reduce the incidence of adverse reactions, infection rate, and recurrence rate.

Favorable therapeutic efficacy of low-density lipoprotein apheresis for nephrotic syndrome with impaired renal function.

Many reports have shown the therapeutic efficacy of LDL apheresis (LDL-A) in drug-resistant nephrotic syndrome (NS) for improvement of heavy proteinuria and severely impaired renal function. To obtain comprehensive results in a large number of cases, a post hoc analysis of the Prospective Observational survey on the Long-Term Effects of the LDL-Apheresis on the Drug Resistant Nephrotic Syndrome (POLARIS) study was performed by stratifying enrolled cases according to the pretreatment estimated glomerular filtration rate (eGFR) levels indicating normal (N) (≥60 ml/min/1.73 m2 ), moderately impaired (M) (≥30 to <60 ml/min/1.73 m2 ), and severely impaired (S) (<30 ml/min/1.73 m2 ) renal function. Significant improvements of proteinuria and renal function were found in Group N and, most interestingly, in Group M. A tendency for improvement in proteinuria was found in Group S. Most cases in all groups had not entered end-stage renal disease at 2 years after LDL-A treatment. These results suggest that LDL-A has therapeutic efficacy even in cases in which renal function has declined to 30 ml/min/1.73 m2 .

Serum levels of plasminogen activator urokinase receptor and cardiotrophin-like cytokine factor 1 in patients with nephrotic syndrome.

The pathogenesis of primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) remains unknown to date. Some circulating permeability factors are being discussed. This work assessed molecule candidates for permeability in serum samples of patients with nephrotic syndrome (NS). MATERIALS AND METHODS: 41 patients with chronic glomerulonephritis (CGN) were included in our study. 17 patients had FSGS, 7 patients had MCD, 5 patients had membranoproliferative glomerulonephritis (MPGN), 6 patients had IgA nephropathy, and 6 patients had membranous nephropathy (MN). The laboratory data were compared with the clinical and histological features of nephritis. Serum levels of plasminogen activator urokinase receptor (uPAR) and cardiotrophin-like cytokine factor 1 (CLCF-1)were measured by ELISA. RESULTS: The serum levels of uPAR were higher in FSGS patients before treatment than in patients with other morphological forms (MCD, IgA nephropathy, MN, and MPGN). The levels of uPAR in serum did not correlate with daily proteinuria, serum creatinine/eGFR, arterial hypertension, the number of sclerosed glomeruli, or tubulointerstitial fibrosis. No correlations were found between the levels of CLCF-1 in serum and creatinine levels/glomerular filtration rate, the percentage of sclerosed glomeruli, or the severity of tubulointerstitial fibrosis. There were no significant differences between the histological variants of nephritis. However, we found correlations between CLCF-1 levels and proteinuria and lipid levels. CONCLUSION: The data indicate an increase in the serum uPAR levels of FSGS before treatment. CLCF-1 levels in serum do not depend on histological forms of CGN, kidney function, or immunosuppressive treatment, but they correlate with proteinuria and serum lipids in patients with NS.

Adherence to the Mediterranean Diet Improves Fatty Acids Profile in Pediatric Patients with Idiopathic Nephrotic Syndrome.

The fatty acid profiles of patients with idiopathic nephrotic syndrome (INS) are different from that of healthy controls, even during remission, revealing an increase of the pro-inflammatory omega 6 series. It is still unknown whether the concomitance of nephrotic syndrome affects the potential positive effects of the Mediterranean diet on the levels of omega 3 and 6 fatty acids. We performed a cross-sectional study to evaluate the association between the adherence to the Mediterranean diet and fatty acid profile in 54 children with INS. The dietary habits were assessed through the validated Kidmed questionnaire. Patients with higher adherence had lower levels of linoleic acid and total omega-6. Moreover, a negative correlation between proteinuria and the anti-inflammatory omega-3 series was found. In conclusion, patients with INS with proteinuria and low adherence to the Mediterranean diet have an imbalance in the omega-6/omega-3 ratio that may benefit from following the Mediterranean diet.

Case report: a 5-year-old with new onset nephrotic syndrome in the setting of COVID-19 infection.

BACKGROUND: This is a case report of an asymptomatic SARS-CoV-2 infection associated with new-onset nephrotic syndrome in a pediatric patient. This is the third case of new-onset nephrotic syndrome in children associated with SARS-CoV-2 infection, but is the first case report describing a new-onset nephrotic syndrome presentation in a patient who had asymptomatic COVID-19 infection. CASE PRESENTATION: This is a case of a previously healthy 5 year old female who presented with new-onset nephrotic syndrome in the setting of an asymptomatic COVID-19 infection. She presented with progressive edema, and laboratory findings were significant for proteinuria and hypercholesterolemia. She was treated with albumin, diuretics, and corticosteroid therapy, and achieved clinical remission of her nephrotic syndrome within 3 weeks of treatment. Though she was at risk of hypercoagulability due to her COVID-19 infection and nephrotic syndrome, she was not treated with anticoagulation, and did not develop any thrombotic events. CONCLUSIONS: Our case report indicates that SARS-CoV-2 infection could be a trigger for nephrotic syndrome, even in the absence of overt COVID-19 symptoms.

Circulating extracellular vesicles of patients with steroid-sensitive nephrotic syndrome have higher RAC1 and induce recapitulation of nephrotic syndrome phenotype in podocytes.

Since previous research suggests a role of a circulating factor in the pathogenesis of steroid-sensitive nephrotic syndrome (NS), we speculated that circulating plasma extracellular vesicles (EVs) are a candidate source of such a soluble mediator. Here, we aimed to characterize and try to delineate the effects of these EVs in vitro. Plasma EVs from 20 children with steroid-sensitive NS in relapse and remission, 10 healthy controls, and 6 disease controls were obtained by serial ultracentrifugation. Characterization of these EVs was performed by electron microscopy, flow cytometry, and Western blot analysis. Major proteins from plasma EVs were identified via mass spectrometry. Gene Ontology classification analysis and Ingenuity Pathway Analysis were performed on selectively expressed EV proteins during relapse. Immortalized human podocyte culture was used to detect the effects of EVs on podocytes. The protein content and particle number of plasma EVs were significantly increased during NS relapse. Relapse NS EVs selectively expressed proteins that involved actin cytoskeleton rearrangement. Among these, the level of RAC-GTP was significantly increased in relapse EVs compared with remission and disease control EVs. Relapse EVs were efficiently internalized by podocytes and induced significantly enhanced motility and albumin permeability. Moreover, relapse EVs induced significantly higher levels of RAC-GTP and phospho-p38 and decreased the levels of synaptopodin in podocytes. Circulating relapse EVs are biologically active molecules that carry active RAC1 as cargo and induce recapitulation of the NS phenotype in podocytes in vitro.NEW & NOTEWORTHY Up to now, the role of extracellular vesicles (EVs) in the pathogenesis of steroid-sensitive nephrotic syndrome (NS) has not been studied. Here, we found that relapse NS EVs contain significantly increased active RAC1, induce enhanced podocyte motility, and increase expression of RAC-GTP and phospho-p38 expression in vitro. These results suggest that plasma EVs are biologically active molecules in the pathogenesis of NS.

Effect of voriconazole combined with glucocorticoid on nephrotic syndrome in children.

OBJECTIVE: To explore the efficacy of voriconazole combined with glucocorticoid on the nephrotic syndrome in children. PATIENTS AND METHODS: A total of 62 children with nephrotic syndrome were enrolled in this study. They were treated in our hospital from February 2016 to August 2019, including 35 children treated with voriconazole in a control group, and 27 children treated with glucocorticoid combined with voriconazole in a research group. The efficacy was evaluated, and a logistic regression analysis was carried out to find out the risk factors affecting the efficacy. The enzyme-linked immunosorbent assay (ELISA) was used to determine the serum creatinine and urine protein expression before and after treatment. In addition, receiver operating characteristic (ROC) curves were drawn to analyze the predictive value of serum creatinine and urine protein expression. RESULTS: The marked efficacy and total effective rate in the research group were significantly higher than those in the control group, while the non-efficacy in the research group was significantly lower than that in the control group (p<0.05). After treatment, the expression of serum creatinine and urine protein in the research group was significantly lower than that in the control group (p<0.05). The area under the curve (AUC) of urine protein was 0.798. The AUC of serum creatinine was 0.724. Multivariate logistic regression analysis revealed that serum albumin, high edema, infection, serum creatinine, and urine protein were independent risk factors. CONCLUSIONS: Glucocorticoid can improve clinical efficacy. Serum creatinine and urine protein can be adopted as predictive factors for efficacy on children with nephrotic syndrome. Serum albumin, high edema, infection, serum creatinine, and urine protein were independent risk factors for the efficacy on children with nephrotic syndrome.

Vascular Endothelial Growth Factor (VEGF) and Neopterin Levels in Children with Steroid-sensitive and Steroid-resistant Nephrotic Syndrome.

BACKGROUND: The most common glomerular disease in children is nephrotic syndrome. Steroid-resistant nephrotic syndrome tends to have a worse disease course, which bears a significant risk of chronic kidney disease in children. OBJECTIVE: To compare VEGF and neopterin levels between children with steroid-sensitive nephrotic syndrome (SSNS), steroid-resistant nephrotic syndrome (SRNS), and also healthy (control) children. METHODS: This cross-sectional study was conducted at H. Adam Malik General Hospital, Indonesia from January to December 2018. There were 160 children aged 1 to 8 years with confirmed nephrotic syndrome and without end-stage renal disease and systemic diseases, divided into SSNS, SRNS, and control groups. Data regarding age, gender, urine albumin creatinine ratio (UACR), serum albumin, total cholesterol, urea, creatinine, VEGF, and neopterin levels were collected. A p-value of less than 0.05 is considered statistically significant. RESULTS: There were no differences between groups in gender (p = 0.269) and age (p = 0.375), but there was significant difference of UACR, albumin level, total cholesterol level, and VEGF level between groups, (all p< 0.001). There was a moderate positive correlation between VEGF level and UACR (r(158) = 0.439, p< 0.001) and a moderate negative correlation between neopterin level and albumin level (r(158)= -0.312, p = 0.005). CONCLUSION: There were no differences in serum VEGF and neopterin levels between steroid-sensitive and steroid-resistant nephrotic syndrome groups. Serum VEGF level was positively correlated with UACR while serum neopterin level was negatively correlated with serum albumin level.

Dose tailoring of tacrolimus based on a non-linear pharmacokinetic model in children with refractory nephrotic syndrome.

The population pharmacokinetics (PPK) of tacrolimus (TAC) in children with refractory nephrotic syndrome (RNS) have not been well-characterized. This study aimed to investigate the significant factors affecting the TAC PPK characteristics of children with RNS and to optimize the dosing regimen. A total of 494 concentrations from 108 children were obtained from routine therapeutic drug monitoring between 2016 and 2018. Information regarding the demographic features, laboratory test results, genetic polymorphisms of CYP3A5 (rs776746) and co-therapy medications were collected. PPK analysis was performed using the nonlinear mixed-effects modelling (NONMEM) software and two modelling strategies (the linear one-compartment model and nonlinear Michaelis-Menten model) were evaluated and compared. CYP3A5 genotype, weight, daily dose of TAC and daily dose of diltiazem were retained in the final linear model. The absorption rate constant (Ka) was set at 4.48 h-1 in the linear model, and the apparent clearance (CL/F) and volume of distribution (V/F) in the final linear model were 14.2 L/h and 172 L, respectively. CYP3A5 genotype, weight and daily dose of diltiazem were the significant factors retained in the final nonlinear model. The maximal dose rate (Vmax) and the average steady-state concentration at half-Vmax (Km) in the final nonlinear model were 2.15 mg/day and 0.845 ng/ml, respectively. The nonlinear model described the pharmacokinetic data of TAC better than the linear model in children with RNS. A dosing regimen was proposed based on weight, CYP3A5 genotype and daily dose of diltiazem according to the final nonlinear PK model, which may facilitate individualized drug therapy with TAC.