Active Nephrotic Syndrome Research Articles

#1389 Identification of serum lipidomic profile in nephrotic syndrome patients

Abstract Background and Aims Nephrotic syndrome describes a collection of symptoms, mainly heavy proteinuria leading to kidney function loss, that can be caused by different underlying kidney diseases. Common primary causes of nephrotic syndrome include focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD) and membranous nephropathy (MN). Nephrotic syndrome is often characterized by plasma lipid abnormalities with elevations in cholesterol, triglycerides and lipoproteins. Here we set out to generate a detailed lipidomic analysis of FSGS, MCD and MN patient's plasma to find lipid changes common to nephrotic syndrome or specific for the underlying disease. Method For this lipidomic study, we included patients with primary FSGS (2 cohorts with n = 5), genetic FSGS (n = 5), MCD (n = 5) and MN (n = 5) in whom serum had been collected at the time they presented at our center with active nephrotic syndrome. We compared the serum lipidome of nephrotic syndrome patients with age matched healthy controls (n = 5), and with age matched patients with familial hypercholesterolemia (n = 5) who, like patients with nephrotic syndrome, have significantly elevated lipid values. Serum was analyzed using the Shotgun Lipidomics platform by Lipotype GmbH (Dresden, Germany), as previously described [1]. Results The lipidomic profile of patients with nephrotic syndrome was markedly different compared to control groups (Fig. 1A). In particular, lower levels of lyso-phophatidylcholine (LPC) and higher concentrations of phosphatidylethanolamine (PE) and lyso-PE (LPE) compared to control groups were most prominent (Fig. 1B). Subspecies analysis identified LPC 16:0;0 to be highly downregulated in patients with nephrotic syndrome (Fig. 2A), whereas LPE 18:0;0 and nearly all PE subspecies were increased compared to control groups (Fig. 2B and C). The lipidomic profile was largely comparable between different underlying diseases and we could not identify lipid classes specifically different for certain diseases. Conclusion Our lipidomic data show that patients with nephrotic syndrome have a distinct lipid profile compared to healthy controls or other disease controls. We identified LPCs, PEs and LPEs to be changed in nephrotic syndrome. We could not identify lipids specific for certain diseases underlying nephrotic syndrome, but rather identified a general nephrotic syndrome lipid profile. This suggests that lipid changes are rather a consequence of disease manifestation in these patients with various underlying causes. Further research should focus on confirming this lipid profile in larger cohorts and unraveling the mechanisms leading to the observed lipid changes.

ОСОБЕННОСТИ ИММУННОГО СТАТУСА У БОЛЬНЫХ ГЛОМЕРУЛОНЕФРИТАМИ С РЕФРАКТЕРНЫМ НЕФРОТИЧЕСКИМ СИНДРОМОМ

Abstract. Introduction. Research in the issues related to glomerulonephritis with nephrotic syndrome is an important problem of modern medicine due to their prevalence among the global population and mainly in the younger age group, with a significant proportion of patients with refractory nephrotic syndrome (frequent relapses, persistent course). Currently, there are no ways to predict the development of glomerulonephrites with refractory nephrotic syndrome. Due to the immunological nature of glomerulonephrites, it seems advisable to search for predictors of refractory nephrotic syndrome among the indicators characterizing the patient’s immune status. Aim of the study was to study the characteristic features of the immune status and their prognostic value in glomerulonephritis with refractory nephrotic syndrome. Materials and Methods. We examined 136 glomerulonephritis patients with active nephrotic syndrome, hospitalized in the nephrology department in 2015-2021. Along with conventional examinations, humoral and T-cell immunity indicators were tested in the patients. The end point of the study was in 2022 where the the clinical course of the disease was assessed in patients, and patients with nephrotic syndrome who showed refractory to steroid therapy were placed into one group, while those with non–refractory nephrotic syndrome were placed into another one. Within the selected groups of patients, we performed the comparative study of demographic, clinical and laboratory parameters, the indicators of humoral and T-cell immunity, and the ROC analysis of indicators correlating with the nephrotic syndrome recurrence frequency. Results and Discussion. In the group of patients with a refractory course of the disease, an increase was detected in the number of T helper phenotype cells and of the activated T cells carrying activation markers, HLA-DR and CD38, on their surfaces. At the same time, the relative content of regulatory T cells (Treg) among T helper cells decreased. The B system was characterized by an increase in the number of B lymphocytes, an increase in the levels of circulating immune complexes and IgM, and a decrease in IgG levels. The changes detected in the parameters of humoral and T-cell immunity may be essential to the development of refractory nephrotic syndrome. In the refractory nephrotic syndrome pathogenesis, the most important is the decrease in the number of Tregs, which correlated most closely with the nephrotic syndrome recurrence frequency. Conclusions. An association was found between refractory nephrotic syndrome and the pronounced activation of humoral immunity, and a significant imbalance was detected between various immunoregulatory and activated T-lymphocyte subpopulations. The Treg content in the blood can be a prognostic indicator: Treg content values of under 1.9% indicate a high probability of developing refractory nephrotic syndrome.

#4013 LIPIDOMIC ANALYSIS OF PFSGS PATIENTS' SERUM TO IDENTIFY POTENTIAL CANDIDATES FOR THE CIRCULATING PERMEABILITY FACTOR(S) IN THE LIPID DOMAIN

Abstract Background and Aims Patients with primary focal segmental glomerulosclerosis (pFSGS) present with nephrotic syndrome. Whereas the exact pathogenesis is largely unknown, there is strong evidence that one or more circulating permeability factors in the circulation induce podocyte injury. Podocyte injury eventually leads to foot process effacement, massive proteinuria and kidney function loss. Historically, research into the cause of pFSGS has focused primarily on identifying the circulating factor in the protein domain, but reports of successful treatment with lipid apheresis suggest that it could also be a lipid compound. Here, we set out to investigate the lipidome of pFSGS patients’ serum to identify potential candidates for the circulating permeability factor(s) in the lipid domain. Method For this lipidomics study, we included 5 patients with pFSGS in whom serum had been collected at the time they presented at our center with active nephrotic syndrome. We compared the serum lipidome of the pFSGS patients with age matched healthy controls (n = 5), and with age matched patients with familial hypercholesterolemia (n = 5) who, like pFSGS patients, have significantly elevated lipid values. Serum was analyzed using the Shotgun Lipidomics platform by Lipotype GmbH (Dresden, Germany), as previously described [1]. The amount of lipids were normalized to the total amount of lipids present within the sample. Results The lipidomic profile of patients with pFSGS was markedly different from the profile of healthy controls and patients with hypercholesterolemia. We found differences in various lipid classes in pFSGS patients, including cholesterol esters (CE), lyso-phophatidylcholine (LPC), phophatidylethanolamine (PE), diacylglycerol (DAG) and triacylglycerol (TAG) that were significantly changes compared to both healthy controls and FH patients. Diacylglycerols (DAG) were identified as the most significantly increased lipid species in pFSGS. By analyzing the subspecies we discovered that DAGs with carbon chains greater than 38 carbon atoms in both chains combined (long carbon chain DAGs, lccDAGs) were exclusively present in patients with pFSGS. Conclusion Our lipidomics data show that patients with pFSGS have a substantially different lipid profile than healthy controls and patients with familial hypercholesterolemia. We identified lccDAGs as unique lipids in patients with pFSGS, that were not present in controls. This is an interesting finding since the DAG-analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG) is known to be able to induce podocyte injury in vitro [2]. In further research, we will focus on confirming whether lccDAGs are unique to pFSGS patients, whether it is suitable as a biomarker, and whether it plays a causal role in the disease process.

Predictive value of platelet indices in children with idiopathic nephrotic syndrome

Introduction: Different biomarkers have been investigated for prognosis of patients with nephrotic syndrome. Qualitative and quantitative changes have been reported in platelets in these patients. Objectives: The aim of this study was to identify platelet abnormalities and their prognostic value of steroid response in children with idiopathic nephrotic syndrome. Patients and Methods: Platelet counts and indices (mean platelet volume [MPV], platelet distribution width [PDW] and platelet larger cell ratio [PLCR]) were evaluated and compared in 122 children with active nephrotic syndrome (64%; steroid resistant and 36%; steroid sensitive). Results: Mean age at diagnosis was 55 months (6 to169 months), and males outnumbered females (1.7/1). Steroid resistant patients had significantly higher platelet counts and lower PLCR, compared to steroid sensitive group. Regarding area under the ROC curve, low MPV, high PDW and low PLCR showed relatively acceptable correlation with steroid resistance. Conclusion: Increased platelet counts in addition to low PLCR are the suggestive indicators of steroid resistance in children with idiopathic nephrotic syndrome.

Evaluation of Serum Iron and Transferrin in Idiopathic Nephrotic Syndrome Patients Attending Al-Hussein Pediatric Nephrology Clinic

Background: Nephrotic syndrome is characterized by excessive urinary excretion of albumin and other intermediated-size plasma proteins such as transferrin.. Excessive urinary losses of transferrin can produce low serum transferrin level that may lead to low plasma iron concentration and consequently the development of iron resistant microcytic hypochromic anemia. The aim of the work to evaluate changes in serum iron and transferrin and the relationship between the serum and urinary transferrin in the active and remission state of nephrotic syndrome Patients and methods: The present work included fifty children with idiopathic nephrotic syndrome (INS), divided into 2 groups: group A (25 cases in activity) and group B (25 cases in remission). These two groups were age and sex matched with a mean age of (7.74 ± 2.45). All patients in this work were clinically evaluated together with routine laboratory investigations. Serum albumin and urinary alb. /creatinine were assessed. Levels of serum iron, serum ferritin, serum transferrin and urinary transferrin were measured. Results: This work shows that the level of hemoglobin, MCV, HCT were statistically significantly lower in the cases in active state than cases in remission. The mean serum iron, serum ferritin and serum transferrin were significantly lower in the cases in active state than in the cases in remission .The mean urinary transferrin was statistically significantly higher in the cases in active state than in the cases with remission. Conclusion: Urinary transferrin can be considered a reliable parameter for early prediction of iron deficiency anemia in children with active nephrotic syndrome.

Subclinical pulmonary congestion is prevalent in nephrotic syndrome.

In patients with nephrotic syndrome (NS), the lung is considered an organ protected from the risk of edema. However, data on objectively measured lung water in NS patients is lacking. Here we measured lung water by an ultrasound (US) technique as well as by transthoracic impedance in 42 asymptomatic patients with active NS, in 14 stage G5D CKD patients on chronic hemodialysis, and in 21 healthy individuals. In patients with active NS, the median number of US-B lines (a metric of lung water) after 5 min in a supine position was significantly higher (12; interquartile range: 7-25) compared with that in healthy individuals (4; 2-9) but similar to that in hemodialysis patients (23; 10-39). The difference between NS patients and healthy individuals was significantly amplified (16; 10-35 vs. 4; 2-9) after 60 min of supine resting and significantly attenuated after 5 min of standing (10; 7-25 vs. 3; 1-6). Posture-dependent changes in lung water in patients with active NS were significantly accentuated compared with both hemodialysis patients and healthy individuals. After NS remission, the number of US-B lines was significantly reduced to 5 (4-18) at 5 min and to 6 (5-22) at 60 min approaching the normal range. Lung congestion in patients with active NS was confirmed by transthoracic impedance. Thus, asymptomatic pulmonary congestion is pervasive in patients with NS. A clinical trial is needed to assess the utility of lung US for the management of patients with NS.

Vitamin K antagonists in children with central venous catheter on chronic haemodialysis: a pilot study.

To date, no study has investigated the use of vitamin K antagonists (VKA) in children undergoing chronic haemodialysis (HD) with a central venous catheter (CVC). Consecutive patients aged <18years with a newly placed tunnelled CVC for chronic HD were enrolled over a 3-year period. Children with active nephrotic syndrome or a history of venous thrombosis received warfarin (VKA group) with therapeutic target international normalised ratios of between 2.0 and 3.0. Patients at standard risk of CVC malfunction were not treated with VKA (standard group). The primary end-point was overall CVC survival. The VKA group consisted of nine patients (median age 10.6years; range 1.2-15.3 years) with 11 CVC, and the standard group comprised eight patients (11.8years; 6.1-17.3 years) with ten CVC. The 6- and 12-month CVC survival was significantly longer in the VKA group than in the standard group (100 vs. 60% and 83.3 vs. 16.7%, respectively; p < 0.05), with a median survival of 369 and 195days, respectively (p < 0.05). None of the CVC in the VKA group required removal due to malfunction, as compared to four in the standard group. No major bleeding episodes occurred in either group. Therapy with VKA would appear to be safe in children on chronic HD and may improve CVC survival in patients at increased risk of CVC thrombosis.

Aberrant glomerular filtration of urokinase-type plasminogen activator in nephrotic syndrome leads to amiloride-sensitive plasminogen activation in urine.

In nephrotic syndrome, aberrant glomerular filtration of plasminogen and conversion to active plasmin in preurine are thought to activate proteolytically epithelial sodium channel (ENaC) and contribute to sodium retention and edema. The ENaC blocker amiloride is an off-target inhibitor of urokinase-type plasminogen activator (uPA) in vitro. It was hypothesized that uPA is abnormally filtered to preurine and is inhibited in urine by amiloride in nephrotic syndrome. This was tested by determination of Na(+) balance, uPA protein and activity, and amiloride concentration in urine from rats with puromycin aminonucleoside (PAN)-induced nephrotic syndrome. Urine samples from 6 adult and 18 pediatric patients with nephrotic syndrome were analyzed for uPA activity and protein. PAN treatment induced significant proteinuria in rats which coincided with increased urine uPA protein and activity, increased urine protease activity, and total plasminogen/plasmin concentration and Na(+) retention. Amiloride (2 mg·kg(-1)·24 h(-1)) concentration in urine was in the range 10-20 μmol/l and reduced significantly urine uPA activity, plasminogen activation, protease activity, and sodium retention in PAN rats, while proteinuria was not altered. In paired urine samples, uPA protein was significantly elevated in urine from children with active nephrotic syndrome compared with remission phase. In six adult nephrotic patients, urine uPA protein and activity correlated positively with 24 h urine protein excretion. In conclusion, nephrotic syndrome is associated with aberrant filtration of uPA across the injured glomerular barrier. Amiloride inhibits urine uPA activity which attenuates plasminogen activation and urine protease activity in vivo. Urine uPA is a relevant target for amiloride in vivo.

Serum immunoglobulin E and interleukin-13 levels in children with idiopathic nephrotic syndrome.

Serum IgE and IL-13 levels were estimated in 40 idiopathic nephrotic syndrome and 16 controls. There were 15 first episode nephrotic syndrome (FENS), 15 infrequent relapsing nephrotic syndrome (IRNS) and 10 patients belonged to frequent relapsing nephrotic syndrome (FRNS). Serum IgE and IL-13 levels were significantly increased in active nephrotic syndrome and its sub-groups as compared to controls and remission (p < 0.001). IgE levels did not differ significantly among different subgroups, while Il-13 was significantly higher in FRNS in comparison with FENS (p = 0.041). Both IgE and IL-13 levels were comparable in nephrotic patients with and without bronchial asthma. Serum IL-13 had significant positive correlation with IgE (r = 0.605, p < 0.001). Thus, raised levels of IgE and IL-13 are found in nephrotic syndrome and could have a role in the pathogenesis of disease.

Mineral metabolism in patients on chronic peritoneal dialysis

Children with chronic kidney disease (CKD) and receiving peritoneal dialysis (PD) have disorders of mineral metabolism that impact their growth, survival and cardiovascular functions. New molecular markers offer a better understanding of the pathophysiology of this disease. To characterize some components of mineral metabolism, with emphasis on FGF23/Klotho and cardiovascular functions (CV) of these patients. Prospective observational cohort study. serum 25 (OH) vitamin D < 20 ng/ml, peritonitis within the last two months and active nephrotic syndrome. Calcemia, phosphemia, parathyroid hormone (PTH), 25 (OH) vitD3, 1.25 (OH) vitD3, FGF23 and Klotho in plasma were measured. FGF23 and Klotho were quantified in healthy children as a control group. Echocardiography was performed calculating the left ventricular mass index (LVMI). Descriptive statistics analysis, Pearson correlation coefficient for association among variables and multivariate analysis were conducted. 33 patients, 16 males, aged between 1.2 and 13.4 years were included. Age of onset for PD: 7.3 ± 5.0 years, time receiving PD: 13.5 ± 14.5 months. The plasma concentration of 25 (OH) vitD3 was 34.2 ± 6.3 pg/ml. Calcemia and phosphemia values were 9.8 ± 0.71 and 5.4 ± 1.0 mg/dl respectively. PTH was 333 ± 287 pg/ml. FGF23 in plasma was 225.7 ± 354.3 pg/ml and Klotho 131.6 ± 72 pg/ml, and in the controls ( n = 16 ), it was 11.9 ± 7.2 pg/ml and 320 ± 119 pg/ml, respectively. The residual and total dose of dialysis (KtV) was 1.6 ± 1.3 and 2.9 ± 1.6, respectively. FGF23 levels significantly correlated with calcium (p < 0.001, r = 0.85), and inversely with residual KtV, showing no relationship with phosphemia. Klotho level correlated negatively with residual KtV and also, it showed a negative association with chronological age and age at onset of PD. LVMI > 38 g/m² was confirmed in 20/28 patients. The values of FGF23, and PTH are elevated in children with CKD on PD. Klotho levels in CKD patients are lower than control children. A strong association of calcemia with FGF23 and PTH is reported. Residual renal function is inversely associated with FGF23 and Klotho. A high incidence of left ventricular hypertrophy was found evidencing a cardiovascular compromise in these patients.

Increased serum CXCL16 is highly correlated with blood lipids, urine protein and immune reaction in children with active nephrotic syndrome

BackgroundPrimary nephrotic syndrome (NS) is a common disease in children. Lipid nephrotoxicity and cellular immune dysfunction are known features of this disease. Recently, CXCL16 was found to participate in inflammation and mediate cellular uptake of lipids. Here, we investigated the involvement of CXCL16 in the occurrence and development of primary NS.MethodsSerum CXCL16, blood lipids and albumin, 24-hour urine protein, interferon-γ and immune cells were detected in 25 children with steroid sensitive NS during their active nephrotic and remissive stages. Twenty healthy children served as the control group.ResultsLevels of serum CXCL16, blood lipids, interferon-γ and CXCR6+ T cells were significantly increased and albumin and NK cell number were significantly decreased in the active status group compared with remissive status and control groups. Correlation analysis showed that serum CXCL16 was positively correlated with blood lipids, 24-hour urine protein, interferon-γ and CXCR6+ T cells but negatively correlated with albumin in patients with active NS.ConclusionSerum CXCL16 was increased in patients with active NS and correlated with blood lipids, urine protein and immune and inflammation responses, suggesting that CXCL16 may serve as a useful index or biomarker for disease activity in children with nephrotic syndrome.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1120468411154766.

The mini-PET in pediatric peritoneal dialysis: A useful tool to predict volume overload?

Cardiovascular disease (CVD) in patients on chronic peritoneal dialysis (PD) is a major cause of death and is closely linked to hypertension and volume overload. The mini-Pet has been proposed as a useful tool to evaluate free-water transport (FWT) and characterize ultrafiltration across the peritoneum. Knowledge regarding FWT could be of great value to predict volume overload in PD patients. Our objective in this study was to characterize FWT through the peritoneum in children on PD. We studied clinically stable patients with >2 months on PD. Exclusion criteria were a peritonitis episode up to 2 months prior to entrance into the study and active nephrotic syndrome. A 1-h mini-peritoneal equilibration test (mini-PET) was performed with 3.86 % glucose. Calculations (see text for full definitions) were: Dip Na (Na dial min60 - Na dial min1), Dip D/PNa (D/PNa60 - D/PNa1), total Na removal (NaR = total Na dial60 - Na dial1), ultrafiltration small pores [(UFSP = NaR × 1,000)/Nap], and FWT (UF-UFSP). Peritoneal equilibration test (PET), left ventricular mass index (LVMI, g/m(2)), daily UF, and residual renal function were evaluated. Pearson's correlation coefficient was used to establish correlation between variables. Sixteen patients were included, with a mean age of 11.8 ± 3.8 years. Free water transport normalized to body surface area (BSA) (FWTn) was 133.9 ± 85.7 ml/m(2); creatinine dialysate-to-plasma (D/P) and glucose dialysate at X dwell time-to-0 dwell time (Dx/D0) ratios were 0.38 ± 0.1 and 0.65 ± 0.09, respectively. LVMI was 46.6 ± 14.8 g/m(2); 2-h creatinine D/P and glucose Dx/D0 showed no correlation with FWTn, UF, and LVMI. FWTn showed a significant inverse correlation with LVMI (r 0.58, p 0.02). This study characterized FWT in PD children through the mini-PET. Left ventricular hypertrophy showed a high prevalence in this group, and a significant correlation between LVMI and FWT was found. FWT could be a useful tool to evaluate UF in PD children.

Toll-like receptor 3 ligand, polyIC, induces proteinuria and glomerular CD80, and increases urinary CD80 in mice

We have reported that children with biopsy-proven minimal change disease (MCD) express CD80 (also known as B7.1) in their podocytes and excrete high levels of CD80 in their urine during active nephrotic syndrome. We also reported that polyIC, a Toll-like receptor 3 ligand, increases CD80 mRNA and protein expression in cultured human podocytes dose-dependently, with actin re-organization and a reduction in synaptopodin expression. To determine the effect of polyIC in the kidney, we subjected mice to systemic injection of polyIC or phosphate buffered saline. Mice injected with polyIC developed significant proteinuria with increased urinary CD80 excretion. Glomeruli from mice injected with polyIC were normal by light microscopic examination, but showed increased CD80 production in podocytes by immunofluorescence staining. In isolated glomeruli from mice injected with polyIC, expressions of CD80 and interleukin 10 significantly increased with a mild non-significant increase in CTLA-4, and synaptopodin expression decreased significantly. Our study demonstrates that systemically administered polyIC can induce transient proteinuria and urinary CD80 excretion with an increase in CD80 production in podocytes, increased glomerular CD80 and reduced synaptopodin expression. These findings may be relevant to the pathogenesis of proteinuria in MCD.

Remission of nephrotic syndrome resolves plasminogen/plasminuria and reverses the ability of urine to activate ENaC

Recently it was reported that urinary plasmin activates the epithelial sodium channel (ENaC) and may mediate sodium retention. The present study investigates if remission of nephrotic syndrome (NS) affects glomerular filtration of plasminogen, its activation to plasmin, and the ability of the patients urine to activate ENaC.A paired design study was conducted collecting samples during active nephrotic syndrome and at stable remission. Single cell patch clamp experiments were performed on single collecting duct cells (CDC) with urine samples from six patients investigating the potential to generate an ENaC mediated current.Urine samples from active NS significantly increased the inward current in CDC (201 ± 31%, n=6), whereas at remission, the observed current was significantly lower (29 ± 10%, n=6). The ability of nephrotic urine to enhance inward current was abolished by amiloride (2 μM) (19 ± 10%, n=6).Our data demonstrate significantly increased inward (ENaC) current induced by urine collected during active NS compared to remission, suggesting ENaC inhibition by amiloride to be a new therapeutic target for oedema control.

NGAL distinguishes steroid sensitivity in idiopathic nephrotic syndrome

Idiopathic nephrotic syndrome (NS) is the most common glomerular disorder of childhood. Invasive biopsy remains the diagnostic method of choice for NS. Prognosis correlates with steroid responsiveness, from sensitive (SSNS) to resistant (SRNS). Neutrophil gelatinase-associated lipocalin (NGAL) has been demonstrated to be a powerful risk marker of chronic kidney disease progression. We set out to determine if urine NGAL can distinguish between patients with SRNS, SSNS, and healthy controls. Urine and clinical data were collected from patients at Cincinnati Children's Hospital who were recently diagnosed with active nephrotic syndrome as well as healthy controls. Participants included SRNS (n = 15), SSNS (n = 14), and healthy controls (n = 10). Urinary NGAL was measured by ELISA and normalized to creatinine. Median NGAL was significantly (p < 0.001) higher in SRNS (172.3 ng/ml, IQR 18.8-789) than both SSNS (6.3 ng/ml, IQR 4.9-9.9) and healthy controls (6.5 ng/ml, IQR 4.2-9.1). The area under the curve (AUC) for NGAL to distinguish SRNS from SSNS was 0.91 (p < 0.0001). NGAL levels demonstrated a significant negative correlation with glomerular filtration rate (r = -0.5, p < 0.001). Results did not change with NGAL corrected for urine creatinine and were independent of the degree of proteinuria. NGAL levels differentiate SSNS from SRNS and correlate with disease severity in SRNS.

Oxidant and Antioxidant Status in Childhood Nephrosis and its Relation to Hyperlipidemia

Background: Oxidative damage by free radicals has been implicated in a number of clinical disorders including renal injury. An abnormality in the oxidative system in patients with nephrotic syndrome (NS) has been reported.Objective: To assess the oxidant status (red cell MDA) and antioxidant status (red cell GSH, SOD' and plasma vitamin E, copper, zinc) in relation to hyperlipidemii in children with active nephrotic syndrome (NS) and during remission.Methods: This study was conducted on 65 children with NS; 35 with active NS (Group 1) & 30 with NS during remission (Group 2) and 20 healthy controls. Red cell glutathione (GSH), superoxide dismutase (SOD) and malonfiialdehyde (MDA) concentrations as well as plasma levels of vitamin E, copper, zinc and plasma lipids (total cholesterol ТС, triglycerides high density lipoprotein cholesterol and low density lipoprotein cholesterol LDL-C) were measured in children with NS and in controls.Results: SOD concentrations significantly increased in both group I & group 2 when compared to the controls. MDA concentrations significantly increased in both group 1 & group 2 compared to the controls. GSH concentrations along with plasma vitamin E concentrations significantly decreased in both group I & group 2 compared to controls. A significant decrease in plasma copper and zinc concentrations was observed in group 1 compared to controls. However, a non-significant decrease in plasma copper and zinc concentra-tions was observed in group 2 compared to controls. Plasma TC, TG, LDL-C concentrations significantly increased while plasma HDL-C significantly decreased in both group 1 & group 2 compared to controls. Significant +ve correlation was found between MDA and each of TC, TG, LDL-C, while significant -ve correlation existed between MDA and HDL-C. Significant -ve correlations existed between each of albumin, SOD, vitamin E, zinc, copper and each of TC, TG, LDL-C. Meanwhile, significant +ve correlations existed between HDL-C and each of albumin, SOD, vitamin E, zinc and copper.Conclusion: Increased pro-oxidant status with compensatory changes in antioxidant concentrations occur in children with NS. These changes are linked to lipid disorders in NS patients and may be related to the pathogenesis of NS.

Antioxidant status of children with idiopathic nephrotic syndrome

The production of free radicals can cause renal injury and play an important role in the pathogenesis of idiopathic nephrotic syndrome. Markers of reactive oxygen species (ROS) were evaluated in 48 patients with active nephrotic syndrome (ANS) and 30 age- and gender-matched healthy children. Plasma malondialdehyde (MDA), protein carbonyl, nitrite, copper, zinc, selenium, ascorbic acid, and superoxide dismutase (SOD) levels were estimated in patients with ANS and controls. Measurements were repeated in 39 cases after achievement of remission, and in 10 other children who were in remission of >6 months' duration. Plasma MDA and nitrite levels were significantly higher and selenium was lower in ANS patients compared with controls. Plasma protein carbonyl, copper ascorbic acid, zinc, and superoxide dismutase levels were comparable in ANS patients and controls. Plasma copper level was significantly higher in active cases than in the remission and long-term remission groups. Selenium value showed a rise and then normalized in long-term remission. Among different sub-groups of ANS, no significant differences were found in the levels of various parameters, except plasma selenium, which was significantly lower in first-attack nephrotic syndrome (FANS) in comparison to infrequently relapsing nephrotic syndrome (IRNS) and frequently relapsing nephrotic syndrome (FRNS) patients. Thus, we observed evidence of oxidative stress and impaired antioxidant defense during acute nephrotic syndrome. Antioxidant status recovered completely only during long-term remission.

Lymphocyte adenosine deaminase activity in children with idiopathic nephrotic syndrome

Adenosine deaminase (ADA) activity, as a marker of cell-mediated immunity, was evaluated in the serum (S-ADA) and lymphocytes (L-ADA) of 47 children with idiopathic nephrotic syndrome, and 23 healthy controls. The mean S-ADA and L-ADA levels were significantly raised in active nephrotic syndrome (ANS) and in its sub-groups in comparison with controls. The ADA activity was significantly more elevated in relapsers than for the first attack of nephrotic patients, and the frequent relapsers had the highest enzymatic levels both in serum as well as lymphocytes. A significant positive correlation was found between serum and lymphocyte ADA levels (r =0.736, p <0.01). In remission, the S-ADA showed a significant fall in comparison with their corresponding ANS value (p <0.001) and reached the level of controls. The mean L-ADA also showed reduction but the difference was statistically insignificant and the value was significantly raised, when compared with controls. The enzyme activity in serum and lymphocytes normalized in the long-term remission group. Thus, ADA activity was abnormal in ANS cases, and L-ADA demonstrated change both in active as well as remission stage of the disease.

Serum immunoglobulin E in idiopathic nephrotic syndrome.

Serum immunoglobulin E (IgE) and absolute eosinophil count (AEC) were assayed in 48 children with idiopathic nephrotic syndrome and 20 controls. The mean serum IgE (p < 0.001) and AEC (p < 0.05) were significantly raised in active nephrotic syndrome compared with controls. The mean values of IgE and AEC in nephrotic patients were 228.6 and 164.5 per cent of the normal mean, respectively. The serum IgE and AEC were significantly abnormal in all the subgroups (first attack, infrequent, and frequent relapsers), except AEC in infrequent relapses, when compared with the controls. No significant differences in the parameters were observed among the different subgroups of cases. In remission, the mean IgE and AEC were unchanged in comparison with their corresponding values at diagnosis. Thus, the levels are raised not only in active but also in remission, reflecting abnormal immune status even in the disease-free state.

Down-regulation of manganese-superoxide dismutase gene expression in idiopathic nephrotic syndrome

An oxidant stress has been shown to prevail in experimental and clinical nephrotic syndrome. Such oxidant stress may be induced by a reduced activity of antioxidant systems. We examined the altered expression of manganese-superoxide dismutase (Mn-SOD), an antioxidant enzyme, in patients with idiopathic nephrotic syndrome, in whom an increased oxidant stress had been demonstrated. The Mn-SOD activities in peripheral blood mononuclear cells obtained from 12 patients with active nephrotic syndrome (6.0 +/- 1.1 years of age, mean +/- SE) and hypoproteinemia were 42% lower (p < 0.05) than in 12 control subjects (5.5 +/- 0.5 years of age) with normal serum total protein concentrations. Reverse-transcriptase polymerase chain reaction also demonstrated that Mn-SOD messenger RNA expression in the patients with nephrotic syndrome was, on average, 59% lower than in control subjects. Because expressions of some genes are sensitive to serum, the serum dependency of Mn-SOD gene transcription was studied in glomerular endothelial cells transfected with a luciferase reporter gene fused with a rat Mn-SOD DNA fragment of -806 to +22 bp of the transcription initiation site (-806:+22). When these cells were exposed to different concentrations of fetal bovine serum (0.5% to 15%), the transcriptional activities determined by luciferase activities were proportional to serum concentrations. This serum-dependent transcriptional activation was also demonstrated by the fragment (-220:+22) but not by the fragment (-220:-20). When glomerular endothelial cells transfected with the fragment (-220:+22) were treated with 5% serum from patients with active nephrotic syndrome, transcriptional activation was more than 80% less than that by 5% serum from control subjects without nephrosis. These results indicate that Mn-SOD gene transcription is regulated at least in part by serum, and that the serum-dependent transcription of the gene is diminished in patients with idiopathic nephrotic syndrome. The regulatory region of serum-dependent gene transcription resides within its early promoter region. Our findings suggest that down-regulation of antioxidant enzyme transcription may contribute increased oxidant stress in idiopathic nephrotic syndrome.