Salvianolic acid A attenuates steroid resistant nephrotic syndrome through suPAR/uPAR-αvß3 signaling Inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvianolic acid A (SAA) is extracted from traditional Chinese medicine Salvia miltiorrhiza and is the main water-soluble and the biologically active ingredient. SAA possesses a variety of pharmacological activities and has an excellent protective effect on kidney disease, especially steroid resistant nephrotic syndrome (SRNS), and has advantages in improving the efficacy of glucocorticoids, but its mechanism needs to be further explored. PURPOSE: The study was designed to explore the effect of suPAR and uPAR in SRNS patients and evaluate the potential effect of SAA in improving podocyte steroid resistance and explore its mechanism. METHODS AND MATERIALS: The ELISA kits were used to detect the levels of suPAR in the blood and urine of subjects. The levels of uPAR, GRα, and GRß expression in renal tissues of SRNS patients was detected by immunohistochemistry and analyzed using the Pearson method. In vitro studies, steroid resistance model was induced by the TNF-α and IFN-γ. The protein and mRNA expression of Nephrin, GR, GRα and GRß were analyzed using western blot and qRT-PCR. The activity of GR-DNA binding was detected by using TransAM™ GR kits. Adriamycin further induced steroid resistance podocyte. Flow cytometry was used to detect the effect of SAA on podocyte apoptosis. ELISA assay was used to detect the suPAR expression in the podocyte supernatant. Western blot and qRT-PCR were used to detect the protein and mRNA expression of uPAR and Nephrin in podocytes. RESULTS: The serum and urine levels of suPAR were conspicuously higher in SRNS patients than healthy volunteers and SSNS patients, and the expression of uPAR in renal tissue of SRNS patients is negatively correlated with GRα, but positively correlated with GRß. The combination of TNF-α and IFN-γ could conspicuously increase the GRß expression and reduce GRα/GRß, and induce steroid resistance in podocytes. Moreover, we found that SAA could reduce the apoptosis of podocytes and suppress the expression of suPAR/uPAR, and increase the expression of Nephrin. CONCLUSION: The level of suPAR and uPAR expression may have important value in predicting glucocorticoids resistance in patients with idiopathic nephrotic syndrome (INS). The combination of TNF-α and IFN-γ induce podocytes can establish steroid resistance model in vitro. SAA could improve glucocorticoids resistance of podocyte which can be attributed in part to regulate the suPAR/uPAR-αvß3 signaling pathway.

Protein energy-wasting associated with nephrotic syndrome - the comparison of metabolic pattern in severe nephrosis to different stages of chronic kidney disease.

BACKGROUND: Nephrotic syndrome (NS) is associated with a hypercatabolic state expressed as an exacerbated degradation of muscle mass. However, the clinical significance of this phenomenon has not yet been investigated. The aim of the study was to evaluate the nutritional status of patients with severe NS (defined as nephrotic range proteinuria with hypoalbuminemia ≤2.5 g/dL) and estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 in comparison to patients in different stages of chronic kidney disease (CKD). METHODS: Twenty men with severe NS (NS group) and 40 men without proteinuria similar in term of serum creatinine (control group) were included into the study. A retrospective cohort of 40 men with CKD stage G4 (PreD group) and 20 haemodialysis men (HD group) were added to the analysis after matching for age, height and weight using propensity score matching. The bioimpedance spectroscopy and biochemical nutritional markers were evaluated. RESULTS: Nephrotic patients had a significantly lower lean tissue mass (LTM; p = 0.035) and index (a quotient of LTM over height squared, LTI; p = 0.068), with an expected deficiency of LTM by 3.2 kg, and LTI by 0.9 kg/m2 when compared to the control group. A significant lean tissue deficit (defined as LTI below the lower limit of the reference range by 1.0 kg/m2) was observed in 12.5% of patients in the control group in comparison to 31.7% with advanced CKD (PreD+HD; p = 0.032) and 50% with NS (p = 0.003). NS group presented with higher phosphorus (p = 0.029), uric acid (p = 0.002) and blood urea (p = 0.049) than the control group. Blood urea was strongly negatively correlated with LTM in NS (r = - 0.64, p = 0.002). Nine nephrotic patients (45%) were identified as hypercatabolic based on severe hyperphosphatemia (> 5.0 mg/dL) and/or hyperuricemia (> 8.0 mg/dL), and were characterized by higher blood urea and lower prealbumin, as well as LTM lower by 5.6 kg than in less catabolic individuals. CONCLUSIONS: In term of lean tissue amount, NS group was more similar to advanced CKD than to the control group. We concluded that specific metabolic pattern with elevated phosphorus, uric acid and blood urea, and lean tissue deficiency may be defined as protein-energy wasting associated with nephrotic syndrome (neph-PEW).

Nephrotic syndrome due to preeclampsia before 20 weeks of gestation: a case report.

BACKGROUND: Preeclampsia (PE) refers to the development of hypertension and new-onset proteinuria or progressive organ damage (especially kidney) in a previously normotensive pregnant women after 20 weeks of gestation. Thus, new-onset nephrotic syndrome due to PE before 20 weeks of gestation seems to be rare, making its diagnosis difficult in this time period. CASE PRESENTATION: A 28-year-old woman presented with a new-onset nephrotic syndrome at 16 weeks of gestation. A high dose of oral glucocorticoids (prednisolone, 40 mg) was initiated for presumed glomerulonephritis since she presented with severe nephrotic syndrome before 20 weeks of gestation, however, the treatment was not effective. At 21 weeks of gestation, we confirmed that the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio was very high (sFlt-1, 13,400 pg/mL; PlGF, 21.9 pg/mL; serum sFlt-1/PlGF ratio 611.9). Therefore, we diagnosed nephrotic syndrome due to PE, and oral glucocorticoids were discontinued. After she underwent a cesarean section at 24 weeks & 3 days, we performed a kidney biopsy. Focal segmental sclerotic lesions with epithelial cell hyperplasia and foam cells in the tubular poles were seen on light microscopy. On immunofluorescence tests, C4d staining showed linear peripheral patterns in the glomeruli. Electron microscopy revealed diffuse subendothelial edema with focal foot process effacement. The histological diagnosis was severe glomerular endotheliosis with focal segmental glomerulosclerosis. Furthermore, the histology of placenta was consistent with PE. Eight months after delivery, her proteinuria disappeared completely. CONCLUSIONS: We not only confirmed an abnormal serum sFlt-1/PlGF ratio but also presented the histology compatible with pure PE in the kidney and placenta in a case of nephrotic syndrome before 20 weeks of gestation. The serum sFlt-1/PlGF ratio may be useful in determining the treatment strategy for atypical cases of pregnant women with nephrotic syndrome, particularly before 20 weeks of gestation.

Bone mineral density in children with relapsing nephrotic syndrome: A hospital-based study.

This cross-sectional analytical study was conducted from January 2012 to November 2014 in the Department of Pediatric Nephrology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh, to evaluate the bone mineral density (BMD) values in children with relapsing nephrotic syndrome (NS). Thirty relapsing nephrotic patients were enrolled in this study. They were divided into two groups: Group I - Frequent Relapse (FR) with 21 patients and Group II - Infrequent Relapse (IFR) with nine patients. Children included were both males and females aged between four and 15 years with relapsing NS with normal renal function. Steroid-resistant NS or those with abnormal renal functions or who were on cyclosporine and calcium supplement with Vitamin D or children with secondary NS were excluded from the study. All the study population underwent dual-energy X-ray absorptiometry scan to see the BMD value. Mean age of the patients of Group I (8.43 ± 2.61 years) was lower than that of Group II (9.41 ± 2.94 years (P = 0.4043). Mean BMD Z-scores of Group I was significantly lower than that of Group II (-2.70 ± 1.28 vs. -1.30 ± 1.54, respectively; P = 0.0317). A significantly higher cumulative dose of prednisolone was administered to Group I compared with Group II (P = 0.00003). On multivariate analysis, the total dose of prednisolone (P = 0.03693), body mass index (BMI) (P = 0.00703), and age of onset of disease (P = 0.03465) had a linear relationship with dependent variable BMD Z-score. On univariate regression analysis, statistically significant inverse relationship was observed between cumulative dose of prednisolone (in grams) (P = 0.049) and BMI (P = 0.00) with BMD Z-score, but no relation was observed with duration of illness. Children with relapsing NS, especially those receiving higher doses of steroids, were at risk for low BMD.

Characteristics of patients diagnosed with renal vein thrombosis and glomerulopathy: a case series.

BACKGROUND: Few contemporary studies have evaluated the clinical characteristics of patients with biopsy-proven glomerulopathy diagnosed with renal vein thrombosis (RVT). METHODS: Retrospective case series study within an integrated health system in a 12-year period (January 1, 2000 through December 31, 2011) investigating clinical characteristics of all adult patients who underwent native or transplant kidney biopsy and also had a diagnosis of RVT. Patient characteristics, diagnostic studies, and outcomes were evaluated. RESULTS: Among 3763 eligible patients, 17 had imaging confirmed RVT. Of these, 15 had membranous nephropathy (idiopathic or secondary to autoimmune disease). Although the biopsy population included primary and secondary glomerular disease patients, all 17 RVT patients had severe nephrotic syndrome and profound hypoalbuminemia with mean (SD) of albumin: 1.5 g/dL (0.66). CONCLUSION: Clinically significant RVT in patients with glomerulopathy appears to be a rather rare entity, occurring predominantly in patients with severe nephrotic syndrome due to idiopathic membranous nephropathy and membranous nephropathy secondary to autoimmune disease.

Thrombotic complications of neonates and children with congenital nephrotic syndrome.

Congenital nephrotic syndrome (CNS) refers to a disease presenting with massive proteinuria in association with hypoalbuminemia, hyperlipidemia, and edema at birth or within the first three months of life. In the past, most children with CNS had extremely poor prognosis and succumbed to various complications, usually within the first 6 months. Recent advancements in protein supplementation and nutritional support, renal replacement therapy and renal transplantation in infancy, render these patients to have much better outcomes. However, there are still many hurdles in the management of this disease. Thromboembolism is an uncommon, yet important complication which the healthcare givers must be aware of. This article reviews the challenges in the management of the thrombotic complications with special emphasis on the unique characteristics of the newborn hemostasis system and anti-thrombin (AT) depletion in nephrotic syndrome. Due to the relatively low incidence of CNS in children and scarce information in the literature on the optimal management of the thromboembolic complications, most of the recommendations are based on the authors' experience.

Bone health in children and adolescents with steroid-sensitive nephrotic syndrome assessed by DXA and QUS.

BACKGROUND: The management of steroid-sensitive nephrotic syndrome (SSNS) requires treatment with high-dose glucocorticoids (GCs), but GC usage causes the most frequent form of drug-induced osteoporosis. The aim of our study was to evaluate the impact of GCs on bone mineralization in patients with SSNS using two diagnostic tools, dual-energy X-ray densitometry (DXA) and quantitative ultrasound (QUS), and to compare the diagnostic efficacy of these two imaging tools. METHODS: A total of 30 children with SSNS (age 5.20 ± 2.20 years) were evaluated at the start (T0) and after 1 (T1), 2.44 ± 0.75 (T2, 18 patients) and 5.96 ± 2.33 years (T4, 12 patients) of GC treatment. Patients who stopped at T2 were also evaluated at the 1-year timepoint after ceasing GC treatment (T3). RESULTS: Of the patients assessed at T2, 11 had bone mineralization at the lower limit of normal versus those at T0 and T1, with bone mineralization rescue at the 1-year timepoint after GC discontinuation. At T4, 6/12 patients had densitometric parameters at the lower limit of normal values, and 3/12 patients showed reduced bone mineralization. The parameters derived from measurements of DXA and QUS were significantly related to each timepoint. CONCLUSIONS: Patients with SSNS receiving GC therapy undergo bone status alteration related to the dosage and duration of the therapy. In terms of diagnostic efficacy, DXA and QUS were comparable, indicating that QUS is a reliable tool to evaluate bone health in children with SSNS.

The change-over of yin-yang and gene regulation in kidney deficiency syndromes.

The present paper studies gene regulation in kidney deficiency syndromes from the simple Nephrotic Syndrome and with the principle of positive-negative regulation to control the change-over of yin-yang, the modern molecular biological techniques can be used, such as gene chip, representational difference analysis (RDA) and gene sequence analysis, so as to investigate the inner relationship between the genes and kidney deficiency syndromes and prove the effect given by these genes on the pathophysiological status of change-over of yin-yang in kidney deficiency syndromes. This philosophical approach and method can also be adopted for studies of the related genes in other TCM syndromes.

[Important action of improving adrenocortical function for certain diseases recovery].

It has been found that the hypofunction status of hypothalamus-pituitary-adrenal (HPA) axis exists in patients with Shen-yang deficiency syndrome of TCM, also presents in most asthma patients. Seasonal attack of asthma can be prevented with Shen-tonifying drugs by improving adrenocortical function. Since patients subject to long-term glucocorticoids display hypofunction condition of HPA axis, Shen-tonifying drugs should be helpful to gluocorticoid withdrawal for getting higher success rate. Basic researches also indicated that the activating of adrenocortical stem cells and promoting regeneration of adrenal cortex is one of the mechanisms underlying improvement of adrenocortical function. Series of research showed that hypofunction of adrenocortex is the general pathological change in some diseases, so, Shen-tonifying drugs act a part in unitarily modulating the adrenocortical function, to get the therapeutic effect of both regulating the whole and improving the local.

L-carnitine ameliorates doxorubicin-induced nephrotic syndrome in rats.

AIM: Effects of L-carnitine on nephrotoxicity and oxidative stress induced by doxorubicin (DOX) in rats were investigated. METHODS: The rats were divided into four groups: group 1, control (0.9% NaCl); group 2, DOX injection (7.5 mg/kg, i.v.); group 3, DOX plus low dose (40 mg/kg) L-carnitine; and group 4, DOX plus high dose (200 mg/kg) L-carnitine. L-carnitine was administered 1 h before doxorubicin injection and daily thereafter for 15 days. RESULTS: Rats in group 2 were associated with hypoalbuminaemia, hyperlipidaemia, high urinary excretion of protein and elevated plasma creatinine and urea nitrogen. The glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) decreased with increased renal vascular resistance (RVR). Kidney catalase (CAT) activity was decreased. In group 3 and 4, plasma triglyceride and cholesterol declined. L-carnitine improved renal functions by elevated GFR and ERPF and decreased plasma creatinine and urea nitrogen. The kidney CAT activity were increased significantly compared with group 2. From histopathological results, group 2 rats were found to have glomerular capillary dilation and tubular dilation. The lesions were less in group 3 and 4 rats. CONCLUSION: L-carnitine can protect renal impairment functionally, biochemically and histopathologically with a corresponding reduction of oxidative stress.

Increased expression but not targeting of ENaC in adrenalectomized rats with PAN-induced nephrotic syndrome.

Sodium retention is a hallmark of nephrotic syndrome (NS). Puromycin aminonucleoside (PAN)-induced NS is associated with high aldosterone levels and increased ENaC expression and apical targeting. However, the mechanisms associated with increased apical targeting of ENaC in NS remain undefined, and it is unclear whether this is secondary to high aldosterone levels and whether aldosterone and/or apical ENaC targeting are important for the development of sodium retention. This study aimed at uncovering 1) whether aldosterone is essential for sodium retention in PAN-induced NS, 2) whether ENaC expression or apical targeting is secondary to high aldosterone levels, and 3) the role of aldosterone in the dysregulation of sodium transporters in NS. Puromycin treatment of adrenalectomized (ADX) rats supplemented with dexamethasone induced sodium retention despite the absence of aldosterone. Immunocytochemical analyses revealed an absence of enhanced apical targeting of ENaC subunits in PAN-treated ADX (ADX-PAN) rats, with distribution of labeling similar to adrenalectomized dexamethasone-treated control rats (ADX). Moreover, ENaC subunit abundance was increased in ADX-PAN rats. The abundance of aquaporin-2 was unchanged, whereas apical targeting was enhanced. Key sodium transporters were downregulated as previously observed in nonadrenalectomized puromycin-treated rats (Kim SW, Wang W, Nielsen J, Praetorius J, Kwon TH, Knepper MA, Frøkiaer J, and Nielsen S. Am J Physiol Renal Physiol 286: F922-F935, 2004), whereas the global expression of the alpha1-subunit of the Na-K-ATPase was unchanged. In conclusion, PAN treatment in the absence of aldosterone induced sodium retention, increased ENaC expression, but did not change the subcellular distribution of ENaC. This indicates that the previously observed enhanced apical targeting of ENaC in PAN-induced NS (Kim SW, Wang W, Nielsen J, Praetorius J, Kwon TH, Knepper MA, Frøkiaer J, and Nielsen S. Am J Physiol Renal Physiol 286: F922-F935, 2004) is caused by aldosterone and that development of sodium retention can occur in the absence of aldosterone in NS.

[Protective effects of Chailing Guiqi Decoction combined with lumbrukinase on renal function in rats with adriamycin nephropathy].

OBJECTIVE: To study the protective efffects of Chailing Guiqi Decoction (CLGQD) combined with lumbrukinase on renal function in rats with adriamycin nephropathy. METHODS: Thirty-six SD rats were randomly divided into four groups: normal control group, untreated group, simvastatin-treated group and CLGQD -treated group. Adriamycin nephropathy was induced by intravenous injection with 5 mg/kg adriamycin. After seven-day treatment, quantitative measurement of 24-h urine protein was determined with trichloroacetic acid, and serum total protein (TP), albumin (Alb), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), creatinine (Cr) and blood urea nitrogen (BUN) were assessed using automatic biochemistry analyzer. The pathomorphological changes of renal tissues were observed with light and electron microscopes. RESULTS: In the untreated group, the 24-h urine protein excretion, serum TC, TG, LDL, Cr and BUN were significantly higher than those in the normal control group (P<0.05 or P<0.01), while the serum TP, Alb, HDL were significantly lower than those in the normal control group (P<0.01). In the CLGQD-treated group, the 24-h urine protein excretion, serum TC, TG, LDL, Cr and BUN were significantly lower as compared with those in the untreated group (P<0.05 or P<0.01), while the serum TP, Alb and HDL were significantly higher as compared with those in the untreated group (P<0.05 or P<0.01). The pathomorphological findings of the renal tissues under the light microscope in the untreated group showed focal segmental glomerulosclerosis in a few of glomerulus, degenerated and swelled proximal tubular epithelial cells, proteins in cast formation in some renal tubules and scattered fibrosis in interstitial tissues of the kidney, while the electron microscope images showed the fusion of foot processes in glomerular epithelial cells. The pathomorphological changes in the CLGQD-treated group were slighter than those in the untreated group. CONCLUSION: CLGQD combined with lumbrukinase can reduce proteinuria, regulate lipid metabolism, protect renal function, and delay progressive renal damage in rats.

Long-term, high-dose glucocorticoids and bone mineral content in childhood glucocorticoid-sensitive nephrotic syndrome.

BACKGROUND: Glucocorticoids suppress bone formation, impair growth, and induce obesity. We determined the effects of long-term treatment with glucocorticoids on bone mineral content in children with glucocorticoid-sensitive nephrotic syndrome, a disorder with minimal known independent effects on bone. METHODS: We performed dual-energy x-ray absorptiometry of the whole body and spine in 60 children and adolescents with the nephrotic syndrome and 195 control subjects. We used linear regression analysis of log-transformed values to compare the bone mineral content in patients with that in controls. RESULTS: Patients had received an average of 23,000 mg of glucocorticoids and were shorter (P=0.008) and had a greater body-mass index (P<0.001) than controls. The bone mineral content of the spine, adjusted for bone area, age, sex, degree of maturation (Tanner stage), and race, did not differ significantly between patients and controls (ratio, 0.99; 95 percent confidence interval, 0.96 to 1.02; P=0.51). After adjustment for the z score for body-mass index, the bone mineral content of the spine was significantly lower in patients than in controls (0.96; 95 percent confidence interval, 0.92 to 0.99; P=0.01). Whole-body bone mineral content, adjusted for height, age, sex, degree of maturation, and race, was significantly higher in patients than in controls (ratio, 1.11; 95 percent confidence interval, 1.05 to 1.18; P<0.001); however, the addition of the z score for body-mass index to the model eliminated the association with the nephrotic syndrome (ratio, 0.99; 95 percent confidence interval, 0.94 to 1.03; P=0.55). CONCLUSIONS: Intermittent treatment with high-dose glucocorticoids during growth does not appear to be associated with deficits in the bone mineral content of the spine or whole body relative to age, bone size, sex, and degree of maturation. Glucocorticoid-induced increases in body-mass index were associated with increased whole-body bone mineral content and maintenance of the bone mineral content of the spine.

[Protective effects of astragali injection on tubular in patients with primary nephrotic syndrome].

OBJECTIVE: To determine the effects of astragali injection on tubular and its possible mechanisms. METHODS: Sixty patients with primary nephritic syndrome (PNS) were randomly divided into astragali group (n = 30) and control group (n = 30). The surm albumin (sALB) and urinary excretion of retinol-binding protein (RBP), N-Acety-P-beta-Glucosaminidase (NAG), beta2- Microglobulin (beta2MG) were measured before and after the treatment. RESULTS: After the one month treatment, sALB was significantly higher, and ubeta2MG, uNAG, uRBP, and 24 huP were significantly lower in astragali group (P <0.01, P < 0.05). CONCLUSION: Astragali injection on tubular plays a protective role in PNS.

Garlic ameliorates hyperlipidemia in chronic aminonucleoside nephrosis.

Nephrotic syndrome (NS) is characterized by proteinuria, oxidative stress and endogenous hyperlipidemia. Hyperlipidemia and oxidative stress may be involved in coronary heart disease and the progression of renal damage in these patients. Garlic has been suggested to be beneficial in various disease states. Some of the beneficial effects of garlic may be secondary to its hypolipidemic and antioxidant properties. Therefore, the effect of a 2% garlic diet on acute and chronic experimental NS induced by puromycin aminonucleoside (PAN) was studied in this work. Acute NS was induced by a single injection of PAN to rats which were sacrificed 10 days later. Chronic NS was induced by repeated injections of PAN to rats which were sacrificed 84 days after the first injection. Garlic treatment was unable to modify proteinuria in either acute or chronic NS, and hypercholesterolemia and hypertriglyceridemia in acute NS. However, garlic treatment diminished significantly total-cholesterol, LDL-cholesterol and triglycerides, but not HDL-cholesterol in chronic NS. Garlic induced no change in the percentage of sclerotic glomeruli in chronic NS and a significative decrease on the percentage of sclerotic area of these glomeruli (33 +/- 3% in NS+Garlic group vs. 47 +/- 4% in NS group, p = 0.0126). The enhanced in vivo renal H2O2 production and the diminished renal Cu, Zn-SOD and catalase activities in acute NS, and the decreased renal catalase activity in chronic NS were not prevented by garlic treatment. These data indicate that garlic treatment ameliorates hyperlipidemia and renal damage in chronic NS which is unrelated to proteinuria or antioxidant enzymes.

Vascular hyperpermeability in nephrotic edema.

BACKGROUND/AIM: There is increasing evidence that hypoalbuminemia and the inability of the renal distal tubule to excrete salt are not the only factors responsible for nephrotic edema. We tested the possibility that vascular hyperpermeability also plays a role in the pathophysiology of nephrotic edema in human primary glomerulonephritis. METHODS: We investigated the capillary permeability by means of a standardized test using albumin labelled with technetium (99mTc-albumin) in 20 healthy adults and in 101 nephrotic adult patients comprising 60 patients with idiopathic nephrotic syndrome (INS; minimal-change nephropathy and segmental glomerulosclerosis), 32 with idiopathic membranous nephropathy (IMN) and 9 patients with idiopathic type I membranoproliferative glomerulonephritis (MPGN). The patients and healthy controls were also compared with a group of women (n = 25) with idiopathic cyclic edema, a disease in which an increase in capillary permeability plays a pivotal role. The capillary permeability measured by the Landis isotope test is normal in edematous patients with cardiac and renal impairment unrelated to glomerular disease, cirrhosis, hypothyroidism, lymphatic obstruction and diuretic abuse. As values were not normally distributed, nonparametric analysis of variance was used (Kruskal-Wallis test), and patient groups were compared with healthy controls and with women with idiopathic cyclic edema by means of the two-tailed nonparametric Mann-Whitney test. The effects of high-dose steroids and Ginkgo biloba extract (Tanakan); an agent able to improve capillary permeability) were analyzed by means of the two-tailed nonparametric Wilcoxon test. RESULTS: The capillary permeability was significantly increased (Mann-Whitney test) in each glomerular disease group compared with the healthy controls. 99mTc-albumin extravasation values (%; median and range in parentheses were the following: healthy controls 0 (0-8.4); idiopathic cyclic edema patients 11.5 (8-24), p < 0.001; INS 20 (0-50), p < 0.0001; IMN 12.5 (0-40), p < 0.001, and MPGN 10 (0-40), p < 0.05. An increase in capillary permeability exceeding the upper limit of control values (>8% of 99mTc-albumin extravasation) was observed in 88% of INS, in 53% of IMN and in 44% of MPGN patients. The increase in capillary permeability (%) was greater in idiopathic nephrotic patients than in idiopathic cyclic edema patients (p < 0. 005, Mann-Whitney test) and was markedly reduced in nephrotic patients receiving high-dose steroids (n = 8) [before 25 (8-40); after 0 (0-25), p < 0.005 (Wilcoxon's test)] and high doses of G. biloba extract (n = 16) [before 30 (8-50); after 2.5 (0-20, p < 0. 0005 (Wilcoxon's test)]. CONCLUSIONS: We conclude that capillary permeability is severely altered in most of the nephrotic patients with primary glomerulonephritis. These results strongly suggest that the capillary hyperpermeability plays a role in the pathophysiology of nephrotic edema in primary glomerular disease, especially in INS. We postulate that this widespread abnormality in capillary permeability is related to the release of vascular permeability factor and other cytokines by immune cells.

Treatment of edematous disorders with diuretics.

Generalized edema results from alterations in renal sodium homeostasis that ultimately result in an expansion of extracellular fluid volume and accumulation of interstitial fluid. The common edematous disorders include congestive heart failure, cirrhosis, nephrotic syndrome, and renal insufficiency. The abnormalities of sodium homeostasis contributing to edema formation in each condition are discussed. Management of volume homeostasis, with an emphasis on the role of diuretic therapy, is reviewed.

Bone histology in patients with nephrotic syndrome and normal renal function.

BACKGROUND: The prevalence of metabolic bone disease in patients with nephrotic syndrome (NS) at normal level of renal function remains uncertain. METHODS: To address this issue, we studied 30 patients (20 men and 10 women, mean age 27.3 +/- 11.7 years) with NS who had normal renal function (mean creatinine clearance 103 +/- 4 ml/min). We evaluated their serum calcium, phosphorus, alkaline phosphatase, immunoreactive parathyroid hormone (iPTH), vitamin D metabolites, urinary calcium, and skeletal survey. The extent of bone mineralization was analyzed by histomorphometric analysis of iliac crest bone biopsy specimens in all patients. The findings on bone histology were correlated with biochemical parameters. RESULTS: The mean duration of NS was 35.5 +/- 26.9 months, with a protein excretion of 7.3 +/- 3.2 g/24 hr and a serum albumin of 2.2 +/- 0.8 g/dl. Total serum calcium was 7.8 +/- 0.8 mg/dl, whereas ionized calcium was 5.7 +/- 0.7 mg/dl, phosphorus 3.2 +/- 1.2 mg/dl, and alkaline phosphatase 149 +/- 48.6 U/liter. Serum iPTH levels were normal in all except two patients. The mean serum 25-hydroxyvitamin D [25(OH)D] level was 3.9 +/- 1.2 ng/ml (normal 15 to 30 ng/ml), whereas 1,25-dihydroxyvitamin D was 24 +/- 4.7 pg/ml (normal 16 to 65). There was an inverse correlation between serum levels of 25(OH)D and the magnitude of proteinuria (r = -0.42, P < 0.05). The mean 24-hour urinary calcium excretion was 82 +/- 21 mg/day. The skeletal survey was normal in all patients. Bone histology was normal in 33.3% of the patients, whereas 56.7% had isolated osteomalacia (OSM), and 10% had an increased bone resorption in association with defective mineralization. The severity of OSM measured by mineralization lag time correlated linearly with the duration (r = 0.94, P < 0.0001) and the amount (r = 0.97, P < 0.0001) of proteinuria. All patients with NS for more than three years had histological changes. Patients with OSM had lower 25(OH)D and serum albumin as compared with those with normal histology (P < 0.005). Bone mineralization had no significant correlation with serum iPTH, divalent ions, or vitamin D levels. CONCLUSIONS: OSM is a frequent finding in adult patients with NS, even at a normal level of renal function. Its severity correlates with the amount and duration of proteinuria.