Population-based identification and temporal trend of children with primary nephrotic syndrome: The Kaiser Permanente nephrotic syndrome study.

INTRODUCTION: Limited population-based data exist about children with primary nephrotic syndrome (NS). METHODS: We identified a cohort of children with primary NS receiving care in Kaiser Permanente Northern California, an integrated healthcare delivery system caring for >750,000 children. We identified all children <18 years between 1996 and 2012 who had nephrotic range proteinuria (urine ACR>3500 mg/g, urine PCR>3.5 mg/mg, 24-hour urine protein>3500 mg or urine dipstick>300 mg/dL) in laboratory databases or a diagnosis of NS in electronic health records. Nephrologists reviewed health records for clinical presentation and laboratory and biopsy results to confirm primary NS. RESULTS: Among 365 cases of confirmed NS, 179 had confirmed primary NS attributed to presumed minimal change disease (MCD) (72%), focal segmental glomerulosclerosis (FSGS) (23%) or membranous nephropathy (MN) (5%). The overall incidence of primary NS was 1.47 (95% Confidence Interval:1.27-1.70) per 100,000 person-years. Biopsy data were available in 40% of cases. Median age for patients with primary NS was 6.9 (interquartile range:3.7 to 12.9) years, 43% were female and 26% were white, 13% black, 17% Asian/Pacific Islander, and 32% Hispanic. CONCLUSION: This population-based identification of children with primary NS leveraging electronic health records can provide a unique approach and platform for describing the natural history of NS and identifying determinants of outcomes in children with primary NS.

A Review of the Current Practice of Diagnosis and Treatment of Idiopathic Membranous Nephropathy in China.

Idiopathic membranous nephropathy (IMN), a common pathological type of nephrotic syndrome, is one of the main causes of kidney failure. With an increasing prevalence, IMN has received considerable attention in China. Based on recent studies, we discuss advances in the diagnosis of IMN and the understanding of its genetic background. Although the pathogenesis of IMN remains unclear, our understanding has been substantially enhanced by the discovery of new antigens such as phospholipase A2 receptor, thrombospondin type-1 domain-containing 7A, exostosin1/exostosin2, neural epidermal growth factor-like 1 protein, neural cell adhesion molecule 1, semaphorin 3B, and factor H autoantibody. However, due to ethnic, environmental, economic, and lifestyle differences and other factors, a consensus has not yet been reached regarding IMN treatment. In view of the differences between Eastern and Western populations, in-depth clinical evaluations of biomarkers for IMN diagnosis are necessary. This review details the current treatment strategies for IMN in China, including renin-angiotensin system inhibitors, corticosteroid monotherapy, cyclophosphamide, calcineurin inhibitors, mycophenolate mofetil, adrenocorticotropic hormone, and traditional Chinese medicine, as well as biological preparations such as rituximab. In terms of management, the 2012 Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines do not fully consider the characteristics of the Chinese population. Therefore, this review aims to present the current status of IMN diagnosis and treatment in Chinese patients, and includes a discussion of new approaches and remaining clinical challenges.

Primary coenzyme Q10 nephropathy, a potentially treatable form of steroid-resistant nephrotic syndrome.

Steroid-resistant nephrotic syndrome (SRNS) is a genetically heterogeneous kidney disease that is the second most frequent cause of kidney failure in the first 2 decades of life. Despite the identification of mutations in more than 39 genes as causing SRNS, and the localization of its pathogenesis to glomerular podocytes, the disease mechanisms of SRNS remain poorly understood and no universally safe and effective therapy exists to treat patients with this condition. Recently, genetic research has identified a subgroup of SRNS patients whose kidney pathology is caused by primary coenzyme Q10 (CoQ10) deficiency due to recessive mutations in genes that encode proteins in the CoQ10 biosynthesis pathway. Clinical and preclinical studies show that primary CoQ10 deficiency may be responsive to treatment with CoQ10 supplements bypassing the biosynthesis defects. Coenzyme Q10 is an essential component of the mitochondrial respiratory chain, where it transports electrons from complexes I and II to complex III. Studies in yeast and mammalian model systems have recently identified the molecular functions of the individual CoQ10 biosynthesis complex proteins, validated these findings, and provided an impetus for developing therapeutic compounds to replenish CoQ10 levels in the tissues/organs and thus prevent the destruction of tissues due to mitochondrial OXPHOS deficiencies. In this review, we will summarize the clinical findings of the kidney pathophysiology of primary CoQ10 deficiencies and discuss recent advances in the development of therapies to counter CoQ10 deficiency in tissues.

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.

Tripterygium glycoside fraction n2 ameliorates adriamycin-induced nephrotic syndrome in rats by suppressing apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium wilfordii Hook F. (TwHF), a traditional Chinese herb medicine, has been widely used for clinical treatment of various rheumatic immune diseases. Tripterygium glycosides (TG) extracted from TwHF has been verified to process multiple bioactivities, including immunosuppressive, anti-inflammatory and anti-cancer effects. However, the clinical application of TG is limited due to its severe toxicity and narrow therapeutic window. For the clinical safety of TG usage, attenuation of toxicity is the key issue to be solved. PURPOSE: Tripterygium glycoside fraction n2 (TG-n2) is a detoxified mixture obtained from TG using a new preparation method. In our previous study, we have demonstrated that TG-n2 has a lower toxicity than TG. The aim of the present study was to screen the renal protective effect of TG-n2 in nephrotic syndrome (NS) induced by adriamycin (ADR) in rats and its effect on apoptosis, as well as the effective difference between TG-n2 and TG. MATERIALS AND METHODS: The ADR-induced NS rat model was established. Rats were intravenously injected with ADR (6 mg/kg), then treated with either TG-n2 (10 mg/kg/day) or TG (10 mg/kg/day) by oral gavage for 4 weeks. Clinical indexes in each group were determined. HE staining and electron microscopic analysis were used to evaluate renal histopathological damage. Caspase-3 activity reagent and TUNEL staining were used to estimate renal apoptosis. Protein levels of caspase-3, caspase-9, caspase-8, caspase-12, Bax, Bcl-2, p53, TNF-R1, FLIP and podocin were measured by Western Blot. RESULTS: TG-n2 and TG intervention ameliorated renal function as assessed by the levels of 24-h proteinuria, Cr, BUN, TC, TG, ALB and LDL-c. TG-n2 and TG alleviated the decrease of podocin protein expression and morphological injury of podocyte as screened by Western Blot and electron microscopic analysis. Besides, renal tubular injury was reduced as inspected by light microscopic analysis. TG-n2 and TG could significantly inhibit the apoptosis and activity of caspase-3 in kidney tissues as examined by fluorescence microscopic analysis and reagent. After intervention of TG-n2 and TG, protein levels of cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, Bax, p53 and TNF-R1 in renal issues were significantly decreased compared with ADR group. In contrast, protein level of Bcl-2 was elevated remarkedly. CONCLUSIONS: Our data suggested that attenuated TG-n2 may have a similar protective effect with TG in ADR-induced NS in rats by inhibiting activation of apoptosis.

3D organoid-derived human glomeruli for personalised podocyte disease modelling and drug screening.

The podocytes within the glomeruli of the kidney maintain the filtration barrier by forming interdigitating foot processes with intervening slit diaphragms, disruption in which results in proteinuria. Studies into human podocytopathies to date have employed primary or immortalised podocyte cell lines cultured in 2D. Here we compare 3D human glomeruli sieved from induced pluripotent stem cell-derived kidney organoids with conditionally immortalised human podocyte cell lines, revealing improved podocyte-specific gene expression, maintenance in vitro of polarised protein localisation and an improved glomerular basement membrane matrisome compared to 2D cultures. Organoid-derived glomeruli retain marker expression in culture for 96 h, proving amenable to toxicity screening. In addition, 3D organoid glomeruli from a congenital nephrotic syndrome patient with compound heterozygous NPHS1 mutations reveal reduced protein levels of both NEPHRIN and PODOCIN. Hence, human iPSC-derived organoid glomeruli represent an accessible approach to the in vitro modelling of human podocytopathies and screening for podocyte toxicity.

CoQ10 supplementation rescues nephrotic syndrome through normalization of H2S oxidation pathway.

Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most common phenotype associated with primary coenzyme Q10 (CoQ10) deficiency and is very responsive to CoQ10 supplementation, although the pathomechanism is not clear. Here, using a mouse model of CoQ deficiency-associated NS, we show that long-term oral CoQ10 supplementation prevents kidney failure by rescuing defects of sulfides oxidation and ameliorating oxidative stress, despite only incomplete normalization of kidney CoQ levels and lack of rescue of CoQ-dependent respiratory enzymes activities. Liver and kidney lipidomics, and urine metabolomics analyses, did not show CoQ metabolites. To further demonstrate that sulfides metabolism defects cause oxidative stress in CoQ deficiency, we show that silencing of sulfide quinone oxido-reductase (SQOR) in wild-type HeLa cells leads to similar increases of reactive oxygen species (ROS) observed in HeLa cells depleted of the CoQ biosynthesis regulatory protein COQ8A. While CoQ10 supplementation of COQ8A depleted cells decreases ROS and increases SQOR protein levels, knock-down of SQOR prevents CoQ10 antioxidant effects. We conclude that kidney failure in CoQ deficiency-associated NS is caused by oxidative stress mediated by impaired sulfides oxidation and propose that CoQ supplementation does not significantly increase the kidney pool of CoQ bound to the respiratory supercomplexes, but rather enhances the free pool of CoQ, which stabilizes SQOR protein levels rescuing oxidative stress.

Plantago asiatica L. Ameliorates Puromycin Aminonucleoside-Induced Nephrotic Syndrome by Suppressing Inflammation and Apoptosis.

OBJECTIVE: Nephrotic syndrome, a kidney disease with a variety of causes, is mainly characterized by heavy proteinuria, hypoproteinemia, and ascites. This study was designed to evaluate the underlying mechanism of action of Plantago asiatica L. (PAL) in treating nephrotic syndrome induced by puromycin aminonucleoside. METHODS: PAL has been used in Asia as a traditional medicine and dietary health supplement. Sprague-Dawley (SD) rats were intravenously injected with puromycin aminonucleoside (75 mg/kg/day), then treated with either Losartan (30 mg/kg/day) or PAL (200 mg/kg/day) by oral gavage for seven days. RESULTS: PAL significantly decreased ascites, proteinuria level, and plasma lipid parameters. In addition, treatment with PAL attenuated histological damage and hypoalbuminemia. Treatment with PAL also restored podocin expression and reduced inflammation markers such as intracellular adhesion molecules (ICAM-1), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α) and high-mobility group box-1 (HMGB1). Lower expression levels of the apoptosis markers Bax, caspase-3 and capase-9 were documented in SD rats receiving PAL. PAL also significantly decreased the phosphorylation levels of MAPKs such as ERK, JNK and p38. CONCLUSION: As a multifunctional agent, PAL has a renoprotective effect in nephrotic syndrome rat models. The anti-inflammatory and anti-apoptotic properties, along with reductions in hyperlipidemia and ascites, represent important therapeutic effects. These results indicate that Plantago asiatica is likely to be a promising agent in the treatment of nephrotic syndrome.

Histopathological Changes in Arsenic Kushta Induced Nephrotoxicity in Wistar Rats.

OBJECTIVE: To determine the nephrotoxic effects of arsenic kushta (Kushta Sam-ul-Far) in Wistar rats. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Department of Morbid Anatomy and Histopathology, University of Health Sciences, Lahore from May to August 2014. METHODOLOGY: This experimental study was conducted on 48 healthy Wistar rats, each weighing 200 - 250 grams. The rats were randomly divided into 4 experimental groups each containing 12 rats. Group I was taken as control given flour pellets. Group II was given single dose (180 mg/kg) of arsenic kushta for 2 weeks. Group III received 150 mg/kg of arsenic kushta for 12 weeks; whereas, group IV was also given 150 mg/kg of arsenic kushta for 12 weeks along with 75 mg of BSA (bovine serum albumin). Histopathological changes in glomeruli, tubules and interstitium were noted in the kidney. RESULTS: Mesangial proliferation, thickening of basement membrane, necrosis, and interstitial edema were mainly observed in all the above groups except group I which served as control. These changes were seen in greater severity in high dose groups and the group given BSA injection along with kushta (group III, IV). CONCLUSION: Herbo-mineral preparations of arsenic kushta are nephrotoxic in rats and may have similar toxic effects in human beings.

Soy protein and genistein improves renal antioxidant status in experimental nephrotic syndrome.

BACKGROUND AND OBJECTIVES: Nephrotic syndrome is a chronic disease especially common in the childhood and adolescence. Reactive oxygen species (ROS) and free radicals have significant role in the pathogenesis of nephrotic syndrome. The aim of this study was to evaluate the effect of soy protein and genistein (main isoflavone of soybean) on renal antioxidant status of nephrotic rats. METHODS: This study was done for 8 weeks on 40 adult male Sprague-Dawley rats divided into four groups of 10 rats each. Study groups included: 1-Control, 2-Nephrotic syndrome, 3-Nephrotic syndrome+soy protein diet and 4-Nephrotic syndrome+soy protein diet+genistein. Urine protein and urine creatinine were measured. After homogenization of kidney, total antioxidant capacities (TAC), activities of catalase enzyme, the concentration of malondialdehydes (MDA) and carbolynated proteins were determined spectrophotometrically. Pathological examination was done on kidneys with light microscope. Cell viability was evaluated with MTT assay on WEHI-164 fibro sarcoma cell line. The MMP2 enzyme activity was evaluated in different concentrations of genistein. RESULTS: Total antioxidant capacity was significantly increased in soy genistein. Catalase activity was significantly increased in soy and soy genistein groups. Protein carbonyl and MDA were significantly lower in soy and soy genistein groups. The scores of pathological examination showed significant improvement in soy and soy genistein groups. Genistein decreased the proliferation of the WEHI-164 fibrosarcoma cell line. CONCLUSION: It seems that soy protein decreases kidney damages in nephrotic syndrome. Adding genistein to soy protein causes improvements in antioxidant status of kidney tissue. Genistein decreases proliferation of cell.

Qi-Dan Fang ameliorates adriamycin-induced nephrotic syndrome rat model by enhancing renal function and inhibiting podocyte injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Nephrotic syndrome (NS) is a clinical syndrome with a variety of causes, mainly characterized by heavy proteinuria. Podocyte injury plays a key role in proteinuria, one of the principal means for the control of NS is to prevent podocyte injury. Qi-Dan Fang consists of two of the most extensively applied herbal remedies among Traditional Chinese Medicine (TCM) (Radix Astragali Mongolici and Radix Salviae Miltiorrhizae, with a weight ratio of 5:1) which are specifically used for the treatment of various kidney diseases. In previous studies, we found that Qi-Dan Fang provides improvement to patients with adriamycin-induced nephrotic syndrome by alleviating proteinuria and serum lipid. The aim of this study is to study the efficiency of Qi-Dan Fang on NS model rat with renal dysfunction and podocyte injury, something which has not been carried out yet. MATERIALS AND METHODS: The rats were divided into Normal, Model, Jin Gui Shen Qi Pill (4.12 g/kg), Qi-Dan Fang (3.09, 6.17 and 12.34 g/kg/d) groups, they were each given a single tail intravenous injection of Adriamycin (6.0 mg/kg) except for the Normal group and were orally administered dosages of Qi-Dian Fang and Jin Gui Shen Qi pills once daily for 7 weeks. Following the treatment, the content of cystation C (CysC), blood urea nitrogen (BUN), serum creatinine (Scr) were measured with an autobiochemical analyser. The pathomorphological changes to the glomeruli, the mRNA expressions of nephrin, podocin, CD2AP genes and p53, bax, bcl-2 proteins expressions were also carried out to probe the effects of Qi-Dan Fang. RESULTS: (1) Qi-Dan Fang treatment raised the level of CysC in blood serum while lowering the content of BUN and Scr in the adriamycin-induced nephrotic syndrome rat model; (2) Long-term administration of Qi-Dan Fang was able to ameliorate pathomorphological change of glomeruli and repair the organization structure of Glomerulus; (3) Qi-Dan Fang could increase the mRNA expression of nephrin, podocin and CD2AP genes, down-regulate the expression of p53, bax proteins, while increased bcl-2 protein to protect the podocyte and restore Glomerular selective filtration function. CONCLUSIONS: Results of our present studies reveal that Qi-Dan Fang is able to enhance renal function, inhibit podocyte injury to provide improvements to the Adriamycin-induced nephrotic syndrome.

Early myoclonic epilepsy, hypertrophic cardiomyopathy and subsequently a nephrotic syndrome in a patient with CoQ10 deficiency caused by mutations in para-hydroxybenzoate-polyprenyl transferase (COQ2).

BACKGROUND: Primary coenzyme Q10 (CoQ10) deficiencies are heterogeneous autosomal recessive disorders. CoQ2 mutations have been identified only rarely in patients. All affected individuals presented with nephrotic syndrome in the first year of life. METHODS: An infant is studied with myoclonic seizures and hypertrophic cardiomyopathy in the first months of life and developed a nephrotic syndrome in a later stage. RESULTS: At three weeks of age, the index patient developed myoclonic seizures. In addition, he had hypertrophic cardiomyopathy and increased CSF lactate. A skeletal muscle biopsy performed at two months of age disclosed normal activities of the oxidative phosphorylation complexes. The child was supplemented with CoQ10 (5 mg/kg/day). At the age of four months, brain MR images showed bilateral increased signal intensities in putamen and cerebral cortex. After that age, he developed massive proteinuria. The daily dose of CoQ10 was increased to 30 mg/kg. Renal biopsy showed focal segmental glomerulosclerosis. Biochemical analyses of a kidney biopsy sample revealed a severely decreased activity of succinate cytochrome c reductase [complex II + III] suggesting ubiquinone depletion. Incorporation of labelled precursors necessary for CoQ10 synthesis was significantly decreased in cultured skin fibroblasts. His condition deteriorated and he died at the age of five months. A novel homozygous mutation c.326G > A (p.Ser109Asn) was found in COQ2. CONCLUSIONS: In contrast to previously reported patients with CoQ2 the proband presented with early myoclonic epilepsy, hypertrophic cardiomyopathy and only in a later stage developed a nephrotic syndrome. The phenotype of this patient enlarges the phenotypical spectrum of the multisystem infantile variant.

Efficacy and safety of traditional chinese medicine (Shenqi particle) for patients with idiopathic membranous nephropathy: a multicenter randomized controlled clinical trial.

BACKGROUND: To compare the safety and efficacy of the traditional Chinese medicine Shenqi particle and standard therapy with prednisone and cyclophosphamide (control) in adult patients with idiopathic membranous nephropathy (IMN). STUDY DESIGN: Open-label, multicenter, parallel, randomized, controlled clinical trial. SETTING & PARTICIPANTS: From April 2008 to February 2011, a total of 190 patients with biopsy-proven IMN from 7 hospitals in China participated in the study. All patients had nephrotic syndrome with estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m(2). INTERVENTION: Shenqi particle (9.6 g 3 times per day) or prednisone (1 mg/kg/d tapering to 0.17 mg/kg/d) and cyclophosphamide (total dose of 9-12 g per square meter of body surface area) for 48 weeks. OUTCOMES: Primary outcomes included complete remission, defined as proteinuria (24-hour urine protein excretion) ≤0.3 g/d, or partial remission, defined as proteinuria with protein excretion >0.3-<3.5 g/d and a 50% reduction from its peak value at 48 weeks. Secondary outcomes included serum albumin level, eGFR, doubling of serum creatinine level, end-stage renal disease, and death. RESULTS: Baseline values for proteinuria and eGFR were 5.34 ± 2.74 g/d and 84.0 ± 27.4 mL/min/1.73 m(2) for the Shenqi particle group and 5.33 ± 2.47 g/d and 83.8 ± 24.9 mL/min/1.73 m(2) for the control group, respectively. 132 patients (63 Shenqi particle group, 69 control group) completed the study. Change in urinary protein excretion in the Shenqi particle group was -3.01 (95% CI, -3.68 to -2.34) g/d, and in the control group, -3.28 (95% CI, -3.98 to -2.58) g/d; the mean difference between groups was 0.27 (95% CI, -0.70 to 1.23) g/d (P = 0.6). Changes in eGFR were 12.3 (95% CI, 4.99 to 19.6) mL/min/1.73 m(2) in the Shenqi particle group and -2.8 (95% CI, -10.32 to 4.77) mL/min/1.73 m(2) in the control group; the mean difference between groups was 15.1 (95% CI, 4.56 to 25.55) mL/min/1.73 m(2) (P = 0.005). Severe adverse events occurred in only the control group (14.5%) and included lung infection, liver injury, and pneumonia. LIMITATIONS: High rate of loss to follow-up and lack of observation period prior to the study. CONCLUSIONS: Shenqi particle may be a promising alternative therapy for adults with IMN and nephrotic syndrome.

Inhibition of calcium(2+)/calmodulin-dependent protein kinase type IV ameliorates experimental nephrotic syndrome.

OBJECTIVE: Evidence has demonstrated that Ca(2+)/calmodulin-dependent protein kinase type IV (CaMKIV) contributes to altered cytokine production by promoting the production of inflammatory cytokines. This study aimed to explore the protective role and underlying mechanisms of CaMKIV inhibition in experimental nephrotic syndrome. METHODS: BALB/c mice received single intravenous injections of adriamycin (10 mg/kg) then were sacrificed at two, four and six weeks. In the second study, treatment with KN-93, a CaMKIV inhibitor, or vehicle administered via intraperitoneal injection was started five days after adriamycin injection. Functional and pathologic parameters, the presence of inflammatory infiltration and the expressions of pro-inflammatory cytokines were assessed. RESULTS: The CaMKIV protein expression levels were upregulated in the mice with adriamycin nephropathy, which was significantly inhibited by KN-93 (p<0.01). As compared with the vehicle-treated controls, KN-93 treatment resulted in marked suppression of proteinuria and serum creatinine at week 6 (p<0.01), but not at two weeks after induction of the disease. KN-93 inhibited glomerulosclerosis and the development of tubulointerstitial lesions. The renal alpha-smooth muscle actin (α-SMA) expression was also significantly suppressed by KN-93 treatment at week 6 (p<0.01). Moreover, KN-93 inhibited the renal monocyte chemoattractant protein-1 (MCP-1) expression, paralleled by a reduction in the interstitial infiltration of macrophages and T-cells (p<0.01). CONCLUSION: Our findings suggest that activation of CaMKIV signaling is involved in the progression of glomerular diseases with a proteinuric state. Our data therefore justify the development of small molecule CaMKIV inhibitors for the treatment of clinical nephrotic syndrome.

Combined renin angiotensin blockade in childhood steroid-resistant nephrotic syndrome.

BACKGROUND: Reduced proteinuria results in delayed deterioration of renal function and remission of proteinuria predicts a good long-term prognosis in steroid-resistant nephrotic syndrome (SRNS). The aim of this study was to analyze the effects of the combined angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker in reducing proteinuria in SRNS. METHODS: A prospective study of eight patients with SRNS was conducted at the Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University from September 2003 to December 2007. Enalapril was given at 0.1 mg/kg/day and was increased by 0.1 mg/kg/day every 4 weeks up to 0.6 mg/kg/day (maximum 40 mg/day) and 1 mg/kg/day of losartan was added for 4 weeks and stepped up to 2 mg/kg/day (maximum 100 mg/day) for another 4 weeks. RESULTS: There were five boys (62.5%) and three girls (37.5%). The mean age at diagnosis was 8.3 ± 4.1 years (range 2.05-13 years) and age at enrollment was 11.7 ± 3.8 years (range 6-16 years). Renal histology revealed seven focal segmental glomerulosclerosis and one immunoglobulin M nephropathy. The results showed significant reduction on mean spot urine protein : creatinine ratio from 9.6 ± 2.3 to 3.6 ± 1.6 (P < 0.05) and 24-h urine protein from 182.8 ± 59.6 to 28.7 ± 8.2 mg/m(2) /h (P < 0.05). Urine protein reduction ratio at the end of the study was 50% (P= 0.08). Serum cholesterol, albumin, potassium, blood pressure and renal function had no significant change. No clinical and laboratory side-effects were reported. CONCLUSION: Combined high-dose angiotensin II receptor blocker to high-dose angiotensin-converting enzyme inhibitor therapy is safe and effective in reducing proteinuria in childhood SRNS. However a large-scale study should be conducted to validate this result.

Looking at appearance of urine before performing a renal biopsy in nephrotic syndrome.

Chyluria results from an abnormal connection between lymphatic bed and urinary tract, causing lymph leakage into the urine. The clinical picture often begins with the appearance of cloudy, milky urines accompanied by monolateral flank pain, malnutrition, weight loss and weakness. We report a case of chyluria that occurred in a young woman who was referred to our unit for nephrotic-range proteinuria. Before performing a renal biopsy, we found that urine analysis demonstrated a massive lipiduria. Therefore, we collected urine samples from each kidney with a selective ureteral catheterization, demonstrating a monolateral source of lipids and proteins. We suspended the renal biopsy and performed a lymphography that showed an inherited lymphangioma on the left lumbar lymphatic bed. Sclerosing solution instillation, renal pedicle lymphatic disconnection or laser therapy are invasive therapeutical options that may cause severe adverse effects. Instead of these procedures, a conservative therapy based on a low-fat diet supplemented with medium-chain triglycerides was chosen. This dietetic schedule was followed by complete resolution of proteinuria and lipiduria. The patient progressively gained body weight and improved quality of life. No relapses were observed after 3 years of follow-up. This case emphasizes the possible role of a noninvasive therapeutical option for patients with chyluria.

Effect of Shen-qi-di-huang decoction on reducing proteinuria by preserving nephrin in adriamycin-induced nephropathy rats.

The aim of this study is to investigate the effect of Shen-qi-di-huang decoction on reducing proteinuria and to discuss the mechanism of its action in Adriamycin (ADR)-induced nephropathy rats. The rats were randomly divided into three groups (n=12 each group): normal control (group A); ADR model control (group B); ADR + Shen-qi-di-huang decoction (group C). In group B and C, the rats were intravenously injected with ADR (6.5mg/kg). The rats in group C were orally administrated with Shen-qi-di-huang decoction after the injection of ADR. On day 7, 14, 28, 56 after ADR injection, 24h urine protein was detected. On day 28, 56 after ADR injection, ALB, ALT, serum creatinine (Scr) and BUN were examined. The morphological changes of the kidneys were observed by light microscope and electron microscope on day 28, 56 after ADR injection. The expression of nephrin was determined by immunohistochemistry and RT-PCR on day 28, 56 after ADR injection. Compared with group B, 24h urine protein and Scr decreased in group C on day 56 (P<0.05). The expression of nephrin determined by immunohistochemistry and RT-PCR increased in group C on day 28, 56 (P<0.05). The morphology observed by light microscope and electron microscope improved in group C on day 28, 56. Shen-qi-di-huang decoction decreases proteinuria, protects kidney function, and ameliorates histopathology in ADR-induced rats by preserving nephrin expression.

Amelioration of anti-cancer agent adriamycin-induced nephrotic syndrome in rats by Wulingsan (Gorei-San), a blended traditional Chinese herbal medicine.

Anti-cancer agent adriamycin (ADR) has demonstrated high anti-tumor efficacy. However, its use in chemotherapy has been limited largely due to its diverse toxicities, including renal toxicity, such as nephrotic syndrome with proteinuria. Podocyte injury leads to glomeruli proteinuria. Wulingsan (WLS) is a blended traditional Chinese herbal medicine specifically used for various kidney diseases. In the present study, we found that a water extract of WLS (480 mg/kg, p.o., x 28 days) reduced ADR-induced increase in urine protein excretion, plasma total cholesterol and triglyceride, and decrease in plasma total protein and albumin in rats. Furthermore, the results of electron microscopy demonstrated suppression by WLS of ADR-induced increase in width of foot process, increase in surface density and decrease in volume density. These results suggest that WLS ameliorates ADR-induced proteinuria and podocyte injury. Gene analysis results demonstrated a suppression of renal overexpression of nephrin mRNA and protein by WLS. Radioimmunoassay showed that WLS suppressed ADR-induced increased renal angiotensin II content in rats. Thus our results demonstrate that WLS ameliorates ADR-induced nephrotic syndrome in rats possibly by suppressing ADR-induced hyperactivity of renal renin-angiotensin system to modulate renal nephrin gene expression, thereby protecting podocyte from injury.

Chinese herbal formula Qilong-Lishui granule improves puromycin aminonucleoside-induced renal injury through regulation of bone morphogenetic proteins.

BACKGROUND: The Chinese herbal formula Qilong-Lishui granule (QLG) is an effective natural product for treatment of renal disorder. It was composed of six Chinese herbs according to our clinical practice in the treatment of patients with kidney disease. However, molecular and cellular mechanisms of QLG are still unclear. Therefore, the objective of the current study is to investigate molecular and cellular mechanisms of QLG in puromycin aminonucleoside (PAN)-induced nephrotic syndrome. METHOD: Wistar rats were divided into six groups of sham operation, PAN model, PAN model with high-dosage QLG (QLG-H), PAN model with median-dosage QLG (QLG-M), PAN model with low-dosage QLG (QLG-L), and PAN model with fosinopril (FP). The PAN model was induced by jugular vein injection of PAN at a dose of 5 mg/100 g body weight. Quantities of 24 h urinary protein excretion were examined on days 5, 10, 15, 20, 25 and 30. All rats were sacrificed on day 31 for blood biochemistry, kidney histology and reverse transcriptase-polymerase chain reaction analysis. RESULTS: PAN-induced nephrotic syndrome was successfully produced in rats. Treatment of QLG significantly reduced protein excretion and blood urea nitrogen and creatinine. QLG and FP treatments also improved protein content in blood, and reduced total cholesterol and triglyceride in blood. Moreover, QLG and FP improved the damage of interstitial induced by PAN. Furthermore, CYP and FP were able to reverse BMPRII and Smad1 mRNAs abundance caused by PAN. CONCLUSION: QLG attenuates PAN-induced kidney injury possibly through the bone morphogenetic protein signal transduction pathway.

[Correlation analysis on blood stasis syndrome, clinical features and renal pathology in 174 patients with primary glomerular diseases].

OBJECTIVE: To investigate the relationship between degree of TCM blood-stasis syndrome (BSS) with clinic features and renal pathological type of primary glomerular disease (PGD). METHODS: On-site investigation was adopted, 174 patients with PGD conforming to the inclusive/exclusive criteria were enrolled, and their degree of BSS and deficiency syndrome were scored in 3 days before renal biopsies. The relation of clinical indexes, including age, course of disease, symptoms of deficiency syndrome, 24-h urinary protein excretion (Upro), condition of hypertension and its controlling, glomerular filtrating rate (GFR) based on the predigesting equation of MDRD, and blood levels of uric acid (UA), triglyceride (TG), cholesterol (CHO), hemoglobin (Hb), and albumin (ALB), with the renal pathological type and the BSS score were analyzed. RESULTS: (1) Among the 174 patients, 159 cases (91.38%) were differentiated as BSS, with the degree of moderate in 111 cases and severe in 48 cases; (2) The BSS score was significantly correlated with the level of Upro, CHO, TG, ALB and deficiency syndrome (P < 0.01), but showed insignificant correlation with age, course of disease, grade of the hypertension, and GFR, UA and Hb levels. Multivariate stepwise regression analysis showed that the level of Upro and TG and score of deficiency syndrome had significance for regression equation establishment (P<0.01). (3) Further analysis on renal pathological type in 119 patients of non-nephrotic syndrome showed that the BSS score was insignificantly different among patients with different renal pathological types as the minor/minimal type (3 cases), the focal/segmental glomerular type (72 cases), and the diffuse glomerulonephritis (44 cases, P > 0.05). Further stratified analysis on the 72 cases with focal/segmental lesion showed that BSS score in patients of focal proliferative sclerosing glomerulonephritis were significantly higher than that in those of focal proliferative glomerulonephritis (P < 0.01). CONCLUSION: BSS is a TCM syndrome most commonly seen in patients with primary glomerular disease, BSS score is significantly correlated with the level of Upro, TG and deficiency syndrome score, and exhibits a higher level in patients with focal proliferative glomerulonephritis accompanying glomerulus sclerosis, indicating that the BSS could give certain clues of the renal chronic changes of primary glomerular disease, being one of risk factors in TCM syndrome in the development of renal diseases.