The Prognostic Value of Anti-PLA2R Antibodies Levels in Primary Membranous Nephropathy.

Anti-PLA2R antibodies (Ab) are a diagnostic and prognostic biomarker in primary membranous nephropathy (PMN). We assessed the relationship between the levels of anti-PLA2R Ab at diagnosis and different variables related to disease activity and prognosis in a western population of PMN patients. Forty-one patients with positive anti-PLA2R Ab from three nephrology departments in Israel were enrolled. Clinical and laboratory data were collected at diagnosis and after one year of follow-up, including serum anti-PLA2R Ab levels (ELISA) and glomerular PLA2R deposits on biopsy. Univariable statistical analysis and permutation-based ANOVA and ANCOVA tests were performed. The median [(interquartile range (IQR)) age of the patients was 63 [50-71], with 28 (68%) males. At the time of diagnosis, 38 (93%) of the patients had nephrotic range proteinuria, and 19 (46%) had heavy proteinuria (≥8 gr/24 h). The median [IQR] level of anti-PLA2R at diagnosis was 78 [35-183] RU/mL. Anti-PLA2R levels at diagnosis were correlated with 24 h proteinuria, hypoalbuminemia and remission after one year (p = 0.017, p = 0.003 and p = 0.034, respectively). The correlations for 24 h proteinuria and hypoalbuminemia remained significant after adjustment for immunosuppressive treatment (p = 0.003 and p = 0.034, respectively). Higher levels of anti-PLA2R Ab at diagnosis in patients with active PMN from a western population are associated with higher proteinuria, lower serum albumin and remission one year after the diagnosis. This finding supports the prognostic value of anti-PLA2R Ab levels and their possible use in stratifying PMN patients.

Status of Nutrition In Hemodialysis Patients Survey (SNIPS): Malnutrition risk by diabetes status.

BACKGROUND: Increased malnutrition risk has been observed in more than 40% people on haemodialysis in Israel. It is not clear that this risk is homogeneously distributed among people with versus without diabetes. OBJECTIVES: To examine the influence of diabetes on malnutrition risk among people on haemodialysis. METHODS: This cross-sectional study included a representative sample of 375 individuals on haemodialysis treated in hospital dialysis centres throughout Israel. Of these, 126 had diabetes. Dietary intake, biochemistry, anthropometric and hemodynamic measures were recorded. Malnutrition risk categories were defined: "minimal": body mass index (BMI) ≥23 kg/m2 and serum albumin ≥38 mmol/L; "mild": BMI <23 kg/m2 and albumin ≥38 mmol/L; "moderate": BMI ≥23 kg/m2 and albumin <38 mmol/L; "severe": BMI<23 k/m2 and serum albumin <38 mmol/L. These categories were dichotomized to "minimal" versus elevated malnutrition risk. RESULTS: Despite greater BMI, elevated malnutrition risk was identified in 58.8% of individuals with versus 39.3% without diabetes. Adherence to International Society for Renal Nutrition and Metabolism nutrition guidelines was poor regardless of diabetes status. In multivariable logistic regression analysis, diabetes: OR 2.15; C-reactive protein (nmol/L): OR 1.02; delivered dialysis dose (Kt/V): OR 6.07; and haemoglobin (g/L): OR 0.79, predicted elevated malnutrition risk, even after controlling for age, sex and years on haemodialysis. DISCUSSION: Individuals on haemodialysis who have diabetes have elevated malnutrition risk compared to those without diabetes despite greater BMI.

Long term metabolic and renal outcomes of kidney donors compared to controls with excellent kidney function.

BACKGROUND: Only few studies of living kidney donors have included controls that were similarly healthy, including excellent kidney function. METHODS: In this study, we aimed to estimate long term metabolic and renal outcome in a cohort of 211 living donors compared to two control groups: paired-matched controls, and another control group of 2534 healthy individuals with excellent kidney function. RESULTS: Donors presented with higher estimated Glomerular Filtration Rate (eGFR): (97.6 ± 15.2 vs 96.1 ± 12.2 vs 94.5 ± 12.4 ml/min/1.73m2) and lower urine albumin to creatinine ratio (UACR) (4.3 ± 5.9 vs 5.9 ± 6.1 vs 6.1 ± 6.9 mg/g) for donors, matched controls and healthy controls, respectively (p <  0.001). In a mean follow up period of 5.5 for donors, donors presented with positive eGFR slopes during the first 3 years post donation, followed by negative slopes, compared to constantly negative slopes presented in the control group (p <  0.05). The variables related to the slope were being a donor, baseline eGFR, Body Mass Index (BMI) and age but not eGFR on the last day of follow-up or increased delta UACR. There was a significant increase in UACR in donors, as well as a higher rate of albuminuria, associated with a longer time since donation, higher pre-donation UACR and higher pre-donation BMI. Healthy controls had a lower BMI at baseline and gained less weight during the follow up period. Donors and controls had similar incidence of new onset diabetes mellitus and hypertension, as well as similar delta systolic and diastolic blood pressure. Donors were more likely to develop new onset metabolic syndrome, even after adjustment for age, gender and BMI. The higher incidence of metabolic syndrome resulted mainly from increased triglycerides and impaired fasting glucose criteria. However, prevalence of major cardiovascular events was not higher in this group. CONCLUSIONS: Donors are at increased risk to develop features of the metabolic syndrome in addition to the expected mild reduction of GFR and increased urine albumin excretion. Future studies are needed to explore whether addressing those issues will impact post donation morbidity and mortality.

Ultrapure Filter does not Confer Short-Term Benefits over Two Reverse Osmosis Systems in Chronic Hemodialysis Patients.

BACKGROUND: Dialysate purity contributes to the inflammatory response that afflicts hemodialysis patients. OBJECTIVES: To compare the clinical and laboratory effects of using ultrapure water produced by a water treatment system including two reverse osmosis (RO) units in series, with a system that also includes an ultrapure filter (UPF). METHODS: We performed a retrospective study in 193 hemodialysis patients during two periods: period A (no UPF, 6 months) and period B (same patients, with addition of UPF, 18 months), and a historical cohort of patients treated in the same dialysis unit 2 years earlier, which served as a control group. RESULTS: Mean C-reactive protein, serum albumin and systolic blood pressure worsened in period B compared to period A and in the controls. CONCLUSIONS: A double RO system to produce ultrapure water is not inferior to the use of ultrapure filters.

Bile acid receptors and the kidney.

PURPOSE OF REVIEW: Bile acids act as activating signals of endogenous renal receptors: the nuclear receptor farnesoid X receptor (FXR) and the membrane-bound G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5). In recent years, bile acids have emerged as important for renal pathophysiology by activating FXR and TGR5 and transcription factors relevant for lipid, cholesterol and carbohydrate metabolism, as well as genes involved in inflammation and renal fibrosis. RECENT FINDINGS: Activation of bile acid receptors has a promising therapeutic potential in prevention of diabetic nephropathy and obesity-induced renal damage, as well as in nephrosclerosis. During the past decade, progress has been made in understanding the biology and mechanisms of bile acid receptors in the kidney and in the development of specific bile acid receptor agonists. SUMMARY: In this review, we discuss current knowledge on the roles of FXR and TGR5 in the physiology of the kidney and the latest advances made in development and characterization of bile acid analogues that activate bile acid receptors for treatment of renal disease.

Mineralocorticoid receptor blockade improves arginine transport and nitric oxide generation through modulation of cationic amino acid transporter-1 in endothelial cells.

Blockade of the mineralocorticoid receptor (MCR) has been shown to improve endothelial function far beyond blood pressure control. In the current studies we have looked at the effect of MCR antagonists on cationic amino acid transporter-1 (CAT-1), a major modulator of endothelial nitric oxide (NO) generation. Using radio-labeled arginine, {[3H] l-arginine} uptake was determined in human umbilical vein endothelial cells (HUVEC) following incubation with either spironolactone or eplerenone with or without silencing of MCR. Western blotting for CAT-1, PKCα and their phosphorylated forms were performed. NO generation was measured by using Griess reaction assay. Both Spironolactone and eplerenone significantly increased endothelial arginine transport, an effect which was further augmented by co-incubation with aldosterone, and blunted by either silencing of MCR or co-administration of amiloride. Following MCR blockade, we identified two bands for CAT-1. The addition of tunicamycin (an inhibitor of protein glycosylation) or MCR silencing resulted in disappearance of the extra band and prevented the increase in arginine transport. Only spironolactone decreased CAT-1 phosphorylation through inhibition of PKCα (CAT-1 inhibitor). Subsequently, incubation with either MCR antagonists significantly augmented NO2/NO3 levels (stable NO metabolites) and this was attenuated by silencing of MCR or tunicamycin. GO 6076 (PKCα inhibitor) intensified the increase of NO metabolites only in eplerenone treated cells. In conclusion spironolactone and eplerenone augment arginine transport and NO generation through modulation of CAT-1 in endothelial cells. Both MCR antagonists activate CAT-1 by inducing its glycosylation while only spironolactone inhibits PKCα.

Cancer Risk Among Children Undergoing Renal Replacement Therapy: Results From the Israel National Renal Replacement Therapy Registry, 1990-2012.

BACKGROUND: Patients with end-stage renal disease who undergo chronic renal replacement therapy (RRT) have a higher incidence of cancer. A limited number of studies addressed the risk for cancer in children exposed to RRT. The purpose of the present study was to examine whether children undergoing RRT in Israel are at increased risk for all-site and specific cancers. SUBJECTS AND METHODS: The study population comprised 674 children 0 to 19 years of age who were registered between January 1990 and December 2012 in the Israel National Renal Replacement Therapy Registry. The Registry database was linked with the Israel National Cancer Registry to trace cancer incidence. Variables associated with malignancy were estimated by univariate analysis. Standardized incidence ratios for cancer were calculated using the general Israel population 0 to 15 years of age, for the corresponding years 1990-2012, as a reference. RESULTS: Seventeen children developed cancer during the follow-up period. Younger age at RRT initiation was the only variable associated with malignancy in the univariate analysis (hazard ratio, 0.91; 95% confidence interval, 0.84-0.99; P=0.03). Cancer incidence was 6.7-fold higher among children undergoing RRT than the general population. CONCLUSIONS: Children treated by chronic RRT have a higher incidence of cancer than their peers, and therefore should be followed closely.

Vascular Endothelial Growth Factor Augments Arginine Transport and Nitric Oxide Generation via a KDR Receptor Signaling Pathway.

BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF) is an endothelium-specific peptide that stimulates angiogenesis via two receptor tyrosine kinases, Flt-1 and KDR. Endothelial nitric oxide synthase (eNOS) plays a major role in VEGF signaling. Delivery of arginine to membrane bound eNOS by the cationic amino acid transporter-1 (CAT-1) has been shown to modulate eNOS activity. The current studies were designed to test the hypothesis that VEGF enhances eNOS activity via modulation of arginine transport by CAT-1. METHODS: Using radio-labeled arginine, {[3H] L-arginine} uptake was determined in human umbilical vein endothelial cells (HUVEC) following incubation with VEGF with and without silencing the VEGF receptors Flt-1 or KDR. Subsequently, western blotting for CAT-1, PKCα, ERK 1/2, JNK, and their phosphorylated forms were performed. NO generation was measured by the Griess reaction. RESULTS: VEGF (50 and 100 ng/ml) significantly augmented endothelial arginine transport in a time dependent manner, an effect which was prevented by Sunitinib (2 µM), a multi targeted receptor tyrosine kinase inhibitor. The increase in arginine transport velocities by VEGF was not affected by silencing Flt-1 while silencing KDR abrogated VEGF effect. Furthermore, incubating cells with 50 and 100 ng of VEGF for 30 minutes significantly augmented CAT-1 abundance. The expression of PKC-α, JNK, and ERK1/2 and their phosphorylated forms were unchanged following incubation of HUVEC with VEGF. The concentration of NO2/NO3 following incubation with VEGF was significantly higher than from untreated cells. This increase was significantly attenuated by silencing KDR. CONCLUSIONS: VEGF increases arginine transport via modulation of CAT-1 in endothelial cells. This effect is exclusively dependent on KDR rather than Flt-1.

Differences in quality of life between Jewish and Arab patients on hemodialysis.

PURPOSE: Higher health-related quality of life (HRQOL) in dialysis patients has been associated with fewer hospitalizations and lower mortality. Since Arab patients on dialysis have better survival rates than Jewish patients, we hypothesized that they would have higher HRQOL. We also studied the impact of several risk factors on HRQOL in each population. METHODS: Based on a national dialysis registry, patients from 64 hemodialysis units were recruited to participate. Patients who consented were interviewed face-to-face, using the Kidney Disease Quality of Life Short Form (KDQOL-SF36) questionnaire. RESULTS: Five hundred and fifty-eight (50.6%) Jewish and 544 (49.4%) Arab patients participated in the study. For Arab patients mean crude scores for the "mental component summary" and KDQOL scores were significantly lower than for Jewish patients [31.6 (95% Cl 30.0-33.3) vs. 38.0 (95% Cl 36.1-39.9), p < 0.0001 and 55.6 (95% Cl 54.5-56.7) vs. 59.8 (95% Cl 58.6-60.9), p < 0.0001, respectively]. Much lower scores were observed for Arabs in the "emotional role" and "work status" subscales. The two populations had similar general health assessments and albumin level. For both, HRQOL was positively associated with higher educational level, higher albumin level, and dialysis connection by fistula or graft; and negatively associated with low income and diabetes. HRQOL was negatively associated with previous cerebrovascular accident among Arabs and with female gender among Jews. CONCLUSIONS: Differences between Jews and Arabs in subscales related to psychosocial factors suggest that cultural differences in the perceptions of sickness and health may be relevant here. Future studies should explore such possibility and focus on the large gap in the "work status" subscale.

Exercise-induced albuminuria is related to metabolic syndrome.

Microalbuminuria (MA) is a known marker for endothelial dysfunction and future cardiovascular events. Exercise-induced albuminuria (EiA) may precede the appearance of MA. Associations between EiA and metabolic syndrome (MS) have not been assessed so far. Our aim was to investigate this association in a large sample of apparently healthy individuals with no baseline albuminuria. This was a cross-sectional study of 2,027 adults with no overt cardiovascular diseases who took part in a health survey program and had no baseline MA. Diagnosis of MS was based on harmonized criteria. All patients underwent an exercise test (Bruce protocol), and urinary albumin was measured before and after the examination. Urinary albumin-to-creatinine ratio (ACR) values before and after exercise were 0.40 (0.21-0.89) and 1.06 (0.43-2.69) mg/g for median (interquartile range) respectively. A total of 394 (20%) subjects had EiA; ACR rose from normal rest values (0.79 mg/g) to 52.28 mg/g after exercise (P < 0.001); this effect was not shown for the rest of the study population. EiA was related to higher prevalence of MS (13.8% vs. 27.1%, P < 0.001), higher metabolic equivalents (P < 0.001), higher baseline blood pressure (P < 0.001), and higher levels of fasting plasma glucose, triglycerides, and body mass index (P < 0.001). Multivariate binary logistic regression model showed that subjects with MS were 98% more likely to have EiA (95% confidence interval: 1.13-3.46, P = 0.016). In conclusion, EiA in the absence of baseline MA is independently related to MS.

Dimethyl sulfoxide attenuates nitric oxide generation via modulation of cationic amino acid transporter-1 in human umbilical vein endothelial cells.

Dimethyl sulfoxide (DMSO) is a solvent that is commonly used in medicine. Conflicting data exist as to its effects on endothelial function. Endothelial cell dysfunction (ECD) is characterized by decreased endothelial nitric oxide synthase (eNOS) activity. Cationic amino acid transporter-1 (CAT-1), the specific arginine transporter for eNOS, has been shown to modulate eNOS activity. We hypothesize that DMSO inhibits eNOS activity through modulation of its selective arginine supplier CAT-1. We studied the effect of DMSO on arginine transport, NO2/NO3 generation as an index of NO production, as well as CAT-1 and Protein Kinase C alpha (PKC-α) (CAT-1 inhibitor) protein expression in human umbilical vein endothelial cell cultures (HUVECs). DMSO 2.5% and 3.5% (v/v) significantly attenuated arginine transport, a phenomenon which was prevented by co-incubation with l-arginine (1 mM). The aforementioned findings were accompanied by a decrease in NO2/NO3 generation. DMSO significantly increased the abundance of phosphorylated CAT-1 (the inactive form) and phosphorylated PKC-α protein, an effect that was attenuated by l-arginine. GO 6976 (PKC-α antagonist) prevented the decrease in arginine transport caused by DMSO. DMSO also induced profound transient morphological changes in HUVECs' structure but these were not related to its effect on arginine transport. In conclusion, DMSO inhibits NO generation by endothelial cells through modulation of CAT-1 activity.

Estradiol augments while progesterone inhibits arginine transport in human endothelial cells through modulation of cationic amino acid transporter-1.

Decreased generation of nitric oxide (NO) by endothelial NO synthase (eNOS) characterizes endothelial dysfunction (ECD). Delivery of arginine to eNOS by cationic amino acid transporter-1 (CAT-1) was shown to modulate eNOS activity. We found in female rats, but not in males, that CAT-1 activity is preserved with age and in chronic renal failure, two experimental models of ECD. In contrast, during pregnancy CAT-1 is inhibited. We hypothesize that female sex hormones regulate arginine transport. Arginine uptake in human umbilical vein endothelial cells (HUVEC) was determined following incubation with either 17ß-estradiol (E2) or progesterone. Exposure to E2 (50 and 100 nM) for 30 min resulted in a significant increase in arginine transport and reduction in phosphorylated CAT-1 (the inactive form) protein content. This was coupled with a decrease in phosphorylated MAPK/extracellular signal-regulated kinase (ERK) 1/2. Progesterone (1 and 100 pM for 30 min) attenuated arginine uptake and increased phosphorylated CAT-1, phosphorylated protein kinase Cα (PKCα), and phosphorylated ERK1/2 protein content. GO-6976 (PKCα inhibitor) prevented the progesterone-induced decrease in arginine transport. Coincubation with both progesterone and estrogen for 30 min resulted in attenuated arginine transport. While estradiol increases arginine transport and CAT-1 activity through modulation of constitutive signaling transduction pathways involving ERK, progesterone inhibits arginine transport and CAT-1 via both PKCα and ERK1/2 phosphorylation, an effect that predominates over estradiol.

TGFß1-dependent podocyte dysfunction.

PURPOSE OF REVIEW: The glomerular filtration barrier is a unique structure characterized by a specialized framework of podocytes. Transforming growth factor-ß1 (TGFß1) upregulation occurs in virtually all chronic kidney diseases and is associated with podocyte injury and proteinuria. This review is aimed at describing the latest advances made in the understanding of TGFß-induced podocyte injury. RECENT FINDINGS: During the past decade, progress has been made in understanding the biology and mechanisms of TGFß-induced podocyte injury. Most forms of glomerular diseases, including diabetic nephropathy, are associated with increased TGFß1 signaling and thus TGFß1 plays a central role in the pathogenesis of podocytopathy. The mechanism of podocyte injury is complex, involving a number of independent and overlapping cellular and molecular pathways. This review will examine these direct and indirect effects of TGFß1 on podocyte dysregulation as reflected in their growth, differentiation, and motility. SUMMARY: These new developments in understanding the podocyte response to injury are critical for establishing better therapeutic interventions that target specific pathways, which otherwise could lead to irreversible injury.

C-reactive protein and carotid and femoral intima media thickness: predicting inflammation.

BACKGROUND: C-reactive protein (CRP) is a recognized marker of systemic inflammation. Its association with carotid and femoral intima media thickness (surrogate measures of atherosclerosis) may explain excess cardiovascular disease risk in hemodialysis patients. OBJECTIVES: To estimate the association between CRP and both carotid and femoral IMT in hemodialysis (HD) patients; to predict CRP in these patients. METHODS: The present cross-sectional study is nested in the Sevelamer hydrochloride and ultrasound-measured femoral and carotid intima media thickness progression in end-stage renal disease (SUMMER) clinical trial. Carotid (common, internal, and bifurcation) and femoral arteries were visualized in B-mode ultrasonography. CRP was measured in serum. RESULTS: The study cohort included 144 HD patients (39.5% female, mean age 67.8 ± 11.5 years). All measures of both carotid and femoral IMT were significantly positively associated with CRP. Subjects with a history of smoking or coronary revascularization had significantly higher CRP levels, while subjects treated with sevelamer hydrochloride had significantly lower CRP. CRP was significantly positively associated with serum phosphorus, calcium, alkaline phosphatase, and PTH, and significantly inversely associated with HDL and albumin. CONCLUSIONS: CRP is significantly positively associated with both femoral and carotid IMT. Treatment with sevelamer hydrochloride is associated with lower CRP in HD patients.

Electrolyte Imbalance in Anti-LGI1 Encephalitis: It Is Not All in Your Head.

BACKGROUND AND OBJECTIVES: Antileucine-rich glioma-inactivated 1 (anti-LGI1) autoimmune encephalitis was first described in 2010 and is today the most common type of limbic encephalitis. During the course of the disease, 60%-88% of the patients develop hyponatremia. The etiology of the sodium disorder is unclear, often presumed to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Other electrolyte abnormalities have not been reported in association with anti-LGI1 antibody encephalitis. Due to the presence of hypomagnesemia and hypophosphatemia in our patients, we set out to try to find the expression of LGI1 protein in the kidney as an explanation for these abnormalities. METHODS: We reviewed the medical files of all patients diagnosed with anti-LGI1 antibody encephalitis, at the Department of Neurology in the Tel Aviv Medical Center between January 2011 and December 2020, exploring for electrolyte abnormalities. Using tissue staining, Western blot, mass spectrometry, and RNA expression techniques, we tried to demonstrate the expression of LGI1 protein in the human kidney. RESULTS: We identified 15 patients diagnosed with anti-LGI1 antibody encephalitis. Their average age was 65 years (44-80), and 9 were male individuals. Thirteen of the 15 patients (87%) developed varying degrees of hyponatremia. Laboratory studies demonstrated low serum osmolality, low serum blood urea nitrogen, and low uric acid, with a high urinary sodium and inappropriately high urine osmolality, supporting the presumable diagnosis of SIADH. One patient with hyponatremia that was tested, had high levels of copeptin, supporting the diagnosis of SIADH. In addition to hyponatremia, 7 patients (47%) exhibited other electrolyte abnormalities; 5 patients (33%) had overt hypophosphatemia, 4 patients (27%) had overt hypomagnesemia, and 2 other patients (13%) had borderline low magnesium levels. Western blot analysis of human kidney lysate, mass spectrometry, and qRT-PCR failed to demonstrate the expression of LGI1 protein in the kidney. DISCUSSION: Hyponatremia in patients with anti-LGI1 antibody encephalitis is due to SIADH as previously assumed. Other electrolyte abnormalities such as hypomagnesemia and hypophosphatemia occur in at least 40% of patients and may be another clue for the diagnosis of anti-LGI1 antibody encephalitis. Because we failed to demonstrate LGI1 expression in the kidney, the results of our study suggest that renal losses lead to these disturbances, most probably due to SIADH.

Renal Tubular CD24 Upregulation Aggravates Folic Acid Induced Acute Kidney Injury: A Possible Role for T Regulatory Cells Inhibition in Mice.

Acute kidney injury (AKI) is characterized by cell death and inflammation. CD24 is a protein induced during tissue damage and is not expressed in mature renal tissue. We explored the role of CD24 in the pathogenesis of folic acid-induced AKI (FA-AKI) in mice. A single Intraperitoneal (IP) injection of folic acid induced AKI in WT and CD24-/- mice. Renal function tests, histological analysis, immunohistochemistry, Western blot analysis, and ELISA were performed to assess the severity of renal damage and the intensity of the inflammatory response. FA-AKI induced CD24 in the distal tubular epithelial cells. Compared to WT mice, FA-AKI CD24-/- mice exhibited an attenuated reduction in renal function and histological injury, lower serum IL-10 and interferon γ, and decreased expression of renal TNFα. In contrast, renal and systemic IL-33 upregulation were augmented. CD24-/- FA-AKI animals exhibited increased splenic margination and renal infiltration of regulatory T cells (Tregs). At day 7, FA-AKI CD24-/- mice exhibited increased expression of tubular pro-apoptotic and decreased anti-apoptotic proteins compared to WT animals. Anti-CD24 antibody administration to FA-AKI mice attenuated the decrease in renal function as well as the histological injury. Renal biopsies from patients with ATN stained strongly for CD24 in the distal tubules. In conclusion, during AKI, upregulation of CD24 promotes renal inflammation through inhibition of Treg infiltration and diversion of cell death towards necrosis rather than apoptosis. Neutralization of CD24 may prove a target for future therapies in AKI.

Attenuated glomerular arginine transport prevents hyperfiltration and induces HIF-1α in the pregnant uremic rat.

Pregnancy worsens renal function in females with chronic renal failure (CRF) through an unknown mechanism. Reduced nitric oxide (NO) generation induces renal injury. Arginine transport by cationic amino acid transporter-1 (CAT-1), which governs endothelial NO generation, is reduced in both renal failure and pregnancy. We hypothesize that attenuated maternal glomerular arginine transport promotes renal damage in CRF pregnant rats. In uremic rats, pregnancy induced a significant decrease in glomerular arginine transport and cGMP generation (a measure of NO production) compared with CRF or pregnancy alone and these effects were prevented by l-arginine. While CAT-1 abundance was unchanged in all experimental groups, protein kinase C (PKC)-α, phosphorylated PKC-α (CAT-1 inhibitor), and phosphorylated CAT-1 were significantly augmented in CRF, pregnant, and pregnant CRF animals; phenomena that were prevented by coadministrating l-arginine. α-Tocopherol (PKC inhibitor) significantly increased arginine transport in both pregnant and CRF pregnant rats, effects that were attenuated by ex vivo incubation of glomeruli with PMA (a PKC stimulant). Renal histology revealed no differences between all experimental groups. Inulin and p-aminohippurate clearances failed to augment and renal cortical expression of hypoxia inducible factor-1α (HIF-1α) significantly increased in CRF pregnant rat, findings that were prevented by arginine. These studies suggest that in CRF rats, pregnancy induces a profound decrease in glomerular arginine transport, through posttranslational regulation of CAT-1 by PKC-α, resulting in attenuated NO generation. These events provoke renal damage manifested by upregulation of renal HIF-1α and loss of the ability to increase glomerular filtration rate during gestation.

ß-D-xylosides stimulate GAG synthesis in chondrocyte cultures due to elevation of the extracellular GAG domains, accompanied by the depletion of the intra-pericellular GAG pools, with alterations in the GAG profiles.

The familial disease of hereditary multiple exostoses is characterized by abnormal skeletal deformities requiring extensive surgical procedures. In hereditary multiple exostoses patients there is a shortage in the pericellular glycosaminoglycan (GAG) of heparan sulfate (HS), related to defective activity of HS glycosyltransferases, mainly in the pericellular regions of chondrocytes. This study searched for a novel approach employing xylosides with different aglycone groups priming a variety of GAG chains, in attempting to alter the GAG compositional profile. Cell cultures of patients with osteochondroma responded to p-nitrophenyl ß-D-xyloside by a significant increase in total GAG synthesis, expressed mainly in the extracellular domains, limited to chondroitin sulfate). The different ß-D-xylosides, in addition to increasing the synthesis of extracellular GAGs, led to a significant depletion of the intracellular GAG domains. In mouse chondrocyte cultures, ß-D-xylosides with different aglycones created a unique distribution of the GAG pools. Of special interest was the finding that the naphthalene methanol ß-D-xyloside showed the highest absolute levels of HS-GAGs in both extracellular and intra-pericellular moieties compared with other ß-D-xylosides and with controls without xyloside. In summary, ß-D-xylosides can be utilized in chondrocyte cultures to modify the distribution of GAGs between the extracellular and intracellular compartments. In addition, xylosides may alter the profile of specific GAG chains in each moiety.

Care of undocumented-uninsured immigrants in a large urban dialysis unit.

BACKGROUND: Medical, ethical and financial dilemmas may arise in treating undocumented-uninsured patients with end-stage renal disease (ESRD). Hereby we describe the 10-year experience of treating undocumented-uninsured ESRD patients in a large public dialysis-unit. METHODS: We evaluated the medical files of all the chronic dialysis patients treated at the Tel-Aviv Medical Center between the years 2000-2010. Data for all immigrant patients without documentation and medical insurance were obtained. Clinical data were compared with an age-matched cohort of 77 insured dialysis patients. RESULTS: Fifteen undocumented-uninsured patients were treated with chronic scheduled dialysis therapy for a mean length of 2.3 years and a total of 4953 hemodialysis sessions, despite lack of reimbursement. All undocumented-uninsured patients presented initially with symptoms attributed to uremia and with stage 5 chronic kidney disease (CKD). In comparison, in the age-matched cohort, only 6 patients (8%) were initially evaluated by a nephrologist at stage 5 CKD. Levels of hemoglobin (8.5 ± 1.7 versus 10.8 ± 1.6 g/dL; p < 0.0001) and albumin (33.8 ± 4.8 versus 37.7 ± 3.9 g/L; p < 0.001) were lower in the undocumented-uninsured dialysis patients compared with the age-matched insured patients at initiation of hemodialysis therapy. These significant changes were persistent throughout the treatment period. Hemodialysis was performed in all the undocumented-uninsured patients via tunneled cuffed catheters (TCC) without higher rates of TCC-associated infections. The rate of skipped hemodialysis sessions was similar in the undocumented-uninsured and age-matched insured cohorts. CONCLUSIONS: Undocumented-uninsured dialysis patients presented initially in the advanced stages of CKD with lower levels of hemoglobin and worse nutritional status in comparison with age-matched insured patients. The type of vascular access for hemodialysis was less than optimal with regards to current guidelines. There is a need for the national and international nephrology communities to establish a policy concerning the treatment of undocumented-uninsured patients with CKD.

Energy Harvesting by Mesoporous Reduced Graphene Oxide Enhanced the Mediator-Free Glucose-Powered Enzymatic Biofuel Cell for Biomedical Applications.

Harnessing electrochemical energy in an engineered electrical circuit from biochemical substrates in the human body using biofuel cells is gaining increasing research attention in the current decade due to the wide range of biomedical possibilities it creates for electronic devices. In this report, we describe and characterize the construction of just such an enzymatic biofuel cell (EBFC). It is simple, mediator-free, and glucose-powered, employing only biocompatible materials. A novel feature is the two-dimensional mesoporous thermally reduced graphene oxide (rGO) host electrode. An additionally novelty is that we explored the potential of using biocompatible, low-cost filter paper (FP) instead of carbon paper, a conductive polymer, or gold as support for the host electrode. Using glucose (C6H12O6) and molecular oxygen (O2) as the power-generating fuel, the cell consists of a pair of bioelectrodes incorporating immobilized enzymes, the bioanode modified by rGO-glucose oxidase (GOx/rGO), and the biocathode modified by rGO-laccase (Lac/rGO). Scanning electron microscopy/energy-dispersive X-ray spectroscopy (SEM/EDX), transmission electron microscopy, and Raman spectroscopy techniques have been employed to investigate the surface morphology, defects, and chemical structure of rGO, GOx/rGO, and Lac/rGO. N2 sorption, SEM/EDX, and powder X-ray diffraction revealed a high Brunauer-Emmett-Teller surface area (179 m2 g-1) mesoporous rGO structure with the high C/O ratio of 80:1 as well. Results from the Fourier transform infrared spectroscopy, UV-visible spectroscopy, and electrochemical impedance spectroscopy studies indicated that GOx remained in its native biochemical functional form upon being embedded onto the rGO matrix. Cyclic voltammetry studies showed that the presence of mesoporous rGO greatly enhanced the direct electrochemistry and electrocatalytic properties of the GOx/rGO and Lac/rGO nanocomposites. The electron transfer rate constant between GOx and rGO was estimated to be 2.14 s-1. The fabricated EBFC (GOx/rGO/FP-Lac/rGO/FP) using a single GOx/rGO/FP bioanode and a single Lac/rGO/FP biocathode provides a maximum power density (Pmax) of 4.0 nW cm-2 with an open-circuit voltage (VOC) of 0.04 V and remains stable for more than 15 days with a power output of ∼9.0 nW cm-2 at a pH of 7.4 under ambient conditions.