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Proteinuria
Kinds of Proteinuria Selected AbstractsENDOTHELIAL FUNCTION OF CONDUIT AND RESISTANCE ARTERIES IN NEPHROTIC RANGE PROTEINURIANEPHROLOGY, Issue 3 2000G. Dogra OBJECTIVE: To test the hypothesis that endothelial dysfunction occurs in nephrotic range proteinuria primarily as a consequence of dyslipidaemia. METHODS: Brachial artery and forearm microcirculatory endothelial function was compared among patients with nephrotic range proteinuria (NRP, n = 14 ), primary hyperlipidaemia (HL, n = 15) and normal controls (NC, n = 16). Endothelial function was studied by measuring post-ischaemic flow-mediated dilatation (FMD) of the brachial artery using high resolution ultrasonography. Endothelium-independent, glyceryl trinitrate (GTN) mediated brachial artery vasodilatation was also measured. Basal and post-ischaemic blood flow of the forearm microcirculation was measured using venous-occlusion strain gauge plethysmography. RESULTS: Serum creatinine was similar among groups. The proteinuric group had a mean albumin of 27.6g/L(1.8) and 24-hour urinary protein excretion of 6.3g(1.3). Plasma lipids and lipoproteins were not statistically different between the NRP and HL groups. Brachial artery FMD was significantly lower in the NRP and HL groups compared with the controls (NRP 4.7%(1.3)*, HL 4.9%(0.7)* and NC 8.3%(0.6), *p = 0.012 vs. NC); GTN mediated dilatation and basal and post-ischaemic forearm blood flow were not statistically different among the three groups. CONCLUSION: Patients with nephrotic range proteinuria have endothelial dysfunction of conduit arteries in the peripheral circulation, similar to that observed in patients with primary hyperlipidaemia. This suggests dyslipoproteinaemia is the principal cause of endothelial dysfunction of conduit arteries in nephrotic range proteinuria. Confirmation of this should be sought with an intervention trial of lipid-regulating therapy. [source] LIPID-LOWERING IMPROVES ENDOTHELIAL FUNCTION IN NEPHROTIC RANGE PROTEINURIANEPHROLOGY, Issue 3 2000G. Dogra OBJECTIVE: To determine whether lipid-modifying therapy with atorvastatin improves impaired endothelial function in patients with nephrotic range proteinuria (NRP). METHODS: A sequential, open-label study of the effects of atorvastatin on dyslipidaemia and endothelial dysfunction in 9 patients with NRP. Endothelial function was assessed at baseline, after 12 weeks of atorvastatin treatment and after an 8 week wash-out period. Brachial artery endothelial function was studied by measuring post-ischaemic flow-mediated dilatation (FMD) using ultrasonography. Endothelium- independent, glyceryl trinitrate (GTN) mediated vasodilatation was also measured. RESULTS: At baseline, median serum albumin was 31g/L (range 20-40) and 24 hour protein excretion was 4.7g (1.0-16.23). There was no significant change in serum creatinine and 24 hour protein excretion during the study. Total cholesterol (TC) and triglycerides (TG) were significantly lower following treatment with atorvastatin 20mg (20-40): TC 8.1mmol/L (5.9-14.9) vs. 5.2 (4.0-8.6), TG 2.9mmol/L (1.3-15.0) vs. 1.6 (1.0-3.5), both p < 0.05. Brachial artery FMD improved significantly following atorvastatin treatment: 2.1% (-1.2- 5.2%) to 4.7% (0.8-16.3%), p < 0.05. At the end of the 8 week wash-out, FMD had significantly deteriorated to 3.2% (-2.8-8.2), p < 0.05 vs. week 12 FMD, and was similar to pre-treatment values. GTN mediated dilatation was unchanged through the study. CONCLUSION: Atorvastatin significantly reduced the hyperlipidaemia of NRP. This was associated with improved conduit artery endothelial function after 12 weeks of treatment. This is consistent with the hypothesis that dyslipoproteinaemia is the primary cause of endothelial dysfunction in NRP. [source] Collagen type VIII expression in human diabetic nephropathyEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 10 2007J. Gerth Abstract Background, Collagen type VIII is a non-fibrillar short-chain collagen that may modulate migration, proliferation and adherence of various cells. Only very sparse information exists on collagen type VIII expression in human diabetic nephropathy. Material and methods, We retrospectively studied mRNA expression for the two collagen type VIII chains (COL8A1 and COL8A2) in 20 biopsies with histologically confirmed diabetic nephropathy by real-time PCR, and compared glomerular and tubular expression with normal kidney [pre-transplant biopsies (n = 10)]. Expression of collagen type VIII was also studied in biopsies from patients with benign nephrosclerosis (BNS; n = 16) and focal-segmental glomerulosclerosis (FSGS; n = 9). Results, A strong specific induction of COL8A1 mRNA was found in diabetic nephropathy in both glomerular and tubular compartments. There was also a robust induction of COL8A2 in diabetic nephropathy, but overall expression was lower than that of COL8A1 transcripts. No significant increase in COL8A1 and COL8A2 mRNAs expression was found in biopsies from patients with BNS and FSGS compared with normal kidneys. The cross-reactivity of the used anti-,1(VIII) antibody with human tissue was confirmed by Western blots. Immunohistological analysis revealed only little staining for collagen type VIII in the normal kidney, localized to vessels. There was an up-regulation of collagen type VIII protein expression as shown by immunohistochemistry in the diabetic nephropathy biopsies mainly localized to mesangial cells, tubules and the interstitium. Proteinuria and serum creatinine did not correlate with glomerular or tubular COL8A1 and COL8A2 mRNA expression in diabetic patients. Conclusion, Our study systemically investigates collagen type VIII expression in human biopsies. Induction of collagen type VIII was specific for diabetic nephropathy and did not occur in the other renal diseases studied. More specific factors of the diabetic environment are likely involved in the stimulated expression because there was no correlation of collagen type VIII mRNA expression with proteinuria. Since collagen type VIII may influence proliferation and migration of cells, it is possible that an increase in renal expression of collagen type VIII initiates other pathophysiological processes (e.g. proliferation of renal fibroblasts) involved in diabetic nephropathy. [source] Microalbuminuria predicts overt proteinuria among patients with HIV infectionHIV MEDICINE, Issue 7 2010LA Szczech Background This study examines the association between microalbuminuria and the development of proteinuria among HIV-infected persons. Methods A total of 948 subjects provided urine samples for albumin, protein and creatinine measurements semiannually. Microalbuminuria was defined as an albumin-to-creatinine ratio of >30 mg/g. Proteinuria was defined as a protein-to-creatinine ratio of ,0.350 mg/mg. The progression from microalbuminuria to proteinuria was described. Results At baseline, 69.4% of the subjects had no detectable proteinuria, 20.2% had microalbuminuria, and 10.4% had proteinuria. Subjects with microalbuminuria and proteinuria were more likely to be black (P=0.02), have lower CD4 cell counts (P=0.02 comparing subjects without abnormal urine protein excretion to subjects with microalbuminuria; P=0.0001 comparing subjects with microalbuminuria to subjects with proteinuria), and have a higher HIV RNA level (P=0.08 and 0.04, respectively). Among 658 subjects with normal urine protein, 82.7% continued to have no abnormality, 14.3% developed microalbuminuria, and 3.0% developed proteinuria. Subjects without baseline proteinuria (i.e. either normal protein excretion or microalbuminuria) who developed proteinuria were more likely to have microalbuminuria (P=0.001), a lower CD4 cell count (P=0.06), and a higher plasma HIV RNA (P=0.03) than those who did not progress to proteinuria. In multivariate analysis, only microalbuminuria remained associated with the development of proteinuria (odds ratio 2.9; 95% confidence interval 1.5, 5.5; P=0.001). Conclusion Microalbuminuria predicts the development of proteinuria among HIV-infected persons. Because proteinuria has been linked to poorer outcomes, strategies to affect microalbuminuria should be tested. [source] Microalbuminuria: Definition, Detection, and Clinical SignificanceJOURNAL OF CLINICAL HYPERTENSION, Issue 2004Robert D. Toto MD Proteinuria is a sign of abnormal excretion of protein by the kidney but is a nonspecific term including any or all proteins excreted. In contrast, albuminuria specifically refers to an abnormal excretion rate of albumin. Microalbuminuria refers to an abnormally increased excretion rate of albumin in the urine in the range of 30,299 mg/g creatinine. It is a marker of endothelial dysfunction and increased risk for cardiovascular morbidity and mortality especially, but not exclusively, in high-risk populations such as diabetics and hypertensives. Testing for microalbuminuria is now made easy by in-office dipstick tests (semi-quantitative) and widely available laboratory testing (quantitative). Physicians should screen all diabetics for albuminuria and strongly consider screening hypertensives to identify those at higher risk for cardiovascular disease. Appropriate intervention, including use of drugs that block the renin-angiotensin-aldosterone system, may be appropriate in such cases as suggested by the American Diabetes Association and the Seventh Report of Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. [source] "+1" Proteinuria in the Nondiabetic HypertensiveJOURNAL OF CLINICAL HYPERTENSION, Issue 4 2002Raymond R. Townsend MD No abstract is available for this article. [source] Survival and the Development of Azotemia after Treatment of Hyperthyroid CatsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 4 2010T.L. Williams Background: Hyperthyroidism complicates the diagnosis of chronic kidney disease (CKD) as it increases glomerular filtration rate. No practical and reliable means for identifying those cats that will develop azotemia after treatment for hyperthyroidism has been identified. Hyperthyroidism is associated with proteinuria. Proteinuria has been correlated with decreased survival of cats with CKD and with progression of CKD. Hypothesis: Proteinuria and other clinical parameters measured at diagnosis of hyperthyroidism will be associated with the development of azotemia and survival time. Animals: Three hundred client owned hyperthyroid cats treated in first opinion practice. Methods: Retrospective, cohort study relating clinical parameters in hyperthyroid cats at diagnosis to the development of azotemia within 240 days of diagnosis and survival time (all cause mortality). Multivariable logistic regression analysis was used to identify factors that were predictive of the development of azotemia. Multivariable Cox regression analysis was used to identify factors associated with survival. Results: Three hundred cats were eligible for survival analysis and 216 cats for analysis of factors associated with the development of azotemia. The median survival time was 417 days, and 15.3% (41/268) cats developed azotemia within 240 days of diagnosis of hyperthyroidism. Plasma concentrations of urea and creatinine were positively correlated with the development of azotemia. Plasma globulin concentration was negatively correlated with the development of azotemia. Age, urine protein : creatinine ratio, and the presence of hypertension were significantly correlated with decreased survival time. Urine specific gravity and PCV were significantly correlated with increased survival time. Conclusions and Clinical Importance: The proteinuria associated with hyperthyroidism is not a mediator of progression of CKD; however, it does correlate with all cause mortality. [source] Day-to-Day Variation of the Urine Protein: Creatinine Ratio in Female Dogs with Stable Glomerular Proteinuria Caused by X-Linked Hereditary NephropathyJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 3 2007Mary B. Nabity Background:Interpretation of serial urine protein: creatinine (UPC) values is confounded by a lack of data regarding random biologic variation of UPC values in dogs with stable glomerular proteinuria. Hypothesis:That there is minimal day-to-day variability in the UPC of dogs with unchanging proteinuria and the number of measurements needed to reliably estimate UPC varies with the magnitude of proteinuria. Animals:Forty-eight heterozygous (carrier) female dogs with X-linked hereditary nephropathy (XLHN) causing stable proteinuria. Methods:Urine samples were obtained daily by cystocentesis for 3 consecutive days on 183 occasions (549 samples). The UPC was measured for each sample with a single dry-film chemistry auto-analyzer. Data were analyzed retrospectively by a power of the mean model because the variance of UPC values within the 3-day evaluation periods increased as the magnitude of proteinuria increased. Results:To demonstrate a significant difference (P < .05) between serial values in these proteinuric dogs, the UPC must change by at least 35% at high UPC values (near 12) and 80% at low UPC values (near 0.5). One measurement is adequate to reliably estimate the UPC when UPC < 4, but 2,5 determinations are necessary at higher UPC values. Conclusions and Clinical Importance: These guidelines for interpretation of serial UPC values in female dogs with XLHN may also be helpful for interpretation of UPC values in dogs with other glomerulopathies. [source] Editorial: Proteinuria in Chronic Kidney Disease in Cats,Prognostic Marker or Therapeutic Target?JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 5 2006Jonathan Elliott No abstract is available for this article. [source] Minimal renal dysfunction in inflammatory bowel disease is related to disease activity but not to 5-ASA useALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2001K. R. Herrlinger Background: Conflicting data exist about proteinuria in inflammatory bowel diseases. It is still unclear whether the occurrence of proteinuria in inflammatory bowel disease patients is an extra-intestinal manifestation of disease or the result of adverse effects to medication, especially to aminosalicylates (ASA). Methods: A total of 95 patients (51 with Crohn's disease and 44 with ulcerative colitis) were enrolled in the study. Disease activity was assessed by Crohn's Disease Activity Index (CDAI) or the Truelove index, respectively. Urine was collected over 24 h and protein excretion of specific marker proteins for tubular (,1-microglobulin-,1-MG) and glomerular (albumin-Alb, Immunoglobulin G-IgG) dysfunction was measured using a highly sensitive immunoluminometric assay. Results: Out of 51 Crohn's disease patients, 20 showed elevated urinary ,1-MG. The amount of ,1-MGuria was strongly correlated to the CDAI (r=0.6, P < 0.001). Only four Crohn's disease patients showed slightly elevated values for glomerular proteins in urine. Similar results were obtained for ulcerative colitis: whereas only two ulcerative colitis patients showed albuminuria, tubular proteinuria was detected in 28 out of 44 ulcerative colitis patients. Proteinuria was strongly dependent on disease activity (P < 0.01) but was not related to ASA treatment. Conclusions: Proteinuria of tubular marker proteins occurs in the majority of inflammatory bowel disease patients and is related to disease activity rather than to ASA treatment. Tubular proteinuria seems to reflect a renal extra-intestinal manifestation of inflammatory bowel disease and may serve as a new relevant marker of disease activity. [source] Predictors for progression in immunoglobulin A nephropathy with significant proteinuriaNEPHROLOGY, Issue 2 2010HYEON SEOK HWANG ABSTRACT: Aim: Proteinuria is a primary factor requiring treatment in immunoglobulin (Ig)A nephropathy. The purpose of this study was to assess the relevance of treatment response and relapse of proteinuria with renal function decline. Methods: One hundred and twenty-five biopsy-proven primary IgA nephropathy patients who had more than 1.0 g/day proteinuria at the first assessment were studied. All patients underwent anti-proteinuric treatment, and the association of the rate of renal function decline with treatment responsiveness, clinical and laboratory data was investigated. Results: The treatment response of the patients was: 30.4% complete response (<0.3 g/day proteinuria), 32.8% partial response (0.3,1.0 g/day), 23.2% minimal response (decrement but not reduced to <1 g/day) and 13.6% no response (no decrement of proteinuria). The slope of renal function decline (,1.06 vs,1.24 mL/min per 1.73 m2/year, P = 0.580) was comparable between complete and partial response groups, but they were slower than those of minimal or non-response groups (P < 0.001). In multivariate analysis including other parameters, mean arterial pressure (MAP; , = ,0.240, P = 0.004) during follow up, minimal (, = ,0.393, P < 0.001) and non-response (, = ,0.403, P < 0.001) were significant predictors. In further investigation of complete and partial response groups, MAP (, = ,0.332, P = 0.001) and relapse of proteinuria (, = ,0.329, P = 0.001) were independently associated with slope of renal decline. Conclusion: Achievement of less than 1.0 g/day proteinuria and MAP were important for limiting the loss of renal function, and relapse of proteinuria should be closely monitored in proteinuric IgA nephropathy. [source] Urinary proteins from patients with nephrotic syndrome alters the signalling proteins regulating epithelial,mesenchymal transitionNEPHROLOGY, Issue 1 2010QIONG WEN ABSTRACT: Aim: Proteinuria plays an important role in the progression of tubulointerstitial fibrosis, but the mechanism for the differential renal damage induced by proteinuria is unknown. This study examined the effects of urinary proteins from patients with idiopathic minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) on several epithelial,mesenchymal transition (EMT)-related marker proteins in cultured proximal tubular HK-2 cells. Methods: Urinary proteins from MCD and FSGS patients were extracted by ultrafiltration and incubated with HK-2 cells; the expression of the cytokeratin-18, ,-smooth muscle actin (,-SMA) and vimentin were assessed. p38 and extracellular regulated kinase (ERK) activation were measured by western blotting, and SB203580 (a p38 inhibitor) and PD98059 (an ERK1/2 inhibitor) were used to inhibit their activation. Results: It was observed that urinary proteins from FSGS patients more significantly induced the expression of ,-SMA and vimentin and reduced cytokeratin-18 expression than those from MCD patients in HK-2 cells. Both ERK1/2 and p38 were activated by urinary proteins from MCD or FSGS patients. Pretreatment of the cells with SB203580 or PD98059 abolished the effect of urinary proteins from FSGS patients on the expression of ,-SMA, vimentin and cytokeratin-18, while only SB203580 elicited this effect when cells were treated with urinary proteins from MCD patients. Conclusion: The urinary proteins from MCD and FSGS patients induced significant changes of EMT-related proteins through activation of distinct mitogen-activated protein kinase-related signalling pathways. Quality of proteinuria may play an important role in determining the severity and progression of tubular injury associated with different kidney diseases. [source] Sources of urinary proteins and their analysis by urinary proteomics for the detection of biomarkers of diseasePROTEOMICS - CLINICAL APPLICATIONS, Issue 9 2009Bruce A. Julian Abstract Renal disorders account for a substantial fraction of the budget for health care in many countries. Proteinuria is a frequent manifestation in afflicted patients, but the origin of the proteins varies based on the nature of the disorder. The emerging field of urinary proteomics has the potential to replace kidney biopsy as the diagnostic procedure of choice for patients with some glomerular forms of renal disease. To fully realize this potential, it is vital to understand the basis for the urinary excretion of protein in physiological and pathological conditions. In this review, we discuss the structure of the nephron, the functional unit of the kidney, and the process by which proteins/peptides enter the urine. We discuss several aspects of proteinuria that impact the proteomic analysis of urine of patients with renal diseases. [source] Loss of Nephrin Expression in Glomeruli of Kidney-Transplanted Patients Under m-TOR Inhibitor TherapyAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2010L. Biancone The development of proteinuria has been observed in kidney-transplanted patients on m-TOR inhibitor (m-TORi) treatment. Recent studies suggest that m-TORi(s) may alter the behavior and integrity of glomerular podocytes. We analyzed renal biopsies from kidney-transplanted patients and evaluated the expression of nephrin, a critical component of the glomerular slit-diaphragm. In a group of patients on ,de novo' m-TORi-treatment, the expression of nephrin within glomeruli was significantly reduced in all cases compared to pretransplant donor biopsies. Biopsies from control transplant patients not treated with m-TORi(s) failed to present a loss of nephrin. In a group of patients subsequently converted to m-TORi-treatment, a protocol biopsy performed before introduction of m-TORi was also available. The expression of nephrin in the pre-m-TORi biopsies was similar to that observed in the pretransplant donor biopsies but was significantly reduced after introduction of m-TORi(s). Proteinuria increased after the m-TORi inititiation in this group. However, in some cases proteinuria remained normal despite reduction of nephrin. In vitro, sirolimus downregulated nephrin expression by human podocytes. Our results suggest that m-TORi(s) may affect nephrin expression in kidney-transplanted patients, consistently with the observation in vitro on cultured podocytes. [source] Clinical Predictors of Proteinuria after Conversion to Sirolimus in Kidney Transplant RecipientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2010A. Padiyar Proteinuria is an increasingly recognized effect of sirolimus (SRL) therapy in kidney transplant recipients. Predictors of proteinuria after conversion to SRL are not well described, and in particular the risk in African-American (AA) kidney recipients is unknown. We sought to analyze risk factors for proteinuria with SRL therapy in a cohort of 39 patients (44% AA) converted from tacrolimus to SRL at a mean time of 4 months posttransplantation. Patients were maintained on therapy with mycophenolate mofetil while most patients underwent early steroid withdrawal. Urinary protein to creatinine ratio (Up/cr) at a mean of 14 months postconversion increased to ,500 mg/g in 65% of AAs versus 14% of non-AAs (p = 0.001). Mean arterial blood pressure at the time of conversion and pretransplant proteinuric kidney disease were also predictors of proteinuria after SRL conversion. In conclusion, AAs appear to be at high risk for proteinuria and should be monitored closely after conversion to SRL in calcineurin inhibitor sparing protocols. [source] Nephron Dosing and ProteinuriaAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2006J.-M. Halimi No abstract is available for this article. [source] Obesity is Associated with Worsening Cardiovascular Risk Factor Profiles and Proteinuria Progression in Renal Transplant RecipientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2005Kirsten A. Armstrong Obesity is associated with adverse cardiovascular (CV) parameters and may be involved in the pathogenesis of allograft dysfunction in renal transplant recipients (RTR). We sought the spectrum of body mass index (BMI) and the relationships between BMI, CV parameters and allograft function in prevalent RTR. Data were collected at baseline and 2 years on 90 RTR (mean age 51 years, 53% male, median transplant duration 7 years), categorized by BMI (normal, BMI , 24.9 kg/m2; pre-obese, BMI 25,29.9 kg/m2; obese, BMI , 30 kg/m2). Proteinuria and glomerular filtration rate (eGFRMDRD) were determined. Nine percent RTR were obese pre-transplantation compared to 30% at baseline (p < 0.001) and follow-up (25 ± 2 months). As BMI increased, prevalence of metabolic syndrome and central obesity increased (12 vs 48 vs 85%, p < 0.001 and 3 vs 42 vs 96%, p < 0.001, respectively). Systolic blood pressure, fasting blood glucose and lipid parameters changed significantly with BMI category and over time. Proteinuria progression occurred in 65% obese RTR (23 (13,59 g/mol creatinine) to 59 (25,120 g/mol creatinine)). BMI was independently associated with proteinuria progression (ß 0.01, p = 0.008) but not with changing eGFRMDRD. In conclusion, obesity is common in RTR and is associated with worsening CV parameters and proteinuria progression. [source] Early Low-Grade Proteinuria: Causes, Short-Term Evolution and Long-Term Consequences in Renal TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2005Jean-Michel Halimi Proteinuria 1 year after transplantation is associated with poor renal outcome. It is unclear whether low-grade (<1 g/24 h) proteinuria earlier after transplantation and its short-term change affect long-term graft survival. The effects of proteinuria and its change on long-term graft survival were retrospectively assessed in 484 renal transplant recipients. One- and 3-month proteinuria correlated with donor age, donor cardiovascular death, prolonged cold and warm ischemia times and acute rejection. One- and 3-month proteinuria (per 0.1 g/24 h, hazard ratio (HR): 1.07 and 1.15, p < 0.0001),especially low-grade proteinuria (HR: 1.20 and 1.26, p < 0.0001),were powerful, independent predictors of graft loss. Its short-term reduction correlated with arterial pressure (AP) (the lower the 3-month diastolic and 12-month systolic AP, the lower the risk of increasing proteinuria during 1,3 months and 3,12 months periods, respectively: Odds ratio (OR) per 10 MmHg: 0.78, p = 0.01 and 0.85, respectively, p = 0.02), and was associated with decreased long-term graft loss (per 0.1 g/24 h: HR: 0.88 and 0.98, respectively, p < 0.0001), independently of initial proteinuria. Early low-grade proteinuria due to pre-transplant renal lesions, ischemia-reperfusion and immunologic injuries is a potent predictor of graft loss. Short-term reduction in proteinuria is associated with improved long-term graft survival. [source] Selective blockade of BAFF for the prevention and treatment of systemic lupus erythematosus nephritis in NZM2410 miceARTHRITIS & RHEUMATISM, Issue 5 2010Meera Ramanujam Objective To determine whether BAFF or combined BAFF/APRIL blockade is effective in a mouse model of systemic lupus erythematosus (SLE) nephritis characterized by rapidly progressive glomerulosclerosis. Methods NZM2410 mice at early and late stages of SLE nephritis were treated with a short course of BAFF-R-Ig or TACI-Ig fusion protein. Proteinuria and serologic profile were evaluated every 2 weeks. Immunohistochemical, flow cytometric, and enzyme-linked immunospot analyses of the spleen, kidney, and bone marrow were performed after 8 weeks and after 33 weeks. Results A short course of selective blockade of BAFF alone was sufficient to prevent and treat SLE nephritis in NZM2410 mice, despite the formation of pathogenic autoantibodies. Decreases in spleen size and B cell depletion persisted for more than 33 weeks after treatment and resulted in secondary decreases in CD4 memory T cell formation and activation of splenic and peripheral monocytes. Immune complex deposition in the kidneys was dissociated from renal damage and from activation of renal endothelial and resident dendritic cells. Conclusion Selective blockade of BAFF alone, which resulted in B cell depletion and splenic collapse, was sufficient to prevent and treat the disease in this model of noninflammatory SLE nephritis. This shows that the inflammatory microenvironment may be a determinant of the outcome of B cell modulation strategies. [source] An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupusARTHRITIS & RHEUMATISM, Issue 5 2008Frances Rena Bahjat Objective To assess whether R788, an orally bioavailable small molecule inhibitor of spleen tyrosine kinase (Syk),dependent signaling, could modulate disease in lupus-prone (NZB × NZW)F1 (NZB/NZW) mice via inhibition of Fc receptor (FcR) and B cell receptor signaling. Methods R788 was administered to NZB/NZW mice before and after disease onset. Proteinuria, blood urea nitrogen levels, and autoantibody titers were examined periodically, and overall survival and renal pathologic features were assessed following long-term treatment (24,34 weeks). The distribution and immunophenotype of various splenic T cell and B cell subpopulations were evaluated at the time of study termination. Arthus responses in NZB/NZW mice pretreated with R788 or Fc-blocking antibody (anti-CD16/32) were also examined. Results When R788 was administered prior to or after disease onset, it delayed the onset of proteinuria and azotemia, reduced renal pathology and kidney infiltrates, and significantly prolonged survival of lupus-prone NZB/NZW mice; autoantibody titers were minimally affected throughout the study. Dose-dependent reductions in the numbers of CD4+ activated T cells expressing high levels of CD44 or CD69 were apparent in spleens from R788-treated mice. Minimal effects on the numbers of naive T cells expressing CD62 ligand and total CD8+ T cells per spleen were observed following long-term drug treatment. R788 pretreatment resulted in reduced Arthus responses in NZB/NZW mice, similar to results obtained in mice pretreated with FcR-blocking antibody. Conclusion We demonstrate that a novel Syk-selective inhibitor prevents the development of renal disease and treats established murine lupus nephritis. These data suggest that Syk inhibitors may be of therapeutic benefit in human lupus and related disorders. [source] Deficiency of the type I interferon receptor protects mice from experimental lupus,ARTHRITIS & RHEUMATISM, Issue 11 2007Dina C. Nacionales Objective Systemic lupus erythematosus (SLE) is diagnosed according to a spectrum of clinical manifestations and autoantibodies associated with abnormal expression of type I interferon (IFN-I),stimulated genes (ISGs). The role of IFN-I in the pathogenesis of SLE remains uncertain, partly due to the lack of suitable animal models. The objective of this study was to examine the role of IFN-I signaling in the pathogenesis of murine lupus induced by 2,6,10,14-tetramethylpentadecane (TMPD). Methods IFN-I receptor,deficient (IFNAR,/,) 129Sv mice and wild-type (WT) 129Sv control mice were treated intraperitoneally with TMPD. The expression of ISGs was measured by real-time polymerase chain reaction. Autoantibody production was evaluated by immunofluorescence and enzyme-linked immunosorbent assay. Proteinuria and renal glomerular cellularity were measured and renal immune complexes were examined by immunofluorescence. Results Increased ISG expression was observed in the peripheral blood of TMPD-treated WT mice, but not in the peripheral blood of TMPD-treated IFNAR,/, mice. TMPD did not induce lupus-specific autoantibodies (anti-RNP, anti-Sm, anti,double-stranded DNA) in IFNAR,/, mice, whereas 129Sv controls developed these specificities. Although glomerular immune complexes were present in IFNAR,/, mice, proteinuria and glomerular hypercellularity did not develop, whereas these features of glomerulonephritis were found in the TMPD-treated WT controls. The clinical and serologic manifestations observed in TMPD-treated mice were strongly dependent on IFNAR signaling, which is consistent with the association of increased expression of ISGs with lupus-specific autoantibodies and nephritis in humans. Conclusion Similar to its proposed role in human SLE, signaling via the IFNAR is central to the pathogenesis of autoantibodies and glomerulonephritis in TMPD-induced lupus. This lupus model is the first animal model shown to recapitulate the "interferon signature" in peripheral blood. [source] Proteinuria on dipstick urine analysis after sexual intercourseBJU INTERNATIONAL, Issue 1 2006LIRAN DOMACHEVSKY OBJECTIVE To examine the role of sexual intercourse as a cause of proteinuria, and establishes its duration, as a knowledge of benign causes of proteinuria is required to avoid unnecessary testing. SUBJECTS AND METHODS Twenty-four married couples were instructed to produce a urine sample before and after sexual intercourse; their urine was tested for proteinuria by dipstick analysis. RESULTS Samples were assayed from 22 men and 11 women. Whereas none of the 24 men originally assessed for the study had proteinuria before sexual intercourse, six of the 22 who were eventually enrolled had proteinuria after intercourse (27.3%, 95% confidence interval, 10,50%; P = 0.008). None of the women had proteinuria after sexual intercourse (95% confidence interval, 70,100%). The time to disappearance of proteinuria was <12 h. CONCLUSION Sexual intercourse is confirmed as a benign cause of proteinuria in men. Whenever possible, it is wise to avoid sexual intercourse at least 12 h before urinary dipstick testing. [source] Serum and 24-hour Urine Analysis in Adult Cyanotic and Noncyanotic Congenital Heart Disease PatientsCONGENITAL HEART DISEASE, Issue 3 2009Efrén Martínez-Quintana MD ABSTRACT Introduction., Glomerulopathy is a complication of congenital heart disease patients. The risk of developing renal impairment is particularly high in cyanotic patients. Objective., The aim of this study was to determine the prevalence of renal dysfunction and microalbumiuria in adult cyanotic and non cyanotic congenital heart disease patients. Methods., Fourteen cyanotic and 22 noncyanotic congenital heart disease patients were studied in the Adult Congenital Heart Disease Unit at the Complejo Hospitalario Universitario Insular-Materno Infantil. Demographic characteristics, complete blood count, and 24-hour urianalysis were obtained, including abdominal ultrasound in those with cyanosis. Results., No differences were seen between age (years) (27.4 ± 8.2; 26.4 ± 8.3; P = .71), sex, size, weight, or glomerular filtration rate (mL/min/1.73 m2) (81.1 ± 22.9 vs. 84.9 ± 9.2, P = .482) between cyanotic and noncyanotic patients. However, Eisenmenger patients had significantly impaired renal function when compared with noncyanotic patients (73.0 ± 17.3 vs. 84.9 ± 9.2 mL/min/1.73 m2, P = .023). Significant differences were obtained in oxygen saturation (%) (83.8 ± 5.8 vs. 97.8 ± 0.8; P = .000), hematocrit (%) (59.3 ± 8.1 vs. 40.9 ± 8.5; P = .000), platelets (103/µL) (161.5 ± 70.5 vs. 277.9 ± 57.6; P = .000), serum uric acid (mg/dL) (7.5 ± 2.3 vs. 5.6 ± 1.5; P = .008) and microalbuminuria (mg/24 hours) (12.8 [0, 700.2] vs. 2.4 [0, 18.9]; P = .000) between cyanotic and noncyanotic patients. Five cyanotic patients (35.7%) had microalbuminuria (>30 mg/24 hours) and three of them (21.4%) proteinuria (>1 g/24 hours). No significant differences were seen between serum and urine parameters between cyanotic patients who had microalbuminuria (>30 mg/24 hours) and those cyanotic patients who did not have it (<30 mg/24 hours). Conclusions., Renal impairment is frequently seen in congenital heart disease patients, being associated occasionally with proteinuria and microalbuminuria in cyanotic ones. [source] Glucometabolic state of in-hospital primary hypertension patients with normal fasting blood glucose in a sub-population of ChinaDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2009Yang-Xin Chen Abstract Background There is a high prevalence of abnormal glucometabolism (AGM) in patients with coronary heart disease (CHD) and primary hypertension (PH). However, little is known about the glucometabolic state of PH patients with normal fasting blood glucose (FBG). Methods Oral glucose tolerance test (OGTT) was performed for 445 in-hospital PH patients with normal FBG and re-performed for those patients with impaired glucose tolerance (IGT) during the follow-up period. Results Diabetes mellitus (DM), IGT, and AGM (including IGT and DM) accounted for 4.4, 24.5, and 28.9% of patients, respectively. Prevalence of AGM in patients with higher haemoglobin A1c (HbA1c) (,6.0%), risk factors (CHD, overweight, hyperlipidaemia, proteinuria) was significantly higher than that in patients without these factors. Regression analysis showed that age, overweight, proteinuria, HbA1c, and CRP were the independent risk factors of AGM. Follow-up data in 98 IGT patients showed that no improvement of glucometabolism was found, but contrarily, a significant increase of new onset of impaired fasting glucose (IFG) and DM was found after 9 months (P < 0.05), even if diet control and moderate exercise were adopted. Conclusions AGM is prevalent and underestimated in PH patients with normal FBG, and it will develop even if therapeutic life-style changes are adopted. Except for FBG, more attention should be paid to postprandial blood glucose. OGTT should be a routine procedure for PH patients, especially in-hospital PH patients, regardless of normal FBG, and active drug intervention for IGT patients with PH may be recommended. Copyright © 2009 John Wiley & Sons, Ltd. [source] Treatment of diabetic nephropathy in its early stagesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 2 2003Giacomo Deferrari Abstract Diabetic nephropathy is one of the most frequent causes of end-stage renal disease (ESRD), and, in recent years, the number of diabetic patients entering renal replacement therapy has dramatically increased. The magnitude of the problem has led to numerous efforts to identify preventive and therapeutic strategies. In normoalbuminuric patients, optimal glycemic control (HbA1c lower than 7.5%) plays a fundamental role in the primary prevention of ESRD [weighted mean relative risk reduction (RRR) ,37% for metabolic control versus trivial renoprotection for intensive anti-hypertensive therapy or ACE-inhibitors (ACE-I)]. In the microalbuminuric stage, strict glycemic control probably reduces the incidence of overt nephropathy (weighted mean RRR ,50%), while blood pressure levels below 130/80 mmHg are recommended according to the average blood pressure levels obtained in various studies. In normotensive patients, ACE-I markedly reduce the development of overt nephropathy almost regardless of blood pressure levels; in hypertensive patients, ACE-I are less clearly active (weighted mean RRR ,23% versus other drugs), whereas angiotensin-receptor blockers (ARB) appear strikingly renoprotective. Once overt proteinuria appears, it is uncertain whether glycemic control affects the progression of nephropathy. In type 1 diabetes, various anti-hypertensive treatments, mainly ACE-I, are effective in slowing down the progression of nephropathy; in type 2 diabetes, two recent studies demonstrate that ARB are superior to conventional therapy or calcium channel blockers (CCB). In clinical practice, pharmacological tools are not always used to the best benefit of the patients. Therefore, clinicians and patients need to be educated regarding the renoprotection of drugs inhibiting the renin-angiotensin system (RAS) and the overwhelming importance of achieving target blood pressure. Copyright © 2003 John Wiley & Sons, Ltd. [source] Stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long-term treatment with an aldose reductase inhibitor, epalrestatDIABETIC MEDICINE, Issue 7 2008N Hotta Abstract Aims The long-term efficacy of epalrestat, an aldose reductase inhibitor, in improving subjective symptoms and nerve function was comprehensively assessed to identify patients with diabetic peripheral neuropathy who responded to epalrestat treatment. Methods Stratified analyses were conducted on data from patients in the Aldose Reductase Inhibitor,Diabetes Complications Trial (ADCT). The ADCT included patients with diabetic peripheral neuropathy, median motor nerve conduction velocity , 40 m/s and with glycated haemoglobin (HbA1c) , 9.0%. Longitudinal data on HbA1c and subjective symptoms of the patients for 3 years were analysed (epalrestat n = 231, control subjects n = 273). Stratified analyses based on background variables (glycaemic control, grades of retinopathy or proteinuria) were performed to examine the relationship between subjective symptoms and nerve function. Multiple logistic regression analyses were conducted. Results Stratified subgroup analyses revealed significantly better efficacy of epalrestat in patients with good glycaemic control and less severe diabetic complications. In the control group, no improvement in nerve function was seen regardless of whether symptomatic benefit was obtained. In the epalrestat group, nerve function deteriorated less or improved in patients whose symptoms improved. The odds ratio of the efficacy of epalrestat vs. control subjects was approximately 2 : 1 (4 : 1 in patients with HbA1c , 7.0%). Conclusion Our results suggest that epalrestat, an aldose reductase inhibitor, will provide a clinically significant means of preventing and treating diabetic neuropathy if used in appropriate patients. [source] Research into the glomerular podocyte,is it relevant to diabetic nephropathy?DIABETIC MEDICINE, Issue 7 2006K. E. White Abstract The cause of proteinuria in renal disease is the subject of intensive research and, latterly, the podocyte, a specialized epithelial cell of the kidney glomerulus, has been the focus of much of this endeavour. It is a complex cell with functions and structural features that have an important role in the development of proteinuria. This review explores some of the characteristics of the podocyte and how abnormalities of its structure and function may have particular relevance to the development and progression of clinical diabetic nephropathy. [source] Unchanged incidence of diabetic nephropathy in Type 1 diabetes: a nation-wide study in IcelandDIABETIC MEDICINE, Issue 2 2005G. Tryggvason Abstract Aims Diabetic nephropathy is an uncommon cause of end-stage renal disease in Iceland in contrast to most industrialized countries. The aim of this study was to examine the incidence of diabetic nephropathy in Iceland. Methods All patients diagnosed with Type 1 diabetes in Iceland before 1992 were studied retrospectively. Patients diagnosed before age 30, who were insulin dependent from the onset, were defined as having Type 1 diabetes. Diabetic nephropathy was defined as persistent proteinuria measured with a dipstick test (Albustix) on three consecutive clinic visits at least 2 months apart. Patients were followed to the end of year 1998, to their last recorded outpatient visit, or until death. The cumulative incidence of diabetic nephropathy was calculated with the Kaplan,Meier method and presented according to the duration of diabetes divided into 5-year intervals. Results A total of 343 patients with Type 1 diabetes were identified. The mean follow-up period was 20.2 ± 11.4 (mean ± sd) years. Only 9.3% of patients were lost to follow-up. Sixty-five patients developed diabetic nephropathy. The cumulative incidence was 22.6% at 20 years and levelled off at 40.3% after approximately 35 years of diabetes duration. No significant changes in cumulative incidence were observed over time. Mean glycated haemoglobin was 8.4% in patients with proteinuria and 7.8% in a group of patients without proteinuria that was matched for age, gender and duration of diabetes (P = 0.04). Conclusions The cumulative incidence of diabetic nephropathy in Iceland is comparable with previously reported cumulative incidence rates and has remained unchanged. Glycaemic control was significantly better in patients without proteinuria. [source] Longitudinal study of urinary albumin excretion in young diabetic patients,-Wessex Diabetic Nephropathy ProjectDIABETIC MEDICINE, Issue 5 2001S. Twyman Summary Aims This study was established to follow changes in albumin/creatinine ratio (ACR) and to determine the prevalence and degree of progression of microalbuminuria (MA) or of clinical proteinuria (CP) in children with Type 1 diabetes. The study has investigated subjects for up to 12 years in establishing the correlation between MA and gender, age, duration of diabetes and glycated haemoglobin (HbA1c). The study has defined clinical cut-offs for MA in daytime clinic urine samples in young diabetic subjects. Methods Three hundred and sixty-one patients were involved in the study, with 221 (61.2%) having over six sets of data. Urine samples were collected at routine annual clinic visits and analysed without prior freezing for ACR. Blood samples were taken for HbA1c measurement. Data including sex, age and duration of diabetes were recorded. Results A random clinic ACR of <,4.5 mg/mmol (males) and 5.2 mg/mmol (females) creatinine was used as the ,clinical cut-off' to define the presence of MA. The presence of MA was independent of HbA1c and duration of diabetes but appeared be associated with the adolescent years (> 10 years). There was little evidence of progression from normoalbuminuria to MA, or from MA to CP. Of patients aged 10,18 years, 30.9% of males and 40.4% of females had one or more episodes of MA. Conclusions Persistent MA and random episodes of MA or CP may be associated with the adolescent years but not with duration of diabetes. Further study will reveal if the substantial increases in ACR sometimes seen during adolescence are predictive of diabetic nephropathy. Clinical cut-offs of <,4.5 and <,5.2 mg/mmol creatinine for males and females, respectively, are suggested for the interpretation of changes in ACR in random urine samples in young people with Type 1 diabetes. [source] Clinico-pathological features of postural hypotension in diabetic autonomic neuropathyDIABETIC MEDICINE, Issue 2 2000K. I. Khawaja Summary We report the clinico-pathological features and management of a 49-year-old male with a 30-year history of Type 1 diabetes mellitus who had nephropathy (proteinuria 1.81 g/24 h, creatinine 136 ,mol/l), proliferative retinopathy and severe somatic and autonomic neuropathy. A sural nerve biopsy demonstrated marked myelinated fibre loss with unmyelinated fibre degeneration and regeneration combined with extensive endoneurial microangiopathy. The management of the patient's blood pressure problems (supine hypertension) and symptomatic postural hypotension is discussed. [source] | |||||||||||||||||||||||||||||||||||||