Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Different susceptibility to anti-GBM glomerulonephritis (GN) among animal strains has been reported. Using our rat model for T cell-mediated anti-GBM GN, this study initiated an investigation on the mechanism related with GN susceptibility. Anti-GBM GN was induced either through immunization with the nephritogenic T cell epitope pCol(28-40) from Col4alpha3NC1 or through the transfer of specific T cells. WKY rats were highly susceptible to GN while immuno-compatible LEW rats were GN-resistant. GN-resistance in LEW rats was not associated to the immune response to pCol(28-40). First, both strains mounted a Th1 T cell response to pCol(28-40) with identical specificities; transfer of T cells from LEW to WKY rats induced glomerular injury. Second, co-transfer of antibody from WKY to LEW failed to induce GN. Time-course studies revealed that LEW rats did develop T cell-mediated inflammation in glomeruli at early stages similar to WKY rats, as evidenced by histopathology, proteinuria, CD4(+) T cell infiltration in glomeruli, and glomerular expression of inflammatory molecules. However, glomerular inflammation in LEW rats was transient followed by a full recovery. Thus, GN-resistance in LEW rats was due to its ability to contain early T cell-mediated autoimmune glomerular damage. Our model may reveal a potential tolerance mechanism after autoimmune tissue damage has been initiated.
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PMID:Spontaneous recovery from early glomerular inflammation is associated with resistance to anti-GBM glomerulonephritis: tolerance and autoimmune tissue injury. 1805 99

The role of renal dendritic cells (DCs) in glomerulonephritis is unknown. This question was addressed in nephrotoxic nephritis, a murine model of human necrotizing glomerulonephritis, which is dependent on CD4(+) Th1 cells and macrophages. DCs in nephritic kidneys showed signs of activation, accumulated in the tubulo-interstitium, and infiltrated the periglomerular space surrounding inflamed glomeruli. In ex vivo coculture experiments with antigen-specific CD4(+) T cells, DCs stimulated the secretion of IL-10, which is known to attenuate nephrotoxic nephritis, and the Th1 cytokine IFNgamma. Endogenous renal CD4(+) T cells produced both of these cytokines as well, but those from nephritic mice secreted increased amounts of IL-10. Renal DCs were found to express ICOS-L, an inducer of IL-10. To evaluate the in vivo role of renal DCs in disease, CD11c(+) DCs were depleted on days 4 and 10 after the induction of nephritis by injecting CD11c-DTR/GFP mice with diphtheria toxin. Sparing DCs until day 4 did not affect the autologous phase of nephritis. The number of renal DCs was reduced by 70% to 80%, the number of renal macrophages was unchanged, and periglomerular infiltrates were eliminated. On days 11 to 14, we observed aggravated tubulointerstitial and glomerular damage, reduced creatinine clearance, and increased proteinuria. These findings demonstrate that renal DCs exert a renoprotective effect in nephrotoxic nephritis, possibly by expressing ICOS-L and/or by inducing IL-10 in infiltrating CD4(+) Th1 cells.
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PMID:Renal dendritic cells stimulate IL-10 production and attenuate nephrotoxic nephritis. 1823 94

T-bet is a transcription factor that is essential for T helper (Th)1 lineage commitment and optimal IFN-gamma production by CD4(+) T cells. We examined the role of T-bet in the development of experimental crescentic glomerulonephritis, which is induced by Th1-predominant, delayed-type hypersensitivity-like responses directed against a nephritogenic antigen. Anti-glomerular basement membrane (GBM) glomerulonephritis was induced in T-bet(-/-) and wild-type C57BL/6 mice. Compared with wild-type controls, renal injury was attenuated in T-bet(-/-) mice with glomerulonephritis, evidenced by less proteinuria, glomerular crescents, and tubulointerstitial inflammation. Accumulation of glomerular CD4(+) T cells and macrophages was decreased, and was associated with reduced intrarenal expression of the potent Th1 chemoattractants CCL5/RANTES and CXCL9/Mig. Supporting the pro-inflammatory nature of T-bet signaling, assessment of systemic immunity confirmed that T-bet(-/-) mice had a reduction in Th1 immunity. The kinetic profile of T-bet mRNA in wild-type mice supported the hypothesis that T-bet deficiency attenuates renal injury in part by shifting the Th1/Th2 balance away from a Th1 phenotype. Expression of renal and splenic IL-17A, characteristically expressed by the Th17 subset of effector T cells, which have been implicated in the pathogenesis of autoimmune disease, was increased in T-bet(-/-) mice. We conclude that T-bet directs Th1 responses that induce renal injury in experimental crescentic glomerulonephritis.
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PMID:T-bet deficiency attenuates renal injury in experimental crescentic glomerulonephritis. 1823 99

A 13-year-old girl with obesity and hyperinsulinism developed steroid-resistant nephrotic syndrome due to collapsing glomerulopathy with dominant C1q-containing mesangial immune deposits (CG/C1qN). She became overtly diabetic while receiving alternate-day prednisone and tacrolimus, requiring insulin injections. Despite the addition of mycophenolate mofetil to the treatment regimen, renal function subsequently declined. Rituximab (four weekly doses of 375 mg/m2) was tried 6 months after initial presentation and 3 months after weaning all glucocorticoids. Glomerular filtration rate (GFR) and proteinuria improved. Unexpectedly, blood sugar control normalized 6 weeks after antibody infusion. Rituximab was readministered 20 months after the first course because of deteriorating renal function, but the effect on GFR and proteinuria was modest. A retrospective analysis revealed that tubulointerstitial infiltrates present in the biopsies prior to treatment with rituximab contained numerous CD20+ and CD3+ (CD4 > CD8) lymphocyte aggregates. Rebiopsy 10 weeks after repeat rituximab therapy demonstrated the elimination of B-cell infiltrates and the apparent decrease of interstitial T-cell infiltrates, yet persistent, advanced global glomerulosclerosis, interstitial fibrosis and tubular atrophy. In conclusion, CG/C1qN was associated with B- and T-cell-rich tubulointerstitial infiltrates. B-cell-directed therapy delayed clinical progression during early disease but failed to prevent or ameliorate chronic changes, despite effective tissue B-cell clearance. The incidental resolution of diabetes was noted after rituximab treatment.
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PMID:Rituximab treatment of collapsing C1q glomerulopathy: clinical and histopathological evolution. 1835 94

Steroid-sensitive nephrotic syndrome (SSNS) is classically thought to be a T-cell disorder. The aim of this study was to examine whether or not thymus homeostasis was affected in SSNS. Mature and naive T cell recent thymic emigrants were quantified in the peripheral blood of nephrotic patients and controls. Because the generation of new T cells by the thymus ultimately depends on hematopoietic stem cells, CD34+ cells were also included in the study. Nineteen patients with SSNS during relapse, 13 with SSNS during proteinuria remission, and 18 controls were studied. Cell-surface markers (CD3, CD4, CD8, CD19, CD16, CD56, CD45RA, CD62L, CD34, and CD38) were analyzed by flow cytometric analysis. T-cell rearrangement excision circles (TRECs) were quantified in CD2+ cells by real-time polymerase chain reaction. Stroma cell-derived factor-1 (SDF-1) genotype and metalloproteinase-9 (MMP-9) plasma levels were also determined. Mature T cells (CD4+ and CD8+), circulating naive T cells (CD62L+ and CD3+ CD62L+), and recent thymic emigrants (CD45RA+) as well as TRECs, that measure thymus production, had a similar level in the three groups of patients. Conversely, CD34+ hematopoietic stem cells displayed a two-fold increase in SSNS patients during relapse either compared with controls or SSNS patients at remission. In addition, compared with controls, SSNS patients at remission displayed (1) a decrease in CD19+ cells (B cells) and (2) an increase in CD16CD56+ cells [natural killer (NK) cells]. In conclusion, thymus homeostasis is not significantly affected in nephrotic patients. Hematopoietic stem-cell mobilization at proteinuria relapse, as well as changes in B and NK cells during remission, suggest that SSNS might be due to a general disturbance of hematopoietic and immune cell trafficking.
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PMID:Stem cell mobilization in idiopathic steroid-sensitive nephrotic syndrome. 1845 57

We investigated the prevalence of CKD and factors associated with CKD in HIV-infected patients who were under stable medical control. We retrospectively abstracted the medical records of 748 HIV-infected outpatients(659 males and 89 females). Their mean age was 44.9+/-11.7 (range; 21 to 79) years. The following parameters were reviewed: urinalysis including proteinuria and microscopic hematuria, urinary N-acetyl-beta-glucosaminidase (NAG) level as a marker of tubular damage, serum creatinine level, estimated glomerular filtration rate calculated based on the Modification of Diet in Renal Disease formula (eGFR), CD4 count in peripheral blood, HIV-RNA copies in serum, use and vintage of highly active antiretroviral therapy (HAART), and use of anti-hypertensive drugs (AHTD). Stages of CKD were determined based on the K/DOQI stages of kidney disease. Chronic renal failure (CRF) was defined as an eGFR value of less than 60 mL/min/1.73 m2. The chi-square test was used to evaluate differences in the prevalence of dichotomous variables. Multivariable logistic regression analysis was applied to assess independent contributors to existence of CRF, proteinuria, and tubular damage. Proteinuria was positive in 50.0 % and hematuria was positive in 11.3 %. Both were positive in 8.41%. Tubular damage (> 11 U/L of urinary NAG levels) was positive in 42 out of 112(37.5 %). Prevalence of CKD and CRF was 87.8 % and 16.2 %, respectively. Stages of CKD were: stage 5D, 4 patients (0.53 %); stage 5, 0 patients (0%); stage 4, 3 patients (0.40 %); stage 3, 114 patients (15.2 %); stage 2, 487 patients (65.1%); stage 1, 49 patients (6.6%); and non-CKD, 91 patients (12.2 %). Statistically, use of HAART, urinary NAG level, and age were significant contributors to proteinuria. Proteinuria, age, and use of AHTD were strong predictors for CRF. Tubular damage was related to HAART vintage, age, and TG levels. In addition, HAART vintage of more than 2.5 years was statistically associated with the existence of tubular damage in HIV-infected patients. Prevalence of CKD in stable HIV-infected patients was unexpectedly high in our hospital. Aged patients with a long HAART vintage who have proteinuria and hypertension are predisposed to the development of CRF through tubular damage.
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PMID:[Prevalence of chronic kidney disease (CKD) and significant contributors to CKD in HIV-infected patients]. 1854 81

To correlate CD 4 counts with albuminuria and glomerular lesions in patients infected with human immunodeficiency virus (HIV), we studied 104 HIV positive patients (68 males, 36 females) of whom 100 patients were infected by heterosexual contact, 3 by transfusion, and 1 by i.v. drug abuse. We screened over nine months for albuminuria by urine dip stick method, and performed renal biopsy on patients with albuminuria 2+ or more. Histological examination was accomplished by light microscopy in all and by electron microscopy when it was feasible. Albuminuria was observed in 29 (27%) patients, and it revealed a significant negative correlation with CD4 count (p<0.01). Patients with CD4 cells <350 cells/mm(3) disclosed a 3.5 fold increased risk of albuminuria as compared with patients with CD4 >350 cells/mm(3). There was no significant correlation between proteinuria and the duration of infection from the time of diagnosis. Albuminuria also demonstrated a significant negative correlation with the levels of hemoglobin (p<0.05). In addition, low numbers of CD4 cells were associated with lower levels of hemoglobin (p<0.001). Only 10 patients received renal biopsies, and the results revealed HIV-associated nephropathy (HIVAN) in 7 (70%) patients, chronic tubulointerstitial nephritis in 1, membranous glomerulopathy in 1, and diffuse proliferative glomerulonephritis in 1. Acute renal failure was present in 5 patients, of whom four had a pre renal component and one had multiorgan dysfunction syndrome. We conclude that our study demonstrates that both proteinuria and HIVAN are common in HIV infected patients. Proteinuria has a negative correlation with the CD4 counts and hemoglobin levels.
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PMID:Correlation of CD4 counts with renal disease in HIV positive patients. 1858 20

Agonists of the type 1 sphingosine-1-phosphate (S1P) receptor inhibit lymphocyte migration, causing their sequestration in lymphoid tissue. The S1P agonist FTY720 prolongs the survival of organ allografts and blocks T-cell mediated autoimmune diseases in experimental models; however, it is a non-selective agonist of four of the five S1P receptors. In this study female MRL/lpr mice, which develop an aggressive form of spontaneous autoimmune kidney disease, were treated with a more selective agonist of the type 1 receptor (KRP-203) or vehicle at 12 or 16 weeks of age. Eighty percent of the mice treated at 12 weeks, before the onset of visible disease, survived to the 24 weeks end point with decreased tubulointerstitial disease and significantly fewer infiltrating CD4(+) and CD8(+) T-cells. Only half of the control vehicle-treated mice survived. All of the mice treated at 16 weeks survived with reduced proteinuria. Mice in both groups had significant reductions in circulating lymphocytes. Mice receiving KRP-203 for 8-12 weeks had significant reductions in T-cells and consequently less adenopathy. Ex vivo treatment of lymphocytes from MRL/lpr mice with KRP-203 enhanced their apoptosis. Our study indicates that KRP-203 attenuates kidney injury in MRL/lpr mice, in part, by reducing T-cell infiltrates.
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PMID:Increased survival and reduced renal injury in MRL/lpr mice treated with a novel sphingosine-1-phosphate receptor agonist. 1876 69

A genetically-prone murine lupus model was used to assess the developmental effects of trichloroethylene (TCE) exposure on disease symptom onset (e.g., autoantibody production and proteinuria), lymphocyte proliferation, splenic B-cell populations, and thymic and splenic T-cell populations. MRL +/+ mice were exposed to TCE (0, 1,400 or 14,000 ppb) via drinking water beginning on gestation day (GD) 0 and continuing until 12 months of age. With the exception of splenic CD4-/CD8-cells in female mice only, no alterations were observed in splenic T-cell populations, numbers of splenic B220+ cells, or in lymphocyte proliferation at 12 months of age. Furthermore, populations of all thymic T-cell subpopulations were decreased in male but not female mice following exposure to 14,000 ppb TCE. Autoantibody levels (anti-dsDNA and anti-GA) were assessed periodically from 4 to 12 months of age. Over this period, no increase in autoantibody levels as compared to control was detected, suggesting that TCE did not contribute to or accelerate the development of autoimmune disease markers following lifetime exposure. Not only does this study offer encouraging results, but it is the first study to approach the development of autoimmunity in a novel lifetime exposure paradigm, using an autoimmune prone model, at environmentally relevant exposure levels.
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PMID:Lifetime exposure to trichloroethylene (TCE) does not accelerate autoimmune disease in MRL +/+ mice. 1908 2

Studies in rodents showed that antibodies are able to induce tolerance of allografts. As clinical results are unsatisfactory and deceased donors are still the main source of organ transplants, we investigated whether donor brain-death impacts on tolerance induction after experimental kidney transplantation. Anti-CD4 monoclonal antibodies (RIB 5/2; 2.5 mg/kg x 5 days) treated and untreated recipients of brain-dead donor grafts were compared with RIB 5/2 treated and untreated recipients of living donor grafts (F344-to-Lewis). All recipients received low-dose CsA (1.5 mg/kg x 10 days). Kidneys were recovered 4, 16 and 40 weeks after transplantation and examined by morphology, immunohistology and flow cytometry. Renal function was monitored monthly. RIB 5/2 treatment significantly decreased proteinuria in recipients of living donor allografts when compared with living donor controls. After 40 weeks, inflammatory cell infiltration and MHC class II expression were reduced while morphologic alterations were minimal. In contrast, treatment of brain-dead graft recipients had no impact on graft function. Structural changes and graft infiltration were comparable to brain-dead donor controls at all time points. RIB 5/2 treatment significantly improved graft function in recipients of living donor grafts; however, it was not effective in recipients of brain-dead donor organs.
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PMID:Donor brain death significantly interferes with tolerance induction protocols. 1895 65


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