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)

An increasing number of studies indicate that a subset of CD4(+) T cells with regulatory capacity (regulatory T cells; T(regs)) can function to control organ-specific autoimmune disease. To determine whether abnormalities of thymic-derived T(regs) play a role in systemic lupus erythematosus, we evaluated T(reg) prevalence and function in (New Zealand Black x New Zealand White)F(1) (B/W) lupus-prone mice. To explore the potential of T(regs) to suppress disease, we evaluated the effect of adoptive transfer of purified, ex vivo expanded thymic-derived T(regs) on the progression of renal disease. We found that although the prevalence of T(regs) is reduced in regional lymph nodes and spleen of prediseased B/W mice compared with age-matched non-autoimmune mice, these cells increase in number in older diseased mice. In addition, the ability of these cells to proliferate in vitro was comparable to those purified from non-autoimmune control animals. Purified CD4(+)CD25(+)CD62L(high) B/W T(regs) were expanded ex vivo 80-fold, resulting in cells with a stable suppressor phenotype. Adoptive transfer of these exogenously expanded cells reduced the rate at which mice developed renal disease; a second transfer after treated animals had developed proteinuria further slowed the progression of renal disease and significantly improved survival. These studies indicate that thymic-derived T(regs) may have a significant role in the control of autoimmunity in lupus-prone B/W mice, and augmentation of these cells may constitute a novel therapeutic approach for systemic lupus erythematosus.
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PMID:Suppression of disease in New Zealand Black/New Zealand White lupus-prone mice by adoptive transfer of ex vivo expanded regulatory T cells. 1684 51

Drug-induced interstitial nephritis can be caused by a plethora of drugs and is characterized by a sudden impairment of renal function, mild proteinuria, and sterile pyuria. For investigation of the possible pathomechanism of this disease, drug-specific T cells were analyzed, their function was characterized, and these in vitro findings were correlated to histopathologic changes that were observed in kidney biopsy specimens. Peripheral blood mononuclear cells from three patients showed a proliferative response to only one of the administered drugs, namely flucloxacillin, penicillin G, and disulfiram, respectively. The in vitro analysis of the flucloxacillin-reactive cells showed an oligoclonal immune response with an outgrowth of T cells bearing the T cell receptor Vbeta9 and Vbeta21.3. Moreover, flucloxacillin-specific T cell clones could be generated from peripheral blood, they expressed CD4 and the alphabeta-T cell receptor, and showed a heterogeneous cytokine secretion pattern with no clear commitment to either a Th1- or Th2-type response. The immunohistochemistry of kidney biopsies of these patients revealed cell infiltrations that consisted mostly of T cells (CD4+ and/or CD8+). An augmented presence of IL-5, eosinophils, neutrophils, CD68+ cells, and IL-12 was observed. In agreement with negative cytotoxicity assays, no cytotoxicity-related molecules such as Fas and perforin were detected by immunohistochemistry. The data indicate that drug-specific T cells are activated locally and orchestrate a local inflammation via secretion of various cytokines, the type of which depends on the cytokine pattern secreted and which probably is responsible for the renal damage.
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PMID:Involvement of drug-specific T cells in acute drug-induced interstitial nephritis. 1695 23

Amyloidosis is an uncommon cause of renal disease in HIV-positive patients. Diagnosis is challenging, treatment options are limited, and prognosis remains poor. We discuss an HIV-positive patient with acute renal failure and nephrotic range proteinuria. The differential diagnosis included nephropathy due to trimethoprim/sulfamethoxazole, tenofovir, HIV, hepatitis C, heroin, or multifactorial causes. Serum and urine study findings were inconclusive. Rapid clinical deterioration ensued and a renal biopsy was performed. Pathologic examination revealed eosinophilic, amorphous material in the glomerular tufts that stained red-orange with Congo red stain. Immunohistochemical analysis confirmed amyloid A (AA) amyloidosis. AA amyloidosis occurs as a complication of chronic infection or chronic inflammatory disease. It has been reported in intravenous or subcutaneous drug abusers, some of whom were HIV-positive. This case underscores the importance of tissue diagnosis to determine the cause of renal disease in HIV-positive patients. Clinical diagnosis, based on CD4 count, viral load, and degree of proteinuria, may not predict the pathological diagnosis in HIV-positive patients.
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PMID:Acute renal failure and nephrotic range proteinuria due to amyloidosis in an HIV-infected patient. 1717 Jun 30

Myeloperoxidase (MPO) is an enzyme that is found in neutrophils and monocytes/macrophages. Intracellularly, it plays a major role in microbial killing, but extracellularly, it may cause host tissue damage. The role of endogenous MPO was studied during neutrophil-mediated (heterologous) and T helper 1 (Th1)/macrophage-mediated (autologous) phases of crescentic glomerulonephritis. Glomerulonephritis was induced in C57BL/6 wild-type (WT) and MPO-deficient (MPO(-/-)) mice by intravenous injection of sheep anti-mouse glomerular basement membrane globulin. MPO activity was increased in kidneys of WT mice during both the heterologous and autologous phases of glomerulonephritis. During the heterologous phase of glomerulonephritis, proteinuria was decreased, whereas glomerular neutrophil accumulation and P-selectin expression were enhanced in MPO(-/-) mice. In the autologous, crescentic phase of glomerulonephritis, MPO(-/-) mice had increased accumulation of CD4(+) cells and macrophages in glomeruli compared with WT mice. However, no difference in renal injury (crescent formation, proteinuria, and serum creatinine levels) was observed. Neutrophils and macrophages from MPO(-/-) mice exhibited reduced production of reactive oxygen species. Assessment of systemic immunity to sheep globulin showed that MPO(-/-) mice had increased splenic CD4(+) cell proliferation, cytokine production, and dermal delayed-type hypersensitivity, as well as enhanced levels of circulating IgG, IgG1, and IgG3. MPO(-/-) mice also had an augmented Th1:Th2 ratio compared with WT mice (IFN-gamma:IL-4 and IgG3:IgG1 ratios). These results suggest that endogenous MPO locally contributes to glomerular damage during neutrophil-mediated glomerulonephritis, whereas it attenuates initiation of the adaptive immune response inducing crescentic, autologous-phase glomerulonephritis by suppressing T cell proliferation, cytokine production, and Th1:Th2 ratio.
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PMID:Endogenous myeloperoxidase promotes neutrophil-mediated renal injury, but attenuates T cell immunity inducing crescentic glomerulonephritis. 1726 45

Autoimmune crescentic glomerulonephritis is characterized by severe immune response with glomerular crescentic formation and fibrosis in the kidney. Recent studies indicate that overexpression of renal Smad7 attenuates both renal fibrosis and inflammation in rat remnant kidney. However, little attention has been paid to the potential role of TGF-beta/Smad signaling in autoimmune kidney disease. This study tested the hypothesis that blocking TGF-beta signaling by overexpression of Smad7 may have a therapeutic effect in a mouse model of autoimmune crescentic glomerulonephritis that was induced in C57BL/6 x DBA/2J F1 hybrid mice by giving DBA/2J donor lymphocytes. Smad7 gene was transfected into the kidney using the ultrasound-microbubble-mediated system. Results showed that overexpression of Smad7 blocked both renal fibrosis and inflammatory pathways in terms of Smad2/3 and NF-kappaB activation (P < 0.01), thereby inhibiting alpha-smooth muscle actin; collagen I, III, and IV accumulation; and expression of inflammatory cytokines (IL-1beta and IL-6), adhesion molecule/chemokine (intercellular adhesion molecule-1, monocyte chemoattractant protein-1), and inducible nitric oxide synthase (all P < 0.01). Leukocyte infiltration (CD4(+) cells and macrophages) was also suppressed (P < 0.005). Severe histologic damage (glomerular crescent formation and tubulointerstitial injury) and functional injury including proteinuria were significantly improved (all P < 0.05). This study provides important evidence that overexpression of Smad7 may have therapeutic potential for autoimmune kidney disease.
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PMID:Smad7 gene therapy ameliorates an autoimmune crescentic glomerulonephritis in mice. 1747 16

Steroids are still the mainstay of therapy in primary chronic glomerulonephritis (PCGN), regardless of underlying disturbance or pathology. Moreover, relationship between known abnormalities and disease manifestation is stochastic, therefore treatment continues to be empirical. It is not known whether responsiveness is related to immune phenotype. We performed flowcytometric lymphocyte (Ly) phenotyping (CD19, CD3, CD3CD4, CD3CD8, CD56/16) on 16 patients (pts) (12M, 4F), mean age 37.6+/-13 years with primary chronic glomerulonephritis (PCGN): minimal change disease (MCD)--6 pts, focal and segmental glomerulosclerosis (FSGS)--4 pts, mesangial proliferative glomerulonephritis--5 pts, mesangiocapillary glomerulonephritis--1 pt, before and at 7 days of oral Prednisone 1 mg/kg/day (in 2 divided doses). Before steroids: 4/16 pts(25%) had elevated BP; 9/16(56.2) showed nephrotic proteinuria. Serum creatinine was >1.2 mg% in 6/16(37.5%). At 7 days WBC count increased (13,079.37+/-4966.4/microl vs. 8021.25+/-2077.4/microl; p=0.0007), Ly percentage (%) decreased (20.30+/-9% vs. 29.9+/-10.4%; p=0.0095), while absolute (abs.) Ly count remained unchanged. Both CD19 Ly% and CD19 Ly abs. count increased (16.13+/-6.5% vs. 9.52+/-3.7%; p=0.0015, and 410.012+/-29.7/microl vs. 223.56+/-123.8/microl; p=0.0077, respectively). NK (natural killer)% decreased (9.15+/-5.2% vs. 14.19+/-7.1%; p=0.0296). CD3, CD3CD4, CD3CD8 Ly subsets and CD4/CD8 ratio showed no change. Variation in proteinuria (2.88+/-2.1 g/24 h vs. 3.45+/-1.7 g/24 h; p=0.4) did not reach statistical significance (Wilcoxon-Mann-Whitney). In 11 pts we performed an additional analysis at 1 month. Compared to levels before steroids, there was an increase in WBC, CD19 Ly% and CD19 Ly abs. count and a decrease in NK% and NK abs. count. Other Ly subsets and CD4/CD8 ratio remained unchanged. Variation in clinical parameters (proteinuria, serum Creatinine, BP) did not reach statistical significance. Changes in Ly profile precede changes in clinical parameters and thus are divergent. While our patients proved to be early non-responders, further studies to elucidate whether profile changes provide for response specification are warranted.
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PMID:The effect of steroids on lymphocyte profile in primary chronic glomerulonephritis. Empirical or tailored therapy? 1763 Feb 6

Protease-activated receptor-2 (PAR-2) is a cellular receptor expressed prominently on epithelial, mesangial, and endothelial cells in the kidney and on macrophages. PAR-2 is activated by serine proteases such as trypsin, tryptase, and coagulation factors VIIa and Xa. It induces pleiotropic effects including vasodilatation, increasing plasminogen activator inhibitor (PAI-1) expression, mesangial cell proliferation, and cytokine production by macrophages. The role of PAR-2 in renal inflammation was studied in antiglomerular basement membrane antibody-induced crescentic glomerulonephritis (CGN) using PAR-2-deficient (PAR-2(-/-)) mice and wild-type littermate controls. PAR-2(-/-) mice had reduced crescent formation, proteinuria, and serum creatinine compared with wild-type mice 21 days after initiation of CGN. Glomerular accumulation of CD4(+) T cells and macrophages and the number of proliferating cells in glomeruli were similar in both groups. Glomerular fibrin deposition was significantly reduced in PAR-2(-/-) mice, and this was associated with reduced renal plasminogen activator inhibitor expression and increased renal matrix-metalloprotinase-9 activity. These results demonstrate a proinflammatory role for PAR-2 in CGN that is independent of effects on glomerular leukocyte recruitment and mesangial cell proliferation. PAR-2-mediated augmentation of renal plasminogen activator inhibitor expression and inhibition of matrix-metalloprotinase-9 activity may contribute to increased glomerular fibrin accumulation and glomerular injury in CGN.
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PMID:Protease-activated receptor-2 augments experimental crescentic glomerulonephritis. 1764 Sep 68

Experimental systemic lupus erythematosus (SLE) can be induced in mice following immunization with an anti-DNA mAb expressing a major Id, 16/6Id. Treatment with a peptide, designated human CDR1 (hCDR1; Edratide), that is based on the sequence of CDR1 of the 16/6Id ameliorated disease manifestations. In the present study, we investigated the roles of apoptosis and related molecules in BALB/c mice with induced experimental SLE following treatment with hCDR1. A higher state of activation and increased rate of apoptosis were found in lymphocytes of SLE-afflicted mice as compared with healthy controls. The latter effects were associated with up-regulated caspase-8 and caspase-3, and down-regulated Bcl-x(L). The ameliorative effects of hCDR1 were associated with down-regulation of caspase-8 and caspase-3, up-regulation of Bcl-x(L), and a reduced rate of apoptosis. Treatment of diseased mice with an apoptosis-reducing compound that inhibited caspases down-regulated the secretion of the pathogenic cytokine IFN-gamma and lowered the intensity of glomerular immune complex deposits and the levels of proteinuria. Furthermore, coincubation of Bcl-x(L) inhibitors with hCDR1-treated cells abrogated the ability of hCDR1 to reduce the activation state of lymphocytes and to down-regulate the secretion of IL-10 and IFN-gamma. Moreover, the Bcl-x(L)-expressing CD4(+)CD25(+) cells from hCDR1-treated mice induced the expression of Bcl-x(L) in CFSE-labeled CD4(+)CD25(-) cells of the SLE-afflicted mice. Thus, the reduction of apoptosis and the up-regulation of Bcl-x(L), which plays an apparent role in tolerance induction, contribute to at least part of the beneficial effects of hCDR1 on lupus manifestations.
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PMID:The role of apoptosis in the ameliorating effects of a CDR1-based peptide on lupus manifestations in a mouse model. 1791 82

Human immunodeficiency virus (HIV)-related glomerular disease is a cause of end-stage renal disease, though there is no recent data from Brazil concerning this syndrome. Persistent proteinuria (PPt) is the main marker for glomerular disease, especially levels above 1.5 g. We examined the prevalence of and associated risk factors for PPt, along with the prevalence of HIV-associated nephropathy (HIVAN) among AIDS patients. We interviewed 411 patients who were attended at the HIV/AIDS section of the Clinical Hospital of the Federal University of Pernambuco (Brazil) from January through June 2004. PPt was defined as a positive urine dipstick exam on at least two occasions. The analyzed risk factors were: black race, a low CD4 lymphocyte count (<200 cells/mm(3)), an HIV RNA level of >100,000 copies/mL and patients on highly-active antiretroviral therapy (HAART). The patients were classified according to urinary protein/creatinine ratio (Up/Uc) < 1.0, 1.0-3.0 and > 3.0. Patients with Up/Uc >3.0 were submitted to renal biopsy. Among the 411 HIV/AIDS patients, the mean age was 37 years, 70% were male, 37.5% were black, the mean CD4 count was 363 cells/mm(3) (+/- 95), the mean RNA HIV count was 44,475 copies/mL (+/- 40,369), and 92% were on HAART. The prevalence of PPt was 5.6% (95% CI = 3.6 to 8.3%), and it was significantly associated with a low CD4 lymphocyte count (p<0.048). HIVAN was found in just one patient, and two patients improved after HAART.
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PMID:Prevalence of persistent proteinuria in stable HIV/AIDS patients and its association with HIV nephropathy. 1796 69

Human immunodeficiency virus-associated nephropathy (HIVAN) has rarely been reported in African children. In this single-center study, we analyzed ten children diagnosed with HIVAN from January 2000 to October 2006. There were eight boys and two girls, with a male:female ratio of 4:1. Their ages were from 5 months to 15 years (mean 6.8+/-6.2 years), with a peak age of 5-9 years. The presenting complaints included generalized edema (60%) and hypertension (50%). All patients had proteinuria on urine dipstick, with four (40%) at nephrotic range (proteinuria >or=500 mg/dl). Nine (90%) patients were in renal failure, with elevated serum creatinine (6.3-24 mg/dl) and serum urea (70-120 mg/dl). Renal disease was the first manifestation of HIV infection in six patients, whereas the diagnosis was made on autopsy in three. The duration from HIV infection to development of HIVAN ranged from 5 months to 10 years. CD4(+) cell count, done in only three patients due to financial constraints, was below 200/mm(3). The kidneys were hyperechoic on abdominal ultrasound in all patients, and three (30%) showed grossly enlarged kidneys. Histology of renal tissues available by autopsy in three patients showed mainly collapsing focal segmental glomerulosclerosis. Treatments given were angiotensin-converting enzyme (ACE) inhibitors and highly active antiretroviral therapy (HAART) in four and two patients, respectively, and one patient underwent peritoneal dialysis. On outcome analysis, seven (70%) patients died, two were lost to follow-up, and one was alive on HAART therapy at the writing of this article. In conclusion, HIVAN occurs in Nigeria children, and the mortality is very high from uremia.
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PMID:Human immunodeficiency virus-associated nephropathy (HIVAN) in Nigerian children. 1798 61


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