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Background. Blockade of CD40–CD40 ligand (CD154) interactions protects against renal injury in adriamycin nephropathy (AN) in immunocompetent mice. To investigate whether this protection relied on adaptive or cognate immunity, we tested the effect of CD40–CD154 blockade in severe combined immunodeficient (SCID) mice. [ABSTRACT FROM PUBLISHER]

In a previous study we found that an episode of acute subclinical nephrotoxicity with gentamicin (G) (but not that induced by another proximal tubular cell nephrotoxin: ferric nitrilotriacetate, FeNTA), paradoxically reduced the progression of renal function and injury in uninephrectomized rats with nephrotic glomerular disease due to Adriamycin nephropathy (AN). Here, we hypothesized that subclinical exposure to G reduces early renal cortical tubulointerstitial inflammation and NF-κB activation in AN. To test this hypothesis, male Wistar rats with established AN received either G (10, 40, or 80 mg/kg by daily s.c.i. for 3 days), FeNTA (1.25, 5, or 10 mg/kg by a single i.p.i.), or vehicle (n = 8 per group), 13 to 15 days after disease induction. Although G and FeNTA caused acute tubular necrosis in a dose-dependant manner (day 17), only the highest doses (10 mg/kg and 80 mg/kg) produced an acute elevation in the serum creatinine. On day 33, chronic tubulointerstitial inflammation (tubular atrophy, interstitial ED-1 + /CD8 + cell accumulation) and NF-κB activation were exacerbated only in the groups that caused functional nephrotoxicity. These data suggest that: 1) the protective effect of subclinical G nephrotoxicity in chronic AN does not involve early changes in interstitial inflammation or NF-κB activation; and 2) a single episode of G exposure must be accompanied by clinically apparent nephrotoxicity in order to accelerate progression in a nonuremic model of chronic glomerular disease. [ABSTRACT FROM AUTHOR]

The need for early nephrology referral. The incidence of end-stage renal disease is increasing. Progression to end stage can be slowed if kidney damage is detected at an early stage. Prognosis and outcomes in patients with chronic kidney disease have been related to the quality of predialysis care and the timing of referral. Many patients with chronic kidney disease are referred to a nephrologist close to commencement of renal replacement therapy. This leads to suboptimal management of complications of chronic renal insufficiency, and increased morbidity and mortality of patients on renal replacement therapy.This article addresses the evidence that examines the view that patients need to be referred early in order to avoid complications of chronic renal insufficiency.Early referral can be achieved through improved communication between primary health care givers and nephrology services. A multidisciplinary approach has a significant impact on outcomes. In the face of rising incidence of chronic kidney disease, early referral of all patients is not possible. Therefore, identification of patients at risk for rapid deterioration of renal function is important in order to rationalize and reduce health care expenditure. [ABSTRACT FROM AUTHOR]

Editorial. Focuses on the role of mast cells in causing tubulointerstitial fibrosis (TIF). Etiology of the disease; Signs and symptoms of TIF; Function of mast cells in human kidney; Change in the number of mast cells in renal interstitium during renal diseases.

Presents the abstract 'Partial Depletion of Macrophages By ED7 Reduces Renal Injury in Adriamycin Nephropathy,' by Yiping Wang, Yuet-Ching Tay, Tim Spicer, Lucas Kairaitis, Yang Wang, Ling Zheng and David C.H. Harris.

Presents the abstract 'Blockade of CD40-CD50 Ligand Reduced Renal Injury in Chronic Proteinuric Renal Disease,' by Yiping Wang, Lukas Kairaitis, Yuet-Ching Tay, Yang Wang, Ling Zheng and David C.H. Harris.

Can murine diabetic nephropathy be separated from superimposed acute renal failure? Background. Streptozotocin (STZ) is commonly used to induce diabetes in experimental animal models, but not without accompanying cytotoxic effects. This study was undertaken to ( 1) determine an optimal dose and administration route of STZ to induce diabetic nephropathy in wild-type mice but without the concurrent acute renal injury resulting from cytotoxic effects of STZ and ( 2) evaluate the pattern of tubular injury and interstitial inflammation in this model. Methods. Male Balb/c mice received either ( 1) STZ (225 mg/kg by intraperitoneal injection.); or ( 2) two doses of STZ 5 days apart (150 mg/150 mg/kg; 75 mg/150 mg/kg; 75 mg/75 mg/kg; and 100 mg/100 mg/kg by intravenous injection). Another strain of mice, C57BL/6J, also received STZ (200 mg/kg intravenously or intraperitoneally). Renal function and histology were examined at weeks 1, 2, 4, and 8 after induction of diabetes. In initial optimization studies, animals were sacrificed at week 1 or week 2 and histology examined for acute renal injury. Results. Following a single intraperitoneal injection of 225 mg/kg of STZ, only two thirds of animals developed hyperglycemia, yet the model was associated with focal areas of acute tubular necrosis (ATN) at week 2. ATN was also observed in C57BL/6J mice given a single intravenous or intraperitoneal dose of STZ (200 mg/kg), at week 2 post-diabetes. At an optimal diabetogenic dose and route (75 mg/150 mg/kg by intravenous injection 5 days apart), all mice developed diabetes and no ATN was observed histologically. However, even with this regimen, glomerular filtration rate (GFR) was significantly impaired from week 2. This regimen was accompanied by progressive histologic changes, including tubular and glomerular hypertrophy, mesangial area expansion, as well as interstitial macrophage, CD4+ and CD8+ T-cell accumulation. Conclusion. By careful optimization of STZ dose, a stable and reproducible diabetic murine model was established. However, even in this optimized model, renal functional impairment was observed. The frequency of ATN and functional impairment casts doubt on conclusions about experimental diabetic nephropathy drawn from reports in which ATN has not been excluded rigorously. [ABSTRACT FROM AUTHOR]

DNA vaccination with naked DNA encoding MCP-1 and RANTES protects against renal injury in adriamycin nephropathy.Background.We have previously shown that monocyte chemoattractant protein-1 (MCP-1) and regulated upon activation, normal T-cell expressed and secreted (RANTES) are significantly increased in renal cortex in adriamycin nephropathy. In this study, we tested the effect of DNA vaccination encoding the C-C chemokines MCP-1 and RANTES in a rat model of adriamycin nephropathy.Methods.Both reverse transcription-polymerase chain reaction (RT-PCR) products of MCP-1 and RANTES used as constructs were cloned into a pTarget vector for naked DNA vaccination. Two hundred micrograms of DNA was injected into the tibialis anterior muscle four times at weekly intervals. One week after the last DNA vaccination, rats received adriamycin. All animals were sacrificed 4 weeks after adriamycin administration. Changes in renal function and histologic features were assessed. Enzyme-linked immunosorbent assay (ELISA) and Western blot were used for autoantibody determination. Antibody specificity was assessed in in vitro transmigration assays.Results.Chemokine DNA vaccination significantly reduced proteinuria (P<0.05) and ameliorated creatinine clearance (P<0.05) at 2, 3, and 4 weeks after adriamycin administration. Morphometric analysis showed less glomerular sclerosis (P<0.001) and interstitial infiltrates (P<0.005) in chemokine DNA vaccination group compared with control groups. Anti-MCP-1 and RANTES autoantibodies were detected in higher concentrations in chemokine DNA vaccinated rats than in control rats (P<0.001) and serum from vaccinated rats blocked T-cell transmigration to MCP-1 and RANTES.Conclusion.In this study, we have shown that naked DNA vaccination against MCP-1 and RANTES ameliorates the progression of renal disease in the rat adriamycin nephropathy model of chronic proteinuric renal disease. The protective mechanism may involve the production of autoantibodies against MCP-1 and RANTES. [ABSTRACT FROM AUTHOR]

Transcriptome analysis using microarray technology represents a powerful unbiased approach for delineating pathogenic mechanisms in disease. Here molecular mechanisms of renal tubulointerstitial fibrosis (TIF) were probed by monitoring changes in the renal transcriptome in a glomerular disease-dependent model of TIF (adriamycin nephropathy) using Affymetrix (mu74av2) microarray coupled with sequential primary biological function-focused and secondary "baited"-global cluster analysis of gene expression profiles. Primary cluster analysis focused on mRNAs encoding matrix proteins and modulators of matrix turnover as classified by Onto-Compare and Gene Ontology and identified both molecules and pathways already implicated in the pathogenesis of TIF (e.g. transforming growth factor β1CTGF-fibronectin-1 pathway) and novel TIF-associated genes (e.g. SPARC and Matrilin-2). Specific gene expression patterns identified by primary extracellular matrix-focused cluster analysis were then used as bioinformatic bait in secondary global clustering, with which to search the renal transcriptome for novel modulators of TIF. Among the genes clustering with ECM proteins in the latter analysis were endoglin, clusterin, and gelsolin. In several notable cases (e.g. claudin-1 and meprin1β) the pattern of gene expression identified in adriamycin nephropathy in vivo was replicated during transdifferentiation of renal tubule epithelial cells to a fibroblast-like phenotype in vitro on exposure to transforming growth factor-β and epidermal growth factor suggesting a role in fibrogenesis. The further exploration of these complex gene networks should shed light on the core molecular pathways that underpin TIF in renal disease. [ABSTRACT FROM AUTHOR]

Blockade of CD40-CD40 ligand protects against renal injury in chronic proteinuric renal disease. Background. Interaction between CD40 and CD40 ligand (CD40L) is involved in both cognate and innate immune responses. Blockade of CD40-CD40L interactions reduces severity of renal injury in murine lupus nephritis and membranous nephropathy. We hypothesized that CD40-CD40L could contribute to renal injury in models that are not antibody-dependent, and that anti-CD40L could diminish inflammation and fibrosis in murine adriamycin nephropathy. Methods. Male BALB/c mice were divided into three groups (N = 6 per group): (1 ) saline-treated, age-matched control; (2 ) adriamycin only; and (3 ) MR1 + adriamycin. In group 3, mice were treated with intraperitoneal injections of anti-CD40L antibody (clone MR1, 0.4 mg per mouse) after the onset of proteinuria at days 5, 7, 9, and 11 after adriamycin treatment. Animal subgroups were compared at 14 and 42 days after induction of adriamycin nephropathy. Functional and pathologic markers of disease severity, cellular components of interstitial inflammation, and the degree of CD40 expression were assessed. Relative cortical RNA expression of the chemokine monocyte-chemoattractant protein-1 (MCP-1) and regulated on activation normal T cell expressed and secreted (RANTES) was also compared between animal groups. Results. CD40 was weakly expressed in tubules of normal mice but was expressed in tubules, interstitium, and glomeruli of mice with adriamycin nephropathy in a time-dependent manner. MR1 treatment resulted in a significant attenuation of the severity of adriamycin nephropathy at day 42 [e.g., glomerular sclerosis (%), group 3, 20.1 ± 4.7 vs. group 2, 30.2 ± 7.2, P < 0.001]. CD40L blockade significantly reduced tubulointerstitial injury as well [tubular diameter (μm), group 3, 42.5 ± 6.9 vs. group 2, 66.3 ± 13.7, P < 0.001; and group 1, 37.3 ± 5.7, P < 0.01; tubular cell height (μm), group 3, 16.3 ± 1.7 vs. group 2, 11 ± 1.8, P < 0.01; and group 1, 18.2 ± 1.9, P < 0.01; interstitial volume (%), group 3, 13.9 ± 5.1 vs. group 2, 26.2 ± 4.9, P < 0.001; and group 1, 1.3 ± 0.7, P < 0.001; proteinuria (mg/24 hours), group 3, 1.8 ± 0.6 vs. group 2, 4.3 ± 0.8, P < 0.001; and group 1, 0.7 ± 0.2, P < 0.05; and creatinine clearance (μL/min), group 3, 75 ± 4 vs. group 2, 35 ± 2, P < 0.001; and group 1, 82 ± 4, P < 0.01] were also improved by MR1. MR1 treatment also resulted in a significant reduction in the number of cortical macrophages at both 14 and 42 days after adriamycin (P < 0.01). Cortical expression of MCP-1 and RANTES was significantly reduced by MR1 treatment at 42 days after adriamycin (P < 0.01 and P < 0.05, respectively). Conclusion. Blockade of CD40-CD40L interaction protects against renal structural and functional injury in this murine model of chronic proteinuric renal disease. [ABSTRACT FROM AUTHOR]

Examines the role of CD8[sup+] cells in the progression of murine adriamycin nephropathy. Effects of antibody treatment to CD8[sup+] cell levels; Increase of creatinine clearance; Reduction of interstitial expansion by CD8 depletion.

Investigates the sequence of histologic and immunohistochemical events of progressive adriamycin nephropathy in mice. Characterization of progressive renal disease; Analysis of leukocytic inflammatory pattern; Detection of overt proteinuria.