Overexpression of chemokines, fibrogenic cytokines, and myofibroblasts in human membranous nephropathy

Overexpression of chemokines, fibrogenic cytokines, and myofibroblasts in human membranous nephropathy.BackgroundProteinuria plays a central role in the progression of glomerular disease, and there is growing evidence suggesting that it may determine tubular cell activation with release of chemokines and fibrogenic factors, leading to interstitial inflammatory reaction. However, most studies on this subject have been performed in experimental models, and the experience in human kidney biopsies has been scarce. We analyzed the tissue sections of patients with idiopathic membranous nephropathy (IMN), a noninflammatory glomerular disease that may follow a progressive disease with heavy persistent proteinuria, interstitial cell infiltration, and decline of renal function.MethodsParaffin-embedded biopsy specimens from 25 patients with IMN (13 progressive and 12 nonprogressive) were retrospectively studied by immunohistochemistry [monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted chemokine (RANTES), osteopontin (OPN), platelet-derived growth factor-BB (PD-GF-BB)] and in situ hybridization [MCP-1, RANTES, PDGF-BB, transforming growth factor-β1 (TGF-β1)]. Moreover, we studied the presence of myofibroblasts, which were identified by the expression of α-smooth muscle actin (α-SMA), the monocytes/macrophages (CD68-positive cells), and T-cell infiltration (CD4+ and CD8+ cells). All of the patients were nephrotic and without treatment at time of the biopsy.ResultsA strong up-regulation of MCP-1, RANTES, and OPN expression was observed, mainly in tubular epithelial cells, with a significant major intensity in the progressive IMN patients. A strong correlation between the mRNA expression and the corresponding protein was noted. The presence of these chemokines and OPN was associated with interstitial cell infiltration. TGF-β and PDGF were also up-regulated, mainly in tubular epithelial cells, with a stronger expression in the progressive IMN, and an association with the presence of myofibroblasts was found.ConclusionsPatients with severe proteinuria and progressive IMN have an overexpression in tubular epithelial cells of the chemokines MCP-1, RANTES, and OPN and the profibrogenic cytokines PDGF-BB and TGF-β. Because this up-regulation was associated with an interstitial accumulation of mononuclear cells and an increase in myofibroblastic activity, it is suggested that those mediators are potential predictors of progression in IMN. Finally, based on experimental data and the findings of this article, we speculate that severe proteinuria is the main factor responsible for the up-regulation of these factors in tubular epithelial cells

Renal angiotensin II up-regulation and myofibroblast activation in human membranous nephropathy

Renal angiotensin II up-regulation and myofibroblast activation in human membranous nephropathy.BackgroundThe molecular mechanisms of renal injury and fibrosis in proteinuric nephropathies are not completely elucidated but the renin-angiotensin system (RAS) is involved. Idiopathic membranous nephropathy (MN), a proteinuric disease, may progress to renal failure. Our aim was to investigate the localization of RAS components in MN and their correlation with profibrotic parameters and renal injury.MethodsRenal biopsies from 20 patients with MN (11 with progressive disease) were studied for the expression of RAS components [angiotensin-converting enzyme (ACE) and angiotensin II (Ang II)] by immunohistochemistry. Transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF)-BB were studied by by in situ hybridization, and myofibroblast transdifferentiation by α-smooth muscle actin (α-SMA) staining.ResultsACE immunostaining was elevated in tubular cells and appeared in interstitial cells colocalized in α-actin–positive cells in progressive disease. Elevated levels of Ang II were observed in tubules and infiltrating interstitial cells. TGF-β and PDGF mRNAs were up-regulated mainly in cortical tubular epithelial cells in progressive disease (P < 0.01) and correlated with the myofibroblast transdifferentiation (r = 0.8, P < 0.01 for TGF-β; r = 0.6, P < 0.01 for PDGF). Moreover, in serial sections of progressive cases, the ACE and Ang II over-expression was associated with the tubular expression of these pro-fibrogenic factors, and with the interstitial infiltration and myofibroblast activation.ConclusionIntrarenal RAS is selectively activated in progressive MN. De novo expression of ACE at sites of tubulointerstitial injury suggests that the in situ Ang II generation could participate in tubular TGF-β up-regulation, epithelial-myofibroblast transdifferentiation, and disease progression. These results suggest a novel role of Ang II in human tubulointerstitial injury

Lesiones renales en el lupus eritematoso diseminado: ausencia de relación entre datos clínicos e histológicos

Resumen: Antecedentes: La presencia y patrón morfológico del compromiso renal afecta el pronóstico del lupus eritematoso sistémico, información que puede ser indispensable para tomar decisiones terapéuticas apropiadas. Objetivo: Evaluar relación estadística entre datos clínicos e histológicos en pacientes con nefropatía lúpica biopsiada. Métodos: Revisión de información clínica en solicitudes de biopsias renales de adultos, informadas entre 2002 y 2014, con diagnóstico clínico e histopatológico inequívoco de compromiso renal por lupus eritematoso sistémico. Resultados: Ciento treinta y cuatro casos (86% mujeres), edad 15-59 años. Cuadro clínico: 30% alteraciones urinarias asintomáticas, 9% proteinuria nefrótica sin hipoalbuminemia, 19% síndrome nefrótico y 40% por insuficiencia renal, existiendo 2 casos sin manifestaciones clínicas renales. Las lesiones más frecuentes fueron proliferativas puras (68%). De los que tenían alteraciones urinarias asintomáticas, 35% eran clase IV, 30% clase III, 23% mixtas, 10% clase V y 2% clase II. Entre los de proteinuria nefrótica, 75% clase IV, 17% mixtas y 8% III. De los de síndrome nefrótico, 46% clase IV, 27% V, 19% mixtas y 8% clase III. Entre los de insuficiencia renal, el 67% eran IV, 22% mixtas, 7% III y 4% V. Estas proporciones no fueron estadísticamente diferentes. Aunque la peor función renal fue observada en la clase IV, casi la mitad (44%) de aquellos sin insuficiencia renal eran de esta misma clase. Conclusión: No se demuestra una relación clínico-histológica consistente que permita predecir los patrones ni la gravedad de los hallazgos histológicos a partir del cuadro clínico en el lupus eritematoso sistémico con manifestaciones renales. Esos resultados refuerzan la importancia de la biopsia como herramienta diagnóstica fundamental en esta enfermedad. Abstract: Background: The existence and type of renal involvement influences the prognosis of systemic lupus erythematosus and this information may be critical when it comes to taking appropriate therapeutic decisions. Objective: To evaluate statistical correlations between clinical and histological data in patients with biopsied lupus nephropathy. Methods: Review of clinical information in adult kidney biopsy requests reported between 2002 and 2014 with a definitive clinical and histopathological diagnosis of renal involvement in systemic lupus erythematosus. Results: 134 cases (86% women), aged 15–59 years. Indication for renal biopsy: asymptomatic urinary abnormalities (30%), nephrotic proteinuria without hypoalbuminaemia (9%), nephrotic syndrome (19%), renal failure (40%) and two cases without clinical renal manifestations. The most common lesions were purely proliferative (68%). In patients with asymptomatic urinary abnormalities, 35% were class IV, 30% class III, 23% mixed, 10% class V and 2% class II. In subjects with nephrotic proteinuria, 75% were class IV, 17% mixed and 8% class III. In nephrotic syndrome patients, 46% were class IV, 27% class V, 19% mixed and 8% class III. In renal failure subjects, 67% were class IV, 22% mixed, 7% class III and 4% class V. These proportions were not statistically different. Although class IV showed the worst renal function, almost half (44%) of those without renal failure belonged to this class. Conclusion: We could not demonstrate a consistent clinical-pathological relationship that predicts patterns or severity of histological findings based on the clinical profile in patients with systemic lupus erythematosus and renal manifestations. These results highlight the importance of biopsy as a key diagnostic tool in this disease. Palabras clave: Nefritis lúpica, Biopsia renal, Decisiones clínicas, Keywords: Lupus nephritis, Renal biopsy, Clinical decision-makin

A consensus of the chilean nephrology and rheumatology societies on renal involvement in systemic lupus erythematosus Recomendaciones sobre el manejo del compromiso renal del lupus eritematoso sistémico. documento de consenso de las sociedades chilenas de

© 2015, Sociedad Medica de Santiago. All rights reserved. Renal involvement affects over one half of patients with Systemic Lupus Erythematosus increasing their mortality and morbidity, including chronic renal disease and the need of renal replacement therapies. Aiming to achieve a consensus in the most relevant topics on diagnosis, therapy and follow-up of patients with lupus renal disease, the Chilean Societies of Nephrology and Rheumatology constituted a workgroup that, based on a critical review of the available literature and their experience, raised and answered by consensus a set of relevant questions. This document includes aspects related to the clinical diagnosis, the importance of a suitable histological classification, therapeutic alternatives to induce and maintain disease remission, strategies for follow-up, additional therapies and ginecological-obstetric issues

Tubular overexpression of gremlin induces renal damage susceptibility in mice.

A growing number of patients are recognized worldwide to have chronic kidney disease. Glomerular and interstitial fibrosis are hallmarks of renal progression. However, fibrosis of the kidney remains an unresolved challenge, and its molecular mechanisms are still not fully understood. Gremlin is an embryogenic gene that has been shown to play a key role in nephrogenesis, and its expression is generally low in the normal adult kidney. However, gremlin expression is elevated in many human renal diseases, including diabetic nephropathy, pauci-immune glomerulonephritis and chronic allograft nephropathy. Several studies have proposed that gremlin may be involved in renal damage by acting as a downstream mediator of TGF-β. To examine the in vivo role of gremlin in kidney pathophysiology, we generated seven viable transgenic mouse lines expressing human gremlin (GREM1) specifically in renal proximal tubular epithelial cells under the control of an androgen-regulated promoter. These lines demonstrated 1.2- to 200-fold increased GREM1 expression. GREM1 transgenic mice presented a normal phenotype and were without proteinuria and renal function involvement. In response to the acute renal damage cause by folic acid nephrotoxicity, tubule-specific GREM1 transgenic mice developed increased proteinuria after 7 and 14 days compared with wild-type treated mice. At 14 days tubular lesions, such as dilatation, epithelium flattening and hyaline casts, with interstitial cell infiltration and mild fibrosis were significantly more prominent in transgenic mice than wild-type mice. Tubular GREM1 overexpression was correlated with the renal upregulation of profibrotic factors, such as TGF-β and αSMA, and with increased numbers of monocytes/macrophages and lymphocytes compared to wild-type mice. Taken together, our results suggest that GREM1-overexpressing mice have an increased susceptibility to renal damage, supporting the involvement of gremlin in renal damage progression. This transgenic mouse model could be used as a new tool for enhancing the knowledge of renal disease progression