Obstructive Uropathy

Abstract

Chronic tubulointerstitial nephritis (TIN), characterized by tubular atrophy, interstitial fibrosis and inflammation, is a major prognostic determinant of chronic kidney disease, regardless of the original cause of the kidney disease. Understanding the pathogenesis of TIN has been hampered by the lack of an adequate experimental model. However, the demonstration that the renal lesions of obstructive uropathy induced by experimental urinary obstruction (UO) has provided an excellent model to study the pathogenesis of TIN in general and especially congenital obstructive nephropathy, the most common cause of pediatric end-stage renal disease. Since relief of experimental UO is technically possible, this model is particularly useful for studying the potential reversibility of TIN. Experimental UO is usually created by the unilateral ligation of a ureter. This induces progressive tubular epithelial cell injury, including apoptosis, proliferation, loss of differentiation and atrophy; interstitial inflammatory cell infiltrates composed predominantly of macrophages and T cells; and interstitial fibrosis characterized by an increase and activation of interstitial fibroblasts, deposition of extracellular matrix proteins and loss of peritubular capillaries. These changes collectively lead to progressive scarring and the loss of renal parenchyma and kidney function. The glomeruli and large blood vessels remain either normal or show mild changes later in the course of the disease. In addition to TIN, congenital obstructive nephropathy causes marked derangement of renal and glomerular development. Relief of UO does not seem to reverse TIN. In fact, the renal lesions of obstructive uropathy not only persist, but also progress long after UO is relieved in both adult and neonatal rats. The pathogenesis of UO-induced TIN has been well studied, at least in part because of the ready application of this model to mice, in which genetic manipulation including gene deletion or transfection of putative pathogenic molecules is technically feasible. Experimental UO immediately induces mechanical stretching of tubular epithelial cells and activates the renin-angiotensin system, leading to profound changes of the cells, including neo-expression of a large number of molecules which control cell cycle (e.g. caspases, intrinsic and extrinsic death pathway molecules, inhibitors of cyclin-dependent kinases p27 and p21, reactive oxygen species, and catalase), hypoxic response (HIF- α), epithelial-mesenchymal transformation (e.g. hepatocyte growth factor, bone morphogenic protein 7 and nestin), and the upregulation of cytokines and growth factors (e.g. TGFβ-1, EGF, PDGF, VEGF and TNF-α) as well as chemokines (MCP-1, osteopontin, IL-1, ICAM-1, VCAM-1 and selectins). Inflammatory cells are recruited immediately after UO, probably under the effect of the renin-angiotensin system and later by tubular cell-derived chemokines. Several chemokines and their receptors are also expressed by the infiltrating inflammatory cells, thereby augmenting the recruitm...

Quantification of Kidney Fibrosis Using Ultrasonic Shear Wave Elastography

“…Unilateral ureteral obstruction is a well-known cause of chronic tubulointerstitial nephritis and is known to be an excellent experimental model of chronic tubulointerstitial injury. 37,38 However, in this study, hydronephrosis and tubular dilatation may have been confounding factors that affected the tissue stiffness in group I kidneys. Renal venous occlusion is not a frequent cause of chronic kidney disease.…”

Inflamação na doença renal crônica: papel de citocinas

“…No entanto, atualmente se sabe que as nefropatias obstrutivas podem lesar o tecido renal mesmo após alívio do processo obstrutivo, produzindo inflamação, fibrose intersticial e atrofia tubular. 23,55 . Em geral, as lesões permanentes se devem a apoptose tubular e fibrose renal.…”

“…As células epiteliais lesadas produzem infrarregulação do fator de crescimento epidérmico e ativam o SRA. 55 Essas duas alterações estimulam a expressão do TGF-β1 e a geração de espécies reativas de oxigênio, que, por sua vez, levam ao recrutamento de macrófagos intersticiais e à produção de MCP-1/CCL2, moléculas de adesão e TNF-α. 23 Esta sequência de eventos resulta em atrofia tubular e lesão de capilares peritubulares e glomérulos.…”

“…23 Esta sequência de eventos resulta em atrofia tubular e lesão de capilares peritubulares e glomérulos. 23,55 Além disso, alterações fenotípicas transformam células epiteliais em miofibroblastos, que promovem fibrose intersticial através da expansão da matriz extracelular. 23 O resultado final é a perda progressiva de todas as estruturas do néfron, conforme mostrado na Figura 1.…”

Rosuvastatin Preserves Renal Structure following Unilateral Ureteric Obstruction in the Neonatal Rat

“…Sustained ureteric obstruction elicits a fibrotic progression in the affected kidney, characterized by fibroblast activation and attendant extracellular matrix deposition in the tubulointerstitium [11]. …”