Chronic renal failure pathophysiology: Difference between revisions
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===Inflammation=== | ===Inflammation=== | ||
Angiotensin II has also been linked to and increase in inflammation after renal injury. It has been shown to activate the transcription factor NF-κB, an important player in the inflammatory response mediating transcription of several cytokines and chemokines. ATII has also been shown to stimulate endothelin-1 leading to the recruitment of T-cells and macrophages. Beyond that, it upregulates the expression of adhesion molecules notably integrins, intracellular adhesion molecule-1, and vascular cellular adhesion molecule-1 all of which lead to and increase in leukocyte concentration in the area. This creates a vicious cycle as lymphocytes can be a source of angiotensin II themselves amplifying its maladaptive effects. | |||
===Accelerated Fibrosis=== | ===Accelerated Fibrosis=== | ||
Revision as of 23:14, 26 October 2013
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]
Overview
Pathophysiology
The pathophysiologic mechanisms leading to chronic kidney disease stem from the underlying etiologies responsible for the primary renal damage. The initial insult is responsible for a decrease in the number of functional nephrons. However; beyond that initial insult, a form of maladaptive systemic and renal response arises that maintains and perpetuates the existing renal disease. With the activation of the renin-angiotensin-aldosterone system, a combination of mechanisms herald a progressive loss of nephrons. Broadly, 3 main mechanisms exist related in part to the activation of the RAAS: hyperfiltration, inflammation, and accelerated fibrosis.
Hyperfiltration
The landmark works of Brenner et al were the first to propose the maladaptive changes that occur after renal injury. The team showed that after significant loss of nephron mass, major alterations in glomerular hemodynamics occur. The changes lead to glomerular hypertension with an increase in single nephron glomerular filtration rate termed hyperfiltration. Hyperfiltration is a direct result of the increase in glomerular plasma flow and hydrostatic pressure in response to a decrease in preglomerular arteriolar resistance more than the decrease in postglomerular resistance with a net vasocontrictive effect on the efferent arteriole.
The observed alterations occur due to the activation of the RAAS system. Initially, the juxtaglomerular apparatus increases the release of renin in response to the decreased perfusion pressure and solute delivery to the macula densa. Renin converts angiotensinogen to angiotensin I which is then converted to angiotensin II is then produced by angiotensin converting enzyme (ACE). Angiotensin II has been shown to be the main perpetrator in the maladaptation of the kidney to significant damage.
Most animal models exploring glomerular hypertension and hyperfiltration show progressive glomerular sclerosis and eventual proteinuria that usually occurs at a linear rate compared to the extent of nephron loss. Furthermore, studies examining the prevention or reduction of glomerular hypertension and single nephron GFR have almost invariably shown a reduction in the rate of progression of renal disease. Among the proposed interventions include dietary protein restriction, ACE inhibitors, and angiotensin receptor blockers (ARBs).
Inflammation
Angiotensin II has also been linked to and increase in inflammation after renal injury. It has been shown to activate the transcription factor NF-κB, an important player in the inflammatory response mediating transcription of several cytokines and chemokines. ATII has also been shown to stimulate endothelin-1 leading to the recruitment of T-cells and macrophages. Beyond that, it upregulates the expression of adhesion molecules notably integrins, intracellular adhesion molecule-1, and vascular cellular adhesion molecule-1 all of which lead to and increase in leukocyte concentration in the area. This creates a vicious cycle as lymphocytes can be a source of angiotensin II themselves amplifying its maladaptive effects.
Accelerated Fibrosis
The increase in angiotensin II has also been directly associated with accelerated fibrosis in the remaining nephrons independently of the hemodynamic changes. Angiotensin II is thought to exert direct effects in the glomerular micromilieu leading to extracellular matrix (ECM) expansion. Angiotensin II has been shown to increase mRNA encoding type I procollagen and fibronectin in cultured mesangial cells. This effect is multiplied by the increase in expression of TGF-β further activating ECM protein production. In normal renal tissue, the balance between ECM synthesis and degradation is essential to prevent fibrotic glomerular changes. Beyond the increase in ECM production, angiotensin II also disrupts this balance. Via ATI receptors, it activates tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) both of which shift the balance towards ECM accumulation.
Another method of accelerated fibrosis is a process called epithelial-to-mesenchymal transition (EMT) where tissue epithelial cells transform into active fibroblasts. Although previously recognized as a physiologic mechanism during embryologic development, it has come to light as a process that provides fibroblasts during organ fibrosis after injury. Experimentally, more than one third of fibroblast at the site of renal injury were shown to originate from the renal tubular epithelial cells. The prototypical factor linked to EMT is TGF-β which is usually elevated after renal injury; however, other local factors also induce EMT including epidermal growth factor (EGF), Insulin growth factor II (IGF-II), and fibroblast growth factor (FGF-2).