Sepsis induces albuminuria and alterations in the glomerular filtration barrier: a morphofunctional study in the rat

Abstract

IntroductionIncreased vascular permeability represents one of the hallmarks of sepsis. In the kidney, vascular permeability is strictly regulated by the 'glomerular filtration barrier' (GFB), which is comprised of glomerular endothelium, podocytes, their interposed basement membranes and the associated glycocalyx. Although it is likely that the GFB and its glycocalyx are altered during sepsis, no study has specifically addressed this issue. The aim of this study was to evaluate whether albuminuria -- the hallmark of GFB perm-selectivity -- occurs in the initial stage of sepsis and whether it is associated with morphological and biochemical changes of the GFB.MethodsCecal ligation and puncture (CLP) was used to induce sepsis in the rat. Tumor necrosis factor (TNF)-alpha levels in plasma and growth of microorganisms in the peritoneal fluid were evaluated at 0, 3 and 7 hours after CLP or sham-operation. At the same times, kidney specimens were collected and structural and ultrastructural alterations in the GFB were assessed. In addition, several components of GFB-associated glycocalyx, syndecan-1, hyluronan (HA) and sialic acids were evaluated by immunofluorescence, immunohistochemistry and lectin histochemistry techniques. Serum creatinine and creatinine clearance were measured to assess kidney function and albuminuria for changes in GFB permeability. Analysis of variance followed by Tukey's multiple comparison test was used.ResultsSeptic rats showed increased TNF-alpha levels and growth of microorganisms in the peritoneal fluid. Only a few renal corpuscles had major ultrastructural and structural alterations and no change in serum creatinine or creatinine clearance was observed. Contrarily, urinary albumin significantly increased after CLP and was associated with diffuse alteration in the glycocalyx of the GFB, which consisted in a decrease in syndecan-1 expression and in HA and sialic acids contents. Sialic acids were also changed in their structure, exhibiting a higher degree of acetylation.ConclusionsIn its initial phase, sepsis is associated with a significant alteration in the composition of the GFB-associated glycocalyx, with loss of GFB perm-selectivity as documented by albumin leakage into urine.

The Central Role of Renal Microcirculatory Dysfunction in the Pathogenesis of Acute Kidney Injury

“…Reactive oxygen species are one of the main culprits in shedding of the glycocalyx, promoting leucocyte adhesion, compromising the endothelial barrier, and causing glomerular filtration dysfunction [38]. During septic renal failure, the glycocalyx is disrupted by the factors described above, leading to albuminuria [39]. In addition to such structures being destroyed in the processes leading to AKI, transmembrane molecules essential for cellular integrity and communication are also compromised.…”

Expression and characterization of anionic components in the tubulointerstitial compartment of rat kidney during polymicrobial sepsis

“…Our research group has recently studied sepsis-associated acute kidney injury (AKI) and, in particular, changes in GBF in an experimental model reliably mimicking human sepsis: the cecal ligation and puncture (CLP) model. Significant alterations in the composition of the GFB anionic components SAs and HA, consisting in decrease and/or structural change associated with loss of GFB permeability-selectivity were revealed (Adembri et al, 2011). Studies performed using different experimental sepsis models have demonstrated various morphofunctional alterations both in the tubules and interstitium, particularly in the cortex (Achparaki et al, 1988;Hurley et al, 1989;Heyman et al, 2002;Aunapuu et al, 2004;Klenzak and Himmelfarb, 2005;Messaris et al, 2008;Heyman et al, 2010;Hsiao et al, 2012), however there are no data regarding the expression of these anionic molecules in the tubulointerstitial compartment.…”

“…Sialic acids (SAs) are considered to be among the most important molecules that contribute to the GFB permeable selectivity (Takeda, 2003;Galeano et al, 2007;Quaggin, 2007;Singh et al, 2007;Harvey and Miner, 2008;Adembri et al, 2011). They represent a large family of nine carboxylated sugars (Angata and Varki, 2002).…”

The Endothelial Glycocalyx and One-Lung Ventilation Induced Lung Injury—New Focus

“…Correcting low blood volume, increasing the effective circulating blood volume in order to ensure effective cardiac output blood flow and organ perfusion are fundamental objective of perioperative fluid therapy (29). Excessive fluid overload is a key factor leading to pulmonary edema and lung injury (30).…”