Progression To Acute Renal Failure Research Articles

PS-B08-9: INHIBITION OF PERIOSTIN PROTECTED FROM EXACERBATION OF INFLAMMATION IN RHABDOMYOLYSIS-INDUCED ACUTE KIDNEY INJURY

Objective: Rhabdomyolysis is the breakdown of damaged skeletal muscle and the leakage of muscle-cell contents, including myoglobin, and other sarcoplasmic proteins into the circulation. These products may be filtered through the glomeruli, leading to acute kidney injury (AKI) via several mechanisms, such as inflammation and intratubular obstruction secondary to protein precipitation. New therapeutic strategy to lessen AKI are urgently needed. Thus far, several cellular pathways, nuclear factor kappa beta (NF-KB) as well as including pro-inflammatory effects on epithelial and tubular epithelial cells, have been identified as the major avenues for the initiation of the matrix-producing cells in AKI. Recently, it is suggested that periostin, extracellular matrix, is involved in the development of inflammation through the modulation of NF-KB pathway. However, periostin on the progression of the inflammation protection in AKI due to rhabdomyolysis is unclear. This study aimed to investigate the role of periostin in a rhabdomyolysis mice model of AKI. Design and method: In vivo, rhabdomyolysis-induced AKI was created by an intramuscular injection of 50% glycerol (5 mg/kg body weight). The expression level of periostin during the progression of acute renal failure after glycerol intramuscular injection for C57BL/6J wild type (WT) mice model was investigated. The mice were sacrificed at 72 hours after glycerol injection. We have developed periostin null mice to examine the role of periostin on acute renal failure. The role of periostin were further investigated through in vitro methods. In vitro, the development of renal inflammation is associated with NF-KB pathway. To investigate the function of periostin, we administrated Hemin(100uM) on NIH-3T3 fibroblast cells and the subsequent signaling pathways was examined. Results: The expression of periostin was highly increased, peaking at approximately 72 hours after gycerol injection. Inflammation-associated mRNA such as Monocyte Chemotactic Protein-1, tumor necrosis factor-alpha and IL6 expression and tubular injury score in H-E staining was more reduced in periostin null mice than WT mice at 72 hours after gycerol injection. Finally, an intraperitoneal injection of periostin antibody suppressed the mortality. These findings suggest a causal link between periostin and inflammation in AKI induced by rhabdomyolysis. In addition, an intraperitoneal injection of antibody for periostin antibody might be a new therapeutic strategy against the development of AKI induced by rhabdomyolysis. Conclusions: Periostin were highly expressed in kidney via rhabdomyolysis, and were a positive regulator of AKI. Targeting periostin might offer a new therapeutic strategy against the development of renal failure.

Assessment of urinary interleukin-18 in the early post-burn period to predict acute kidney injury of various degrees of burn patients

Background: Early detection of acute kidney injury (AKI) in burn-injured patients can help modify the treatment to prevent progression of acute renal failure and reduce the need for renal replacement therapy. The aim of the study was to evaluate urinary interleukin-18 in the early post-burn period to predict the AKI for the various degrees of burn patients.Methods: This prospective observational study was conducted in the department of nephrology, Dhaka medical college in collaboration with burn and plastic surgery unit of the same medical college hospital, from July 2017 to June 2018 for a period of one year. The 48 burn patients (Age>18 years) who attended in the burn unit of Dhaka medical college, Dhaka of both sexes were enrolled in this study. Data were analyzed by using SPSS 22.0. A value of p<0.05 was considered statistically significant for all tests.Results: In this study, mean age of the burn patients was 32.41±10.59 years. Male female ratio was 3.36:1. Urinary IL-18 in diagnosis of AKI showed accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 93.8%, 91.7%, 94.4%, 84.6% and 97.1% respectively. AUC for urinary IL-18 at admission was 0.968 (CI, 0.921-1.000) and AUC for serum creatinine at admission was 0.937 (CI, 0.871-1.000). Conclusions: According to Kappa value, AUC and sensitivity and specificity urinary IL-18 is a good biomarker in predicting of early AKI in burn patients.

Protective Effect of Hydroalcoholic Extract of Stachys pilifera on Oxidant-Antioxidant Status in Renal Ischemia/Reperfusion Injuries in Male Rats.

Background Renal ischemia-reperfusion (I/R) has a pivotal role in the progression of acute renal failure. Reactive oxygen species are considered the major constituents involved in the biochemical and pathophysiological changes that were shown during kidney I/R. The purpose of this study was to examine the renoprotective effects of Stachys pilifera ethanolic extract on oxidant-antioxidant status in renal I/R-injuries in male rats. Material and methods. Twenty-one male Wistar rats were arbitrarily distributed into 3 groups: sham control (SC), I/R, and I/R + Stachys pilifera ethanolic extract (500 mg/kg). The artery and vein of the right kidney were completely blocked, and the right kidney was completely removed in all groups. Then, the left kidney artery was blocked with suture thread for 30 minutes in only I/R and I/R + SP extract groups. Kidney function indices, oxidative stress markers, and hematoxylin and eosin staining were investigated in the plasma and kidney tissues. Results It was shown that the urine Na and K, fractional excretion of Na and K, and protein carbonyl content markedly increased in the merely I/R group as compared to SC rats, while the administration of SP extract markedly reduced these indices (P < 0.05). Also, glomerular filtration rate and total thiol meaningfully reduced in the I/R rats in contrast to the SC group, while the treatment with SP extract markedly augmented these indices (P < 0.05). However, in agreement with renal function tests, SP extract had no significant effects on histopathological examinations. Conclusion It seems that SP extract employs renoprotective effects on renal damage induced by I/R, possibly by improving of oxidant-antioxidant status in favor of the antioxidant system.

Atypical Progression of Acute Renal Failure Associated with Cisplatin Chemotherapy

Cisplatin is commonly used as chemotherapy for solid tumors. Its most important side effect is nephrotoxicity, which typically produces a gradual decline in renal function. Acute tubular necrosis is the usual pathological finding, while other findings are rare. A 75-year-old man presented to the emergency department (ED) with diarrhea and hypoglycemia. He was on 5-fluorouracil (5-FU)/cisplatin chemotherapy after a radical total gastrectomy for gastric cancer. Ten days earlier, he had been discharged after the third cycle of chemotherapy with normal renal function. When he arrived in the ED, he had azotemia (creatinine = 9.2 mg/dL) necessitating emergency hemodialysis. His renal function did not recover despite hydration and conservative treatment. Since he could not receive further chemotherapy due to the renal failure, he died 4 months later due to cancer progression. A renal biopsy performed 3 months after the renal failure showed acute tubular necrosis and severe interstitial fibrosis with normal glomeruli suggesting tubulointerstitial nephritis. (Korean J Med 2013;85:425-429)

Inhibition of tubular cell proliferation by neutralizing endogenous HGF leads to renal hypoxia and bone marrow-derived cell engraftment in acute renal failure

During the progression of acute renal failure (ARF), the renal tubular S3 segment is sensitive to ischemic stresses. For reversing tubular damage, resident tubular cells proliferate, and bone marrow-derived cells (BMDC) can be engrafted into injured tubules. However, how resident epithelium or BMDC are involved in tubular repair remains unknown. Using a mouse model of ARF, we examined whether hepatocyte growth factor (HGF) regulates a balance of resident cell proliferation and BMDC recruitment. Within 48 h post-renal ischemia, tubular destruction became evident, followed by two-waved regenerative events: 1) tubular cell proliferation between 2 and 4 days, along with an increase in blood HGF; and 2) appearance of BMDC in the tubules from 6 days postischemia. When anti-HGF IgG was injected in the earlier stage, tubular cell proliferation was inhibited, leading to an increase in BMDC in renal tubules. Under the HGF-neutralized state, stromal cell-derived factor-1 (SDF1) levels increased in renal tubules, associated with the enhanced hypoxia. Administrations of anti-SDF1 receptor IgG into ARF mice reduced the number of BMDC in interstitium and tubules. Thus possible cascades include 1) inhibition of tubular cell proliferation by neutralizing HGF leads to renal hypoxia and SDF1 upregulation; and 2) BMDC are eventually engrafted in tubules through SDF1-mediated chemotaxis. Inversely, administration of recombinant HGF suppressed the renal hypoxia, SDF1 upregulation, and BMDC engraftment in ARF mice by enhancing resident tubular cell proliferation. Thus we conclude that HGF is a positive regulator for eliciting resident tubular cell proliferation, and SDF1 for BMDC engraftment during the repair process of ARF.

Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced qacute renal failure

The effect of acute renal failure (ARF) induced by ischemia/reperfusion (I/R) of rat kidney on the expression of organic anion transporters (OATs) was examined. The level of serum indoxyl sulfate (IS), a uremic toxin and substrate of OATs in renal tubules, shows a marked increase with the progression of ARF. However, this increase was significantly attenuated by ingestion of cobalt. The level of mRNA and protein of both rOAT1 and rOAT3 were markedly depressed in the ischemic kidney. The uptake of p-aminohippuric acid (PAH) and estrone sulfate (ES) by renal slices of ischemic rats was significantly reduced compared to control rats. Renal slices taken from ischemic rats treated with cobalt displayed significantly elevated levels of ES uptake. Cobalt intake did not affect PAH uptake, indicating the functional restoration of rOAT3 but not rOAT1. The expression of Na(+)/K(+)-ATPase was markedly depressed in the ischemic kidney, suggesting that the inward Na(+) gradient in renal tubular cells had collapsed, thereby reducing the outward gradient of alpha-ketoglutarate, a driving force of both rOATs. The decreased expression of Na(+)/K(+)-ATPase was significantly restored by cobalt treatment. Our results suggest that the downregulation of renal rOAT1 and rOAT3 could be responsible for the increase in serum IS level of ischemic rats. Cobalt treatment has a significant protective effect on ischemia-induced ARF, being accompanied by the restoration of rOAT3 and/or Na(+)/K(+)-ATPase function.

Effect of integrated traditional Chinese and Western medicine therapy on progression of acute renal failure in patients with chronic renal insufficiency: a short-term clinical study

To evaluate the effect of integrated traditional Chinese and Western medicine therapy on the progression of acute renal failure in patients with chronic renal insufficiency. Thirty-two patients with chronic renal insufficiency developed acute renal failure recently were treated with Chinese herbs and western drugs intravenously and clysterizing of Chinese herbs liquid for 30 minutes, and the treatment course was 14 days. Assessment of liver and renal function, blood routine, electrolytes and endogenous creatinine clearance rate (Ccr) was performed before and 2 weeks after the treatment. The levels of hemoglobin (HB), white blood cell count (WBC) and serum electrolytes showed no significant changes after the treatment. The levels of blood urea nitrogen (BUN) and serum creatinine (SCr) decreased, while the level of Ccr increased significantly (P<0.05) after the treatment. The total effective rate was 65.6%. The integrated traditional Chinese and Western medicine therapy can effectively delay the deterioration of renal function in patients with chronic renal insufficiency accompanied by acute renal failure.

Tumor necrosis factor-α and lipopolysaccharide induce apoptotic cell death in bovine glomerular endothelial cells

The glomerular endothelial cell is a specialized microvascular cell type involved in the regulation of glomerular ultrafiltration. During gram-negative sepsis, glomerulonephritis, and acute renal failure, bacterial lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha) may cause severe cell damage. Our aim was to study and compare the direct effects of TNF-alpha and LPS on the induction of apoptosis in bovine glomerular endothelial cells. Primary bovine glomerular endothelial cells were stimulated with TNF-alpha or LPS, and apoptotic cell death was investigated by DNA fragmentation analysis, morphological studies, measurement of cytochrome c efflux and mitochondrial permeability transition, Bak, Bad, Bax, Bcl-2, Bcl-xL protein expression, and caspase-3-like protease activity. TNF-alpha, as well as LPS, elicited apoptotic cell death both time and concentration dependently. Along with DNA ladder formation, we detected the formation of 50 kbp high molecular weight DNA fragments, nuclear condensation, and mitochondrial permeability transition. Concerning all parameters, LPS signaling proved to be more rapid than TNF-alpha. Mechanistically, TNF-alpha-induced cell death was preceded by an efflux of mitochondrial cytochrome c into the cytosol and, subsequently, by a marked increase in the proapoptotic protein Bak and a decrease in the anti-apoptotic Bcl-xL protein content. Comparable but more pronounced effects were seen with LPS. Later, caspase-3-like protease activity was first detectable after 10 hours and was continuously increased up to 24 hours in both TNF-alpha- and LPS-stimulated cells. Correspondingly, we detected an extended cleavage of the nuclear enzyme poly(ADP-ribose) polymerase. Caspase inhibitors Z-Asp-CH2-DCB and Z-VAD-fmk blocked both TNF-alpha- and LPS-induced apoptosis in a comparable manner. Only Z-Asp-CH2-DCB was able to block apoptotic cell death completely. Both bacterial LPS and TNF-alpha potently induced apoptotic cell death in glomerular endothelial cells. Direct endotoxin-induced apoptosis may therefore be relevant in the progression of acute renal failure, which is a frequent complication of gram-negative sepsis.