A case of immersion‐induced acute kidney injury: did momentary hypoxia affect tubular damage?

Aim.Reveal morphological and immunohistochemical predictors of reversibility of dialysis-dependent acute kidney injury (AKI) in patients with myeloma cast nephropathy (MCN) based on the study of kidney biopsy. Materials and methods.Renal pathological findings were studied in 36 patients with MCN and dialysis-dependent stage 3 AKI (AKIN, 2012). The study of biopsy samples was performed by a semi-quantitative and quantitative analysis using computer morphometry. The expression of E-cadherin, vimentin and-smooth muscle actin was determined immunohistochemically in the tubular cells and interstitium. Induction therapy for 26 patients was carried out to bortezomib-based programs; in 10 patients other schemes were used. A comparative analysis of morphological changes in nephrobiopathy depending on the renal response was performed in patients with achieved hematologic remission. Results.Improved renal function was observed only in patients with hematologic response to therapy. There were no differences in the number of sclerotic glomeruli, protein casts, the area of inflammatory interstitial infiltration, and the degree of acute tubular damage in patients with and without renal response. In patients with renal response compared with patients without improving renal function, the area of interstitial fibrosis was less (24.9% and 45.9%, respectively;p=0.001), and the area of E-cadherin expression was larger (15.9% and 7.1%, respectively;p=0.006). Interstitial fibrosis of 40% or more and/or the area of expression of E-cadherin less than 10% of the area of tubulo-interstitium have an unfavorable prognostic value in achieving a renal response in MCN. Conclusion.If the interstitial fibrosis area is 40% or more and the expression area of E-cadherin is less than 10%, the probability of the absence of a renal response is 93.3% (OR=24.5) even when a hematological response to induction therapy is achieved. The number of protein casts, the prevalence of acute tubular damage and inflammatory interstitial infiltration have not prognostic value.

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Soluble receptor for advanced glycation end products protects from ischemia- and reperfusion-induced acute kidney injury

Biology Open ◽

10.1242/bio.058852 ◽

2021 ◽

Author(s):

Taro Miyagawa ◽

Yasunori Iwata ◽

Megumi Oshima ◽

Hisayuki Ogura ◽

Koichi Sato ◽

...

Keyword(s):

Acute Kidney Injury ◽

Advanced Glycation End Products ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Tubular Damage ◽

Advanced Glycation ◽

Renal Tubular Damage ◽

Glycation End Products ◽

End Products ◽

Renal Tubular

The full-length receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor. High-mobility group box 1 (HMGB1) is a RAGE ligand of damage-associated molecular patterns that elicits inflammatory reactions. The shedded isoform of RAGE and endogenous secretory RAGE (esRAGE), a splice variant, are soluble isoforms (sRAGE) that act as organ-protective decoys. However, the pathophysiologic roles of RAGE/sRAGE in acute kidney injury (AKI) remain unclear. We found that AKI was more severe, with enhanced renal tubular damage, macrophage infiltration, and fibrosis, in mice lacking both RAGE and sRAGE than in wild-type control mice. Using murine tubular epithelial cells (TECs), we demonstrated that hypoxia upregulated messenger RNA (mRNA) expression of HMGB1 and tumor necrosis factor α (TNF-α), whereas RAGE and esRAGE expressions were paradoxically decreased. Moreover, the addition of recombinant sRAGE canceled hypoxia-induced inflammation and promoted cell viability in cultured TECs. sRAGE administration prevented renal tubular damage in models of ischemia/reperfusion-induced AKI and of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. These results suggest that sRAGE is a novel therapeutic option for AKI.

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TAK1 deficiency attenuates cisplatin-induced acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00516.2019 ◽

2020 ◽

Vol 318 (1) ◽

pp. F209-F215 ◽

Cited By ~ 2

Author(s):

Jun Zhou ◽

Changlong An ◽

Xiaogao Jin ◽

Zhaoyong Hu ◽

Robert L. Safirstein ◽

...

Keyword(s):

Acute Kidney Injury ◽

Proximal Tubule ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Kidney Injury ◽

Transforming Growth Factor Β ◽

Tubular Epithelial Cell ◽

Tubular Damage ◽

Wild Type ◽

Deficient Mice

Cisplatin can cause acute kidney injury (AKI), but the molecular mechanisms are not well understood. The objective of the present study was to examine the role of transforming growth factor-β-activated kinase-1 (TAK1) in the pathogenesis of cisplatin-induced AKI. Wild-type mice and proximal tubule TAK1-deficient mice were treated with vehicle or cisplatin. Compared with wild-type control mice, proximal tubule TAK1-deficient mice had less severe kidney dysfunction, tubular damage, and apoptosis after cisplatin–induced AKI. Furthermore, conditional disruption of TAK1 in proximal tubular epithelial cells reduced caspase-3 activation, proinflammatory molecule expression, and JNK phosphorylation in the kidney in cisplatin-induced AKI. Taken together, cisplatin activates TAK1-JNK signaling pathway to promote tubular epithelial cell apoptosis and inflammation in cisplatin-induced AKI. Targeting TAK1 could be a novel therapeutic strategy against cisplatin-induced AKI.

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Regulation of Fn14 stability by SCFFbxw7α during septic acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00627.2018 ◽

2019 ◽

Vol 316 (6) ◽

pp. F1273-F1281 ◽

Cited By ~ 1

Author(s):

Shi-Jing Mo ◽

Wei Zhang ◽

Jing-Quan Liu ◽

Min-Hua Chen ◽

Liang Xu ◽

...

Keyword(s):

Acute Kidney Injury ◽

Kidney Injury ◽

Tubular Damage ◽

Adaptive Mechanism ◽

Toll Like Receptor ◽

Effective Protection ◽

Potential Therapeutic Target ◽

Septic Acute Kidney Injury ◽

Lethal Sepsis ◽

Tlr4 Activation

Acute kidney injury (AKI) initiated by sepsis remains a thorny problem despite recent advancements in its clinical management. Having been found to be activated during AKI, fibroblast growth factor-inducible molecule 14 (Fn14) may be a potential therapeutic target because of its involvement in the molecular basis of injury. Here, we report that LPS induces apoptosis of mouse cortical tubule cells mediated by Fn14, for which simultaneous Toll-like receptor (TLR)4 activation is required. Mechanistically, TLR4 activation by lipopolysaccharide, through disassociating E3 ligase SCFFbxw7α from Fn14, dismantles Lys48-linked polyubiquitination of Fn14 and stabilizes it. Pharmacological deactivation of Fn14 with monoclonal antibody ITEM-2 provides effective protection against lethal sepsis and AKI in mice. Our study underscores an adaptive mechanism whereby TLR4 regulates SCFFbxw7α-dependent Fn14 stabilization during inflammatory tubular damage and further supports investigation of targeting Fn14 in clinical trials of patients with septic AKI.

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P1828A PANEL OF URINE BIOMARKERS FOR EARLY KIDNEY INJURY DETECTION IN NEWBORNS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1828 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Irina Pevzner ◽

Kirill Goryunov ◽

Valentina Vtorushina ◽

Vasily Popkov ◽

Denis Silachev ◽

...

Keyword(s):

Acute Kidney Injury ◽

Urinary Excretion ◽

Kidney Injury ◽

Kidney Damage ◽

Urine Samples ◽

Reference Level ◽

Control Group ◽

Tubular Damage ◽

Urine Biomarkers ◽

Rate Of Increase

Abstract Background and Aims Neonatal kidney damage is a wide spread pathology, especially among preterm infants. Acute kidney injury (AKI) in newborns remains one of the most important problems because the features of neonatal nephrogenesis and physiology. The current clinical criteria for the diagnosis of AKI, including pediatric scales pRIFLE and nRIFLE, rely on glomerulal filtration rate (GFR), blood urea nitrogen (BUN), and serum creatinine (SCr), which are the late biomarkers detectable only within days or weeks after kidney damage occurred, and therefore have limitations when used within the first days after birth. Therefore, sensitive and specific tests for early diagnostics of kidney injury are extremely needed in neonatology. Urine biomarkers appear to be promising for early diagnosis of AKI. Quite often renal pathologies result in markedly increased (or decreased) urinary excretion of a number of protein biomarkers, indicating subclinical tubular injury while conventional AKI signs are not manifested yet. The aim of this study was to determine clinical value of urine molecular biomarkers for the prediction of acute kidney injury in newborns. Method Urine samples from newborns with congenital malformation were collected on the 1st day after born, and then once a week until the 21th postnatal day. Urine samples were centrifuged, aliquoted and stored at –80°С until testing. The next urinary biomarkers were analyzed: calbindin 1, clusterin, IL-18, KIM-1, GST-π, MCP-1 and NGAL. Quantitative determination was performed with immunoassay kit Bio-Plex Pro™ RBM Human Kidney Toxicity Panel 1 (Bio-Rad Inc., USA) and Human NGAL ELISA kit (Invitrogen, Germany). Control group included five age-matched healthy infants. Results 8 of 20 patients showed a direct correlation of increased NGAL levels in urine (50-fold compared to control group) with high levels of C-reactive protein in the blood (3-10-fold rise above the reference level). NGAL is the most sensitive marker for assessing AKI or tubular damage. These 8 patients were further investigated for other urine biomarkers. The IL-18 level in urine was slightly increased in 4 patients. IL-18 is proposed to be a predictor for AKI severity and mortality in children with critical illness. KIM-1 has low basal expression in the normal kidney but its appearance is highly specific and sensitive sign for nephrotoxicity in proximal tubules. We observed the increase of KIM-1 urinary excretion for 7 patients. However, we discover the equal occurrence of decrease or increase of urine MCP-1 through studied patients. Elevated levels of urine MCP-1 were earlier observed in experimental maleate induced azotemia, LPS injection and in model of unilateral ureteral obstruction (UUO). An increase of KIM-1 and/or MCP-1 urinary excretion is known to be associated with some risk of AKI development. We found 3-fold growth of urine clusterin in 7 children. It is noticed, that clusterin increased in damaged tubular cells during polycystic kidney disease and renal carcinoma. Additionally, we revealed 7-fold decrease of calbindin 1 in urine of 7 patients. Сalbindin 1 exclusively localized in the kidney distal nephron segment, and its decrease was discribed for models of UUO, glomerulonephritis and cisplatin nephropathy. GST-π protein is found in cells lining the lumen of the distal tubules and is elevated in the urine of patients with sepsis, independently of accompanied AKI. We also observed 10- to 20-fold rising of urine GST-π for all 8 NGAL-positive newborns. Conclusion The specificity, rate of increase, and non-invasive detection of urine markers studied in this work, make them indispensable in clinical practice. However, their use in neonatology is still experimental. We showed potential applicability of wide biomarker panel for early detection and prediction of AKI in newborns.

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Kidney Tubular Damage and Functional Biomarkers in Acute Kidney Injury Following Cardiac Surgery

Kidney International Reports ◽

10.1016/j.ekir.2019.05.005 ◽

2019 ◽

Vol 4 (8) ◽

pp. 1131-1142 ◽

Cited By ~ 5

Author(s):

Javier A. Neyra ◽

Ming-Chang Hu ◽

Abu Minhajuddin ◽

Geoffrey E. Nelson ◽

Syed A. Ahsan ◽

...

Keyword(s):

Acute Kidney Injury ◽

Cardiac Surgery ◽

Kidney Injury ◽

Tubular Damage ◽

Functional Biomarkers

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P2X7 receptor inhibition protects against ischemic acute kidney injury in mice

AJP Cell Physiology ◽

10.1152/ajpcell.00245.2014 ◽

2015 ◽

Vol 308 (6) ◽

pp. C463-C472 ◽

Cited By ~ 37

Author(s):

Yanli Yan ◽

Jianwen Bai ◽

Xiaoxu Zhou ◽

Jinhua Tang ◽

Chunming Jiang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Dysfunction ◽

P2x7 Receptor ◽

Renal Tubule ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Tubular Damage ◽

Protective Effects ◽

Proinflammatory Response ◽

Hypertensive Nephropathy

Activation of the purinergic P2X7 receptor (P2X7R) has been associated with the development of experimental nephritis and diabetic and hypertensive nephropathy. However, its role in acute kidney injury (AKI) remains unknown. In this study, we examined the effects of P2X7R inhibition in a murine model of ischemia-reperfusion (I/R)-induced AKI using A438079, a selective inhibitor of P2X7R. At 24 h after I/R, mice developed renal dysfunction and renal tubular damage, which was accompanied by elevated expression of P2X7R. Early administration of A438079 immediately or 6 h after the onset of reperfusion protected against renal dysfunction and attenuated kidney damage whereas delayed administration of A438079 at 24 h after restoration of perfusion had no protective effects. The protective actions of A438079 were associated with inhibition of renal tubule injury and cell death and suppression of renal expression of monocyte chemotactic protein-1 and regulated upon expression normal T cell expressed and secreted (RANTES). Moreover, I/R injury led to an increase in phosphorylation (activation) of extracellular signal-regulated kinases 1/2 in the kidney; treatment with A438079 diminished this response. Collectively, these results indicate that early P2X7R inhibition is effective against renal tubule injury and proinflammatory response after I/R injury and suggest that targeting P2X7R may be a promising therapeutic strategy for treatment of AKI.

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Methemoglobinemia-Induced Acute Kidney Injury

The Open Urology & Nephrology Journal ◽

10.2174/1874303x01306010036 ◽

2013 ◽

Vol 6 (1) ◽

pp. 36-41 ◽

Cited By ~ 2

Author(s):

Amir H. Qureshi ◽

Daniel J. Soberon ◽

Arif Asif ◽

Tushar Vachharajani ◽

Ali Nayer

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Renal Biopsy ◽

Case Reports ◽

Kidney Injury ◽

Human Case ◽

Morphological Features ◽

Chronic Obstructive ◽

Tubular Damage ◽

Obstructive Pulmonary Disease

IntroductionMethemoglobinemia refers to the presence of increased levels of methemoglobin (Fe3+) in the blood. Methemoglobinemia can cause cyanosis, dyspnea, fatigue, seizure, arrhythmia, coma, and even death. Although methemoglobinemia is shown to cause acute kidney injury in experimental settings, human case reports are exceedingly rare. In addition, morphological features of methemoglobinemia-induced renal disease in humans remain undefined.Case PresentationA 76-year-old man with a history of chronic obstructive pulmonary disease underwent bronchoscopy following local anesthesia with a benzocaine spray. The patient developed benzocaine-induced methemoglobinemia and acute renal failure. Urinalysis disclosed numerous dysmorphic erythrocytes, erythrocyte casts, and granular casts. Urine protein excretion was approximately 1.1 g/day. Serologic tests were negative. Renal biopsy demonstrated minor glomerular abnormalities, severe acute tubular necrosis, and numerous erythrocyte casts in the tubules. Despite supportive care, renal function deteriorated necessitating hemodialysis. Four months later, the patient remained on hemodialysis. To exclude a superimposed pathology, renal biopsy was repeated and showed numerous erythrocyte casts in the tubules and severe tubular damage.ConclusionMethemoglobinemia can cause acute kidney injury in humans. Morphological features resemble those observed in methemoglobin-induced acute kidney injury in experimental settings. This case calls for a heightened awareness of potential adverse effects of methemoglobinemia on renal function.

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2-Methylquinazoline derivative 23BB as a highly selective histone deacetylase 6 inhibitor alleviated cisplatin-induced acute kidney injury

Bioscience Reports ◽

10.1042/bsr20191538 ◽

2020 ◽

Vol 40 (1) ◽

Author(s):

Yan Hao ◽

Fan Guo ◽

Zhuo Huang ◽

Yuying Feng ◽

Zijing Xia ◽

...

Keyword(s):

Acute Kidney Injury ◽

Epithelial Cells ◽

Er Stress ◽

Histone Deacetylases ◽

Kidney Injury ◽

Selective Inhibition ◽

Tubular Damage ◽

Tubular Epithelial Cells ◽

Histone Deacetylase 6 ◽

Hdac6 Inhibitor

Abstract Histone deacetylases 6 (HDAC6) has been reported to be involved in the pathogenesis of cisplatin-induced acute kidney injury (AKI). Selective inhibition of HDAC6 might be a potential treatment for AKI. In our previous study, a highly selective HDAC6 inhibitor (HDAC6i) 23BB effectively protected against rhabdomyolysis-induced AKI with good safety. However, whether 23BB possessed favorable renoprotection against cisplatin-induced AKI and the involved mechanisms remained unknown. In the study, cisplatin-injected mice developed severe AKI symptom as indicated by acute kidney dysfunction and pathological changes, companied by the overexpression of HDAC6 in tubular epithelial cells. Pharmacological inhibition of HDAC6 by the treatment of 23BB significantly attenuated sCr, BUN and renal tubular damage. Mechanistically, 23BB enhanced the acetylation of histone H3 to reduce the HDAC6 activity. Cisplatin-induced AKI triggered multiple signal mediators of endoplasmic reticulum (ER) stress including PERK, ATF6 and IRE1 pathway, as well as CHOP, GRP78, p-JNK and caspase 12 proteins. Oral administration of our HDAC6i 23BB at a dose of 40 mg/kg/d for 3 days notably improved above-mentioned responses in the injured kidney tissues. HDAC6 inhibition also reduced the number of TUNEL-positive tubular cells and regulated apoptosis-related protein expression. Overall, these data highlighted that HDAC6 inhibitor 23BB modulated apoptosis via the inhibition of ER stress in the tubular epithelial cells of cisplatin-induced AKI.

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