For more than 40 years, nephrologists have classified diminished kidney function as two distinct syndromes — acute and chronic kidney failure. Whereas chronic kidney disease was recognized in the 19th century, acute renal dysfunction became evident during the London Blitz of World War II, with the realization that crush injuries could cause dramatic but often reversible cessation of renal function. The disease states and stages of both acute and chronic renal syndromes are delineated according to the serum creatinine concentration or the glomerular filtration rate (GFR), functional markers that were identified in the early 20th century. 1 Advanced renal impairment in both syndromes is treated with dialysis. During the past decade, separate conceptual models for chronic kidney disease 2 and acute kidney injury 3 were developed to facilitate organized approaches to clinical research and trials. However, recent epidemiologic and mechanistic studies suggest that the two syndromes are not distinct entities but rather are closely interconnected — chronic kidney disease is a risk factor for acute kidney injury, acute kidney injury is a risk factor for the development of chronic kidney disease, and both acute kidney injury and chronic kidney disease are risk factors for cardiovascular disease (Fig. 1). 4

/pdf/acute-kidney-injury-and-chronic-kidney-disease-as-5dhyb7ewbm.pdf

Acute kidney injury and chronic kidney disease as interconnected syndromes

Exosomes are nano-sized biovesicles released into surrounding body fluids upon fusion of multivesicular bodies and the plasma membrane. They were shown to carry cell-specific cargos of proteins, lipids, and genetic materials, and can be selectively taken up by neighboring or distant cells far from their release, reprogramming the recipient cells upon their bioactive compounds. Therefore, the regulated formation of exosomes, specific makeup of their cargo, cell-targeting specificity are of immense biological interest considering extremely high potential of exosomes as non-invasive diagnostic biomarkers, as well as therapeutic nanocarriers. In present review, we outline and discuss recent progress in the elucidation of the regulatory mechanisms of exosome biogenesis, the molecular composition of exosomes, and technologies used in exosome research. Furthermore, we focus on the potential use of exosomes as valuable diagnostic and prognostic biomarkers for their cell-lineage and state-specific contents, and possibilities as therapeutic vehicles for drug and gene delivery. Exosome research is now in its infancy, in-depth understanding of subcellular components and mechanisms involved in exosome formation and specific cell-targeting will bring light on their physiological activities.

/pdf/exosomes-biogenesis-biologic-function-and-clinical-potential-ylb0hy1ubp.pdf

Exosomes: biogenesis, biologic function and clinical potential

https://academicworks.medicine.hofstra.edu/cgi/viewcontent.cgi?article=1534&context=articles

HMGB1 in Health and Disease

https://www.kidney-international.org/article/S0085-2538(15)55599-3/pdf

Acute kidney injury and chronic kidney disease: An integrated clinical syndrome

The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG I...

/pdf/angiotensin-ii-signal-transduction-an-update-on-mechanisms-27svg1pkn9.pdf

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology.

https://www.kidney-international.org/article/S0085-2538(15)54974-0/pdf

Chronic kidney disease worsens sepsis and sepsis-induced acute kidney injury by releasing High Mobility Group Box Protein-1.

Chronic kidney disease (CKD) is associated with persistent low-grade inflammation and immunosuppression. In this study we tested the role of Toll-like receptor 4, the main receptor for endotoxin (LPS), in a mouse model of renal fibrosis and in a model of progressive CKD that better resembles the human disease. C3HeJ (TLR4 mutant) mice have a missense point mutation in the TLR4 gene, rendering the receptor nonfunctional. In a model of renal fibrosis after folic acid injection, TLR4 mutant mice developed less interstititial fibrosis in comparison to wild-type (WT) mice. Furthermore, 4 weeks after 5/6 nephrectomy with continuous low-dose angiotensin II infusion, C3HeOuJ (TLR4 WT) mice developed progressive CKD with albuminuria, increased serum levels of BUN and creatinine, glomerulosclerosis, and interstitial fibrosis, whereas TLR4 mutant mice were significantly protected from CKD progression. TLR4 WT mice also developed low-grade systemic inflammation, splenocyte apoptosis and increased expression of the immune inhibitory receptor PD-1 in the spleen, which were not observed in TLR4 mutant mice. In vitro, endotoxin (LPS) directly upregulated NLRP3 inflammasome expression in renal epithelial cells via TLR4. In summary, TLR4 contributes to renal fibrosis and CKD progression, at least in part, via inflammasome activation in renal epithelial cells, and may also participate in the dysregulated immune response that is associated with CKD.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.14814/phy2.12558

TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression

Renal Wilms' tumor-1 (WT-1) staining is used to detect podocyte loss in kidney biopsies We aimed to determine if urinary exosomal WT-1 could serve as a noninvasive biomarker of podocyte injury We examined WT-1 by Western blot in a human podocyte-like cell line, a mouse model of podocyte injury, and human subjects with podocyte disorders WT-1 was detected in exosomal fraction of the conditioned media from podocytes and increased 48 h after hTGF-β1 stimulation Cellular WT-1 decreased in podocytes following hTGF-β1 incubation In mice with induced podocyte injury, urinary exosomal WT-1 was detected 1 wk earlier than albuminuria and also tracked the effects of angiotensin receptor blocker (ARB) treatment In addition, urinary exosomal WT-1 levels at 1 wk post-injury correlated with the severity of glomerular injury at 3 wk later In human subjects, urinary exosomal WT-1 was significantly increased in focal segmental glomerulosclerosis (FSGS) patients compared with healthy volunteers or steroid-sensitive nephrotic syndrome (SSNS) patients Urinary exosomal WT-1 was also significantly decreased in patients in remission for either FSGS or SSNS or following steroid treatment in six SSNS subjects We conclude that urinary exosomal WT-1 is a promising noninvasive biomarker with apparent podocyte specificity that can detect early progression and treatment-induced regression of podocyte injury in FSGS or SSNS These results warrant longitudinal, prospective studies in a large cohort with a range of podocyte diseases

Urinary exosomal Wilms' tumor-1 as a potential biomarker for podocyte injury.

Acute kidney injury (AKI) dramatically increases sepsis mortality, but AKI diagnosis is delayed when based on serum creatinine (SCr) changes, due in part, to decreased creatinine production. During experimental sepsis, we compared serum cystatin C (sCysC), SCr, and blood urea nitrogen (BUN) to inulin glomerular filtration rate (iGFR) before or 3–18 h after cecal ligation and puncture (CLP)-induced sepsis in CD-1 mice. sCysC had a faster increase and reached peak levels more rapidly than SCr in both sepsis and bilateral nephrectomy (BiNx) models. sCysC was a better surrogate of iGFR than SCr during sepsis. Combining sCysC with SCr values into a composite biomarker improved correlation with iGFR better than any biomarker alone or any other combination. We determined the renal contribution to sCysC handling with BiNx. sCysC and SCr were lower post-BiNx/CLP than post-BiNx alone, despite increased inflammatory and nonrenal organ damage biomarkers. Sepsis decreased CysC production in nephrectomized mice without changing body weight or CysC space. Sepsis decreased sCysC production and increased nonrenal clearance, similar to effects of sepsis on SCr. sCysC, SCr, and BUN were measured 6 h postsepsis to link AKI with mortality. Mice with above-median sCysC, BUN, or SCr values 6 h postsepsis died earlier than mice with below-median values, corresponding to a substantial AKI association with sepsis mortality in this model. sCysC performs similarly to SCr in classifying mice at risk for early mortality. We conclude that sCysC detects AKI early and better reflects iGFR in CLP-induced sepsis. This study shows that renal biomarkers need to be evaluated in specific contexts.

https://www.physiology.org/doi/pdf/10.1152/ajprenal.00025.2013

Takayuki Tsuji

Papers

Chronic kidney disease worsens sepsis and sepsis-induced acute kidney injury by releasing High Mobility Group Box Protein-1.

TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression

Urinary exosomal Wilms' tumor-1 as a potential biomarker for podocyte injury.

Comparison of serum creatinine and serum cystatin C as biomarkers to detect sepsis-induced acute kidney injury and to predict mortality in CD-1 mice