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Mucin 1 (or MUC1) is a heterodimeric transmembrane glycoprotein expressed on the apical surface of polarized epithelial cells in several tissues including the kidney. Recent studies have revealed several novel roles for MUC1 in the kidney, potentially including bacterial infection, mineral balance, and genetic interstitial kidney disease, even though MUC1 levels are reduced not only in the kidney but in all tissues due to MUC1 mutations. A careful localization of MUC1 in discrete segments of the nephron is a first step in understanding the multiple functional roles of MUC1 in the kidney. Most published reports of MUC1 expression to date have been largely confined to cultured cells, tumor tissues, selective nephron segments of experimental rodents, and very few studies have been performed using human kidney tissues. Given the rising attention to the role of MUC1 in differing components of renal physiology, we carefully examined the kidney distribution of MUC1 in both human and mouse kidney sections using well-defined markers for different nephron segments or cell types. We further extended our investigation to include sections of early stages of mouse kidney development and upon injury in humans. We included staining for MUC1 in urothelial cells, the highly specialized epithelial cells lining the renal pelvis and bladder. These data implicate a role for MUC1 in antimicrobial defense. Our study provides the groundwork to test the physiological relevance of MUC1 in the urinary tract.

Objectives: Whether metformin exposure is associated with improved outcomes in patients with type 2 diabetes mellitus and sepsis., Design: Retrospective cohort study., Setting: Patients admitted to ICUs in 16 hospitals in Pennsylvania from October 2008 to December 2014., Patients: Adult critical ill patients with type 2 diabetes mellitus and sepsis., Interventions: None., Measurements and Main Results: We conducted a retrospective cohort study to compare 90-day mortality in diabetic patients with sepsis with and without exposure to metformin during hospitalization. Data were obtained from the electronic health record of a large healthcare system in Pennsylvania from October 2008 to December 2014, on patients admitted to the ICU at any of the 16 hospitals within the system. The primary outcome was mortality at 90 days. The absolute and adjusted odds ratio (OR) with 95% CI were calculated in a propensity score-matched cohort. Among 14,847 patients with type 2 diabetes mellitus and sepsis, 682 patients (4.6%) were exposed to metformin during hospitalization and 14,165 (95.4%) were not. Within a total of 2,691 patients subjected to propensity score-matching at a 1:4 ratio, exposure to metformin (n = 599) was associated with decreased 90-day mortality (71/599, 11.9% vs 475/2,092, 22.7%; OR, 0.46; 95% CI, 0.35-0.60), reduced severe acute kidney injury (50% vs 57%; OR, 0.75; 95% CI, 0.62-0.90), less Major Adverse Kidney Events at 1 year (OR, 0.27; 95% CI, 0.22-0.68), and increased renal recovery (95% vs 86%; OR, 6.43; 95% CI, 3.42-12.1)., Conclusions: Metformin exposure during hospitalization is associated with a decrease in 90-day mortality in patients with type 2 diabetes mellitus and sepsis., Competing Interests: Dr. Gomez reports support as principal investigator of the Limiting Acute Kidney Injury Progression in Sepsis (LAPIS) trial from Biomerieux. Drs. Gomez and Murugan report personal fees from AM-Pharma for enrolling patients in clinical trial of recombinant alkaline phosphatase in sepsis-associated acute kidney injury. Drs. Gomez’s, Zuckerbraun’s, and Angus’s institutions received funding from the National Institute of General Medical Sciences. Drs. Gomez, Zuckerbraun, Murugan, and Angus received support for article research from the National Institutes of Health (NIH). Dr. Priyanka disclosed work for hire. Dr. Zuckerbraun’s institution received funding from the Veteran’s Affairs; he disclosed government work. Dr. Murugan’s institution received funding from AM Pharma and Baxter; he received funding from the National Institute of Diabetes and Digestive and Kidney Diseases; and he disclosed the off-label product use of metformin of sepsis-associated acute kidney injury. Dr. Angus’ institution received funding from the NIH (R01 NR018434) and (R01 HS025146). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Acute kidney injury (AKI) is one of the most important complications of critical illness and a significant public health concern. AKI is commonly associated with sepsis, cardiac dysfunction, and exposure to nephrotoxic medication; however, less common causes of AKI can lead to devastating patient outcomes when the underlying diagnosis is missed or delayed. These uncommon causes of AKI fall into 3 large categories: structural, immune mediated, and microvascular, including various types of thrombotic microangiopathy. Kidney imaging, urine studies, and serum hemolytic studies should be a routine part of the evaluation of AKI among critically ill patients., Competing Interests: Disclosure J.A. Kellum discloses grant support and consulting fees from Astute Medical/BioMerieuxand Baxter and is currently a full-time employee of Spectral Medical. H. Gómez discloses grant support and consulting fees from BioMerieux. All other authors declare no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Significance: Acute kidney injury (AKI) is a common and life-threatening complication in hospitalized and critically ill patients. It is defined by an abrupt deterioration in renal function, clinically manifested by increased serum creatinine levels, decreased urine output, or both. To execute all its functions, namely excretion of waste products, fluid/electrolyte balance, and hormone synthesis, the kidney requires incredible amounts of energy in the form of adenosine triphosphate. Recent Advances: Adequate mitochondrial functioning and nicotinamide adenine dinucleotide (NAD + ) homeostasis are essential to meet these high energetic demands. NAD + is a ubiquitous essential coenzyme to many cellular functions. NAD + as an electron acceptor mediates metabolic pathways such as oxidative phosphorylation (OXPHOS) and glycolysis, serves as a cosubstrate of aging molecules ( i.e. , sirtuins), participates in DNA repair mechanisms, and mediates mitochondrial biogenesis. Critical Issues: In many forms of AKI and chronic kidney disease, renal function deterioration has been associated with mitochondrial dysfunction and NAD + depletion. Based on this, therapies aiming to restore mitochondrial function and increase NAD + availability have gained special attention in the last two decades. Future Directions: Experimental and clinical studies have shown that by restoring mitochondrial homeostasis and increasing renal tubulo-epithelial cells, NAD + availability, AKI incidence, and chronic long-term complications are significantly decreased. This review covers some general epidemiological and pathophysiological concepts; describes the role of mitochondrial homeostasis and NAD + metabolism; and analyzes the underlying rationale and role of NAD + aiming therapies as promising preventive and therapeutic strategies for AKI. Antioxid. Redox Signal . 35, 1449-1466.

Aims: We sought to investigate the relationship between macrohemodynamic resuscitation and microcirculatory parameters with the response of microcirculatory flow, tissue-specific parameters of metabolic stress and injury. We hypothesized that early resuscitation based on macrohemodynamic parameters does not prevent the development of organ dysfunction in a porcine model of endotoxemic shock, and that sublingual microcirculatory parameters are associated with markers of tissue metabolic stress and injury. Results: Both resuscitation groups had significant increases in creatinine and neutrophil gelatinase-associated lipocalin as compared with baseline. Neither the macrovascular response to endotoxemia or resuscitation, nor group allocation predicted the development of acute kidney injury (AKI). Only a microvascular flow index (MFI) <2.5 was associated with the development of renal tubular injury and AKI, and with increased renal, liver, peritoneal, and sublingual lactate/pyruvate (L/P) ratio and lactate. Among systemic parameters, only partial pressure of carbon dioxide (PCO 2 ) gap >6 and P(a-v)CO 2 /C(v-a)O 2 >1.8 were associated with increased organ L/P ratio and AKI. Innovation and Conclusion: Our findings demonstrate that targeting macrohemodynamics to guide resuscitation during endotoxemic shock failed to predict tissue metabolic stress and the response of the microvasculature to resuscitation, and was unsuccessful in preventing tubular injury and AKI. Mechanistically, our data suggest that loss of hemodynamic coherence and decoupling of microvascular flow from tissue metabolic demand during endotoxemia may explain the lack of association between macrohemodynamics and perfusion goals. Finally, we demonstrate that MFI, PCO 2 gap, and P(v-a)CO 2 /C(a-v)O 2 ratio outperformed macrohemodynamic parameters at predicting the development of renal metabolic stress and tubular injury, and therefore, that these indices merit further validation as promising resuscitation targets. Antioxid. Redox Signal . 35, 1407-1425.

Acute kidney injury (AKI) is a frequent complication of sepsis that increases mortality and the risk of progression to chronic kidney disease. However, the mechanisms leading to sepsis-associated AKI are still poorly understood. The recognition that sepsis induces organ dysfunction in the absence of overt necrosis or apoptosis has led to the consideration that tubular epithelial cells (TEC) may deploy defense mechanisms to survive the insult. This concept dovetails well with the notion that the defense against infection does not only depend on the capacity of the immune system to limit the microbial load (known as resistance), but also on the capacity of cells and tissues to limit tissue injury (known as tolerance). In this review, we discuss the importance of TEC metabolic reprogramming as a defense strategy during sepsis, and how this cellular response is likely to operate through a tolerance mechanism. We discuss the fundamental role of specific regulatory nodes and of mitochondria in orchestrating this response, and how this opens avenues for the exploration of targeted therapeutic strategies to prevent or treat sepsis-associated AKI.

Sepsis-associated acute kidney injury (S-AKI) is a common and life-threatening complication in hospitalized and critically ill patients. It is characterized by rapid deterioration of renal function associated with sepsis. The pathophysiology of S-AKI remains incompletely understood, so most therapies remain reactive and nonspecific. Possible pathogenic mechanisms to explain S-AKI include microcirculatory dysfunction, a dysregulated inflammatory response, and cellular metabolic reprogramming. In addition, several biomarkers have been developed in an attempt to improve diagnostic sensitivity and specificity of S-AKI. This article discusses the current understanding of S-AKI, recent advances in pathophysiology and biomarker development, and current preventive and therapeutic approaches., Competing Interests: Disclosure H. Gomez received a research grant from TES pharma to study mechanisms of AKI in sepsis, and is site principal investigator of an industry-sponsored grant (AM Pharma) to study the effect of recombinant alkaline phosphatase in sepsis-induced AKI., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The purpose was to determine the role of AMPK activation in the renal metabolic response to sepsis, the development of sepsis-induced acute kidney injury (AKI) and on survival. In a prospective experimental study, 167 10- to 12-week-old C57BL/6 mice underwent cecal ligation and puncture (CLP) and human proximal tubule epithelial cells (TEC; HK2) were exposed to inflammatory mix (IM), a combination of lipopolysaccharide (LPS) and high mobility group box 1 (HMGB1). Renal/TEC metabolic fitness was assessed by monitoring the expression of drivers of oxidative phosphorylation (OXPHOS), the rates of utilization of OXPHOS/glycolysis in response to metabolic stress, and mitochondrial function by measuring O 2 consumption rates (OCR) and the membrane potential (Δψ m ). Sepsis/IM resulted in AKI, increased mortality, and in renal AMPK activation 6-24 hours after CLP/IM. Pharmacologic activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or metformin during sepsis improved the survival, while AMPK inhibition with Compound C increased mortality, impaired mitochondrial respiration, decreased OCR, and disrupted TEC metabolic fitness. AMPK-driven protection was associated with increased Sirt 3 expression and restoration of metabolic fitness. Renal AMPK activation in response to sepsis/IM is an adaptive mechanism that protects TEC, organs, and the host by preserving mitochondrial function and metabolic fitness likely through Sirt3 signaling., (© 2020 Federation of American Societies for Experimental Biology.)

Hemolytic uremic syndrome is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome have a similar clinical presentation. Diagnostic needs to be prompt to decrease mortality, because identifying the different disorders can help to tailor specific, effective therapies. However, diagnosis is challenging and morbidity and mortality remain high, especially in the critically ill population. Development of clinical prediction scores and rapid diagnostic tests for hemolytic uremic syndrome based on mechanistic knowledge are needed to facilitate early diagnosis and assign timely specific treatments to patients with hemolytic uremic syndrome variants., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Sepsis-associated acute kidney injury (S-AKI) is a frequent complication of the critically ill patient and is associated with unacceptable morbidity and mortality. Prevention of S-AKI is difficult because by the time patients seek medical attention, most have already developed acute kidney injury. Thus, early recognition is crucial to provide supportive treatment and limit further insults. Current diagnostic criteria for acute kidney injury has limited early detection; however, novel biomarkers of kidney stress and damage have been recently validated for risk prediction and early diagnosis of acute kidney injury in the setting of sepsis. Recent evidence shows that microvascular dysfunction, inflammation, and metabolic reprogramming are 3 fundamental mechanisms that may play a role in the development of S-AKI. However, more mechanistic studies are needed to better understand the convoluted pathophysiology of S-AKI and to translate these findings into potential treatment strategies and add to the promising pharmacologic approaches being developed and tested in clinical trials., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)