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The use of point-of-care ultrasound (POCUS) is rapidly increasing in nephrology. It provides the opportunity to obtain complementary information that is more accurate than the classic physical examination. One can quickly follow the physical examination with a systematic POCUS evaluation of the kidneys, ureter bladder, inferior vena cava, heart, and lungs, which can provide diagnostic information and an accurate assessment of the patient's hemodynamics and volume status. Moreover, because it is safe and relatively easy to perform, it can be performed in a repeated manner as often as necessary so that the physician can reassess the patient's hemodynamics and volume status and adjust their therapy accordingly, permitting a more personalized approach to patient care (rather than blindly following protocols), especially to patients in acute care nephrology. Despite these advantages, nephrologists have been slow to adopt this diagnostic modality, perhaps because of lack of expertise. This review will provide an overview of the most commonly used POCUS examinations performed by nephrologists in the acute care setting. Its aim is to spark interest in in POCUS and to lay the foundation for readers to pursue more advanced training so that POCUS becomes a readily available tool in your diagnostic arsenal.

Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

Reactive oxygen species (ROS) are highly reactive signaling molecules that maintain redox homeostasis in mammalian cells. Dysregulation of redox homeostasis under pathological conditions results in excessive generation of ROS, culminating in oxidative stress and the associated oxidative damage of cellular components. ROS and oxidative stress play a vital role in the pathogenesis of acute kidney injury and chronic kidney disease, and it is well documented that increased oxidative stress in patients enhances the progression of renal diseases. Oxidative stress activates autophagy, which facilitates cellular adaptation and diminishes oxidative damage by degrading and recycling intracellular oxidized and damaged macromolecules and dysfunctional organelles. In this review, we report the current understanding of the molecular regulation of autophagy in response to oxidative stress in general and in the pathogenesis of kidney diseases. We summarize how the molecular interactions between ROS and autophagy involve ROS-mediated activation of autophagy and autophagy-mediated reduction of oxidative stress. In particular, we describe how ROS impact various signaling pathways of autophagy, including mTORC1-ULK1, AMPK-mTORC1-ULK1, and Keap1-Nrf2-p62, as well as selective autophagy including mitophagy and pexophagy. Precise elucidation of the molecular mechanisms of interactions between ROS and autophagy in the pathogenesis of renal diseases may identify novel targets for development of drugs for preventing renal injury.

We recently showed that α, β, and γ splice variants of neuronal nitric oxide synthase (NOS1) expressed in the macula densa and NOS1β accounts for most of the NO generation. We have also demonstrated that the mice with deletion of NOS1 specifically from the macula densa developed salt-sensitive hypertension. However, the global NOS1 knockout (NOS1KO) strain is neither hypertensive nor salt sensitive. This global NOS1KO strain is actually an NOS1αKO model. Consequently, we hypothesized that inhibition of NOS1β in NOS1αKO mice induces salt-sensitive hypertension. NOS1αKO and C57BL/6 wild-type (WT) mice were implanted with telemetry transmitters and divided into 7-nitroindazole (10 mg/kg/d)–treated and nontreated groups. All of the mice were fed a normal salt (0.4% NaCl) diet for 5 days, followed by a high-salt diet (4% NaCl). NO generation by the macula densa was inhibited by >90% in WT and NOS1αKO mice treated with 7-nitroindazole. Glomerular filtration rate in conscious mice was increased by ≈40% after a high-salt diet in both NOS1αKO and WT mice. In response to acute volume expansion, glomerular filtration rate, diuretic and natriuretic response were significantly blunted in the WT and knockout mice treated with 7-nitroindazole. Mean arterial pressure had no significant changes in mice fed a high-salt diet, but increased ≈15 mm Hg similarly in NOS1αKO and WT mice treated with 7-nitroindazole. We conclude that NOS1β, but not NOS1α, plays an important role in control of sodium excretion and hemodynamics in response to either an acute or a chronic salt loading.

Acute kidney injury (AKI) is a major cause of morbidity and mortality in hospitalized patients. Despite substantial progress being made in understanding the mechanisms contributing to the pathophysiology of AKI, we have so far been unsuccessful in devising adequate therapeutic strategies against the disease. A growing body of evidence suggests that the activation of mineralocorticoid receptors (MRs) may contribute to the exacerbation of AKI. Indeed, several studies have demonstrated the potential of MR antagonists in preventing and treating certain forms of experimental AKI. However, the main drawback of these medications is their side-effect profile. This has been addressed with the development of newer nonsteroidal MR antagonists, which have a comparable therapeutic profile without the side effects. This mini review aims at providing a brief overview of the rationale, potential benefits and challenges associated with the use of MR antagonists, particularly the novel nonsteroidal MR blockers, as therapy against AKI. © 2016 S. Karger AG, Basel.

Estimates of the incidence of radiocontrast-associated nephropathy vary widely and suffer from misclassification of the cause of AKI and confounding. Using the Nationwide Inpatient Sample, we created multiple estimates of the risk of radiocontrast-associated nephropathy among adult patients hospitalized in the United States in 2009. First, we stratified patients according to the presence or absence of 12 relatively common diagnoses associated with AKI and evaluated the rate of AKI between strata. Next, we created a logistic regression model, controlling for comorbidity and acuity of illness, to estimate the risk of AKI associated with radiocontrast administration within each stratum. Finally, we performed an analysis stratified by the degree of preexisting comorbidity. In general, patients who received radiocontrast did not develop AKI at a clinically significant higher rate. Adjusted only for the complex survey design, patients to whom radiocontrast was and was not administered developed AKI at rates of 5.5% and 5.6%, respectively. After controlling for comorbidity and acuity of illness, radiocontrast administration associated with an odds ratio for AKI of 0.93 (95% confidence interval, 0.88 to 0.97). In conclusion, the risk of radiocontrast-associated nephropathy may be overstated in the literature and overestimated by clinicians. More accurate AKI risk estimates may improve clinical decision-making when attempting to balance the potential benefits of radiocontrast-enhanced imaging and the risk of AKI.

Chronic kidney disease (CKD) is a worldwide public health problem that is increasing in prevalence, especially in the elderly. CKD and/or end stage renal disease (ESRD) patients have numerous comorbidities that increase the risk of cognitive impairment and dementia (CI/D). In fact, almost every stage of CKD is associated with an increased risk of CI/D; the risk increases as the severity of CKD increases. The mechanisms responsible for this increased risk are largely due to the accelerated vascular disease of CKD/ESRD that leads to an increase in vascular dementia. However, other factors such as increased risk of thrombotic and hemorrhagic strokes, uremic toxins, and suboptimal aspects of dialytic therapies also contribute to the development and progression of CI/D. The importance of CI/D in CKD/ESRD patients is that it impairs quality of life, and carries with it a greater risk of hospitalization, disability, dialysis withdrawal, and mortality. Despite the magnitude of the problem, CI/D is largely under-recognized in the renal patient, and optimal management strategies are unknown. The aim of this chapter is to provide an overview of the epidemiology, pathogenesis/pathophysiology, diagnostic approaches, and therapeutic considerations for CI/D in patients with CKD/ESRD.

Aim Tubuloglomerular feedback (TGF) is an important mechanism in control of signal nephron glomerular filtration rate. The oxidative stress in the macula densa, primarily determined by the interactions between nitric oxide (NO) and superoxide (O2−), is essential in maintaining the TGF responsiveness. However, few studies examining the interactions between and amount of NO and O2− generated by the macula densa during normal and hypertensive states. Methods In this study, we used isolated perfused juxtaglomerular apparatus to directly measure the amount and also studied the interactions between NO and O2− in macula densa in both physiological and slow pressor Angiotensin II (Ang II)-induced hypertensive mice. Results We found that slow pressor Ang II at a dose of 600 ng kg−1 min−1 for two weeks increased mean arterial pressure by 26.1 ± 5.7 mmHg. TGF response increased from 3.4 ± 0.2 μm in control to 5.2 ± 0.2 μm in hypertensive mice. We first measured O2− generation by the macula densa and found it was undetectable in control mice. However, O2− generation by the macula densa increased to 21.4 ± 2.5 unit min−1 in Ang II-induced hypertensive mice. We then measured NO generation and found that NO generation by the macula densa was 138.5 ± 9.3 unit min−1 in control mice. The NO was undetectable in the macula densa in hypertensive mice infused with Ang II. Conclusions Under physiological conditions, TGF response is mainly controlled by the NO generated in the macula densa; in Ang II induced hypertension, the TGF response is mainly controlled by the O2− generated by the macula densa.

Sodium transport in the thick ascending loop of Henle (TAL) is tightly regulated by numerous factors, especially angiotensin II (Ang II), a key end‐product of the renin‐angiotensin system (RAS). However, an alternative end‐product of the RAS, angiotensin‐(1‐7) [Ang‐(1‐7)], may counter some of the Ang II actions. Indeed, it causes vasodilation and promotes natriuresis through its effects in the proximal and distal tubule. However, its effects on the TAL are unknown. Because the TAL expresses the Mas receptor, an Ang‐(1‐7) ligand, which in turn may increase NO and inhibit Na+ transport, we hypothesized that Ang‐(1‐7) inhibits Na transport in the TAL, via a Mas receptor/NO‐dependent mechanism. We tested this by measuring transport‐dependent oxygen consumption (VO 2) in TAL suspensions. Administering Ang‐(1‐7) decreased VO 2; an effect prevented by dimethyl amiloride and furosemide, signifying that Ang‐(1‐7) inhibits transport‐dependent VO 2 in TAL. Ang‐(1‐7) also increased NO levels, known inhibitors of Na+ transport in the TAL. The effects of Ang‐(1‐7) on VO 2, as well as on NO levels, were ameliorated by the Mas receptor antagonist, D‐Ala, in effect suggesting that Ang‐(1‐7) may inhibit transport‐dependent VO 2 in TAL via Mas receptor‐dependent activation of the NO pathway. Indeed, blocking NO synthesis with L‐NAME prevented the inhibitory actions of Ang‐(1‐7) on VO 2. Our data suggest that Ang‐(1‐7) may modulate TAL Na+ transport via Mas receptor‐dependent increases in NO leading to the inhibition of transport activity.

Previous data from our group have demonstrated (Arany I, Grifoni S, Clark JS, Csongradi, Maric C, Juncos LA. Am J Physiol Renal Physiol 301: F125–F133, 2011) that chronic nicotine (NIC) exposure exacerbates acute renal ischemic injury (AKI) in mice that could increase the risk for development and progression of chronic kidney disease (CKD). It has been shown that proximal tubules of the kidney can acquire characteristics that may compromise structural recovery and favor development of inflammation and fibrosis following injury. Chronic NIC exposure can amplify this epithelial process although the mechanism is not identified. Recently, the unphosphorylated form of signal transducer and activator of transcription-3 (U-STAT3) has emerged as a noncanonical mediator of inflammation and fibrosis that may be responsible for the effects of chronic NIC. We found that levels of transforming growth factor β-1 (TGF-β1), α-smooth muscle actin (α-SMA), fibronectin, monocyte chemotactic protein-1 (MCP-1), and expression of U-STAT3 were increased in the ischemic kidneys of NIC-exposed mice. Chronic NIC exposure also increased TGF-β1-dependent F-actin reorganization, vimentin, fibronectin, and α-SMA expression as well as promoter activity of α-SMA and MCP-1 without significant loss of epithelial characteristics (E-cadherin) in cultured renal proximal tubule cells. Importantly, transduction of cells with a U-STAT3 mimetic (Y705F-STAT3) augmented stress fiber formation and also amplified NIC+TGF-β1-induced expression of α-SMA, vimentin, fibronectin, as well as promoter activity of α-SMA and MCP-1. Our results reveal a novel, chronic NIC-exposure-related and U-STAT3-dependent mechanism as mediator of a sustained transcription of genes that are linked to remodeling and inflammation in the kidney during injury. This process may facilitate progression of AKI to CKD. The obtained data may lead to devising therapeutic methods to specifically enhance the protective and/or inhibit adverse effects of STAT3 in the kidney.

The pivotal discovery of endothelin (ET) by Yanagisawa and colleagues[1][1] in 1988 generated wide interest in this peptide, as evidenced by the nearly 27,000 articles published to date that have examined its role in biology. ET is now recognized as essential to the function of various organs and

Macula densa (MD)-mediated regulation of renal hemodynamics via tubuloglomerular feedback is regulated by interactions between factors such as superoxide (O2−) and angiotensin II (ANG II). We have reported that NaCl-induced O2−in the MD is produced by the NOX2 isoform of NADPH oxidase (NOX); however, the source of ANG II-induced O2−in MD is unknown. Thus we determined the pathways by which ANG II increased O2−in the MD by measuring O2−in ANG II-treated MMDD1 cells, a MD-like cell line. ANG II caused MMDD1 O2−levels to increase by more than twofold ( P < 0.01). This increase was blocked by losartan (AT1receptor blocker) but not PD-123319 (AT2receptor antagonist). Apocynin (a NOX inhibitor) decreased O2−by 86% ( P < 0.01), whereas oxypurinol (a xanthine oxidase inhibitor) and NS-398 (a cyclooxygenase-2 inhibitor) had no significant effect. The NOX-dependent increase in O2−was due to the NOX2 isoform; a short interfering (si)RNA against NOX2 blunted ANG II-induced increases in O2−, whereas the NOX4/siRNA did not. Finally, we found that inhibiting the Rac1 subunit of NOX blunted ANG II-induced O2−production in NOX4/siRNA-treated cells but did not further decrease it in NOX2/siRNA-treated cells. Our results indicate that ANG II stimulates O2−production in the MD primarily via AT1-dependent activation of NOX2. Rac1 is required for the full activation of NOX2. This pathway may be an important component of ANG II enhancement of tubuloglomerular feedback.

Background: Despite massive efforts, progress so far has been modest in isolating the genetic determinants for intracranial aneurysm (IA). More detailed epidemiology data might be essential for successful genome-wide association study. Here, we aimed to investigate epidemiology and identify the key risk factors associated with the pathogenesis of IA in a large specific population. Methods: We investigated the epidemiology and analyzed the risk factors of IA pathogenesis by using an International Classification of Diseases, Ninth Revision database search of the patients treated at the University of Mississippi Medical Center, Jackson, MS, within the past 10-year period (1998-2007). All recruited patients were interviewed to assess multiple risk factors and comorbidities (hypertension, tobacco abuse, females sex, diabetes mellitus, coronary artery disease, coronary obstructive pulmonary disease, alcohol abuse, stroke, hyperlipidemia, illicit drug use, and family history). Result: In this retrospective study, we identified several significant risk factors among well-defined human subjects. The 3 major risk factors identified for our IA population are hypertension, tobacco abuse, and female sex. However, African American race was not a significant risk factor in our study. Furthermore, top two risk factors (hypertension, tobacco abuse) were found to be highly associated with familial cases. Conclusions: In this study, using a specific and well-defined large population, we reported that some key risk factors were further confirmed to be strongly associated with the pathogenesis of IA whereas further investigation into racial factors is apparently needed. Our finding of the confounding effects of top risks with familial cases further complicated the genetic analysis of IA. © 2009 National Stroke Association.

Unilateral renal artery stenosis causes angiotensin II-dependent hypertension and leads to injury of the stenosed ipsilateral, as well as the non-stenosed contralateral kidney. While the hypertension is triggered by hypoperfusion-dependent renin release of the stenotic kidney, dysfunction of the contralateral kidney is what permits the blood pressure to remain elevated, and may even be the driving force behind the hypertension in the late stages. The differential function and crosstalk between the two kidneys are determined by the interaction among several neurohormonal pathways. Understanding the simultaneous processes taking place in both the ipsilateral and the contralateral kidneys should provide a better insight not only on the hypertensive process, but also on the mechanisms to progressive renal injury in this condition.

NAD(P)H oxidase (Nox)2 and Nox4 are the isoforms of Nox expressed in the macula densa (MD). MD-derived superoxide (O2−), primarily generated by Nox2, is enhanced by acute ANG II stimulation. However, the effects of chronic elevations in ANG II during ANG II-induced hypertension on MD-derived O2− are unknown. We infused a slow pressor dose of ANG II (600 ng·min−1·kg−1) for 2 wk in C57BL/6 mice and found that mean arterial pressure was elevated by 22.3 ± 3.4 mmHg ( P < 0.01). We measured O2− generation in isolated and perfused MDs and found that O2− generation by the MD was increased from 9.4 ± 0.9 U/min in control mice to 34.7 ± 1.8 U/min in ANG II-induced hypertensive mice ( P < 0.01). We stimulated MMDD1 cells, a MD-like cell line, with ANG II and found that O2− generation increased from 921 ± 91 to 3,687 ± 183 U·min−1·105 cells−1, which was inhibited with apocynin, oxypurinol, or NS-398 by 46%, 14%, and 12%, respectively. We isolated MD cells using laser capture microdissection and measured mRNA levels of Nox. Nox2 and Nox4 levels increased by 3.7 ± 0.17- and 2.6 ± 0.15-fold in ANG II-infused mice compared with control mice. In MMDD1 cells treated with Nox2 or Nox4 small interfering (si)RNAs, ANG II-stimulated O2− generation was blunted by 50% and 41%, respectively. In cells treated with p22 phox siRNA, ANG II-stimulated O2− generation was completely blocked. In conclusion, we found that a subpressor dose of ANG II enhances O2− generation in the MD and that the sources of this O2− are primarily Nox2 and Nox4.

Men are at greater risk for renal injury and dysfunction after acute ischemia-reperfusion (I/R) than are women. Studies in animals suggest that the reason for the sex difference in renal injury and dysfunction after I/R is the protective effect of estrogens in females. However, a reduction in testosterone in men is thought to play an important role in mediating cardiovascular and renal disease, in general. In the present study, we tested the hypothesis that I/R of the kidney reduces serum testosterone, and that contributes to renal dysfunction and injury. Male rats that were subjected to renal ischemia of 40 min followed by reperfusion had a 90% reduction in serum testosterone by 3 h after reperfusion that remained at 24 h. Acute infusion of testosterone 3 h after reperfusion attenuated the increase in plasma creatinine and urinary kidney injury molecule-1 (KIM-1) at 24 h, prevented the reduction in outer medullary blood flow, and attenuated the increase in intrarenal TNF-α and the decrease in intrarenal VEGF at 48 h. Castration of males caused greater increases in plasma creatinine and KIM-1 at 24 h than in intact males with renal I/R, and treatment with anastrozole, an aromatase inhibitor, plus testosterone almost normalized plasma creatinine and KIM-1 in rats with renal I/R. These data show that renal I/R is associated with sustained reductions in testosterone, that testosterone repletion protects the kidney, whereas castration promotes renal dysfunction and injury, and that the testosterone-mediated protection is not conferred by conversion to estradiol.

Angiotensin II (AngII) causes hypertension (HTN) and promotes renal injury while simultaneously inducing reno-protective enzymes like heme oxygenase-1 (HO-1). We examined the modulatory role of HO on sub-pressor angiotensin II (SP-AngII) induced renal inflammation and injury. We first tested whether the SP-AngII-induced renal dysfunction, inflammation and injury are exacerbated by either preventing (chronic HO-1 inhibition) or reversing (late HO-1 inhibition) SP-AngII-induced HO (using tin protoporphyrin; SnPP). We next examined whether additional chronic or late induction of SP-AngII-induced HO (using cobalt protoporphyrin; CoPP), prevents or ameliorates renal damage. We found that neither chronic nor late SnPP altered blood pressure. Chronic SnPP worsened SP-AngII-induced renal dysfunction, inflammation, injury and fibrosis, whereas late SnPP worsened renal dysfunction but not inflammation. Chronic CoPP prevented HTN, renal dysfunction, inflammation and fibrosis, but surprisingly, not the NGAL levels (renal injury marker). Late CoPP did not significantly alter SP-AngII-induced HTN, renal inflammation or injury, but improved renal function. Thus, we conclude (a) endogenous HO may be an essential determining factor in SP-AngII induced renal inflammation, injury and fibrosis, (b) part of HO’s renoprotection may be independent of blood pressure changes; and (c) further induction of HO-1 protects against renal injury, suggesting a possible therapeutic target.