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Dietary sodium chloride (salt) has long been considered injurious to the kidney by promoting the development of glomerular and tubulointerstitial fibrosis. Endothelial cells throughout the vasculature and glomeruli respond to increased dietary salt intake with increased production of transforming growth factor-β (TGF-β) and nitric oxide. High-salt intake activates large-conductance, voltage- and calcium-activated potassium (BK(Ca)) channels in endothelial cells. Activation of BK(Ca) channels promotes signaling through proline-rich tyrosine kinase-2, cellular-sarcoma (c-Src), Akt (also known as protein kinase B), and mitogen-activated protein kinase pathways that lead to endothelial production of TGF-β and nitric oxide. TGF-β signaling is broadly accepted as a strong stimulator of renal fibrosis. The classic description of TGF-β signaling pathology in renal disease involves signaling through Smad proteins resulting in extracellular matrix deposition and fibrosis. Active TGF-β1 also causes fibrosis by inducing epithelial-mesenchymal transition and apoptosis. By enhancing TGF-β signaling, increased dietary salt intake leads to progressive renal failure from nephron loss and glomerular and tubulointerstitial fibrosis. [ABSTRACT FROM AUTHOR]

The comparative effectiveness of angiotensin-converting enzyme (ACE) inhibitors versus angiotensin II type 1 receptor blockers (ARBs) in real-world older heart failure (HF) patients remains unclear. Of the 8,049 hospitalized HF patients aged ≥ 65 years discharged alive from 106 Alabama hospitals, 4,044 received discharge prescriptions of either ACE inhibitors (n = 3,383) or ARBs (n = 661). Propensity scores for ARB use, calculated for each of 4,044 patients, were used to match 655 (99% of 661) patients receiving ARBs with 661 patients receiving ACE inhibitors. The assembled cohort of 655 pairs of patients was well balanced on 56 baseline characteristics. During >8 years of follow-up, all-cause mortality occurred in 63% and 68% of matched patients receiving ARBs and ACE inhibitors, respectively (hazard ratio [HR] associated with ARB use 0.86, 95% confidence interval [CI] 0.75 to 0.99, p = 0.031). Among the 956 matched patients with data on the left ventricular ejection fraction (LVEF), the association between ARB (vs ACE inhibitor) use was significant in only 419 patients with LVEFs ≥ 45% (HR 0.65, 95% CI 0.51 to 0.84, p = 0.001) but not in the 537 patients with LVEFs < 45% (HR 1.00, 95% CI 0.81 to 1.23, p = 0.999; p for interaction = 0.012). HRs for HF hospitalization associated with ARB use were 0.99 (95% CI 0.86 to 1.14, p = 0.876) overall, 0.80 (95% CI 0.63 to 1.03, p = 0.080) in those with LVEFs ≥45%, and 1.14 (95% CI 0.91 to 1.43, p = 0.246) in those with LVEFs <45% (p for interaction = 0.060). In conclusion, in older HF patients with preserved LVEFs, discharge prescriptions of ARBs (vs ACE inhibitors) were associated with lower mortality and a trend toward lower HF hospitalization, findings that need replication in other HF populations. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is common and is associated with increased mortality in heart failure (HF). However, it is unknown whether the effect of CKD on mortality varies by left ventricular ejection fraction (LVEF). We evaluated the effect of CKD on mortality in patients with systolic (LVEF 45%) HF. Of the 7,788 patients in the Digitalis Investigation Group trial, 3,527 (45%) had CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2). We calculated the propensity score for CKD for each patient, using a multivariate logistic regression model (c statistic 0.76, postmatch absolute standardized differences <5% for all 32 co-variates). We matched 2,399 pairs of patients with and without CKD with similar propensity scores. There were 757 (rate 1,049/10,000 person-years) and 882 (rate 1,282/10,000 person-years) deaths, respectively, in patients without and with CKD (hazard ratio 1.22, 95% confidence interval 1.09 to 1.36, p <0.0001). CKD-associated mortality was higher in those with diastolic HF (371 extra deaths/10,000 person-years, hazard ratio 1.71, 95% confidence interval 1.21 to 2.41, p = 0.002) than in systolic HF (214 extra deaths/10,000 person-years, hazard ratio 1.19, 95% confidence interval 1.07 to 1.32, p = 0.001), which was significant (adjusted p for interaction = 0.034). A graded association was found between CKD-related deaths and LVEF. The hazard ratios for CKD-associated mortality for the LVEF subgroups of <35%, 35% to 55%, and >55% were 1.15 (95% confidence interval 1.02 to 1.29), 1.35 (95% confidence interval 1.11 to 1.64), and 2.33 (95% confidence interval 1.34 to 4.06). In conclusion, CKD-associated mortality was higher in those with diastolic than systolic HF. Patients with diastolic HF should be evaluated for CKD, and the role of inhibitors of the renin-angiotensin system in these patients needs to be investigated. [ABSTRACT FROM AUTHOR]

Background/objectives: Growing reliance on telemedicine has created new triaging challenges. This study investigated how effectively otolaryngology resident auditory-perceptual voice assessments performed via telemedicine determined the need for urgent in-person clinic visits., Methods: Twelve otolaryngology resident physicians (PGY1-PGY5) performed auditory-perceptual assessments on 25 voice samples recorded during initial voice evaluations. Voice samples were balanced in severity and taken in equal numbers from patients with the following diagnoses: benign laryngeal lesions, laryngeal cancer, functional voice disorders, laryngeal edema (associated with LPR), and laryngeal paralysis/paresis. Urgent diagnoses were defined as laryngeal cancer and severe unilateral laryngeal paralysis. For each voice sample, residents were initially blinded to patient medical history. Residents rated severity of voice disorder, predicted patient diagnosis, and determined the urgency of seeing the patient in clinic. Residents then reviewed information from the patient's medical history and again rated urgency of voice disorder., Results: On average, residents identified urgent voice disorders in 56% of cases. After reviewing medical history, this number significantly increased to 77% (P = 0.001). Voice severity, smoking history, time since onset, and course of symptoms were considered most influential when determining medical urgency of voice patients. Year in residency program had no effect on rating accuracy. As expected, diagnostic accuracy of auditory-perceptual assessments was low, ranging from 40% for laryngeal paralysis/paresis to 5% for laryngeal edema., Conclusion: Auditory-perceptual voice assessment, combined with medical history, predicted most medically urgent voice disorders. Further work should investigate if task-specific training might improve these results and which medical history items are most critical. Until accuracy of auditory-perceptual assessment of medical urgency is improved, these data underscore the importance of laryngeal examination in identifying medical urgency and etiology of dysphonia., (Copyright © 2019. Published by Elsevier Inc.)

This study tested if matrix metalloproteinase (MMP)-9 promoted microvascular pathology that initiates hypertensive (HT) kidney disease in salt-sensitive (SS) Dahl rats. SS rats lacking Mmp9 (Mmp9 -/- ) and littermate control SS rats were studied after one week on a normotensive 0.3% sodium chloride (Pre-HT SS and Pre-HT Mmp9 -/- ) or a hypertension-inducing diet containing 4.0% sodium chloride (HT SS and HT Mmp9 -/- ). Telemetry-monitored blood pressure of both the HT SS and HT Mmp9 -/- rats increased and did not differ. Kidney microvessel transforming growth factor-beta 1 (Tgfb1) mRNA did not differ between Pre-HT SS and Pre-HT Mmp9 -/- rats, but with hypertension and expression of Mmp9 and Tgfb1 increased in HT SS rats, along with phospho-Smad2 labeling of nuclei of vascular smooth muscle cells, and with peri-arteriolar fibronectin deposition. Loss of MMP-9 prevented hypertension-induced phenotypic transformation of microvascular smooth muscle cells and the expected increased microvascular expression of pro-inflammatory molecules. Loss of MMP-9 in vascular smooth muscle cells in vitro prevented cyclic strain-induced production of active TGF-β1 and phospho-Smad2/3 stimulation. Afferent arteriolar autoregulation was impaired in HT SS rats but not in HT Mmp9 -/- rats or the HT SS rats treated with doxycycline, an MMP inhibitor. HT SS but not HT Mmp9 -/- rats showed decreased glomerular Wilms Tumor 1 protein-positive cells (a marker of podocytes) along with increased urinary podocin and nephrin mRNA excretion, all indicative of glomerular damage. Thus, our findings support an active role for MMP-9 in a hypertension-induced kidney microvascular remodeling process that promotes glomerular epithelial cell injury in SS rats., (Published by Elsevier Inc.)

Inflammation that develops with the release of chemokines and cytokines during acute kidney injury (AKI) has been shown to participate in functional renal recovery. Although a major research focus has been on the role of macrophages, the family of C-X-C motif chemokines that promote neutrophil adherence and activation also increases with kidney ischemia-reperfusion (I/R) injury. This study tested the hypothesis that intravenous delivery of endothelial cells (ECs) that overexpress (C-X-C motif) chemokine receptors 1 and 2 (CXCR1 and CXCR2, respectively) improves outcomes in kidney I/R injury. Overexpression of CXCR1/2 enhanced homing of endothelial cells to I/R-injured kidneys and limited interstitial fibrosis, capillary rarefaction, and tissue injury biomarkers (serum creatinine concentration and urinary kidney injury molecule-1) following AKI and also reduced expression of P-selectin and the rodent (C-X-C motif) chemokine cytokine-induced neutrophil chemoattractant (CINC)-2β as well as the number of myeloperoxidase-positive cells in the postischemic kidney. The serum chemokine/cytokine profile, including CINC-1, showed similar reductions. These findings were not observed in rats given endothelial cells transduced with an empty adenoviral vector (null-ECs) or a vehicle alone. These data indicate that extrarenal endothelial cells that overexpress CXCR1 and CXCR2, but not null-ECs or vehicle alone, reduce I/R kidney injury and preserve kidney function in a rat model of AKI. NEW & NOTEWORTHY Inflammation facilitates kidney ischemia-reperfusion (I/R) injury. Endothelial cells (ECs) that were modified to overexpress (C-X-C motif) chemokine receptor (CXCR)1/2 (CXCR1/2-ECs) were injected immediately following kidney I/R injury. The interaction of CXCR1/2-ECs, but not ECs transduced with an empty adenoviral vector, with injured kidney tissue preserved kidney function and reduced production of inflammatory markers, capillary rarefaction, and interstitial fibrosis. The study highlights a functional role for the C-X-C chemokine pathway in kidney damage following I/R injury.

B 0 AT1 (Slc6a19) mediates absorption of neutral amino acids in the small intestine and in the kidneys, where it is primarily expressed in early proximal tubules (S1-S2). To determine the role of B 0 AT1 in nephropathy induced by aristolochic acid (AA), which targets the proximal tubule, littermate female B 0 AT1-deficient ( Slc6a19 -/- ), heterozygous ( Slc6a19 +/- ), and wild-type (WT) mice were administered AA (10 mg/kg ip) or vehicle every 3 days for 3 wk, and analyses were performed after the last injection or 3 wk later. Vehicle-treated mice lacking Slc6a19 showed normal body and kidney weight and plasma creatinine versus WT mice. The urinary glucose-to-creatinine ratio (UGCR) and urinary albumin-to-creatinine ratio (UACR) were two to four times higher in vehicle-treated Slc6a19 -/- versus WT mice, associated with lesser expression of early proximal transporters Na + -glucose cotransporter 2 and megalin, respectively. AA caused tubular injury independently of B 0 AT1, including robust increases in cortical mRNA expression of p53 , p21 , and hepatitis A virus cellular receptor 1 ( Havcr1 ), downregulation of related proximal tubule amino acid transporters B 0 AT2 ( Slc6a15 ), B 0 AT3 ( Slc6a18 ), and Slc7a9 , and modest histological tubular damage and a rise in plasma creatinine. Absence of B 0 AT1, however, attenuated AA-induced cortical upregulation of mRNA markers of senescence ( p16 ), inflammation [lipocalin 2 ( Lcn2 ), C-C motif chemokine ligand 2 ( Ccl2 ), and C-C motif chemokine receptor 2 ( Ccr2 )], and fibrosis [tissue inhibitor of metallopeptidase 1 ( Timp1 ), transforming growth factor-β1 ( Tgfb1 ), and collagen type I-α 1 ( Col1a1 )], associated with lesser fibrosis staining, lesser suppression of proximal tubular organic anion transporter 1, restoration of Na + -glucose cotransporter 2 expression, and prevention of the AA-induced fivefold increase in the urinary albumin-to-creatinine ratio observed in WT mice. The data suggest that proximal tubular B 0 AT1 is important for the physiology of renal glucose and albumin retention but potentially deleterious for the kidney response following AA-induced kidney injury. NEW & NOTEWORTHY Based on insights from studies manipulating glucose transport, the hypothesis has been proposed that inhibiting intestinal uptake or renal reabsorption of energy substrates has unique therapeutic potential to improve metabolic disease and kidney outcome in response to injury. The present study takes this idea to B 0 AT1, the major transporter for neutral amino acids in the intestine and kidney, and shows that its absence attenuates aristolochic acid-induced nephropathy.

Prevention of phenotype switching of vascular smooth muscle cells is an important determinant of normal vascular physiology. Hydrogen peroxide (H 2 O 2 ) promotes osteogenic differentiation of vascular smooth muscle cells through expression of Runt related transcription factor 2 (Runx2). In this study, an increase in dietary NaCl increased endothelial H 2 O 2 generation through NOX4, a NAD(P)H oxidase. The production of H 2 O 2 was sufficient to increase Runx2, osteopontin and osteocalcin in adjacent vascular smooth muscle cells from control littermate mice but was inhibited in mice lacking endothelial Nox4. A vascular smooth muscle cell culture model confirmed the direct involvement of the activation of protein kinase B (Akt) with inactivation of FoxO1 and FoxO3a observed in the control mice on the high NaCl diet. The present study also showed a reduction of catalase activity in aortas during high NaCl intake. The findings demonstrated an interesting cell-cell communication in the vascular wall that was initiated with H 2 O 2 production by endothelium and was regulated by dietary NaCl intake. A better understanding of how dietary salt intake alters vascular biology may improve treatment of vascular disease that involves activation of Runx2., (Published by Elsevier B.V.)

Objective: This study examined whether speech-language pathologist auditory-perceptual voice assessments can predict the medical urgency of voice disorders., Methods: Twenty speech-language pathologists (SLPs) evaluated 25 voice samples recorded during initial voice evaluations. Voice samples represented a range of dysphonia severity (mild-severe) balanced across patient diagnoses. Diagnoses included: benign lesions, laryngeal cancer, non-organic voice disorders, laryngeal edema (associated with LPR), and laryngeal paralysis or paresis. Laryngeal cancer and severe unilateral laryngeal paralysis were considered urgent disorders. While blinded to patient information, SLPs rated severity of voice quality, predicted patient diagnosis, and determined whether the patient should be seen urgently by a laryngologist. SLPs were then given basic medical history information and rated medical urgency of voice disorder a second time., Results: On average, SLPs correctly identified 65% of urgent voices and 87% of nonurgent voices when blinded to patient information. Accuracy improved significantly to 86% for urgent voices with medical history information ( P  < .001) and decreased to 77% for nonurgent voices. Accuracy was better when severity of voice quality was severe for urgent voices and mild for nonurgent voices ( P  < .001). SLPs indicated that patient smoking history and severity of dysphonia were most influential in their decision making. Diagnostic accuracy of auditory-perceptual assessments was poor., Conclusions: SLPs identified 86% of medically urgent voice disorders when auditory perceptual assessments were combined with medical history information. Further work is needed to determine what medical history information is most crucial to rating accuracy and what speech tasks might best separate urgent and nonurgent patients.

A major cause of morbidity and mortality in multiple myeloma is kidney injury from overproduction of monoclonal immunoglobulin light chains (FLC). FLC can induce damage through the production of hydrogen peroxide, which activates pro-inflammatory and pro-apoptotic pathways. The present study focused on catalase, a highly conserved antioxidant enzyme that degrades hydrogen peroxide. Initial findings were that FLC increased hydrogen peroxide levels but also decreased catalase levels and activity in proximal tubule epithelium. In order to clarify, we showed that the phosphatidylinositol 3-kinase inhibitor, LY294002, inhibited FLC-induced Akt-mediated deactivation of Forkhead box O class 3a (FoxO3a) and increased catalase activity in proximal tubule cells. Augmented catalase activity decreased FLC-mediated production of hydrogen peroxide as well as the associated increase in High Mobility Group Box 1 (HMGB1) protein release and caspase-3 activity. Coincubation of cells with FLC and an allosteric activator of Sirtuin 1 (SIRT1) was also sufficient to increase catalase activity and promote similar cytoprotective effects. Our studies confirmed that the mechanism of downregulation of catalase by FLC involved deactivation of FoxO3a and inhibition of SIRT1. Mechanistic understanding of catalase regulation allows for future treatments that target pathways that increase catalase in the setting of proximal tubule injury from FLC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) remains a significant clinical problem through its diverse etiologies, the challenges of robust measurements of injury and recovery, and its progression to chronic kidney disease (CKD). Bridging the gap in our knowledge of this disorder requires bringing together not only the technical resources for research but also the investigators currently endeavoring to expand our knowledge and those who might bring novel ideas and expertise to this important challenge. The University of Alabama at Birmingham-University of California-San Diego O'Brien Center for Acute Kidney Injury Research brings together technical expertise and programmatic and educational efforts to advance our knowledge in these diverse issues and the required infrastructure to develop areas of novel exploration. Since its inception in 2008, this O'Brien Center has grown its impact by providing state-of-the-art resources in clinical and preclinical modeling of AKI, a bioanalytical core that facilitates measurement of critical biomarkers, including serum creatinine via LC-MS/MS among others, and a biostatistical resource that assists from design to analysis. Through these core resources and with additional educational efforts, our center has grown its investigator base to include >200 members from 51 institutions. Importantly, this center has translated its pilot and catalyst funding program with a $37 return per dollar invested. Over 500 publications have resulted from the support provided with a relative citation ratio of 2.18 ± 0.12 (iCite). Through its efforts, this disease-centric O'Brien Center is providing the infrastructure and focus to help the development of the next generation of researchers in the basic and clinical science of AKI. This center creates the promise of the application at the bedside of the advances in AKI made by current and future investigators.

Plasma and B cells dyscrasias that overproduce monoclonal immunoglobulin free light chains (FLCs) affect the kidney frequently in various ways. The hematologic dyscrasia responsible for the production of FLCs may or may not meet the criteria for cancer, such as multiple myeloma (MM) or lymphoma, or may remain subclinical. If there is overt malignancy, the accompanying kidney disorder is called myeloma- or lymphoma-associated. If the dyscrasia is subclinical, the associated kidney disorders are grouped as monoclonal gammopathy of renal significance. Glomeruli and tubules may both be involved. The proximal tubule disorders comprise a spectrum of interesting syndromes, which range in severity. This review focuses on the recent insights gained into the patterns and the mechanisms of proximal tubule toxicity of FLCs, including subtle transport disorders, such as proximal tubule acidosis, partial or complete Fanconi syndrome, or severe acute or chronic renal failure. Histologically, there may be crystal deposition in the proximal tubule cells, acute tubule injury, interstitial inflammation, fibrosis, and tubule atrophy. Specific structural alterations in the V domain of FLCs caused by somatic hypermutations are responsible for crystal formation as well as partial or complete Fanconi syndrome. Besides crystal formation, tubulointerstitial inflammation and proximal tubulopathy can be mediated by direct activation of inflammatory pathways through cytokines and Toll-like receptors due to cell stress responses induced by excessive FLC endocytosis into the proximal tubule cells. Therapy directed against the clonal source of the toxic light chain can prevent progression to more severe lesions and may help preserve kidney function.

Renal autoregulation is critical in maintaining stable renal blood flow (RBF) and glomerular filtration rate (GFR). Renal ischemia-reperfusion (IR)-induced kidney injury is characterized by reduced RBF and GFR. The mechanisms contributing to renal microvascular dysfunction in IR have not been fully determined. We hypothesized that increased reactive oxygen species (ROS) contributed to impaired renal autoregulatory capability in IR rats. Afferent arteriolar autoregulatory behavior was assessed using the blood-perfused juxtamedullary nephron preparation. IR was induced by 60 min of bilateral renal artery occlusion followed by 24 h of reperfusion. Afferent arterioles from sham rats exhibited normal autoregulatory behavior. Stepwise increases in perfusion pressure caused pressure-dependent vasoconstriction to 65 ± 3% of baseline diameter (13.2 ± 0.4 μm) at 170 mmHg. In contrast, pressure-mediated vasoconstriction was markedly attenuated in IR rats. Baseline diameter averaged 11.7 ± 0.5 µm and remained between 90% and 101% of baseline over 65-170 mmHg, indicating impaired autoregulatory function. Acute antioxidant administration (tempol or apocynin) to IR kidneys for 20 min increased baseline diameter and improved autoregulatory capability, such that the pressure-diameter profiles were indistinguishable from those of sham kidneys. Furthermore, the addition of polyethylene glycol superoxide dismutase or polyethylene glycol-catalase to the perfusate blood also restored afferent arteriolar autoregulatory responsiveness in IR rats, indicating the involvement of superoxide and/or hydrogen peroxide. IR elevated mRNA expression of NADPH oxidase subunits and monocyte chemoattractant protein-1 in renal tissue homogenates, and this was prevented by tempol pretreatment. These results suggest that ROS accumulation, likely involving superoxide and/or hydrogen peroxide, impairs renal autoregulation in IR rats in a reversible fashion. NEW & NOTEWORTHY Renal ischemia-reperfusion (IR) leads to renal microvascular dysfunction manifested by impaired afferent arteriolar autoregulatory efficiency. Acute administration of scavengers of reactive oxygen species, polyethylene glycol-superoxide dismutase, or polyethylene glycol-catalase following renal IR restored afferent arteriolar autoregulatory capability in IR rats, indicating that renal IR led to reversible impairment of afferent arteriolar autoregulatory capability. Intervention with antioxidant treatment following IR may improve outcomes in patients by preserving renovascular autoregulatory function and potentially preventing the progression to chronic kidney disease after acute kidney injury.

Injured tubule epithelium stimulates a profibrotic milieu that accelerates loss of function in chronic kidney disease (CKD). This study tested the role of signal transducer and activator of transcription 1 (STAT1) in the progressive loss of kidney function in aristolochic acid (AA) nephropathy, a model of CKD. Mean serum creatinine concentration increased in wild-type (WT) littermates treated with AA, whereas Stat1 -/- mice were protected. Focal increases in the apical expression of kidney injury molecule (KIM)-1 were observed in the proximal tubules of WT mice with AA treatment but were absent in Stat1 -/- mice in the treatment group as well as in both control groups. A composite injury score, an indicator of proximal tubule injury, was reduced in Stat1 -/- mice treated with AA. Increased expression of integrin-β 6 and phosphorylated Smad2/3 in proximal tubules as well as interstitial collagen and fibronectin were observed in WT mice following AA treatment but were all decreased in AA-treated Stat1 -/- mice. The data indicated that STAT1 activation facilitated the development of progressive kidney injury and interstitial fibrosis in AA nephropathy.

The long-term impact of Autologous hematopietic stem cell transplantation (ASCT) on renal function, and the impact of renal function on progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma are not known. We retrospectively reviewed the records of 885 patients at our institution. We used linear mixed effect models to study the change in estimated glomerular filtration rate (eGFR) and a joint model approach to assess associations between the eGFR, PFS and OS. Sensitivity analyses were conducted at days 0, 100, 180, and 365 post-SCT. eGFR post-ASCT was significantly lower than at day 0 but stabilized at approximately 80 mL/min/1.73 m 2 . There was no association between eGFR and PFS or OS.; However, relapsed disease and ISS stage were associated with shorter PFS and OS. This data suggests that although there is a modest decline in eGFR post-ASCT, it is not associated with an adverse impact on PFS or OS. KEY POINTS Advanced MM stage at diagnosis was associated with reduced eGFR at all stages of chronic kidney disease. eGFR was not associated with PFS or OS in any of the analyses, but disease-related factors prior to ASCT were all associated with reduced eGFR, PFS and OS. ASCT did not adversely impact kidney function and mitigated the risk of CKD on outcomes in MM.

Free light chains (FLCs) induce inflammatory pathways in proximal tubule cells (PTCs). The role of TLRs in these responses is unknown. Here we present findings on the role of TLRs in FLC-induced PTC injury. We exposed human kidney PTC cultures to κ and λ FLCs and used cell supernatants and pellets for ELISA and gene expression studies. We also analyzed tissues from Stat1-/- and littermate control mice treated with daily i.p. injections of a κ FLC for 10 days. FLCs increased the expression of TLR2, TLR4, and TLR6 via HMGB1, a damage-associated molecular pattern. Countering TLR2, TLR4, and TLR6 through GIT-27 or specific TLR siRNAs reduced downstream cytokine responses. Blocking HMGB1 through siRNA or pharmacologic inhibition, or via STAT1 inhibition, reduced FLC-induced TLR2, TLR4, and TLR6 expression. Blocking endocytosis of FLCs through silencing of megalin/cubilin, with bafilomycin A1 or hypertonic sucrose, attenuated FLC-induced cytokine responses in PTCs. IHC showed decreased TLR4 and TLR6 expression in kidney sections from Stat1-/- mice compared with their littermate controls. PTCs exposed to FLCs released HMGB1, which induced expression of TLR2, TLR4, and TLR6 and downstream inflammation. Blocking FLCs' endocytosis, Stat1 knockdown, HMGB1 inhibition, and TLR knockdown each rescued PTCs from FLC-induced injury.

Light chain cast nephropathy (LCCN) in multiple myeloma often leads to severe and poorly reversible acute kidney injury. Severe renal impairment influences the allocation of chemotherapy and its tolerability; it also affects patient survival. Whether renal biopsy findings add to the clinical assessment in predicting renal and patient outcomes in LCCN is uncertain. We retrospectively reviewed clinical presentation, chemotherapy regimens, hematologic response, and renal and patient outcomes in 178 patients with biopsy-proven LCCN from 10 centers in Europe and North America. A detailed pathology review, including assessment of the extent of cast formation, was performed to study correlations with initial presentation and outcomes. Patients presented with a mean estimated glomerular filtration rate (eGFR) of 13 ± 11 mL/min/1.73 m2, and 82% had stage 3 acute kidney injury. The mean number of casts was 3.2/mm2 in the cortex. Tubulointerstitial lesions were frequent: acute tubular injury (94%), tubulitis (82%), tubular rupture (62%), giant cell reaction (60%), and cortical and medullary inflammation (95% and 75%, respectively). Medullary inflammation, giant cell reaction, and the extent of cast formation correlated with eGFR value at LCCN diagnosis. During a median follow-up of 22 months, mean eGFR increased to 43 ± 30 mL/min/1.73 m2. Age, β2-microglobulin, best hematologic response, number of cortical casts per square millimeter, and degree of interstitial fibrosis/tubular atrophy (IFTA) were independently associated with a higher eGFR during follow-up. This eGFR value correlated with overall survival, independently of the hematologic response. This study shows that extent of cast formation and IFTA in LCCN predicts the quality of renal response, which, in turn, is associated with overall survival.

In the early proximal tubule, Na + -glucose cotransporter 2 (SGLT2) mediates the bulk of renal glucose reabsorption. Gene deletion in mice ( Sglt2 -/- ) was used to determine the role of SGLT2 in acute kidney injury induced by bilateral ischemia-reperfusion (IR). In Sglt2 -/- and littermate wild-type mice, plasma creatinine increased similarly on day 1 after IR. This was associated with an equal increase in both genotypes in the urinary kidney injury molecule-1-to-creatinine ratio, a tubular injury marker, and similarly reduced urine osmolality and increased plasma osmolality, indicating impaired urine concentration. In both IR groups, FITC-sinistrin glomerular filtration rate was equally reduced on day 14 , and plasma creatinine was similarly and incompletely restored on day 23 . In Sglt2 -/- mice subjected to IR, fractional urinary glucose excretion was increased on day 1 but reduced and associated with normal renal Na + -glucose cotransporter 1 (Sglt1) mRNA expression on day 23 , suggesting temporary SGLT1 suppression. In wild-type mice subjected to IR, renal Sglt1 mRNA was likewise normal on day 23 , whereas Sglt2 mRNA was reduced by 57%. In both genotypes, IR equally reduced urine osmolality and renal mRNA expression of the Na + -K + -2Cl - cotransporter and renin on day 23 , suggesting thick ascending limb dysfunction, and similarly increased renal mRNA expression of markers of injury, inflammation, oxidative stress, and fibrosis (kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, transforming growth factor-β1, NADPH oxidase-2, and collagen type 1). This was associated with equal increases in kidney histological damage scores and similar degree of capillary loss in both genotypes. The data indicate that genetic deletion of SGLT2 did not protect the kidneys in the initial injury phase or the subsequent recovery phase in a mouse model of IR-induced acute kidney injury.

Previously, our lab showed that the endoplasmic reticulum (ER) and calcium regulatory protein, calreticulin (CRT), is important for collagen transcription, secretion, and assembly into the extracellular matrix (ECM) and that ER CRT is critical for TGF-β stimulation of type I collagen transcription through stimulation of ER calcium release and NFAT activation. Diabetes is the leading cause of end stage renal disease. TGF-β is a key factor in the pathogenesis of diabetic nephropathy. However, the role of calreticulin ( Calr ) in fibrosis of diabetic nephropathy has not been investigated. In current work, we used both in vitro and in vivo approaches to assess the role of ER CRT in TGF-β and glucose stimulated ECM production by renal tubule cells and in diabetic mice. Knockdown of CALR by siRNA in a human proximal tubular cell line (HK-2) showed reduced induction of soluble collagen when stimulated by TGF-β or high glucose as compared to control cells, as well as a reduction in fibronectin and collagen IV transcript levels. CRT protein is increased in kidneys of mice made diabetic with streptozotocin and subjected to uninephrectomy to accelerate renal tubular injury as compared to controls. We used renal-targeted ultrasound delivery of Cre-recombinase plasmid to knockdown specifically CRT expression in the remaining kidney of uninephrectomized Calr fl/fl mice with streptozotocin-induced diabetes. This approach reduced CRT expression in the kidney, primarily in the tubular epithelium, by 30-55%, which persisted over the course of the studies. Renal function as measured by the urinary albumin/creatinine ratio was improved in the mice with knockdown of CRT as compared to diabetic mice injected with saline or subjected to ultrasound and injected with control GFP plasmid. PAS staining of kidneys and immunohistochemical analyses of collagen types I and IV show reduced glomerular and tubulointerstitial fibrosis. Renal sections from diabetic mice with CRT knockdown showed reduced nuclear NFAT in renal tubules and treatment of diabetic mice with 11R-VIVIT, an NFAT inhibitor, reduced proteinuria and renal fibrosis. These studies identify ER CRT as an important regulator of TGF-β stimulated ECM production in the diabetic kidney, potentially through regulation of NFAT-dependent ECM transcription., Competing Interests: The authors have no competing or conflicting interests., (© 2020 The Author(s).)

Myeloma cast nephropathy (MCN) is a common cause of severe renal impairment in multiple myeloma (MM). The level of free light chain (FLC) that causes MCN varies substantially and there is uncertainty about the threshold level that should be used to inform clinical practice. In a multicentre cohort study of 103 patients with a diagnosis of MM and biopsy-confirmed MCN made between 2002-2014, we report prospectively measured levels of serum FLC at diagnosis obtained using a single nephelometric assay (Freelite®) and we explore the relationship between serum FLC level at diagnosis with renal outcome and patient survival. Using a landmark approach, overall survival (OS) was compared between patients who achieved independence from dialysis compared to those who remained dialysis dependent at 3-month, 6-month, 9-month, and 12-month time points. The median serum FLC level at diagnosis was 7531 mg/L (range 107-114600). Serum creatinine was 535 μmol/L (range 168-2993) and eGFR 7 ml/min/1.73 m 2 (range 1-34). Six patients (5.8%) had an FLC level <1500 mg/L, which is the International Myeloma Working Group threshold for MCN and two patients were below the International Kidney and Monoclonal Gammopathy working group threshold of 500 mg/L; one was hypercalcaemic, and one had high-normal serum calcium level and had received a non-steroidal anti-inflammatory agent. Sixty-nine (67%) patients required haemodialysis treatment of whom 36 (52.1%) recovered independent renal function. Sixty-six (64%) patients died with a median OS of 2.5 years (95% CI 1.8-3.3). A landmark analysis revealed that independence from dialysis was associated with improved survival at 3-months (P = 0.003), 6-months (P = 0.035) and 9-months (P = 0.014); there was no survival benefit observed beyond 12 months (P = 0.146). Serum FLC level at diagnosis was neither associated with renal function recovery nor with OS. This is the largest reported cohort of patients with biopsy-confirmed MCN and prospectively measured serum FLC levels. These results indicate that a serum monoclonal FLC > 500 mg/L should be considered the threshold level associated with the development of MCN.

Prior studies reported that haploinsufficiency of the transcription factor ETS-1 is renoprotective in Dahl salt-sensitive rats, but the mechanism is unclear. Here, we tested whether ETS-1 is involved in hypertension-induced renal microvascular pathology and autoregulatory impairment. Hypertension was induced in salt-sensitive rats and salt-sensitive rats that are heterozygous with 1 wild-type or reference allele of Ets1 (SS Ets1+/- ) by feeding a diet containing 4% sodium chloride for 1 week. Increases in blood pressure did not differ. However, phosphorylated ETS-1 increased in afferent arterioles of hypertensive salt-sensitive rats, but not in hypertensive SS Ets1+/- rats. Afferent arterioles of hypertensive salt-sensitive rats showed increased monocyte chemotactic protein-1 expression and infiltration of CD68 positive monocytes/macrophages. Isolated kidney microvessels showed increased mRNA expression of vascular cell adhesion molecule, intercellular adhesion molecule, P-selectin, fibronectin, transforming growth factor-β, and collagen I in hypertensive salt-sensitive rats compared with hypertensive SS Ets1+/- rats. Using the in vitro blood-perfused juxtamedullary nephron preparation, pressure-mediated afferent arteriolar responses were significantly blunted in hypertensive salt-sensitive rats compared to hypertensive SS Ets1+/- rats. Over a 65-170 mm Hg pressure range tested baseline arteriolar diameters averaged 15.1 μm and remained between 107% and 89% of baseline diameter in hypertensive salt-sensitive rats vs. 114% and 73% in hypertensive SS Ets1+/- rats (significantly different). Thus, ETS-1 participates in renal arteriolar pathology and autoregulation and thereby is involved in hypertension-mediated kidney injury in salt-sensitive rats., (Copyright © 2019 International Society of Nephrology. All rights reserved.)

This study examined the prospective role of urinary sodium and potassium excretion in depressive symptoms among urban, low-income adolescents, and whether these relationships vary by gender. A total of 84 urban adolescents (mean age 13.36 years; 50% male; 95% African American) self-reported on their depressive symptoms at baseline and 1.5 years later. At baseline, the youth also completed a 12-h (overnight) urine collection at home which was used to measure sodium and potassium excretion. After adjusting for baseline depressive symptoms, age, BMI percentile, and pubertal development, greater sodium excretion and lower potassium excretion predicted more severe depressive symptoms at follow-up, with no significant gender differences. The results suggest that consumption of foods high in sodium and low in potassium contributes to the development of depressive symptoms in early adolescence, and that diet is a modifiable risk factor for adolescent depression. Interventions focusing on diet may improve mental health in urban adolescents., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Because of the less-than-robust response to therapy and impact on choice of optimal chemotherapy and prognosis, chronic kidney disease has drawn attention in the treatment of multiple myeloma, a malignant hematologic disorder that can produce significant amounts of monoclonal immunoglobulin free light chains (FLCs). These low-molecular-weight proteins are relatively freely filtered through the glomerulus and are reabsorbed by the proximal tubule. The present study demonstrated that during the process of metabolism of immunoglobulin FLCs, ROS activated the STAT1 pathway in proximal tubule epithelium. STAT1 activation served as the seminal signaling molecule that produced the proinflammatory molecule IL-1β, as well as the profibrotic agent TGF-β by this portion of the nephron. These effects occurred in vivo and were produced specifically by the generation of hydrogen peroxide by the VL domain of the light chain. To the extent that the experiments reflect the human condition, these studies offer insights into the pathogenesis of progressive kidney failure in the setting of lymphoproliferative disorders, such as multiple myeloma, that feature increased circulating levels of monoclonal immunoglobulin fragments that require metabolism by the kidney.

Background: The extra-renal effects of aldosterone on left ventricular (LV) structure and function are exacerbated by increased dietary sodium in persons with hypertension. Previous studies demonstrated endothelial dysfunction and increased oxidative stress with high salt diet in normotensive salt-resistant subjects. We hypothesized that increased xanthine oxidase (XO), a product of endothelial cells, is related to 24-h urinary sodium and to LV hypertrophy and function in patients with resistant hypertension (RHTN)., Methods: The study group included persons with RHTN (n = 91), defined as a blood pressure > 140/90 mmHg on ≥ 3 medications at pharmacologically effective doses. Plasma XO activity and 24-h urine were collected, and cardiac magnetic resonance imaging (MRI) was performed to assess LV function and morphology. Sixty-seven normotensive persons on no cardiovascular medications served as controls. A subset of RHTN (n = 19) received spironolactone without salt restriction for six months with follow-up XO activity measurements and MRI analyses., Results: XO activity was increased two-fold in RHTN vs. normal and was positively correlated with LV mass, LV diastolic function, and 24-h urinary sodium. In RHTN patients receiving spironolactone without salt restriction, LV mass decreased, but LV diastolic function and XO activity did not improve. Baseline urinary sodium was positively associated with rate of change of LV mass to volume ratio and the LV E/A ratio., Conclusions: These results demonstrate a potential role of endothelium-derived oxidative stress and excess dietary salt in the pathophysiology of LV hypertrophy and diastolic dysfunction in persons with RHTN unaffected by the addition of spironolactone., (Copyright © 2019. Published by Elsevier Inc.)

The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.

Objective: Routine outcome monitoring (ROM) has been strongly endorsed by psychotherapy researchers, but has yet to achieve widespread implementation in clinical settings. This article describes the development of the Clinically Adaptive Multidimensional Outcome Survey (CAMOS), an innovative ROM system that allows for local adaptation while providing high quality data., Method: Three-hundred and four clients at a university counseling center and 211 female patients at an eating disorder treatment facility were administered the CAMOS at intake, and 118 took the CAMOS at both intake and discharge. Two models were developed and compared. Both models were developed using exploratory and confirmatory factor analysis., Results: A five-factor model was found to have the best model fit, internal consistency, convergent validity, and discriminant validity., Conclusions: The CAMOS has evidence to support its reliability and validity as a measure of various dimensions of distress. Distinctive tailoring features of the CAMOS compared to other ROM measures are described.

The renal deposition of monoclonal immunoglobulins can cause severe renal complications in patients with B cell and plasma cell lymphoproliferative disorders. The overproduction of a structurally unique immunoglobulin can contribute to the abnormal propensity of monoclonal immunoglobulins to aggregate and deposit in specific organs. A wide range of renal diseases can occur in multiple myeloma or monoclonal gammopathy of renal significance, including tubular and glomerular disorders with organized or unorganized immunoglobulin deposits. The development of reliable experimental models is challenging owing to the inherent variability of immunoglobulins and the heterogeneity of the pathologies they produce. However, although imperfect, animal models are invaluable tools to understand the molecular pathogenesis of these diseases, and advances in creating genetically modified animals might provide novel approaches to evaluate innovative therapeutic interventions. We discuss the strategies employed to reproduce human monoclonal immunoglobulin-induced kidney lesions in animal models, and we highlight their advantages and shortcomings. We also discuss how these models have affected the management of these deposition diseases and might do so in the future. Finally, we discuss hypotheses that explain some limitations of the various models, and how these models might improve our understanding of other nephropathies without immunoglobulin involvement that have similar pathogenic mechanisms.

Studies using Dahl salt-sensitive (SS) rats identified specific quantitative trait loci that predispose animals to hypertension-associated albuminuria and kidney injury. We explored the hypothesis that kidney-specific expression of the transcription factor Ets-1 , located within one of these loci on chromosome 8, mediates glomerular injury in SS hypertension. During the first week on a high-salt diet, SS rats and SS rats with only one functioning Ets-1 gene (ES rats) demonstrated similar increases in BP. However, serum creatinine concentration, albuminuria, and glomerular expression of ETS-1 and two ETS-1 targets, MCP-1 and MMP2, did not increase as substantially in ES rats as in SS rats. Mean BP subsequently increased further in SS rats and remained higher than that of ES rats for the rest of the study. After 4 weeks of high-salt intake, ES rats still showed a lower mean serum creatinine concentration and less albuminuria, as well as less histologic evidence of glomerular injury and kidney fibrosis, than SS rats did. To investigate the specific contribution of renal Ets-1 , we transplanted kidneys from ES or SS rats into salt-resistant SS-Chr 13 BN/ McwiCrl (SS-13BN) rats. Within 10 days on a high-salt diet, BP increased similarly in ES and SS allograft recipients, becoming significantly higher than the BP of control isograft recipients. However, mean serum creatinine concentration and albuminuria remained lower in ES allograft recipients than in SS allograft recipients at 2 weeks, and ES allografts showed less glomerular injury and interstitial fibrosis. In conclusion, reduced renal expression of ETS-1 prevented hypertension-associated kidney injury in SS rats., (Copyright © 2017 by the American Society of Nephrology.)

Vascular calcification is a risk factor that predicts adverse cardiovascular complications of several diseases including atherosclerosis. Reduced dietary potassium intake has been linked to cardiovascular diseases such as hypertension and incidental stroke, although the underlying molecular mechanisms remain largely unknown. Using the ApoE-deficient mouse model, we demonstrated for the first time to our knowledge that reduced dietary potassium (0.3%) promoted atherosclerotic vascular calcification and increased aortic stiffness, compared with normal (0.7%) potassium-fed mice. In contrast, increased dietary potassium (2.1%) attenuated vascular calcification and aortic stiffness. Mechanistically, reduction in the potassium concentration to the lower limit of the physiological range increased intracellular calcium, which activated a cAMP response element-binding protein (CREB) signal that subsequently enhanced autophagy and promoted vascular smooth muscle cell (VSMC) calcification. Inhibition of calcium signals and knockdown of either CREB or ATG7, an autophagy regulator, attenuated VSMC calcification induced by low potassium. Consistently, elevated autophagy and CREB signaling were demonstrated in the calcified arteries from low potassium diet-fed mice as well as aortic arteries exposed to low potassium ex vivo. These studies established a potentially novel causative role of dietary potassium intake in regulating atherosclerotic vascular calcification and stiffness, and uncovered mechanisms that offer opportunities to develop therapeutic strategies to control vascular disease.

Salt resistance/sensitivity refers specifically to the effect of dietary sodium chloride (salt) intake on BP. Increased dietary salt intake promotes an early and uniform expansion of extracellular fluid volume and increased cardiac output. To compensate for these hemodynamic changes and maintain constant BP in salt resistance, renal and peripheral vascular resistance falls and is associated with an increase in production of nitric oxide. In contrast, the decline in peripheral vascular resistance and the increase in nitric oxide are impaired or absent in salt sensitivity, promoting an increase in BP in these individuals. Endothelial dysfunction may pose a particularly significant risk factor in the development of salt sensitivity and subsequent hypertension. Vulnerable salt-sensitive populations may have in common underlying endothelial dysfunction due to genetic or environmental influences. These individuals may be very sensitive to the hemodynamic stress of increased effective blood volume, setting in motion untoward molecular and biochemical events that lead to overproduction of TGF- β , oxidative stress, and limited bioavailable nitric oxide. Finally, chronic high-salt ingestion produces endothelial dysfunction, even in salt-resistant subjects. Thus, the complex syndrome of salt sensitivity may be a function of the endothelium, which is integrally involved in the vascular responses to high salt intake., (Copyright © 2017 by the American Society of Nephrology.)

Disorders of plasma and B cells leading to paraproteinemias are associated with a variety of renal diseases. Understanding the mechanisms of injury and associated nephropathies provides a framework that aids clinicians in prompt diagnosis and appropriate adjunctive treatment of these disorders. Glomerular diseases that may be associated with paraproteinemias include amyloid deposition, monoclonal Ig deposition disease, proliferative GN with monoclonal Ig deposits, C3 glomerulopathy caused by alterations in the complement pathway, immunotactoid glomerulopathy, fibrillary GN, and cryoglobulinemia. Tubular lesions include the classic Fanconi syndrome, light-chain proximal tubulopathy, interstitial fibrosis, and cast nephropathy. These paraproteinemic renal diseases are distinct in their pathogenesis as well as their urinary and kidney biopsy findings. Renal pathology is usually initiated by deposition and direct involvement of the intact monoclonal Ig or Ig fragments with resident cells of the nephron. Our review summarizes current insights into the underlying molecular pathogenesis of these interesting kidney lesions., (Copyright © 2016 by the American Society of Nephrology.)

Purpose: Multiple myeloma (MM) is the most common hematologic malignancy affecting Blacks in the USA, with standardized incidence rates that are twofold to threefold higher than Whites. The rationale for the disparity is unclear., Methods: Using participants enrolled in the Molecular And Genetic Epidemiology study of myeloma (259 MM cases; 461 controls), we examined the risk of MM associated with family history of cancer, differences by race and among cases, defining clinical features. Risk estimates were calculated using odds ratios and corresponding 95% confidence intervals from logistic regression adjusted for confounders., Results: Overall, MM risk in cases with relatives affected with any hematologic malignancy was significantly elevated compared to controls (OR 1.89, 95% CI 1.25-2.86). Myeloma risk associated with a family history of MM was higher than the risk associated with any hematologic malignancy (OR 3.75, 95% CI 1.75-8.05), and the effect was greater for Blacks (OR 20.9, 95% CI 2.59-168) than Whites (OR 2.04, 95% 0.83-5.04), among cases with early onset (≤60 years; OR 4.58, 95% CI 1.21-17.3) and with increasing numbers of affected relatives (p trend = 0.001). Overall, frequencies of end organ damage differed in cases with relatives affected with any hematologic malignancy and significantly more cases exhibited κ light chain restriction (OR 3.23, 95% CI 1.13-9.26)., Conclusions: The excess risk of MM observed in Blacks and the variation in clinical features observed in MM patients according to family history of hematologic malignancy may be attributed to a shared germline and environmental susceptibility.

Endothelial dysfunction has been shown to be predictive of subsequent cardiovascular events and death. Through a mechanism that is incompletely understood, increased dietary salt intake promotes endothelial dysfunction in healthy, salt-resistant humans. The present study tested the hypothesis that dietary salt-induced transforming growth factor (TGF)-β promoted endothelial dysfunction and salt-dependent changes in blood pressure (BP). Sprague-Dawley rats that received diets containing 0.3% NaCl [low salt (LS)] or 8.0% NaCl [high salt (HS)] were treated with vehicle or SB-525334, a specific inhibitor of TGF-β receptor I/activin receptor-like kinase 5, beginning on day 5. BP was monitored using radiotelemetry in four groups of rats (LS, LS + SB-525334, HS, and HS + SB-525334) for up to 14 days. By day 14 of the study, mean daytime systolic BP and mean pulse pressure of the HS group treated with vehicle was greater than those in the other three groups; mean daytime systolic BP and pulse pressure of the HS + SB-525334 group did not differ from the LS and LS + SB-525334-treated groups. Whereas mean systolic BP, mean diastolic BP, and mean arterial pressure did not differ among the groups on the seventh day of the study, endothelium-dependent vasorelaxation was impaired specifically in the HS group; treatment with the activin receptor-like kinase 5 inhibitor prevented the dietary HS intake-induced increases in phospho-Smad2 (Ser(465/467)) and NADPH oxidase-4 in endothelial lysates and normalized endothelial function. These findings suggest that HS-induced endothelial dysfunction and the development of salt-dependent increases in BP were related to endothelial TGF-β signaling.

We investigated the relationships between religiousness and spirituality and various indicators of mental health and positive psychosocial functioning in three separate samples of college students. A total of 898 students at Brigham Young University participated in the three studies. The students ranged in age from 17 to 26 years old, with the average age of 20.9 across all three samples. Our results indicate that intrinsic religiousness, spiritual maturity, and self-transcendence were significantly predictive of better mental health and positive functioning, including lower levels of depression, anxiety, and obsessive-compulsiveness, and higher levels of global self-esteem, identity integration, moral self-approval, and meaning in life. Intrinsic religiousness was not predictive of shame, perfectionism, and eating disorder symptoms. These findings are consistent with many prior studies that have found religiousness and spirituality to be positively associated with better mental health and positive psychosocial functioning in adolescents and young adults.

Transcription factor E26 transformation-specific sequence-1 (ETS-1) is a transcription factor that regulates the expression of a variety of genes, including growth factors, chemokines, and adhesion molecules. We recently demonstrated that angiotensin II increases the glomerular expression of ETS-1 and that blockade of ETS-1 ameliorates the profibrotic and proinflammatory effects of angiotensin II. The Dahl salt-sensitive rat is a paradigm of salt-sensitive hypertension associated with local activation of the renin-angiotensin system. In these studies, we determined whether: (1) salt-sensitive hypertension is associated with renal expression of ETS-1 and (2) ETS-1 participates in the development of end-organ injury in salt-sensitive hypertension. Dahl salt-sensitive rats were fed a normal-salt diet (0.5% NaCl diet) or a high-salt diet (4% NaCl) for 4 weeks. Separate groups on high-salt diet received an ETS-1 dominant-negative peptide (10 mg/kg/d), an inactive ETS-1 mutant peptide (10 mg/kg/d), the angiotensin II type 1 receptor blocker candesartan (10 mg/kg/d), or the combination high-salt diet/dominant-negative peptide/angiotensin II type 1 receptor blocker for 4 weeks. High-salt diet rats had a significant increase in the glomerular expression of the phosphorylated ETS-1 that was prevented by angiotensin II type 1 receptor blocker. ETS-1 blockade reduced proteinuria, glomerular injury score, fibronectin expression, urinary transforming growth factor-β excretion, and macrophage infiltration. Angiotensin II type 1 receptor blocker reduced proteinuria, glomerular injury score, and macrophage infiltration, whereas concomitant ETS-1 blockade and angiotensin II type 1 receptor blocker had additive effects and reduced interstitial fibrosis. Our studies demonstrated that salt-sensitive hypertension results in increased glomerular expression of phosphorylated ETS-1 and suggested that ETS-1 plays an important role in the pathogenesis of end-organ injury in salt-sensitive hypertension., (© 2015 American Heart Association, Inc.)

Kidney involvement is common in paraprotein-related diseases. A diversity of clinical presentations and histopathological features can occur secondary to tissue injury caused by precipitation or deposition of a clonal immunoglobulin, usually an immunoglobulin light chain. The paraprotein is either produced by multiple myeloma or by a clone of B-cell lineage that does not fulfill diagnostic criteria for multiple myeloma. The recent introduction of serum immunoglobulin free light chain assays, which accurately quantify both light chain isotypes to produce a ratio that indicates the presence or absence of a light chain paraprotein, is a major clinical development. However, as the interpretation of the assay can be challenging, the aim of this review is to clarify the role of serum and urinary light chain assays in the screening and diagnosis of paraprotein-related kidney disease.