SGLT2 Inhibition in Patients With Type 2 Diabetes Mellitus Post-Nephrectomy: A Single-Center Case Series.

Background: Nephrectomy is the mainstay of treatment for many kidney cancers, but has been correlated with increased incidence of acute kidney injury (AKI) and chronic kidney disease (CKD). Recently, sodium-glucose cotransporter-2 (SGLT2) inhibition has been shown to decrease the incidence of end-stage kidney disease and death in people with type 2 diabetes mellitus (T2D). However, at present, there has been no description of the use of SGLT2 inhibition in patients with T2D and solitary kidney despite the high risk of CKD progression.

Transcriptome Analysis of Kidney Grafts Subjected to Normothermic Ex Vivo Perfusion Demonstrates an Enrichment of Mitochondrial Metabolism Genes.

Unlabelled: Normothermic ex vivo kidney perfusion (NEVKP) has demonstrated superior outcomes for donation-after-cardiovascular death grafts compared with static cold storage (SCS). To determine the mechanisms responsible for this, we performed an unbiased genome-wide microarray analysis.

Methods: Kidneys from 30-kg Yorkshire pigs were subjected to 30 min of warm ischemia followed by 8 h of NEVKP or SCS, or no storage, before autotransplantation.

The neurorepellent, Slit2, prevents macrophage lipid loading by inhibiting CD36-dependent binding and internalization of oxidized low-density lipoprotein.

Atherosclerosis is characterized by retention of modified lipoproteins, especially oxidized low density lipoprotein (oxLDL) within the sub-endothelial space of affected blood vessels. Recruited monocyte-derived and tissue-resident macrophages subsequently ingest oxLDL by binding and internalizing oxLDL via scavenger receptors, particularly CD36. The secreted neurorepellent, Slit2, acting through its transmembrane receptor, Roundabout-1 (Robo-1), was previously shown to inhibit recruitment of monocytes into nascent atherosclerotic lesions.

Improving Sexual Function in People With Chronic Kidney Disease: A Narrative Review of an Unmet Need in Nephrology Research.

Purpose Of Review: Sexual dysfunction occurs commonly in people with chronic kidney disease (CKD) and has been recognized as a research priority. We sought to evaluate the current state of the literature addressing sexual dysfunction in people with CKD and identify barriers and strategies to improve our management of this important symptom.

Sources Of Information: OVID Medline and Google Scholar were searched for English, peer-reviewed studies using keywords and terms related to "Chronic Kidney Disease," "sexuality," and "sexual dysfunction OR function.

Hyperfiltration, urinary albumin excretion, and ambulatory blood pressure in adolescents with Type 1 diabetes mellitus.

Adolescents with Type 1 diabetes mellitus (T1DM) are at risk for hyperfiltration and elevated urinary albumin-to-creatinine ratio (ACR), which are early indicators of diabetic nephropathy. Adolescents with T1DM also develop early changes in blood pressure, cardiovascular structure, and function. Our aims were to define the relationships between hyperfiltration, ACR, and 24-h ambulatory blood pressure over time in adolescents with T1DM.

Influence of sex on hyperfiltration in patients with uncomplicated type 1 diabetes.

The aim of this analysis was to examine sex-based differences in renal segmental resistances in healthy controls (HCs) and patients with type 1 diabetes (T1D). We hypothesized that hyperfiltration-an early hemodynamic abnormality associated with diabetic nephropathy-would disproportionately affect women with T1D, thereby attenuating protection against the development of renal complications. Glomerular hemodynamic parameters were evaluated in HC ( = 30) and in normotensive, normoalbuminuric patients with T1D and either baseline normofiltration [ = 36, T1D-N, glomerular filtration rate (GFR) 90-134 ml·min·1.

The Gomez' equations and renal hemodynamic function in kidney disease research.

Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease. A major challenge in preventing DKD is the difficulty in identifying high-risk patients at an early, pre-clinical stage. Albuminuria and eGFR as measures of renal function in DKD research and clinical practice are limited by regression of one-third of patients with microalbuminuria to normoalbuminuria and eGFR is biased and imprecise in the normal-elevated range.

AML cells have low spare reserve capacity in their respiratory chain that renders them susceptible to oxidative metabolic stress.

Mitochondrial respiration is a crucial component of cellular metabolism that can become dysregulated in cancer. Compared with normal hematopoietic cells, acute myeloid leukemia (AML) cells and patient samples have higher mitochondrial mass, without a concomitant increase in respiratory chain complex activity. Hence these cells have a lower spare reserve capacity in the respiratory chain and are more susceptible to oxidative stress.

Sodium-glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy.

Purpose Of Review: Renal hyperfiltration has been used as a surrogate marker for increased intraglomerular pressure in patients with diabetes mellitus. Previous human investigation examining the pathogenesis of hyperfiltration has focused on the role of neurohormones such as the renin-angiotensin-aldosterone system (RAAS). Unfortunately, RAAS blockade does not completely attenuate hyperfiltration or diabetic kidney injury.

Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus.

Plasma uric acid (PUA) is associated with metabolic, cardiovascular, and renal abnormalities in patients with type 2 diabetes but is less well understood in type 1 diabetes (T1D). Our aim was to compare PUA levels and fractional uric acid excretion (FEUA) in patients with T1D vs. healthy controls (HC) during euglycemia and hyperglycemia.

Metabolic adaptation to chronic inhibition of mitochondrial protein synthesis in acute myeloid leukemia cells.

Recently, we demonstrated that the anti-bacterial agent tigecycline preferentially induces death in leukemia cells through the inhibition of mitochondrial protein synthesis. Here, we sought to understand mechanisms of resistance to tigecycline by establishing a leukemia cell line resistant to the drug. TEX leukemia cells were treated with increasing concentrations of tigecycline over 4 months and a population of cells resistant to tigecycline (RTEX+TIG) was selected.

Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors.

Despite efforts to understand and treat acute myeloid leukemia (AML), there remains a need for more comprehensive therapies to prevent AML-associated relapses. To identify new therapeutic strategies for AML, we screened a library of on- and off-patent drugs and identified the antimalarial agent mefloquine as a compound that selectively kills AML cells and AML stem cells in a panel of leukemia cell lines and in mice. Using a yeast genome-wide functional screen for mefloquine sensitizers, we identified genes associated with the yeast vacuole, the homolog of the mammalian lysosome.

Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia.

To identify FDA-approved agents targeting leukemic cells, we performed a chemical screen on two human leukemic cell lines and identified the antimicrobial tigecycline. A genome-wide screen in yeast identified mitochondrial translation inhibition as the mechanism of tigecycline-mediated lethality. Tigecycline selectively killed leukemia stem and progenitor cells compared to their normal counterparts and also showed antileukemic activity in mouse models of human leukemia.

The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells.

To identify known drugs with previously unrecognized anticancer activity, we compiled and screened a library of such compounds to identify agents cytotoxic to leukemia cells. From these screens, we identified ivermectin, a derivative of avermectin B1 that is licensed for the treatment of the parasitic infections, strongyloidiasis and onchocerciasis, but is also effective against other worm infestations. As a potential antileukemic agent, ivermectin induced cell death at low micromolar concentrations in acute myeloid leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells.

The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma.

The proteasomal pathway of protein degradation involves 2 discrete steps: ubiquitination and degradation. Here, we evaluated the effects of inhibiting the ubiquitination pathway at the level of the ubiquitin-activating enzyme UBA1 (E1). By immunoblotting, leukemia cell lines and primary patient samples had increased protein ubiquitination.

Bacteria challenge in smoke-exposed mice exacerbates inflammation and skews the inflammatory profile.

Rationale: The pathogenesis of chronic obstructive pulmonary disease is associated with acute episodes of bacterial exacerbations. The most commonly isolated bacteria during episodes of exacerbation is nontypeable Haemophilus influenzae (NTHI).

Objectives: In this study, we investigated the in vivo consequences of cigarette smoke exposure on the inflammatory response to an NTHI challenge.

Cigarette smoke exposure attenuates cytokine production by mouse alveolar macrophages.

Alveolar macrophages (aMs) play a central role in respiratory host defense by sensing microbial antigens and initiating immune-inflammatory responses early in the course of an infection. The purpose of this study was to investigate the effect of cigarette smoke exposure on aMs after stimulation of innate pattern recognition receptors (PRRs) in a murine model. To accomplish this, C57BL/6 mice were exposed for 8 weeks using two models of cigarette smoke exposure, nose-only or whole-body exposure, and aMs isolated from the bronchoalveolar lavage.

Altered expression of disintegrin metalloproteinases and their inhibitor in human dilated cardiomyopathy.

Background: Disintegrin metalloproteinases (ADAMs) may contribute to structural cardiac remodeling by altering cell-surface matrix receptors (integrins) and activating potent biomolecules. We compared expression of ADAMs, their endogenous inhibitor tissue inhibitor of metalloproteinases (TIMP)-3, and integrins in human heart tissue with varied patterns of structural remodeling.

Methods And Results: Myocardium was obtained from patients with dilated cardiomyopathy (n=20), hypertrophic obstructive cardiomyopathy (n=5), and nonfailing donor hearts (n=7).

Cardiac remodeling and failure: from molecules to man (Part III).

Given the lack of a unified theory of heart failure, future research efforts will be required to unify and synthesize our current understanding of the multiple mechanisms that control remodeling in the failing heart. Matrix remodeling and the associated activation of inflammatory cytokines and MMPs have emerged as key pathways in the development of heart failure. As such, attempts to understand the integrated control of ECM homeostasis with the bioactivation of inflammatory cytokines may be of particular relevance to the development of effective anti-remodeling approaches.