Management of traditional risk factors for the development and progression of chronic kidney disease.

Chronic kidney disease (CKD) and its downstream complications (i.e. cardiovascular) are a major source of morbidity worldwide. Additionally, deaths due to CKD or CKD-attributable cardiovascular disease account for a sizeable proportion of global mortality. However, the advent of new pharmacotherapies, diagnostic tools, and global initiatives are directing greater attention to kidney health in the public health agenda, including the implementation of effective strategies that (i) prevent kidney disease, (ii) provide early CKD detection, and (iii) ameliorate CKD progression and its related complications. In this Review, we discuss major risk factors for incident CKD and CKD progression categorized across cardiovascular (i.e. hypertension, dyslipidemia, cardiorenal syndrome), endocrine (i.e. diabetes mellitus, hypothyroidism, testosterone), lifestyle (i.e. obesity, dietary factors, smoking), and genetic/environmental (i.e. CKDu/Mesoamerican nephropathy, APOL1, herbal nephropathy) domains, as well as scope, mechanistic underpinnings, and management.

Dysnatremia and risk of bloodstream infection in dialysis patients.

Background: Emerging data suggest that sodium disarrays including hyponatremia are potential risk factors for infection ensuing from impairments in host immunity, which may be exacerbated by coexisting conditions (i.e. mucosal membrane and cellular edema leading to breakdown of microbial barrier function). While dysnatremia and infection-related mortality are common in dialysis patients, little is known about the association between serum sodium levels and the risk of bloodstream infection in this population. Methods: Among 823 dialysis patients from the national Biospecimen Registry Grant Program who underwent serum sodium testing over the period January 2008-December 2014, we examined the relationship between baseline serum sodium levels and subsequent rate of bloodstream infection. Bloodstream infection events were directly ascertained using laboratory blood culture data. Associations between serum sodium level and the incidence of bloodstream infection were estimated using expanded case mix-adjusted Poisson regression models. Results: In the overall cohort, ∼10% of all patients experienced one or more bloodstream infection events during the follow-up period. Patients with both lower sodium levels <134 mEq/l and higher sodium levels ≥140 mEq/l had higher incident rate ratios (IRRs) of bloodstream infection in expanded case mix analyses (reference 136-<138 mEq/l), with adjusted IRRs of 2.30 [95% confidence interval (CI) 1.19-4.44], 0.77 (95% CI 0.32-1.84), 1.39 (95% CI 0.78-2.47), 1.88 (95% CI 1.08-3.28) and 1.96 (95% CI 1.08-3.55) for sodium levels <134, 134-<136, 138-<140, 140-<142 and ≥142 Eq/l, respectively. Conclusions: Both lower and higher baseline serum sodium levels were associated with a higher rate of subsequent bloodstream infections in dialysis patients. Further studies are needed to determine whether correction of dysnatremia ameliorates infection risk in this population.

The Interplay between Dietary Phosphorous, Protein Intake, and Mortality in a Prospective Hemodialysis Cohort.

(1) Background: Current dietary recommendations for dialysis patients suggest that high phosphorus diets may be associated with adverse outcomes such as hyperphosphatemia and death. However, there has been concern that excess dietary phosphorus restriction may occur at the expense of adequate dietary protein intake in this population. We hypothesized that higher dietary phosphorus intake is associated with higher mortality risk among a diverse cohort of hemodialysis patients. (2) Methods: Among 415 patients from the multi-center prospective Malnutrition, Diet, and Racial Disparities in Kidney Disease Study, we examined the associations of absolute dietary phosphorus intake (mg/day), ascertained by food frequency questionnaires, with all-cause mortality using multivariable Cox models. In the secondary analyses, we also examined the relationship between dietary phosphorus scaled to 1000 kcal of energy intake (mg/kcal) and dietary phosphorus-to-protein ratio (mg/g) with survival. (3) Results: In expanded case-mix + laboratory + nutrition adjusted analyses, the lowest tertile of dietary phosphorus intake was associated with higher mortality risk (ref: highest tertile): adjusted HR (aHR) (95% CI) 3.33 (1.75-6.33). In the analyses of dietary phosphorus scaled to 1000 kcal of energy intake, the lowest tertile of intake was associated with higher mortality risk compared to the highest tertile: aHR (95% CI) 1.74 (1.08, 2.80). Similarly, in analyses examining the association between dietary phosphorus-to-protein ratio, the lowest tertile of intake was associated with higher mortality risk compared to the highest tertile: aHR (95% CI) 1.67 (1.02-2.74). (4) Conclusions: A lower intake of dietary phosphorus was associated with higher mortality risk in a prospective hemodialysis cohort. Further studies are needed to clarify the relationship between specific sources of dietary phosphorus intake and mortality in this population.

CD13 tethers the IQGAP1-ARF6-EFA6 complex to the plasma membrane to promote ARF6 activation, ß1 integrin recycling, and cell migration.

Cell attachment to the extracellular matrix (ECM) requires a balance between integrin internalization and recycling to the surface that is mediated by numerous proteins, emphasizing the complexity of these processes. Upon ligand binding in various cells, the ß1 integrin is internalized, traffics to early endosomes, and is returned to the plasma membrane through recycling endosomes. This trafficking process depends on the cyclical activation and inactivation of small guanosine triphosphatases (GTPases) by their specific guanine exchange factors (GEFs) and their GTPase-activating proteins (GAPs). In this study, we found that the cell surface antigen CD13, a multifunctional transmembrane molecule that regulates cell-cell adhesion and receptor-mediated endocytosis, also promoted cell migration and colocalized with ß1 integrin at sites of cell adhesion and at the leading edge. A lack of CD13 resulted in aberrant trafficking of internalized ß1 integrin to late endosomes and its ultimate degradation. Our data indicate that CD13 promoted ARF6 GTPase activity by positioning the ARF6-GEF EFA6 at the cell membrane. In migrating cells, a complex containing phosphorylated CD13, IQGAP1, GTP-bound (active) ARF6, and EFA6 at the leading edge promoted the ARF6 GTPase cycling and cell migration. Together, our findings uncover a role for CD13 in the fundamental cellular processes of receptor recycling, regulation of small GTPase activities, cell-ECM interactions, and cell migration.