Predialysis serum phosphate and intradialytic hypotension.

INTRODUCTION: Intradialytic hypotension (IDH) is a common complication of hemodialysis (HD) and is associated with excess morbidity and mortality. Higher serum phosphate is associated with adverse cardiovascular outcomes in maintenance HD patients; however, its association with IDH has not previously been assessed. METHODS: This is an analysis of a prospective cohort of 969 HD patients (80,968 HD sessions) receiving HD at a large dialysis organization (LDO) and a post-hoc analysis of 1838 HD patients (10,594 HD sessions) in the Hemodialysis study (HEMO), a multicenter randomized controlled trial that examined standard or high-dose HD and low-flux or high-flux membranes. Unadjusted and adjusted mixed effects regression models were fit to determine the association of pre-HD serum phosphate with IDH, defined as a nadir intra-HD systolic blood pressure (SBP) <90 mmHg. FINDINGS: In the LDO cohort, baseline mean pre-HD serum phosphate was 5.2 ± 1.7 mg/dl. IDH occurred in 15.6% of HD sessions. In the adjusted model, higher pre-HD serum phosphate (per 1 mg/dl) was associated with a 12% increased risk of IDH (aOR 1.12, 95% CI 1.10-1.13, p <0.001). In exploratory models where pre-HD laboratory values were available, the effect estimate was attenuated but remained statistically significant (aOR 1.05; 95% CI 1.02-1.08; p <0.01). Participants in the highest (compared with the lowest) quartile of pre-HD serum phosphate had a 56% greater risk of IDH in the adjusted model (aOR Q4:Q1 1.56; 95% CI 1.44-1.68, p <0.001). The association of higher phosphate with IDH was consistent in the HEMO data. DISCUSSION: Higher pre-HD serum phosphate is independently associated with an increased risk of IDH. As HD may cause an acute decline in serum phosphate, future studies to investigate the mechanisms of this association are warranted.

Mechanisms, Clinical Implications, and Treatment of Intradialytic Hypotension.

Individuals with ESKD requiring maintenance hemodialysis face a unique hemodynamic challenge, typically on a thrice-weekly basis. In an effort to achieve some degree of euvolemia, ultrafiltration goals often involve removal of the equivalent of an entire plasma volume. Maintenance of adequate end-organ perfusion in this setting is dependent on the institution of a variety of complex compensatory mechanisms. Unfortunately, secondary to a myriad of patient- and dialysis-related factors, this compensation often falls short and results in intradialytic hypotension. Physicians and patients have developed a greater appreciation for the breadth of adverse outcomes associated with intradialytic hypotension, including higher cardiovascular and all-cause mortality. In this review, we summarize the evidence for adverse outcomes associated with intradialytic hypotension, explore the underlying pathophysiology, and use this as a basis to introduce potential strategies for its prevention and treatment.

Elevated NADPH oxidase activity contributes to oxidative stress and cell death in Huntington's disease.

A mutation in the huntingtin (Htt) gene produces mutant Htt and Huntington's disease (HD), a neurodegenerative disorder. HD patients have oxidative damage in the brain, but the causes are unclear. Compared with controls, we found brain levels of NADPH oxidase (NOX) activity, which produces reactive oxygen species (ROS), elevated in human HD postmortem cortex and striatum and highest in striatum of presymptomatic individuals. Synaptosome fractions from cortex and striatum of HD(140Q/140Q) mice had elevated NOX activity at 3 months of age and a further rise at 6 and 12 months compared with synaptosomes of age-matched wild-type (WT) mice. High NOX activity in primary cortical and striatal neurons of HD(140Q/140Q) mice correlated with more ROS and neurite swellings. These features and neuronal cell death were markedly reduced by treatment with NOX inhibitors such as diphenyleneiodonium (DPI), apocynin (APO) and VAS2870. The rise in ROS levels in mitochondria of HD(140Q/140Q) neurons followed the rise in NOX activity and inhibiting only mitochondrial ROS was not neuroprotective. Mutant Htt colocalized at plasma membrane lipid rafts with gp91-phox, a catalytic subunit for the NOX2 isoform. Assembly of NOX2 components at lipid rafts requires activation of Rac1 which was also elevated in HD(140Q/140Q) neurons. HD(140Q/140Q) mice bred to gp91-phox knock-out mice had lower NOX activity in the brain and in primary neurons, and neurons had normal ROS levels and significantly improved survival. These findings suggest that increased NOX2 activity at lipid rafts is an early and major source of oxidative stress and cell death in HD(140Q/140Q) neurons.

Reagents that block neuronal death from Huntington's disease also curb oxidative stress.

Patients with Huntington's disease suffer severe neuronal loss and signs of oxidative damage in the brain. Previously we found that primary neurons from embryonic cortex of mice bearing the Huntington's disease mutation (140 glutamines inserted into exon 1 of huntingtin) showed higher levels of reactive oxygen species before cell death. Here, we treated mutant neurons with known neuroprotective agents and determined the effects on neuronal survival and levels of reactive oxygen species. Primary neurons were exposed to the neurotrophin, brain derived neurotrophic factor, the antioxidant N-acetyl-cysteine or a specific inhibitor of glycogen synthase kinase 3-ß, SB216763. Each reagent increased the survival of the mutant neurons compared with untreated mutant neurons and also reduced the levels of reactive oxygen species to levels of wild-type neurons. These results suggest that reducing the levels of reactive oxygen species may be necessary to protect neurons with the Huntington's disease mutation from cell death.

Mutant huntingtin and glycogen synthase kinase 3-beta accumulate in neuronal lipid rafts of a presymptomatic knock-in mouse model of Huntington's disease.

Patients with Huntington's disease have an expanded polyglutamine tract in huntingtin and suffer severe brain atrophy and neurodegeneration. Because membrane dysfunction can occur in Huntington's disease, we addressed whether mutant huntingtin in brain and primary neurons is present in lipid rafts, which are cholesterol-enriched membrane domains that mediate growth and survival signals. Biochemical analysis of detergent-resistant membranes from brains and primary neurons of wild-type and presymptomatic Huntington's disease knock-in mice showed that wild-type and mutant huntingtin were recovered in lipid raft-enriched detergent-resistant membranes. The association with lipid rafts was stronger for mutant huntingtin than wild-type huntingtin. Lipid rafts extracted from Huntington's disease mice had normal levels of lipid raft markers (G(alphaq), Ras, and flotillin) but significantly more glycogen synthase kinase 3-beta. Increases in glycogen synthase kinase 3-beta have been associated with apoptotic cell death. Treating Huntington's disease primary neurons with inhibitors of glycogen synthase kinase 3-beta reduced neuronal death. We speculate that accumulation of mutant huntingtin and glycogen synthase kinase 3-beta in lipid rafts of presymptomatic Huntington's disease mouse neurons contributes to neurodegeneration in Huntington's disease.