Serum phosphate as an independent factor associated with cholesterol metabolism in patients undergoing hemodialysis: a cross-sectional analysis of the DREAM cohort.

BACKGROUND: Hyperphosphatemia is a risk factor for cardiovascular outcomes in patients with chronic kidney disease. In an experimental model, hyperphosphatemia promoted atherosclerosis by activating sterol regulatory element-binding protein 2, which controls cholesterol homeostasis. In the present study, we hypothesized that serum phosphate level is associated with cholesterol metabolism in patients with kidney failure. METHODS: We conducted a single-center cross-sectional study including 492 patients undergoing hemodialysis and 100 healthy controls not on statin or ezetimibe treatment. Serum lathosterol and campesterol levels were measured as a marker of cholesterol synthesis and absorption, respectively. As compared with the control group, the hemodialysis patients had higher median phosphate {5.8 mg/dL [interquartile range (IQR 5.0-6.6) versus 3.3 (3.0-3.6); P < .001], lower lathosterol [1.2 µg/mL (IQR 0.8-1.7) versus 2.6 (1.9-3.4); P < .001] and higher campesterol levels [4.5 µg/mL (IQR 3.6-6.0) versus 4.1 (3.2-5.4); P = .02]. Serum phosphate correlated positively to campesterol in the control group (Spearman's r = 0.21, P = .03) and in hemodialysis patients (Spearman's r = 0.19, P < .001). The positive association between phosphate and campesterol levels in the hemodialysis group remained significant in multivariable-adjusted linear regression analysis. There was no significant association between phosphate and lathosterol in either group. CONCLUSIONS: An independent association was found between phosphate and campesterol levels in patients with kidney failure. This study suggests a novel relationship between phosphate and cholesterol metabolism, both of which could affect cardiovascular outcomes in this population.

Reduced Risk of Progression from Non-Severe to Severe COVID-19 in Hospitalized Dialysis Patients by Full COVID-19 Vaccination.

Coronavirus disease 2019 (COVID-19) vaccination reduces the risk of progression to severe COVID-19 in the general population. To examine that preventive effect in dialysis patients, the association of vaccination status with severe COVID-19 progression was investigated in this retrospective observational study conducted from December 2020 to May 2022 of 100 such patients hospitalized for non-severe COVID-19 at Inoue Hospital (Suita, Japan). Fifty-seven were fully vaccinated, defined as receiving a COVID-19 vaccine second dose at least 14 days prior to the onset of COVID-19, while 43 were not. Among all patients, 13 (13.0%) progressed to severe COVID-19 with a median (interquartile range) time of 6 (2.5-9.5) days, while 87 (87.0%) were discharged after 11 (8-16) days. Kaplan-Meier analysis showed that fully vaccinated patients had a significantly lower rate of progression to severe COVID-19 (p = 0.001, log-rank test). Cox proportional hazard analysis also indicated that full COVID-19 vaccination was significantly associated with reduced instances of progression to severe COVID-19 (hazard ratio 0.104, 95% confidence interval 0.022 to 0.483; p = 0.004) after balancing patient background characteristics using an inverse probability of treatment weight method. These results suggest that full vaccination status contributes to reducing the risk of progression from non-severe to severe COVID-19 in dialysis patients.

Oxidative Stress and Inflammation as Predictors of Mortality and Cardiovascular Events in Hemodialysis Patients: The DREAM Cohort.

AIM: Both oxidative stress and inflammation are involved in the pathogenesis of cardiovascular disease (CVD). The serum level of derivatives of reactive oxygen metabolites (d-ROMs) is a measure of the total amount of hydroperoxides serving as a marker of oxidative stress. We investigated whether d-ROMs could predict the clinical outcomes in hemodialysis patients and whether the associations of d-ROMs with the outcomes are independent of a marker of inflammation, C-reactive protein (CRP). METHODS: This was a prospective cohort study in hemodialysis patients. The key exposures were the serum levels of d-ROMs and CRP. The outcome measures were all-cause mortality and new CVD events. RESULTS: A total of 517 patients were analyzed. d-ROMs correlated positively with CRP. During follow-up for 5 years, 107 patients died, and 190 patients experienced new CVD events. In the Kaplan-Meier analyses, both higher d-ROMs and higher CRP levels predicted higher risks for mortality and CVD events. By Cox proportional-hazard regression analysis adjusted for potential confounders excluding CRP, d-ROMs exhibited a significant association with all-cause mortality, but this association was no longer significant after further adjustment for CRP. Using the same model, CRP exhibited a significant association with all-cause mortality, but this association was no longer significant after further adjustment for d-ROMs. When we analyzed new CVD events as the outcome, CRP was a significant predictor, whereas the level of d-ROMs was not. CONCLUSIONS: Although d-ROMs predicted mortality and CVD events in unadjusted models, the associations of d-ROMs with these outcomes were not independent of CRP. Oxidative stress and inflammation appear to share common causal pathways.

Two Cases of the MYH9 Disorder Fechtner Syndrome Diagnosed from Observation of Peripheral Blood Cells before End-Stage Renal Failure.

As a MYH9 disorder, Fechtner syndrome is characterized by nephritis, giant platelets, granulocyte inclusion bodies (Döhle-like bodies), cataract, and sensorineural deafness. Observation of peripheral blood smear for the presence of thrombocytopenia, giant platelets, and granulocyte inclusion bodies (Döhle-like bodies) is highly important for the early diagnosis of MYH9 disorders. In our two cases, sequencing analysis of the MYH9 gene indicated mutations in exon 24. Both cases were diagnosed as the MYH9 disorders Fechtner syndrome before end-stage renal failure on the basis of the observation of peripheral blood smear.

Altered Serum n-6 Polyunsaturated Fatty Acid Profile and Risks of Mortality and Cardiovascular Events in a Cohort of Hemodialysis Patients.

OBJECTIVE: Alterations in the balance between serum n-3 and n-6 polyunsaturated fatty acids (PUFAs) is predictive of cardiovascular events among hemodialysis patients, although little is known about the serum ratio of n-6 arachidonic acid (AA) to n-6 dihomo-γ-linoleic acid (DGLA) in renal failure. We hypothesized that AA/DGLA ratio is altered in hemodialysis patients resulting in poor clinical outcomes. METHODS: This was a single center cohort study in an urban area in Japan with cross-sectional analyses. Subjects were 517 hemodialysis patients and 122 control subjects. The main exposure was serum AA/DGLA ratio, and the main outcome measures were all-cause mortality and cardiovascular events during 5 years. RESULTS: The hemodialysis patients showed a higher median (interquartile range) AA/DGLA ratio than the control subjects (6.46 [5.22-7.81] versus 4.56 [3.74-6.34], P < .001). In a Cox proportional hazard model adjusted for age, sex, dialysis duration, diabetic nephropathy, prior cardiovascular disease, and the ratio of serum n-3 polyunsaturated fatty acids (eicosapentaenoic acid plus docosahexaenoic acid) to AA, the higher quartiles of AA/DGLA ratio were associated with higher risk for all-cause mortality with hazard ratios (95% confidence interval) of 1.50 (0.84-2.76) for quartile 2, 2.10 (1.18-3.86) for quartile 3, and 2.02 (1.10-3.78) for quartile 4 compared with quartile 1. AA/DGLA ratio showed a similar association with the risk of cardiovascular events. CONCLUSIONS: AA/DGLA ratio was elevated in patients with end-stage renal disease requiring hemodialysis, and a high AA/DGLA ratio was an independent predictor of poor clinical outcomes in this population.

Plasma homocysteine and cerebral small vessel disease as possible mediators between kidney and cognitive functions in patients with diabetes mellitus.

Cognitive impairment is more prevalent in those with decreased kidney function. We tested a hypothesis that an increased homocysteine and/or cerebral small vessel diseases (SVDs) mediate the link between kidney and cognitive functions in a cross-sectional study in 143 type 2 diabetes patients without diagnosis of dementia or prior stroke. The exposure and outcome variables were estimated glomerular filtration rate (eGFR) and cognitive performance evaluated with Modified Mini-Mental State (3 MS) examination, respectively. The candidate mediators were plasma homocysteine concentration, and SVDs including silent cerebral infarction, cerebral microbleed, periventricular hyperintensity, and deep and subcortical white matter hyperintensity by magnetic resonance imaging. In multiple regression models adjusted for 12 potential confounders, eGFR was positively associated with 3 MS score, inversely with homocysteine, but not significantly with the presence of any type of SVD. The association of eGFR with 3 MS remained significant when each of the SVDs was added to the model, whereas it disappeared when homocysteine was included in place of SVD. Mediation analysis indicated nearly significant mediation of homocysteine (P = 0.062) but no meaningful mediations of SVDs (P = 0.842-0.930). Thus, homocysteine, not SVDs, was shown to be the possible mediator between kidney and cognitive functions in patients with type 2 diabetes mellitus.

Cardiothoracic Ratio as a Predictor of Cardiovascular Events in a Cohort of Hemodialysis Patients.

AIM: The cardiothoracic ratio (CTR) on a chest X-ray is an indicator of cardiac enlargement, although its predictive power for cardiovascular disease (CVD) events in chronic kidney disease is unknown. We examined it in a cohort of hemodialysis patients, as compared with an N-terminal fragment of probrain natriuretic peptide (NT-proBNP). METHOD: This was an observational study with cross-sectional and longitudinal analyses including 517 maintenance hemodialysis patients and 122 healthy control subjects. The main predictors were CTR and serum NT-proBNP, and the main outcome was CVD events in 5 years. RESULTS: At baseline, the hemodialysis patients had higher median (interquartile range) levels of CTR [0.487 (0.457-0.520)] than the control group [0.458 (0.432-0.497)]. In the hemodialysis group, CTR was positively correlated with NT-proBNP (Spearman's r=0.44, P＜0.001). During follow-up, 190 CVD events occurred. CTR was significantly associated with the risk of CVD [HR 2.12 (95% CI, 1.38-3.25) for the fourth quartile as compared with the second quartile of CTR] in a multivariate Cox model. In the same model, NT-proBNP (fourth versus first quartile) showed a HR of 3.27 (2.02-5.31). When CTR and NT-proBNP were simultaneously included as predictors, only NT-proBNP remained a significant predictor of CVD events, all-cause mortality and composite of CVD plus all-cause mortality. CONCLUSIONS: We showed that CTR was a significant and independent predictor of CVD in hemodialysis patients. CTR can be used for CVD risk stratification in hemodialysis patients when NT-proBNP is not available.

Kidney function, cholesterol absorption and remnant lipoprotein accumulation in patients with diabetes mellitus.

AIM: Remnant lipoproteins are atherogenic and increased in patients with type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD) and other conditions. Thus far, information is limited regarding the synthesis and absorption of cholesterol in CKD patients and a possible link to the remnant levels. We examined possible alterations in serum markers of cholesterol synthesis and absorption and their potential associations with remnant lipoproteins in patients with CKD. METHODS: The subjects included 146 consecutive patients with T2DM in various stages of CKD. We measured the levels of remnant lipoprotein cholesterol (RemL-C), lathosterol (a cholesterol synthesis marker) and campesterol (a cholesterol absorption marker). The urinary albumin to creatinine ratio (U-ACR) and estimated glomerular filtration rate (eGFR) were used to describe the degree of CKD. RESULTS: The median (interquartile range) levels of RemL-C, lathosterol and campesterol were 14.5 (11.5-23.4) mg/dL, 2.1 (1.7-2.9) µg/mL and 2.3 (1.7-3.0) µg/mL, respectively. The RemL-C level was positively correlated with the U-ACR and inversely correlated with the eGFR. The RemL-C level was positively correlated with both the lathosterol and campesterol levels. The lathosterol level was not significantly correlated with the U-ACR, although it was positively correlated with the eGFR. In contrast, the campesterol level was positively correlated with the ACR and inversely with the eGFR. In the multiple regression analysis, both lathosterol and campesterol were positively associated with the RemL-C level, independent of the U-ACR, eGFR and other variables. CONCLUSIONS: The serum campesterol concentrations are higher in patients with a greater degree of albuminuria and a lower renal funtion. In this study, the markers of cholesterol absorption and synthesis were independent determinants of the RemL-C level. Increased intestinal cholesterol absorption may be an additional mechanism for remnant accumulation in T2DM patients with CKD.