Association between Fiber Intake and Risk of Incident Chronic Kidney Disease: The UK Biobank Study.

OBJECTIVES: Dietary fiber intake is associated with a lower risk of diabetes, cardiovascular disease, and cancer. However, it is unknown whether dietary fiber has a beneficial effect on preventing the development of chronic kidney disease (CKD). DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Using the UK Biobank prospective cohort, 110,412 participants who completed at least one dietary questionnaire and had an estimated glomerular filtration rate ≥60 mL/min/1.73 m2, urinary albumin-to-creatinine ratio <30 mg/g, and no history of CKD were included. The primary exposure was total dietary fiber density, calculated by dividing the absolute amount of daily total fiber intake by total energy intake (g/1,000 kcal). We separately examined soluble and insoluble fiber densities as additional predictors. The primary outcome was incident CKD based on diagnosis codes. RESULTS: A total of 3,507 (3.2%) participants developed incident CKD during a median follow-up of 9.9 years. In a multivariable cause-specific model, the adjusted hazard ratios (aHRs; 95% confidence intervals [CIs]) for incident CKD were 0.85 (0.77-0.94), 0.78 (0.70-0.86), and 0.76 (0.68-0.86), respectively, for the second, third, and highest quartiles of dietary fiber density (reference: lowest quartile). In a continuous model, the aHR for each +∆1.0g/1,000 kcal increase in dietary fiber density was 0.97 (95% CI, 0.95-0.99). This pattern of associations was similar for both soluble and insoluble fiber densities and did not differ across subgroups of sex, age, body mass index, hypertension, diabetes, smoking, and inflammation. CONCLUSION: Increased fiber intake was associated with a lower risk of CKD in this large well-characterized cohort.

The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial.

Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.

Medication adherence and visit-to-visit variability of systolic blood pressure in African Americans with chronic kidney disease in the AASK trial.

Lower adherence to antihypertensive medications may increase visit-to-visit variability of blood pressure (VVV of BP), a risk factor for cardiovascular events and death. We used data from the African American Study of Kidney Disease and Hypertension (AASK) trial to examine whether lower medication adherence is associated with higher systolic VVV of BP in African Americans with hypertensive chronic kidney disease (CKD). Determinants of VVV of BP were also explored. AASK participants (n=988) were categorized by self-report or pill count as having perfect (100%), moderately high (75-99%), moderately low (50-74%) or low (<50%) proportion of study visits with high medication adherence over a 1-year follow-up period. We used multinomial logistic regression to examine determinants of medication adherence, and multivariable-adjusted linear regression to examine the association between medication adherence and systolic VVV of BP, defined as the coefficient of variation or the average real variability (ARV). Participants with lower self-reported adherence were generally younger and had a higher prevalence of comorbid conditions. Compared with perfect adherence, moderately high, moderately low and low adherence was associated with 0.65% (±0.31%), 0.99% (±0.31%) and 1.29% (±0.32%) higher systolic VVV of BP (defined as the coefficient of variation) in fully adjusted models. Results were qualitatively similar when using ARV or when using pill counts as the measure of adherence. Lower medication adherence is associated with higher systolic VVV of BP in African Americans with hypertensive CKD; efforts to improve medication adherence in this population may reduce systolic VVV of BP.

Detection of carotid artery calcification on the panoramic images of post-menopausal females is significantly associated with severe abdominal aortic calcification: a risk indicator of future adverse vascular events.

OBJECTIVES: Outcome studies among post-menopausal females with calcified carotid artery plaque (CCAP) on their panoramic images have not been previously undertaken. We sought to compare the extent of abdominal aortic calcification (AAC) on lateral lumbar spine radiographs (LLSRs), among groups of females with (CCAP+) and without (CCAP-) carotid lesions on their panoramic images. "Severe" levels of AAC have previously been validated as a risk indicator of future adverse cardiovascular events. METHODS: This cross-sectional case-control study included a "CCAP+ group" consisting of females more than 50 years of age having the carotid lesion diagnosed by their dentists and an atherogenic risk factor (age, body mass index, hypertension, diabetes and dyslipidaemia)-matched "CCAP- group". A physician radiologist, using the Framingham index, evaluated the LLSRs for the magnitude of AAC. Summary statistics for key variables were computed and conditional logistic regression techniques were considered. RESULTS: Members of the CCAP+ group were significantly (p=0.038) more likely to demonstrate "severe" levels of AAC on their LLSRs than members of the CCAP group. CONCLUSIONS: This is the first published study demonstrating that CCAP on panoramic images of post-menopausal females is significantly associated with "severe" levels of AACs on LLSRs independent of traditional risk factors. Given that these levels of AAC are a validated risk indicator of future myocardial infarction and stroke, dentists must evaluate the panoramic images of post-menopausal females for the presence of CCAP. Patients with carotid atheromas should be referred to their physicians for further evaluation given the systemic implications.

Coronary artery bypass graft type and outcomes in maintenance dialysis.

AIM: Patients with end-stage renal disease (ESRD) on maintenance dialysis have a high burden of coronary disease. Prior studies in non-dialysis patients show better outcomes in coronary artery bypass surgery using the internal mammary artery (IMA) compared with the saphenous vein graft (SVG), but less is known about outcomes in ESRD. We sought to compare the effectiveness of multivessel bypass grafting using IMA versus SVG in patients on maintenance dialysis in the United States. METHODS: Cohort study using data from the United States Renal Data System to examine IMA versus SVG in patients on maintenance dialysis undergoing multivessel coronary revascularization. We used Cox proportional hazards regression with multivariable adjustment in the full cohort and in a propensity-score matched cohort. The primary outcome was death from any cause; the secondary outcome was a composite of non-fatal myocardial infarction or death. RESULTS: Overall survival rates were low in this patient population (5-year survival in the matched cohort 25.3%). Use of the IMA compared to SVG was associated with lower risk of death (adjusted hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.84-0.92) and lower risk of the composite outcome (adjusted HR 0.89; CI 0.85-0.93). Results did not materially change in analyses using the propensity-score matched cohort. We found similar results irrespective of patient sex, age, race, or the presence of diabetes, peripheral vascular disease or heart failure. CONCLUSION: Although overall survival rates were low, IMA was associated with lower risk of mortality and cardiovascular morbidity compared to SVG in patients on dialysis.

Visit-to-visit systolic blood pressure variability and outcomes in hemodialysis.

Visit-to-visit blood pressure variability (VTV-BPV) is an independent risk factor for cardiovascular events and death in the general population. We sought to determine the association of VTV-BPV with outcomes in patients on hemodialysis, using data from a National Institutes of Health-sponsored randomized trial (the HEMO study). We used the coefficient of variation (CV) and the average real variability in systolic blood pressure (SBP) as metrics of VTV-BPV. In all, 1844 out of 1846 randomized subjects had at least three visits with SBP measurements and were included in the analysis. Median follow-up was 2.5 years (interquartile range 1.3-4.3 years), during which time there were 869 deaths from any cause and 408 (adjudicated) cardiovascular deaths. The mean pre-dialysis SBP CV was 9.9 ± 4.6%. In unadjusted models, we found a 31% higher risk of death from any cause per 10% increase in VTV-BPV. This association was attenuated after multivariable adjustment but remained statistically significant. Similarly, we found a 28% higher risk of cardiovascular death per 10% increase in VTV-BPV, which was attenuated and no longer statistically significant in fully adjusted models. The associations among VTV-BPV, death and cardiovascular death were modified by baseline SBP. In a diverse, well-dialyzed cohort of patients on maintenance hemodialysis, VTV-BPV, assessed using metrics of variability in pre-dialysis SBP, was associated with a higher risk of all-cause mortality and a trend toward higher risk of cardiovascular mortality, particularly in patients with a lower baseline SBP.

Prevalence of calcified carotid artery atheromas on panoramic images of individuals with primary hyperparathyroidism.

OBJECTIVES: Primary hyperparathyroidism (PHPT), affecting 1% of the population, is associated with increased cardiovascular morbidity and mortality. The presence of calcified carotid artery plaque (CCAP) on panoramic images is a validated risk indicator of future adverse cardiovascular events. We hypothesized that military veterans aged 50 years or older diagnosed with PHPT by increased parathyroid hormone and calcium levels would frequently have CCAP on their images. METHODS: We determined the prevalence rates of CCAP on the images of patients diagnosed with PHPT and evaluated their atherogenic risk profiles, including hypertension, dyslipidaemia, diabetes and obesity. Comparisons of atherogenic risk factors were made between subjects with and without observed CCAP on their panoramic images. RESULTS: Of the 60 patients (86.7% males and 13.3% females, mean age 73.2 ± 11.3 years) with PHPT, 40% had atheromas. There were no significant differences between CCAP+ and CCAP- groups in gender or race (p > 0.05). The atherogenic profile (age, body mass index, hypertension, diabetes, hyperlipidaemia) in the CCAP+ and CCAP- groups was not significantly different (p > 0.05). CONCLUSIONS: Calcified carotid artery atheromas are often seen on the panoramic images of patients with PHPT. Thus, dentists must be uniquely vigilant for these lesions when evaluating these studies.

Panoramic images of white and black post-menopausal females evidencing carotid calcifications are at high risk of comorbid osteopenia of the femoral neck.

OBJECTIVES: Femoral neck fractures in older females resulting from decreased bone mineral density (BMD; osteopenia) are associated with increased morbidity and mortality. Bone mineralization inhibition is probably controlled by proteins which also foster vascular calcification. Therefore, we evaluated the relationship between calcified carotid artery plaque (CCAP) on panoramic images and BMD on dual energy X-ray absorptiometry (DXA) bone scans. METHODS: Images and hospital records identified by dentists defined two study groups (20 white females and 24 black females) having CCAP and an incidentally obtained bone scan. Ethnically matched (age±7 years, body mass index ±3 units) control groups with panoramic images devoid of CCAP and accompanying DXA scan were likewise constituted. A physician determined the BMD on the DXA. RESULTS: Females with CCAP had significantly (p = 0.03) poorer BMD at the femoral neck than those without CCAP. Although mean femoral neck BMD was significantly lower (p = 0.009) for white than for black females, there was no significant interaction between race and CCAP (p = 0.80). CONCLUSION: We observed a significant inverse association between the CCAP on panoramic images and femoral neck BMD in post-menopausal white females.

Isolated cardiac sarcoidosis in heart transplantation.

BACKGROUND: Heart transplantation is the ultimate treatment for end-stage heart failure. Cardiac sarcoidosis has rarely been reported in heart transplantation worldwide. Their long-term prognosis after heart transplantation is unknown. Herein we have presented clinical and pathological observations among heart transplantation patients with isolated cardiac sarcoidosis. METHODS: From 1987 to 2011, we performed 411 heart transplantations including five patients retrospectively reviewed due to the presence of sarcoidosis and giant-cell cardiomyopathy in the recipient heart. RESULTS: Among the heart transplantations from 2003 to 2011, the four male and one female patients were ages 31 to 40 years. None of them had extra-cardiac sarcoidosis. All five subjects presented with dilated cardiomyopathy with patent coronary arteries. The commonest clinical presentations were atrioventricular block, ventricular arrhythmia, electrocardiographic findings of ST elevations, and poor left ventricular ejection fractions (17%-23%). All patients survived without allograft heart failure to date with the longest survivor at 8 years postoperatively. No recurrence of sarcoidosis has been observed clinically or among the post-heart transplantation endomyocardial biopsies. CONCLUSION: Heart transplantation is a useful treatment for isolated cardiac sarcoidosis patients suffering end-stage heart failure. Often the diagnosis is difficult to establish before heart transplantation despite endomyocardial biopsy. No recurrence of sarcoidosis was observed among the allografted hearts.

Bilateral bifid mandibular condyles diagnosed with three-dimensional reconstruction.

Bifid mandibular condyles (BMCs) are rare anomalies. The overwhelming majority of prior reports described their predominantly unilateral occurrence diagnosed by panoramic radiography. We present an even rarer case of bilateral BMC initially identified by panoramic radiography and confirmed with colour-enhanced three-dimensional CT. These images substantiate the theory that the secondary condyles arise from the neck of the mandible (Lopez-Lopez et al. Bifid condyle: review of the literature of the last 10 years and report of two cases. Cianio 2010; 28: 136-140).

Systolic blood pressure and mortality in prevalent haemodialysis patients in the HEMO study.

Previous studies of blood pressure and mortality in haemodialysis have yielded mixed results, perhaps due to confounding by comorbid conditions. We hypothesized that after improved accounting for confounding factors, higher systolic blood pressure (SBP) would be associated with higher all-cause mortality. We conducted a secondary analysis of data from the haemodialysis study, a randomized trial in prevalent haemodialysis patients. We used three proportional hazard models to determine the relative hazard at different levels of SBP: (1) Model-BL used baseline SBP; (2) Model-TV used SBP as a time-varying variable; and (3) Model-TV-Lag added a 3-month lag to Model-TV to de-emphasize changes in SBP associated with acute illness. In all the models, pre-dialysis SBP <120 mm Hg was associated with a higher risk of mortality compared with the referent group (140-159 mm Hg); higher pre-dialysis SBP was not associated with higher risk of mortality. In conclusion, we observed a robust association between lower pre-dialysis SBP and higher risk for all-cause and cardiovascular mortality in a well-characterized cohort of prevalent haemodialysis patients. Randomized clinical trials are needed to define optimal blood pressure targets in the haemodialysis population.

Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects.

AIMS/HYPOTHESIS: Maternal diabetes increases oxidative stress in embryos. Maternal diabetes also inhibits expression of embryonic genes, most notably, Pax-3, which is required for neural tube closure. Here we tested the hypothesis that oxidative stress inhibits expression of Pax-3, thereby providing a molecular basis for neural tube defects induced by diabetic pregnancy. METHODS: Maternal diabetes-induced oxidative stress was blocked with alpha-tocopherol (vitamin E), and oxidative stress was induced with the complex III electron transport inhibitor, antimycin A, using pregnant diabetic or non-diabetic mice, primary cultures of neurulating mouse embryo tissues, or differentiating P19 embryonal carcinoma cells. Pax-3 expression was assayed by quantitative RT-PCR, and neural tube defects were scored by visual inspection. Oxidation-induced DNA fragmentation in P19 cells was assayed by electrophoretic analysis. RESULTS: Maternal diabetes inhibited Pax-3 expression and increased neural tube defects, and alpha-tocopherol blocked these effects. In addition, induction of oxidative stress with antimycin A inhibited Pax-3 expression and increased neural tube defects. In cultured embryo tissues, high glucose-inhibited Pax-3 expression, and this effect was blocked by alpha-tocopherol and GSH-ethyl ester, and Pax-3 expression was inhibited by culture with antimycin A. In differentiating P19 cells, antimycin A inhibited Pax-3 induction but did not induce DNA strand breaks. CONCLUSION/INTERPRETATION: Oxidative stress inhibits expression of Pax-3, a gene that is essential for neural tube closure. Impaired expression of essential developmental control genes could be the central mechanism by which neural tube defects occur during diabetic pregnancy, as well as other sources of oxidative stress.

Evidence that elevated glucose causes altered gene expression, apoptosis, and neural tube defects in a mouse model of diabetic pregnancy.

Congenital malformations, including neural tube defects (NTDs), are significantly increased in the offspring of diabetic mothers. We previously reported that in the embryos of a mouse model of diabetic pregnancy, NTDs are associated with reduced expression of the gene Pax-3, which encodes a transcription factor that regulates neural tube development, and that reduced expression of Pax-3 leads to neuroepithelial apoptosis. In this study, we used three approaches to test whether glucose alone could be responsible for these adverse effects of diabetes on embryonic development. First, primary culture of embryo tissue in medium containing 15 mmol/l glucose inhibited Pax-3 expression compared with culture in medium containing 5 mmol/l glucose. Second, inducing hyperglycemia in pregnant mice by subcutaneous glucose administration significantly inhibited Pax-3 expression (P < 0.05), as demonstrated by quantitative reverse transcription-polymerase chain reaction assay of Pax-3 mRNA, and also increased neural tube apoptosis (P < 0.05). NTDs were significantly increased in glucose-injected pregnancies when blood glucose levels were >250 mg/dl (P < 0.002) but not in moderately hyperglycemic pregnancies (150-250 mg/dl, P = 0.37). Third, phlorizin administration to pregnant diabetic mice reduced blood glucose levels and the rate of NTDs. As seen with glucose-injected pregnancies, the rate of NTDs in phlorizin-treated diabetic pregnancies was related to the severity of hyperglycemia, since NTDs were significantly increased in severely hyperglycemic (>250 mg/dl) diabetic pregnancies (P < 0.001) but not in moderately hyperglycemic pregnancies (150-250 mg/dl, P = 0.35). These two findings, that elevated glucose alone can cause the changes in Pax-3 expression observed during diabetic pregnancy and that the NTD rate rises with significant increases in blood glucose levels, suggest that congenital malformations associated with diabetic pregnancy are caused by disruption of regulatory gene expression in the embryo in response to elevated glucose.

Genotoxicity and diabetic embryopathy: impaired expression of developmental control genes as a cause of defective morphogenesis.

Since the advent of insulin therapy for diabetes mellitus, the survival of mothers with diabetes prior to pregnancy and their offspring has greatly improved. Nevertheless, the observation that the earliest stages of organogenesis can be impaired in the offspring of women with diabetes raises the question of how abnormal fuel metabolism disturbs embryogenesis. Research into this process has been made possible in recent years by advances in molecular biology which makes it possible to study gene expression in early embryos, and by the availability of genetically engineered mutant mouse strains. Using these approaches, a model is emerging in which elevated glucose, by disturbing expression of genes which regulate embryonic development and cell cycle progression, causes premature cell death of emerging organ structures, thereby causing defective morphogenesis. Investigation into the signaling mechanisms by which excess glucose metabolism exhibits toxic effects on embryo gene expression will explain how diabetic embryopathy occurs on a molecular and cellular level, as well as increase our understanding of the role of metabolic homeostasis in proper embryonic development.

Gastrointestinal and nutritional problems in children with immunodeficiency and AIDS.

Immunodeficient children pose a challenge to clinicians because of the interrelationship between infectious disease, metabolism, gastrointestinal tract function, psychosocial problems, and immune function. The interplay between these factors is not always clear, and frequently the best course of therapy is obscured because of an inability to determine which factors have the greatest impact on child health. To optimize therapeutic intervention, a multidisciplinary health care team must be involved with the management of children and their families.