Frank Stam

Background. Patients with end-stage renal disease as well as mild renal impairment have an increased risk for the development of cardiovascular disease. It has been suggested that advanced glycation end-products (AGEs) are involved in atherogenesis, possibly through induction of endothelial dysfunction and low-grade inflammation. Methods. In a cross-sectional, single-centre study, we investigated four groups of 20 non-diabetic subjects with a creatinine clearance ranging from normal (>90 ml/min/1.73 m ² ) to 2 . We measured AGE-peptides, markers of endothelial dysfunction (von Willebrand factor, soluble E-selectin, plasminogen activator inhibitor-1, tissue-type plasminogen activator, soluble vascular cell adhesion molecule-1) and markers of inflammatory activity (soluble intercellular adhesion molecule-1, C-reactive protein, secretory phospholipase A ₂ ). We constructed composite endothelial dysfunction and inflammatory activity Z-scores using these markers. Results. AGE-peptides were independently related to creatinine clearance (standardized β −0.55, 95% confidence interval (CI) −0.77 to −0.34, P P = 0.48) or the inflammatory activity Z-score (standardized β −0.05, 95% CI −0.25 to −0.16, P = 0.66). Conclusions. Plasma concentrations of AGE-peptides are associated with creatinine clearance but not with biochemical markers of endothelial dysfunction and inflammatory activity in non-diabetic patients over a wide range of renal function. This suggests that the atherogenic effects of AGE-peptides in individuals with renal functional impairment are not mediated by endothelial dysfunction or inflammatory activity as estimated by the markers used.

Folic acid treatment decreases plasma total homocysteine concentrations in healthy subjects, but the effects on homocysteine metabolism are unknown. In the present study, we investigated the effect of 3 weeks of oral treatment with 5 mg of folic acid on one-carbon flux rates in 12 healthy subjects, using in vivo stable isotope methods. In addition, we determined the effect of folic acid on blood concentrations of amino acids which may have regulatory roles in homocysteine metabolism, i.e. homocysteine, AdoMet (S-adenosylmethionine), AdoHcy (S-adenosylhomocysteine), serine and glycine. Primed, continuous infusions with [2H3-methyl-1-13C]methionine were used to determine flux rates of methionine transmethylation, homocysteine remethylation and homocysteine trans-sulphuration. Metabolic homocysteine clearance was defined as the ratio of trans-sulphuration and plasma homocysteine level. Folic acid treatment increased the homocysteine remethylation rate by 59% [95% CI (confidence interval), 13–97%; P=0.02] and methionine transmethylation rate by 20% (95% CI, 3–41%; P=0.03). Plasma total homocysteine concentration (−18%; 95% CI, −28 to −9%; P<0.01) and the serine/glycine ratio (−20%; 95% CI, −63 to −6%; P<0.01) decreased significantly, and the AdoMet/AdoHcy ratio (11%; 95% CI, 1–20%; P=0.02) increased significantly. Changes in one-carbon flux rates did not correlate significantly with changes in plasma concentration of these amino acids. In conclusion, folic acid treatment lowered plasma homocysteine concentration and increased whole-body remethylation and transmethylation flux in healthy subjects.

Hyperhomocysteinemia is a risk factor for cardiovascular disease and occurs frequently in end-stage renal disease (ESRD), but its pathogenesis is poorly understood. We aimed to evaluate one-carbon flux rates of methionine and homocysteine (Hcy) in ESRD patients and healthy controls. Transmethylation (TM), remethylation (RM), and transsulfuration (TS), as well as Hcy clearance by TS (i.e., TS/plasma total Hcy concentration) and by RM (i.e., RM/plasma total Hcy concentration) were evaluated in relation to body composition, vitamins, and S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet) levels. After a fixed protein diet for 3 days, primed-continuous infusion of [²H₃-methyl-1-¹³C]methionine was performed in the postabsorptive state in 12 hemodialysis patients and 16 healthy volunteers. Hcy clearance by TS (−80%, P < 0.001) and by RM (−77%, P < 0.001) in ESRD patients was decreased compared with healthy controls. The absolute flux rates of TM (−27%, P < 0.01) and RM (−28%, P = 0.02) were lower in the ESRD patients. After adjustment for age, TS was not significantly reduced. Whole blood AdoHcy was significantly elevated in ESRD and was a significant determinant of TM (standardized β = −1.24, P = 0.01) and RM (standardized β = −1.43, P = 0.03). In conclusion, patients with ESRD have impaired Hcy clearance by TS and RM. Elevated whole blood AdoHcy levels are associated with impaired RM and TM flux rates in these patients, and AdoHcy may be a key regulatory compound in one-carbon flux.

A patient who bred exotic turtles as a hobby presented with 2 episodes of severe diarrhea, the second of which was proven to be caused by turtle-associated salmonellosis that was contracted during treatment with a proton-pump inhibitor. The literature about reptile-associated salmonellosis is briefly reviewed.

Background. Patients with end‐stage renal disease (ESRD) as well as those with mild renal insufficiency are at increased risk for the development of cardiovascular disease, which cannot be attributed entirely to traditional risk factors. Endothelial dysfunction and chronic inflammatory activity, two important phenomena in atherogenesis, can be found in ESRD. At present, it is unclear whether endothelial dysfunction and chronic inflammatory activity are related to renal function in the pre‐dialysis stage. Methods. In a cross‐sectional, single‐centre study, four groups of 20 subjects with renal function ranging from a normal, calculated creatinine clearance (>90 ml/min) to a pre‐dialysis situation (2 (sPLA₂) and C‐reactive protein (CRP)]. Using these markers, composite endothelial function and inflammatory activity scores were constructed. Results. Creatinine clearance correlated with the endothelial function score (r=−0.43, Pr=−0.53, Pr=−0.54, Pr=−0.50, P2 (r=−0.28, Pr=−0.61, Pr=−0.54, Pr=−0.44, PP=0.006), plasma vWf (β=−0.37, P=0.022) and sICAM‐1 (β=−0.33, P=0.012). The relationship of creatinine clearance with sVCAM‐1 and endothelial function score was not significant when plasma homocysteine was added to the model. Creatinine clearance was also a determinant of the inflammatory activity score (β=−0.31, P=0.025) and sPLA₂ (β=−0.32, P=0.024), although this was no longer significant after correction for systolic blood pressure. Conclusions. Renal dysfunction is associated with markers of endothelial dysfunction and inflammatory activity. Plasma homocysteine may be an intermediate factor in the relationship between endothelial dysfunction and renal function, while blood pressure may modulate the association between inflammatory activity and renal function.