Alexandra Scholze

Acetylcysteine Reduces Plasma Homocysteine Concentration and Improves Pulse Pressure and Endothelial Function in Patients With End-Stage Renal Failure

Background—Increased oxidative stress, elevated plasma homocysteine concentration, increased pulse pressure, and impaired endothelial function constitute risk factors for increased mortality in patients with end-stage renal failure. Methods and Results—We investigated the metabolic and hemodynamic effects of intravenous administration of acetylcysteine, a thiol-containing antioxidant, during a hemodialysis session in a prospective, randomized, placebo-controlled crossover study in 20 patients with end-stage renal failure. Under control conditions, a hemodialysis session reduced plasma homocysteine concentration to 58±22% predialysis (mean±SD), whereas in the presence of acetylcysteine, the plasma homocysteine concentration was significantly more reduced to 12±7% predialysis (P <0.01). The reduction of plasma homocysteine concentration was significantly correlated with a reduction of pulse pressure. A 10% decrease in plasma homocysteine concentration was associated with a decrease of pulse pressure by 2.5 mm Hg. Analysis of the second derivative of photoplethysmogram waveform showed changes of arterial wave reflectance during hemodialysis in the presence of acetylcysteine, indicating improved endothelial function. Conclusions—Acetylcysteine-dependent increase of homocysteine removal during a hemodialysis session improves plasma homocysteine concentration, pulse pressure, and endothelial function in patients with end-stage renal failure.

Association of transient receptor potential canonical type 3 (TRPC3) channel transcripts with proinflammatory cytokines

We investigated whether expression of non-selective cation channels of the transient receptor potential canonical (TRPC) channel family are associated with proinflammatory cytokines in monocytes. Using quantitative RT-PCR we studied the expression of TRPC3, interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha) in monocytes from 15 patients with essential hypertension and 16 age- and sex-matched normotensive control subjects. We observed an approximately 8-fold increase of TRPC3 transcripts in monocytes from patients with essential hypertension compared to normotensive control subjects (p<0.05). We found an approximately 3-fold increase of IL-1beta, and an approximately 9-fold increase of TNF-alpha in patients with essential hypertension compared to normotensive control subjects (each p<0.05). We observed a significant correlation between TRPC3 transcripts with systolic blood pressure, expression of IL-1beta, and TNF-alpha. Using quantitative RT-PCR we observed an association of TRPC3 transcripts and proinflammatory cytokines in monocytes.

Impaired Renal Allograft Function is Associated with Increased Arterial Stiffness in Renal Transplant Recipients

It is important whether impairment of renal allograft function may deteriorate arterial stiffness in renal transplant recipients. In a cross‐sectional study, arterial vascular characteristics were non‐invasively determined in 48 patients with renal allograft using applanation tonometry and digital photoplethysmography. Mean age was 51 ± 2 years (mean ± SEM), and studies were performed 17 ± 1 months after transplantation. The stage of chronic kidney disease was based on the glomerular filtration rate. We observed a significant association between the stage of chronic kidney disease and arterial stiffness of large arteries S1 and small arteries S2 in renal transplant recipients (each p < 0.05 by non‐parametric Kruskal–Wallis test between groups). Multivariate linear regression analysis showed that male gender of patients with renal allograft (p < 0.01) reduced glomerular filtration rate (p = 0.01), and older age of kidney donor (p = 0.04) were independently associated with an increase of large artery stiffness S1. Furthermore, a significant association between the stage of chronic kidney disease and arterial vascular reactivity during reactive hyperemia was observed (p < 0.05 by non‐parametric Kruskal–Wallis test between groups). It is concluded that impairment of renal allograft function is associated with an increased arterial stiffness in renal transplant recipients.

Alterations of retinol-binding protein 4 species in patients with different stages of chronic kidney disease and their relation to lipid parameters

Retinol-binding protein 4 (RBP4) is elevated in patients with chronic kidney disease (CKD) and has been discussed as marker of kidney function. In addition to an elevated concentration, the existence of truncated RBP4 species, RBP4-L (truncated at last C-terminal leucine) and RBP4-LL (truncated at both C-terminal leucines), has been reported in serum of hemodialysis patients. Since little is known about the occurrence of RBP4 species during the progression of CKD it was the aim of this study to analyse this possible association. The presence of RBP4, RBP4-L, RBP4-LL and transthyretin (TTR) was assessed in serum of 45 healthy controls and 52 patients with stage 2-5 of CKD using ELISA and RBP4 immunoprecipitation with subsequent MALDI-TOF-MS analysis. A reduction of glomerular filtration rate was accompanied by a gradual elevation of RBP4 serum levels and relative amounts of RBP4-LL. Correlation analysis revealed a strong association of the RBP4-TTR ratio with parameters of lipid metabolism and with diabetes-related factors. In conclusion, RBP4 serum concentration and the appearance of RBP4-LL seem to be influenced by kidney function. Furthermore, the RBP4-TTR ratio may provide diagnostic potential with regard to metabolic complications in CKD patients.

Phenylacetic acid and arterial vascular properties in patients with chronic kidney disease stage 5 on hemodialysis therapy.

Background: Phenylacetic acid (PAA) is a recently described uremic toxin that inhibits inducible nitric oxide synthase expression and plasma membrane calcium ATPase and may therefore also be involved in remodeling of arteries. Such vascular effects have not been evaluated yet in patients with chronic kidney disease stage 5. Method: We prospectively measured the plasma concentrations of PAA using nuclear magnetic resonance spectroscopy in 50 patients with chronic kidney disease stage 5 (37 men, 13 women) on maintenance hemodialysis. Arterial vascular properties were quantified by the reflective index obtained from digital photoplethysmography. Results: During the hemodialysis session the plasma PAA concentration was reduced from 3.38 ± 0.24 mmol/l (mean ± SEM; median, 2.85 mmol/l; interquartile range, 2.02–4.52 mmol/l) to 2.25 ± 0.11 mmol/l (median, 2.06 mmol/l; interquartile range, 1.62–2.86 mmol/l; n = 50; p < 0.001). There was a significant correlation between the PAA concentration and the reflective index before the start of the hemodialysis session. Conclusion: The study demonstrates an association of PAA and arterial vascular properties in patients with chronic kidney disease stage 5.

Low expression of thiosulfate sulfurtransferase (rhodanese) predicts mortality in hemodialysis patients

OBJECTIVESnTo test the hypothesis that impaired expression of the thiosulfate sulfurtransferase rhodanese is associated with oxidative stress and may predict mortality in hemodialysis patients.nnnDESIGN AND METHODSnSixty-two hemodialysis patients were investigated to determine protein and mRNA expression of rhodanese in monocytes. Whole cell reactive oxygen species and mitochondrial superoxide production were measured by fluorescence spectrophotometry.nnnRESULTSnCompared to healthy subjects, hemodialysis patients showed significantly lower rhodanese mRNA and protein expression and significantly increased reactive oxygen species. Lower rhodanese protein expression was significantly associated with higher mitochondrial superoxide production. The hazard ratio for mortality in hemodialysis patients with rhodanese mRNA below compared to patients above the median was 2.22. Survival was shorter with rhodanese mRNA below compared to patients above the median.nnnCONCLUSIONnImpaired rhodanese expression is associated with increased whole cell reactive oxygen species as well as higher mitochondrial superoxide production and predicts mortality in hemodialysis patients.

Effect of renal replacement therapy on retinol-binding protein 4 isoforms

BACKGROUNDnRetinol-binding protein 4 (RBP4) levels are elevated in the serum of patients with kidney dysfunction. We recently showed that RBP4 isoforms including apo-RBP4 (RBP4 not bound to retinol) and RBP4 truncated at the C-terminus (RBP4-L, RBP4-LL) are increased in the serum of patients with kidney diseases but not in serum of patients with various liver diseases. The aim of this study was to investigate the effect of renal replacement therapy on RBP4 isoforms.nnnMETHODSnWe investigated serum levels of RBP4, apo-RBP4, holo-RBP4, RBP4-L, RBP4-LL, retinol and transthyretin (TTR) in 18 hemodialysis (HD) patients, 30 patients after renal transplantation (RTx) and in 35 healthy controls. RBP4 and TTR levels were measured by enzyme-linked immunosorbent assay, apo- and holo-RBP4 by native electrophoresis, retinol by high performance liquid chromatography and RBP4-L and RBP4-LL were analyzed by mass spectrometry.nnnRESULTSnHD and RTx patients had elevated RBP4, apo-RBP4 and RBP4-LL levels compared to controls. RTx patients had elevated amounts of RBP4-L compared to controls and elevated RBP4 and apo-RBP4 levels compared to HD patients.nnnCONCLUSIONnThe results demonstrate a strong correlation between kidney function and RBP4 isoforms and provide data for investigating the relation of RBP4 and insulin resistance in these patients.

Noninvasive pulse wave analysis for the determination of central artery stiffness

Central artery stiffness predicts cardiovascular structural damage and clinical outcome. It is controversial whether central artery stiffness can be determined by noninvasive measurements. We compared noninvasive determination of central artery stiffness obtained from applanation tonometry of the peripheral radial artery waveform with invasive measurements of the ratio of pulse-pressure-to-stroke-volume. A total of 112 invasive measurements of the ratio of pulse-pressure-to-stroke-volume and noninvasive determinations of central artery stiffness were performed in 49 patients on the intensive care unit. In 13 out of 112 attempts of noninvasive measurements (12%) radial pulse could not be obtained using applanation tonometry because of cardiac arrhythmia or radial pulse could not be detected. These 13 failing noninvasive measurements were attempted in 7 patients. In the remaining cases we found a significant correlation between noninvasively obtained central artery stiffness and invasive measurements of the ratio of pulse-pressure-to-stroke-volume (Spearman r=0.40; p<0.0001). The association between invasive and noninvasive measurements was confirmed using Bland-Altman plots. Furthermore, a norepinephrine-induced increase of arterial stiffness was detected both invasively and noninvasively. Noninvasive determination of central artery stiffness obtained from peripheral radial artery waveform should be useful in clinical practice although it cannot be performed in every patient.

CARDIOVASCULAR AND SURVIVAL PARADOXES IN DIALYSIS PATIENTS: Role of Leptin in Reverse Epidemiology in Chronic Kidney Disease

Leptin is mainly produced by adipocytes and metabolized in the kidney. Leptin is taken up into the central nervous system by a saturable transport system, and controls appetite in rodents and in healthy subjects. Leptin acts on peripheral tissue and increases the inflammatory response by stimulating the production of tumor necrosis factor alpha, interleukin‐6 and interleukin‐12. In healthy humans, serum leptin concentration is related to the size of adipose tissue mass in the body. The majority of obese subjects have inappropriately high levels of circulating plasma leptin concentrations, indicating leptin resistance. In healthy subjects increased leptin concentration constitutes a biomarker for increased cardiovascular risk. On the other hand, a recent prospective long‐term study in patients with chronic kidney disease stage 5 on hemodialysis therapy showed that reduced serum leptin concentration is an independent risk factor for mortality in these patients.

Impaired vascular reactivity in patients with chronic kidney disease.

Background: Patients with chronic kidney disease (CKD) show increased cardiovascular morbidity. We hypothesized that vascular properties which can be routinely evaluated noninvasively are related to different stages of CKD and their clinical and biochemical characteristics. Methods: Arterial vascular properties were quantified by the reflective index using digital photoplethysmography in 260 patients with CKD. Patients were grouped according to estimated glomerular filtration rate (eGFR). Additional measurements were performed in 50 healthy control subjects. Results: In patients with CKD stage 1 and 2 (n = 115; age 65 ± 1 years) the reflective index was 30 ± 1%, whereas in patients with CKD stage 3 and 4 (n = 60; age 72 ± 1 years) the reflective index was 36 ± 1%, and in patients with CKD stage 5 (n = 85; age 64 ± 1 years) the reflective index was 36 ± 1% (p < 0.01 by Kruskal-Wallis test) indicating increased arterial stiffness in advanced CKD. Arterial vascular reactivity was significantly impaired in patients with advanced stages of CKD (stage 1 and 2, 78 ± 12%; stage 3 and 4, 32 ± 12%; stage 5, 33 ± 12%; p < 0.01). Univariate analysis showed a significant correlation of the reflective index and eGFR (Pearson r = –0.24; p < 0.0001). Multivariate regression analysis showed an independent association of the reflective index and eGFR (adjusted correlation coefficient, –0.24; p < 0.001). Conclusion: The advanced stages of CKD are associated with increased vascular stiffness and impaired vascular reactivity and these changes are already present in CKD stage 3 and 4.